McArdle Disease And Related Glycogen
Storage Disorders
Highly specialized National Service
Ros Quinlivan
Taunton 2018
Muscle glycogen metabolism disorders
Fixed muscle weakness
GSDII
Pompe Disease
GSDIII
GSDXV
Dynamic exercise intolerance
GSDV (MGP)
McArdle disease
GSDVII (PFK)
GSDIX (B kinase)
GSDXIII (beta enolase)
GSDIV (PGM1)
PGAM2
PGK
LDH
Average 20 year delay
between diagnosis and
patient first seeking a medical
opinion
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
McArdle Disease
Autosomal Recessive
Prevalence
1100000 USA
1170000 Spain
1350000 Netherlands
Absence of MGP
Severely limited access to Glycogen stores
Inability to produce lactate during exercise
4
Haller RG Arch Neurol 2000 57923ndash924
Lucia A et alJ Neurol Neurosurg Psychiatr 2012
83322ndash328
van Alfen N et al Neuromuscul Disord 2002
12718ndash783
Godfrey Nature Neurol Rev 2016
Symptoms
Exercise intolerance (99)
Within 1-2 minutes of initiating aerobic activity
Immediate with isometric muscle activity
Canrsquot squat or run
Second wind (86)
Hyperuricaemia gout
Contracture
Acute rhabdomyolysis
Myoglobinuria (60)
Compartment syndrome
Acute renal failure (10)
Quinlivan JNNP 2010
Lucia JNNP 2012
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Muscle glycogen metabolism disorders
Fixed muscle weakness
GSDII
Pompe Disease
GSDIII
GSDXV
Dynamic exercise intolerance
GSDV (MGP)
McArdle disease
GSDVII (PFK)
GSDIX (B kinase)
GSDXIII (beta enolase)
GSDIV (PGM1)
PGAM2
PGK
LDH
Average 20 year delay
between diagnosis and
patient first seeking a medical
opinion
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
McArdle Disease
Autosomal Recessive
Prevalence
1100000 USA
1170000 Spain
1350000 Netherlands
Absence of MGP
Severely limited access to Glycogen stores
Inability to produce lactate during exercise
4
Haller RG Arch Neurol 2000 57923ndash924
Lucia A et alJ Neurol Neurosurg Psychiatr 2012
83322ndash328
van Alfen N et al Neuromuscul Disord 2002
12718ndash783
Godfrey Nature Neurol Rev 2016
Symptoms
Exercise intolerance (99)
Within 1-2 minutes of initiating aerobic activity
Immediate with isometric muscle activity
Canrsquot squat or run
Second wind (86)
Hyperuricaemia gout
Contracture
Acute rhabdomyolysis
Myoglobinuria (60)
Compartment syndrome
Acute renal failure (10)
Quinlivan JNNP 2010
Lucia JNNP 2012
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
McArdle Disease
Autosomal Recessive
Prevalence
1100000 USA
1170000 Spain
1350000 Netherlands
Absence of MGP
Severely limited access to Glycogen stores
Inability to produce lactate during exercise
4
Haller RG Arch Neurol 2000 57923ndash924
Lucia A et alJ Neurol Neurosurg Psychiatr 2012
83322ndash328
van Alfen N et al Neuromuscul Disord 2002
12718ndash783
Godfrey Nature Neurol Rev 2016
Symptoms
Exercise intolerance (99)
Within 1-2 minutes of initiating aerobic activity
Immediate with isometric muscle activity
Canrsquot squat or run
Second wind (86)
Hyperuricaemia gout
Contracture
Acute rhabdomyolysis
Myoglobinuria (60)
Compartment syndrome
Acute renal failure (10)
Quinlivan JNNP 2010
Lucia JNNP 2012
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
McArdle Disease
Autosomal Recessive
Prevalence
1100000 USA
1170000 Spain
1350000 Netherlands
Absence of MGP
Severely limited access to Glycogen stores
Inability to produce lactate during exercise
4
Haller RG Arch Neurol 2000 57923ndash924
Lucia A et alJ Neurol Neurosurg Psychiatr 2012
83322ndash328
van Alfen N et al Neuromuscul Disord 2002
12718ndash783
Godfrey Nature Neurol Rev 2016
Symptoms
Exercise intolerance (99)
Within 1-2 minutes of initiating aerobic activity
Immediate with isometric muscle activity
Canrsquot squat or run
Second wind (86)
Hyperuricaemia gout
Contracture
Acute rhabdomyolysis
Myoglobinuria (60)
Compartment syndrome
Acute renal failure (10)
Quinlivan JNNP 2010
Lucia JNNP 2012
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Symptoms
