Neuromuscular Diagnosis in the Modern Era · Neuromuscular Diagnosis in the Modern Era Kevin J. Felice, D.O. Director, Charles H. Kaman Neuromuscular Center Hospital for Special Care

Neuromuscular Diagnosis in the Modern Era

Kevin J. Felice, D.O.

Director, Charles H. Kaman Neuromuscular Center

Hospital for Special Care

Professor of Neurology

University of Connecticut School of Medicine Teaching Affiliate

Neuromuscular Medicine

2005: Development

of automated and

Next Generation

DNA sequencing

Mid-1800: Duchenne &

Charcot introduce modern

clinicopathological methods

Mid-1900: Refinement of

muscle histopathology,

electron microscopy, and

electomyography

1987: Discovery of the

dystrophin gene by Kunkel,

Hoffman and Brown

1953: Discovery of DNA by

Watson and Crick

1990s: Progressive

Improvements in DNA

diagnosis

Time Line

Hereditary Myopathies

• Duchenne muscular dystrophy (XR)

• Becker muscular dystrophy (XR)

• Facioscapulohumeral muscular dystrophy (AD)

• Emery-Dreifuss muscular dystrophy (XR)

• Myotonic dystrophy (Steinert disease) (AD)

• Limb-girdle muscular dystrophy (AD,AR,XR)

• Oculopharyngeal muscular dystrophy (AD)

• Congenital muscular dystrophy (AR)

• Congenital myopathies (AD,AR,XR)

• Myotonic congenita (AD,AR)

• Periodic paralyses (AD)

• Metabolic myopathies (AR)

• Mitochondrial myopathies (maternal)

• Distal myopathies (AD,AR)

Classification 1980


Muscular dystrophies

28 types

Congenital

muscular dystrophies

19 types

Congenital myopathies

20 types

Distal myopathies

10 types

Myotonic dystrophies

2 types

Metabolic myopathies

30 types

Mitochondrial myopathies

30 types

Channelopathies

4 types

Classification 2015

Genetic Neuromuscular Disorders

761 disease phenotypes

406 different genes

76 mapped loci awaiting gene identification

Neuromuscular Disorders

• Neuromuscular history & exam

• Laboratory & genetic testing

• Neurophysiology/EMG

• Pathology of muscle, nerve, or skin

• Musculoskeletal & neuromuscular

imaging

Five Diagnostic Tools


• Problems

– Phenotypic diversity

– Genetic diversity

– Cost of studies

• Solutions

– Careful exam

– Physician understanding of testing limitations

– Step-wise approach to testing

– Patient understanding & compliance

Five Diagnostic Tools

Myopathy Evaluation

1. Proximal limb-girdle (e.g., BMD, LGMD)

2. Distal-predominant weakness (e.g., Miyoshi, Laing)

3. Proximal arm & distal leg (scapuloperoneal) (e.g., FSHD)

4. Distal arm & proximal leg (e.g., IBM, DM1)

5. Myopathies with blepharoptosis or ophthalmoparesis (e.g., OPMD,

DM1, CPEO)

6. Prominent neck extensor weakness (e.g., INEM, polymyositis)

7. Bulbar weakness (e.g., OPMD, LGMD1A)

8. Episodic weakness with rhabdomyolysis/myoglobinuria (e.g.,

McArdle disease, CPT2)

9. Episodic weakness unrelated to exercise (e.g., periodic paralyses)

10. Stiffness and decreased ability to relax (e.g., DM1, myotonia

congenita)

Patterns of Weakness

Myopathy Evaluation

Pattern of weakness

Distal onset Proximal onset

Familial Acquired Familial Acquired

Muscular dystrophies

Congenital myopathies

Pompe disease

Polymyositis

Dermatomyositis

Toxic myopathies

Laing

Myoshi

Myofibrillar

Inclusion body

myositis

Myopathy Evaluation

• Ptosis & ophthalmoplegia

– CPEO

– DM1

– OPMD

• Facial weakness

– FSHD

– OPMD

• Scapular winging

– FSHD

– LGMD2A

• Dysphagia

– OPMD

• Pseudohypertrophy

– Dystrophinopathy

• Contractures

– EDMD

– Ullrich

• Myotonia

– DM1

– DM2

• Fasciculations

– SMA

• Gynecomastia

– Kennedy

Phenotypic Features

Phenotypic Diversity (Pleiotropy)

• Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD)

• Autosomal recessive EDMD (EDMD-AD) (H222Y)

• Autosomal dominant limb-girdle muscular dystrophy with cardiac conduction system disease (LGMD1B)

• Dilated cardiomyopathy with conduction system disease

• Dunnigan-type familial partial lipodystrophy

• Charcot-Marie Tooth neuropathy, axonal variant

• Mandibuloacral dysplasia, autosomal recessive

• Hutchinson-Gilford progeria

EDMD-AD

Genetic Diversity

• Muscular dystrophies

– FSHD

– Scapuloperoneal MD

– Emery-Dreifuss MD

– LGMD (e.g., calpainopathy)

– Myotonic MD

• Metabolic myopathies

– PFK deficiency

– Acid maltase deficiency

• Congenital myopathies

– Nemaline rod

– Central core

– Myotubular

• Scapuloperoneal SMA

– Without sensory neuropathy

– With sensory neuropathy

(Davidenkow syndrome)

Disorders with Scapular Winging

Neuromuscular Diagnosis

• Importance:

– Verify neuromuscular localization

– Focal neuropathies

– Polyneuropathy evaluation of demyelinating, axonal or

multifocal

– NMJ evaluation of pre- or post-synaptic

– Motor neuron diseases

– Myopathies associated with fibs, positive waves, or

myotonic discharges

• Limitations:

– Mild, metabolic or non-inflammatory myopathies

Neurophysiology

Neuromuscular Diagnosis

• Types:

– Spinal imaging (MRI, CT) to assess for cord and root

disease

– Muscle imaging (MRI, US) to assess for pattern of

involvement

– Neurography (MRI, US) to assess for nerve entrapment,

edema or inflammation

• Limitations:

– Costs

– Availability of other tools

– Insurance coverage in US

Neuroimaging

Muscle Biopsy

Surgical

specimen

Paraffin

sections

Frozen

sections

Immuno

sections

Electron

microscopy

Special

studies

Inflammation

Necrosis

Vasculitis

Histochemistry

Protein-based

analyses

Inclusions

Mitochondrial abn

Excess lipid or glycogen

Enzyme studies

DNA studies

Testing

Muscle Biopsy

• Usually indicated

– Progressive myopathic weakness of unclear etiology

– History of exercise intolerance due to suspected metabolic or mitochondrial disorder

– Recurrent rhabdomyolysis

– Combined muscle & nerve biopsy in cases of suspected vasculitis

– HyperCKemia or myopathic EMG

– To search for suspected systemic disease with skeletal muscle manifestations – amyloid, sarcoid, mitochondrial cytopathy

• Usually not indicated

– When phenotype points to a specific genetic myopathy

– Motor neuron disease

– Polyneuropathy

– Myasthenic syndromes

– Myotonic disorders

– Channelopathies

Indications

Muscle Biopsy

• Primary protein defects – Dystrophin: Xp21 muscular dystrophies

– Sarcoglycans: LGMD 2C-2F

– Dysferlin: LGMD2B, Miyoshi myopathy

– Caveolin-3: LGMD 1A, rippling muscle disease, idiopathic hyperCKemia

– Laminin 2: MDC1A (merosin-deficient MD)

– Collagen VI: Ullrich congenital muscular dystrophy

– Integrin 7: mild congenital MD

– Emerin: X-linked EDMD

– SERCA 1: Brody’s disease

– Plectin: Epidermolysis bullosa with muscular dystrophy

– Calpain-3: LGMD2A (immunoblot only)