Exercise intolerance (99)
Within 1-2 minutes of initiating aerobic activity
Immediate with isometric muscle activity
Canrsquot squat or run
Second wind (86)
Hyperuricaemia gout
Contracture
Acute rhabdomyolysis
Myoglobinuria (60)
Compartment syndrome
Acute renal failure (10)
Quinlivan JNNP 2010
Lucia JNNP 2012
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Children
Difficulty crawling arms collapsing
Complain of leg pains as soon as they can walk want to
be carried everywhere
Unable to run more than a few metres get left behind by
other children in playground
Donrsquot understand second wind until 9-10 years (on
average)
Socially isolated and may have problems integrating in
school
May have some additional learning needs
6
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Examination
Often normal
Muscle hypertrophy 40
Muscle wasting
Muscle weakness 20
shoulder girdle
axial paraspinal
7
Quinlivan et al JNNP 2010
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Late onset axial wasting and weakness
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Upper limb weakness scapular winging
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Maximal exercise Isometric muscle contraction
bull Sprinting running
bull Lifting and carrying
bull Opening jars
bull Squattingcrouching
bull Muscle tension
Pain
Excitement
Fighting
Sex
bull Seizures
Brady et al BMJ 2014
All activities of daily
living are affected
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Contracture and
compartment syndrome
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Ocular involvement
Ptosis
Retinal detachment
Pattern Retinal dystrophy 10 patients all male and over 50yrs
Ophthalmology 11 Oct 2018
Mahroo OA Khan KN et al
12
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Atypical patients
Isolated progressive biceps weakness
Progressive proximal rimmed vacuolar myopathy
Moderate-severe axialshoulder weakness
LGMD phenotype
Late onset myopathy camptocormia and ptosis
Splice site mutation
mild phenotype 3 functioning enzyme
1Scarpelli M et al McArdle disease and sporadic inclusion body myositis Neuropath amp Applied
Neurobiol 35(4)442-5 2009)
2Witting N Duno M Piraud M Vissing J JAMA Neurology 71(1)88-90 2014)
Vissing J et al Brain 132(Pt 6)1545-52 2009)
3Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy
ptosis and camptocormia Muscle Nerve 2017 e pub ahead of print
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Co-morbidities in McArdle disease
N=118 McArdle
Disease
Adult male
population
Diabetes 8 67 48
Angina 10 85 48
MI 13 11 4
CVA 3 15 24
Gout 10 85 5
Sedentary lifestyle leading to chronic fatigue and chronic pain
Psychological issues
Obesity morbid obesity
High incidence of thyroid disease 11 hypothyroid
Thyroid medullary cancer 3 patients (prevalence 1-9100000)
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Coronary artery disease
approx 100 asymptomatic patients screened
bull 18 asymptomatic coronary artery disease
bull 13 CAD requiring medical treatment
bull 5 required urgent intervention
bull 1x double bypass surgery
bull 3x stents
bull 1x Pacemaker
bull McArdle symptoms mask angina
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Investigations Baseline Serum CK almost
always raised
16
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Non-ischaemic forearm exercise test
17
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Muscle Biopsy
Mc Ardle patient
Healthy individual
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
PYGM 11q12-132
20 exons
147 mutations
91 exonic 50 missense
18 deletions13 nonsense
11 splicing
19 (Nogales-Gadea et al Human mutation 2015 36 669ndash678)
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
[pR50 c148CgtT] Stop codon mutation in exon 1
Useful and inexpensive screening test
Nogales-Gadea 2015 Hum Mutat
Screening for R50X and G205S in UK patients prevents muscle biopsy