• Secondary protein defects

– -dystroglycan: MDC1C (FRP), FCMD, MEB, WWS

– Laminin 2: MDC1B, LARGE, MDC1C, FCMD, MEB, WWS

– Sarcoglycans: LGMD 2C-2F

• Protein Accumulation

– Actin: congenital actinopathy, nemaline myopathy

– Myosin: Laing distal myopathy, myosin storage disease

– Desmin: myofibrillar myopathies

Immunohistochemistry

nucleus

mitochondria

chromosome

gene

mitochondrial DNA

Organization of the Human Genome

>406 genes implicated in >761 NMD phenotypes

(Kaplan, www.musclegenetable.org)

Human genome

Nuclear genome

~20,000 genes Mitochondrial genome

37 genes

• Only 1-2% of the entire genome is used for encoding proteins

• A large portion of the human genome is “repetitive DNA”

• Non-coding regions are involved in regulating gene function

Organization of the Human Genome

Mutation

Chromosomal Molecular

Single-base substitutions Length variation

Genetic Defects

• Substitutions in the coding sequence

• Frameshift & premature termination of translation

• Repeat expansion

• Epigenetic silencing / activation


• Chromosomes

– Fluorescent in situ hybridization (FISH)

• DNA

– Restriction fragments (Southern blot analysis)

– PCR

– Sequencing

– Next-Gen panels

– Whole exome or genome sequencing

• mRNA

– Northern blot analysis

– Microarray expression analyses

• Protein

– Immunohistochemistry

– Enzyme assays

– Western blot analysis

Genetic Methods

Neuromuscular Weakness

MND, PN, NMJ Disorder Myopathy

Clinical, EMG and lab assessment

Acquired Genetic

Specificity Highly Probable

Define clinical phenotype utilizing

EMG and muscle path if necessary

Specificity Possible Nonspecific Phenotype

Review clinical features and pedigree

Targeted DNA Testing Next-Gen Slice Whole exome sequencing

Diagnosis

+ -

Diagnosis

+

-

Diagnosis

+ -

Research

Myopathy Evaluation

High specificity

1. Clinical Exam

--DMD

--FSHD1

--DM1

--OPMD

--EDMD

--Miyoshi

--McArdle

--Andersen

2. Clinical + Muscle Path

--DM2

--BMD

--GNE myopathy

--Pompe

3. Clinical + EMG

--DM2

--Myotonia congenita

Focused DNA testing

Diagnostic Approach

Patient: AS (HSC36352)

• Referring service: general medicine

• Referring diagnosis: bilateral foot drop

• Patient: 45-yo woman

• Complaint:

– Progressive leg weakness, foot drop, and gait difficulties for 10

years

– Recent upper extremity weakness

– No pain or sensory symptoms

• Past medical history: right calf muscle biopsy 10 years ago (UVM)

• Family history:

– Born in India

– No weakness in unrelated parents, son, or relatives

History


• Height & weight: 64 inches & 124 lb.

• CN: question mild lower facial weakness; weak whistle

• Motor

– Chair: slight hesitation

– Stance: mildly hyperlordosis

– Gait: steppage pattern

– Deep knee bend, tiptoes, heels: unable

– Strength: see MRC scores

– Atrophy: neck muscles; mild anterior foreleg atrophy; EDBs intact

– Positives: mildly winged & upwardly displaced scapulae

– Negatives: no pseudohypertrophy, scoliosis, contractures, fasciculations, or myotonia

• Sensory: normal

• Reflexes: hypoactive

• UMN or cerebellar signs: none

Exam


MRC Score

UE R L LE R L

Arm abductors 4 4 Hip flexors 3 3

Arm flexors 5 5 Hip extensors 4 4

Arm extensors 5 5 Hip abductors 4 4

Wrist flexors 5 5 Hip adductors 3 3

Wrist extensors 5 5 Knee flexors 4 4

Finger flexors 5 5 Knee extensors 4 4

Finger extensors 4+ 4+ Foot dorsiflexors 2 2

Thumb extensors 5 5 Foot plantar flexors 4 4

Median FPL 5 5 Foot evertors 3 3

Median thenar 5 5 Foot invertors 4 4

Ulnar FDI 5 5 Toe flexors 4 4

Ulnar hypothenar 5 5 Toe extensors 3 3

Jamar grip forces (lb.) (RHD) 40 35 Toe abductors 2 2

Myopathies & Vacuoles

• Storage diseases

– Glycogen storage (e.g., Pompe disease)