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Minutes Heart Rate Walking
speed
kmhr
RPP
1 90 40 0
2 117 55 05
3 140 55 50
4 144 45 30
5 142 45 30
6 152 45 30
7 143 45 30
8 134 45 20
9 116 45 20
10 122 55 20
11 131 55 20
12 133 55 20
Borg RPP
Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease Buckley JP Quinlivan RM Sim J Eston RG Short DS Journal of Sports Sciences 32(16)1561-9 2014
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Walking distance for n=75 patients tested 2014-
2015 (Richard Godfrey and Sherryl Chatfield)
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Mean SF36v2 scores grouped by distance achieved on
12MWT at baseline (Jatin Pattni unpublished data)
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Aerobic Training
Average increase in walking distance (from assessment to
follow-up) = 1173m
(39 follow-up patients)(Sherryl Chatfield)
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
SF 36 Change in Mental Component Score and
Physical Component Scores across 4 visits
(Jatin Pattni)
0
10
20
30
40
50
60
Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16
PCS MCS
Munguiacutea-Izquierdo D Santalla A Lucia A Cardiorespiratory fitness physical activity and quality of life in patients with McArdle disease Med Sci Sports Exerc 2015 Apr47(4)799-808
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Caution with isometric activity
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Skeletal muscle energy metabolism
Greg Glassman 2003
-Creatine phosphate
8-10 seconds =100m
-Anaerobic glycolysis
30-90 seconds =200-400m
-Aerobic 800m-marathon
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Resistance training in McArdle Disease
Aerobic warm up and
Glucose loading essential for
resistance training
Resistance (weight lifting) training in an adolescent with McArdle disease Garcia-Benitez S Fleck SJ Naclerio F Martin MA Lucia A Journal of Child Neurology 28(6)805-8 2013
Report on the EUROMAC McArdle Exercise Testing Workshop Madrid Spain 11-12 July 2014 Quinlivan R Lucia A Scalco RS Santalla A Pattni J Godfrey R Marti R Workshop Participants Neuromuscular Disorders 25(9)739-45 2015 Sep
Feasibility of resistance training in adult McArdle patients clinical outcomes and muscle strength and mass benefits Santalla A Munguia-Izquierdo D Brea-Alejo L Pagola-Aldazabal I Diez-Bermejo J Fleck SJ Ara I Lucia A Frontiers in aging neuroscience 6334 2014
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Phosphofructokinase deficiency
GSDVII (PFKM)
Severe exercise intolerance (nausea and
vomiting)
lsquoOut of wind phenomenonrsquo
Exercise is easier when fasted
Improved with aerobic exercise
Haemolytic anaemia
Gout
Cardiac involvement
Polyglucosan bodies seen on muscle biopsy
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Sex CK 12 MWT
Myoglobinuria Age of onset
other
F 492 840 no child LV trabecular thickening Post partum haemorrhage Vomits with exercise
M 408 110 no child Haem anaemia LVH vomits with exercise
F 98 -unable no child SLE crohns Depression Hypertrophic LV
F 108 900 no child Vomits with exercise
F 891 -unable yes child Haem anaemia Mitral Valve replacement
M 480 446 yes child Gout haemolytic anaemia Vomits with exercise
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
PFKM mutations no genotype phenotype
correlation
Patient Allelle 1 Allele 2
1 Ashkenazi c450+1GgtA c2216del pPro738fs
2 Ashkenazi c450+1GgtA
c450+1GgtA
3 UK Caucasian pVal407 pVal407
4 Ashkenazi c450+1GgtA
c450+1GgtA
5 Pakistani c1340+5GgtA c1340+5GgtA
6 UK Caucasian c1087CgtT c1087CgtT
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
32
Management
Prevention of rhabdomyolysis
Gout preventiontreatment
Diet nutrition
Avoid glucose pre-exercise
Low carb
Fasting
Ketogenic diet
Strategies for exercise
bull Encourage aerobic exercise
Greg Glassman 2003
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Enzyme Gene Inheritance Other features