– Lipid storage (e.g., carnitine deficiency)

• Autophagic (rimmed) vacuoles

– Acquired myopathies (e.g., IBM)

– Hereditary myopathies (e.g., OPMD)

• Empty vacuoles

– Dilated t-tubules (e.g., periodic paralysis)

Types of Vacuoles

Myopathies & Rimmed Vacuoles

• Hereditary inclusion body myopathies

– h-IBM2 or Nonaka myopathy

– h-IBM with Paget disease/FTD

– h-IBM3

• Distal myopathies

– Welander

– Markesbery-Griggs (ZASPopathy)

– Udd (titinopathy)

• Dystrophies

– LGMD1A (myotilin)

– LGMD2A (calpain)

– LGMD2G (telethoninopathy)

– EDMD

– FSHD

– OPMD

Disorders

• Sporadic inclusion body myositis (sIBM)

• Myofibrillar myopathy

– Myotilinopathy (LGMD1A)

– ZASPopathy

– Desminopathy

– Filaminopathy

– Bag3-opathy

– B-crystallin-opathy

– Reducing body myopathy (FHL1-opathy)

• Other myopathies

– Pompe disease

– Danon disease

– X-linked myopathy with excessive autophagy (VMA21)

Distal-Onset Myopathies

• Hereditary distal myopathies

• Sporadic inclusion body

myositis

• Myotonic dystrophy type 1

• Facioscapulohumeral MD

• Oculopharyngeal MD

• Oculopharyngodistal MD

• Emery-Dreifuss MD

• Acid maltase deficiency

Disorders

• LGMD1A (myotilin)

• LGMD1C (caveolin-3)

• LGMD2A (calpain 3)

• LGMD2G (telethonin)

• Debrancher deficiency

• Nemaline myopathy

• Central core disease

• Myotubular myopathy

Hereditary Distal Myopathies

Type Inheritance Locus (gene) Age Initial weakness

Welander AD 2p13 (TIA1) 40-60 Finger & wrist extensors

Udd (tibial muscular dystrophy)

AD 2q31 (titan) 35-50 Anterior foreleg

Markesbery AD 10q22.2 (ZASP) 40-50 Anterior foreleg

Laing AD 14q11.2 (MYH7) 3-25 Anterior foreleg, neck flexors

VCPDM AD 5q31 (matrin 3) 35-60 Anterior foreleg, finger extensors

Myofibrillar AD

AD

AD

AD

AD

AD

XR

AD

2q35 (desmin)

11q22 (-crystallin)

5q31 (myotilin)

10q22.2 (ZASP)

7q32 (filamin)

10q26.11 (BAG3)

Xq26.3 (FHL1)

7q36.3 (DNAJB6)

25-45 Hands or legs

Cardiomyopathy

HIBM2 (Nonaka, DMRV) AR 9p1-q1 (GNE) 15-30 Anterior foreleg

Miyoshi AR 2p13 (dysferlin) 15-30 Posterior foreleg

Hereditary Distal Myopathies

Type CK Pathology

Welander 1-3X Dystrophic, rimmed vacuoles

Udd (tibial muscular dystrophy) 1-4X Dystrophic, rimmed vacuoles

Markesbery 1-4X Myofibrillar myopathy, dystrophic, rimmed vacuoles

Laing 1-3X Mild to moderate dystrophic, fiber type disproportion

VCPDM 1-3X Rimmed vacuoles

Myofibrillar 1-4X Myofibrillar myopathy, dystrophic, rimmed vacuoles

HIBM2 (Nonaka, DMRV) 3-4X Dystrophic, prominent rimmed vacuoles

Miyoshi 20-150X Dystrophic, dysferlin defect

DNA Test


HIBM

• Described by Argov (distal myopathy with rimmed vacuoles) in Israel and Nonaka in Japan in 1984

• Autosomal recessive

• Severe progressive myopathy with anterior foreleg-onset weakness, quadriceps-sparing

• Progresses to wheelchair in mean 12 years

• No bulbar, cardiac, or respiratory muscle involvement

• Caused by a deficiency in first enzyme in sialic acid biosynthetic pathway

• Defect leads to decreased sialylation of key proteins such as neural cell adhesion molecule (NCAM) and GM1

• Gene: (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase [GNE] at 9p1-q1

Features

HIBM

• Affects diverse backgrounds – all ethnic groups

• Iranian Jews 1:1500 births

– Homozygous M712T mutation

• Japanese one frequent founder mutation V572L

• Multiple compound heterozygous missense mutations in kinase and epimerase domains of GNE in other ethnic groups

• Mutations in C-terminal domain (allosteric region) cause sialic storage disease

• About 400 cases reported in medical literature

• Survey of 400 clinics identified 146 patients

• Estimated 1600 to 2000 patients worldwide (1.4% of all myopathy patients)

Features

Myopathy Evaluation

Moderate specificity

1. Clinical Exam

--LGMD

--EDMD

--Metabolic myopathy

--Hypertrophic cardiomyopathy

--Dilated cardiomyopathy

--Periodic paralyses

--Malignant hyperthermia

2. Clinical + Muscle Path

--Congenital myopathy

--Congenital muscular dystrophy

--Myofibrillar myopathy

--Lipid storage myopathy

--Distal myopathy

3. Clinical + EMG

--Unspecified myotonic disorder

DNA panel or slice

Diagnostic Approach

Case 3: JR (UC090878)

• Referring service: general neurology

• Referring diagnosis: spinal muscular atrophy

• Patient: 37-yo man

• Complaint:

– Progressive leg weakness for 2 years

– Mild generalized weakness since childhood

– No pain or sensory symptoms

• Past medical history: unremarkable

• Family history: similar weakness in mother and multiple

maternal relatives

History

Case 3: JR (UC090878)

Family History

Case 3: JR (UC090878)

Family History

?

?

I

II

III

IV

V

VI

1

1

2 3 4 5 6

8 9 10 11 12 13 2 3 4 5 6 7 14 15 16 17 18 19 20

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

5 6 8 7 9 10 11 12

2 3 4 5 6 8 9 7 10

32 33 34 35

affected

reported to have “muscle weakness”

mental retardation – unknown etiology

13 14 15 1 2 3 4

1

examined √

√

√ √ √ √ √ √

√ √ √ √ √

√

sickle cell disease

? unknown if affected

2

5 ?

√

√

√

√

√ 18 22-26

12-13

17 21 20 19

11

16

Case 3: JR (UC090878)

Case 3: JR (UC090878)

• Height & weight: 69 inches & 144 lb

• General: Normal

• CN: Normal

• Motor

– Difficulty arising from chair

– Lumbar hyperlordosis & protuberant abdomen

– Steppage pattern gait

– Atrophy of humeral, brachioradialis, hand, anterior foreleg, EDB

– Marked scapular winging

– No muscle pseudohypertrophy, gynecomastia, enlarged nerves, contractures, fasciculations, myotonia

• Sensory: Normal

• Reflexes: Diffusely hypoactive

• UMN signs: None

• Cerebellar signs: None

Exam

Case 3: JR (UC090878)

• Upper extremity

– Arm abductors: 3/3

– Arm flexors: 3/3

– Arm extensors: 4/4

– Wrist flexors: 4/4

– Wrist extensors: 4/4

– Finger flexors: 2/2

– Finger extensors: 2/2

– Ulnar hand: 3/3

– Median hand: 3/3

– Grips (lb.): 25/25 (RHD)

• Lower extremity

– Hip flexors: 4/4

– Hip extensors: 4/4

– Hip abductors: 4/4

– Hip adductors: 4/4

– Knee flexors: 4/4

– Knee extensors: 4/4

– Plantar flexors: 4/4

– Foot extensors: 2/2

– Toe flexors: 3/3

– Toe extensors: 2/2

MRC Score (R/L)

Genetic Diversity


– FSHD

– Scapuloperoneal MD

– Emery-Dreifuss MD

– LGMD (e.g., calpainopathy)