Phosphorylase B kinase IX
PHKG1 AR
IX PHKA1 AR Exercise intol myoglobinuria
IX PHKA2 XL Liver and muscle disease
IX PHKB XL Liver and muscle disease
Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms
Beta enolase 3
ENO3 AR Ex intolerance
Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates
Phosphoglycerate kinase PGK XL Ex intol myoglobinuria Haemolytic anaemia Learning difficulty
Lactate dehydrogenase
LDHA AR Exercise intolerance myoglobinuria Skin rash
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
NGS panel
ACADVL AGL ALDOA CAV3 CPT1B CPT2 ENO3
ETFA EFTB ETFDH FBP2 GAA GBE1 GYG1
HADHA HADHB ISCU LDHA LPIN1 PFKM PGAM2
PGK1 PGM1 PYGM RBCK1 SLC22A5 PHKA1 RYR1
Cost pound1000
Result available in 4 months
Benefits large number of genes tested
Disadvantages false positive results not
all genes causing rhabdomyolysis
covered
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Recurrent Rhabdomyolysis
28 year old male
Parents 1st cousins
Exercise induced pain and cramps since
childhood
Unable to sprint
Myalgia walking up hills
From 17 years recurrent episodes of
myoglobinuria
Maximum CK 75000 iul
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Examination
bull Normal apart from mild
left sided scapular winging
bull 12 MWT 1000m
onset of pain at 12 mins
bull Decrease in lactate
from 22mmoll pre-exercise
to 10mmoll post exercise
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
MRI
Fatty infiltration soleus
Muscle biopsy
Acid phosphatase glycogen
Phosphorylase PFK B kinase
PGAM2 and RCE all normal
Dystrophin and sarcolemmal
Proteins normal
EM mild increase in Glycogen
Skin fibroblasts
normal FAOD
Genes sequenced
RYR1 LPIN1 PYGM PGM1 PFKM
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Investigations
Resting CK 129mmoll
Carnitine acylcarnitines
normal
OA normal
CoQ10 normal
EMG NCS normal
Ischaemic forearm
exercise test
Time (minutes) 0 1 2 4 6 8 10
Lactate (mmolL 05-165) 142 279 294 298 216 206 187
Pyruvate (mmolL 45-150) 126 195 193 210 172 174 176
Ammonia (micromolL 11-32) 18 89 107 99 50 44 17
Lactatepyruvate ratio (10-20) 1127 1431 1523 1419 1256 1184 1063
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Diagnosis GSDXIII
Homozygous mutations in Beta ENO3
p(Glu187Lys) c559GgtA
Skeletal muscle beta enolase concentration
007nmolminmg prot
Nr 066+- 01
(Ralph Wigley GOSH)
2nd
patient recently diagnosed
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Highly Specialised Service for Mc Ardle
Disease and Related Disorders
Diagnosis and
management clinic
NHNN GOSH
Dr Quinlivan
Sherryl Chatfield
Dr Richard Godfrey
Dr Jatin Pattni
Clinical Fellow
Clinical Nurse
Specialist
Diagnosis
DNA testing
Dr Richard Kirk
Sheffield
Dr Carol Hardy
Birmingham
Muscle
biochemistry
(GOSH)
Professor Simon
Heales
Dr Ralph Wigley
40
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Summary
Disorders of muscle glycogenolysis and glycolysis
present with exercise intolerance
Multi-system disorders
Symptoms occur within minutes of activity
Second wind occurs with GSDV
Out of wind occurs with GSDVII
Avoid carbs
Management includes preventing acute rhabdomyolysis
Progressive muscle atrophy and weakness
Ocular and cardiac involvement
Exercise is not harmful and is beneficial
41
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi
Acknowledgements
NHNN ION
bull Sherryl Chatfield
bull Jatin Pattni
bull Andrew Wakelin
bull Suzanne Booth
bull Richard Godfrey
bull Charlotte Ellerton
bull Rachael Curruthers
bull Renata Scalco
bull Janice Holton
Sheffield Childrenrsquos Hospital
bull Richard Kirk
Birmingham Childrenrsquos Hospital
bull Mary Anne Preece
Great Ormond Street Hospital
bull Ralph Wigley
bull Simon Heales
Ramon Marti Toni Andreu Tomas Pinos
Xavier Ortager Alejandro Lucia Antonio
Toscano John Vissing Miguel Angel
MartinPascal Laforet Andrea Martinuzzi
Matthius Vorgerd Ron Haller Piraya Oflazer
Sabrina Sacconi