– Myotonic MD

• Metabolic myopathies

– PFK deficiency

– Acid maltase deficiency


– Nemaline rod

– Central core

– Myotubular

• Scapuloperoneal SMA

Disorders with Scapular Winging

Case 3: JR (UC090878)

• CK: 46 U/L (n<269)

• Other Labs: Normal

• FVC: 3.66 L (73%)

• NCS: Normal

• EMG:

– Mild myopathic changes

– No fibs, PSWs, myotonia, or fasciculations

• DNA tests (maternal aunt)

– FSHD: negative

– SMA: negative

Studies

Myopathies

• Normal muscle fiber size:

– Males: 40-80 μm diameter

– Females: 30-70 μm diameter

– Mean size by type:

• Type 1: 52 μm

• Type 2: 59 μm

– Fiber type size difference: Mean diameters of type 1 and

type 2 fibers should not differ by more than 12% of the

largest diameter of the largest fiber type

Myofiber Size

Muscle Fiber Type Atrophy

• Type I

– Myotonic dystrophy type I

– Congenital myopathies


• Myotubular myopathy

• Centronuclear myopathy


• Congenital fiber type

disproportion

• Congenital MYH7 myopathy

– Disuse (rare)

• Type II

– Disuse

– Aging

– Weight loss

– Systemic disease

– Stroke

– Myasthenia gravis

– Myotonic dystrophy type II

Considerations

Congenital Myopathies



• Core-rod myopathy

• Centronuclear myopathy

• Multiminicore disease

• Congenital fiber-type

disproportion

• Reducing body myopathy

• Zebra body myopathy

• Fingerprint body myopathy

• Cytoplasmic body myopathy

• Tubular aggregate myopathy

• Type 1 fiber predominance

• Spheroid body myopathy

• Hyaline body myopathy

• Cap disease

• Sarcotubular myopathy

Classification

Nemaline Myopathies

Type MIM# Inheritance

Chromosome

Gene Protein

NEM1 609284 AD 1q21.2 TPM3 -tropomyosin, slow

NEM2 256030 AR 2q22 NEB Nebulin

NEM3 161800 AD 1q42.1 ACTA1 actin 1 (skeletal muscle)

NEM4 609285 AD 9p13 TPM2 -tropomyosin

NEM5 605355 AR 19q13 TNNT1 troponin T type 1 (skeletal, slow)

NEM6 609273 AD 15q ? ?

NEM7 610687 AR 14q12 CFL2 cofilin 2 (muscle)

Classification

ACTA1 Myopathies


• Nemaline myopathy with cores

• Accumulation of thin filaments

• Congenital fiber-type disproportion

• Cap disease

Pathologic Changes

CFTD

• ACTA1

• TPM3

• RYR1

• SEPN1

• MYH7

Implicated Genes

Patient: RG (HSC44194)

• Referring service: neurology

• Referring diagnosis: myopathy


• Complaint:

– Mild leg weakness and gait imbalance for 5 years

– Difficulty climbing stairs

– Previously strong and physically active

• Past medical history:

– Hypertension, asthma,, elevated LFTs (2 negative liver biopsies), left

vastus lateralis muscle biopsy

• Family history:

– Mother had poliomyelitis

– Maternal uncle has multiple sclerosis

– 30-yo daughter is in good health

History


• General:

– Large calf muscle

– No hand or foot deformities, scoliosis, winged scapulae, contractures,

gynecomastia

• Mental status: normal

• Cranial nerve: normal

• Motor:

– Mild waddling gait pattern

– Unable to perform deep knee bend

– Difficulty standing on tiptoes

– Mild proximal leg weakness

• Sensory: normal

• Reflexes: normal

Exam


MRC Score

UE R L LE R L







Finger extensors 5 5 Foot dorsiflexors 5 5






Jamar grip forces (lb.) 102 86 Toe abductors 5 5

Proximal Weakness

• Motor neuronopathies

– Spinal muscular atrophy

– Kennedy disease

– Amyotrophic lateral sclerosis

• Polyneuropathies

– CIDP/AIDP

– Diabetic amyotrophy

– Porphyria

• NMJ Disorders

– Myasthenia gravis

– Lambert-Eaton myasthenic syndrome

– Botulism

– Congenital myasthenic syndromes

Differential Diagnosis

• Myopathies

– Acquired

• Inflammatory myopathies

(PM/DM)

• Toxic myopathies (e.g., statins)

• Endocrine myopathies

– Genetic



• Myotonic dystrophies

• Mitochondrial myopathies

• Myofibrillar myopathies

• Pompe disease


• FVC: 3.34 L (76%)

• CK: 1450 U/L

• Echo/ECG: normal

• EMG: myopathic pattern with fibrillations and

positive sharp waves

• DNA:

– FSHD1: negative

– DM2: negative

Studies

Myopathies

Cell-Based Classification

1. Disorders

2. Neurogenic

3. NMJ transmission

4. Sarcolemma

5. Nuclear proteins

6. Myofibrils

7. Intermediate filaments

8. Mitochondria

9. SR & t-tubules

10. Cytoplasmic proteins

11. Metabolic & storage disorders

12. DNA expansion disorders

13. FSHD

14. Inflammatory myopathies

15. Toxic myopathies

16. Aging and systemic disease

17. Rare structural abnormalities


• Autosomal Dominant

– LGMD Type 1

– EDMD-AD

– FSHD1

– FSHD2

– Myotonic dystrophies type 1 & 2

– Congenital-AD

– OPMD

Muscular Dystrophies

• Autosomal Recessive

– LGMD Type 2

– EDMD-AR

– Congenital-AR

• X-Linked Recessive

– Duchenne

– Becker

– EDMD-XR


Name Inheritance Chromosome Gene Protein

LGMD1A AD 5q31 MYOT Myotilin

LGMD1B AD 1q22 LMNA Lamin A/C

LGMD1C AD 3p25 CAV3 Caveolin-3

LGMD1D AD 7q36.2 DNAJB6 DNAJB6

LGMD1E AD 2q35 DES Desmin

LGMD1F AD 7q32.1-q32.2 TNPO3 Transportin-3

LGMD1G AD 4q21 HNRPDL HNRPDL

LGMD1H AD 3p25.1-p23 ? ?

LGMD, Dominant



LGMD2A AR 15q15.1 CAPN3 Calpain-3

LGMD2B AR 2p13 DYSF Dysferlin

LGMD2C AR 13q12 SGCG γ-SG

LGMD2D AR 17q12-q21.33 SGCA α-SG

LGMD2E AR 4q12 SGCB β-SG

LGMD2F AR 5q33 SGCD δ-SG

LGMD2G AR 17q12 TCAP Telethonin

LGMD2H AR 9q31.2 TRIM32 TRIM32

LGMD2I AR 19q13.3 FKRP Fukutin-related protein

LGMD2J AR 2q31 TTN Titin

LGMD, Recessive



LGMD2K AR 9q34 POMT1 POMT1

LGMD2L AR 11p14.3 ANO5 Anoctamin 5

LGMD2M AR 9q31-q33 FKTN Fukutin

LGMD2N AR 14q24 POMT2 POMT2

LGMD2O AR 1p34 POMGNT1 POMGNT1

LGMD2Q AR 8q24 PLEC1 Plectin

LGMD2R AR 2q35 DES Desmin

LGMD2S AR 4q35.1 TRAPPC11 TRAPPC11

LGMD2T AR 3p21.31 GMPPB GMPPB

LGMD, Recessive

Diagnosis: LGMD, type 2L (ANO5, 11p14.3)

LGMD2L

• Rare autosomal recessive disorder

• Several large families reported of French-Canadian and Finnish ancestry

• Age of onset: 11-50 years

• Phenotype: proximal myopathy, proximal LE myopathy, quadriceps

myopathy, Miyoshi phenotype

• Progressive disorder – some patients wheelchair-bound after 12 years

• No clear genotype-phenotype correlation

• CK: normal to markedly elevated

• EMG: myopathic pattern with fibs and positive sharp waves

• Muscle biopsy: dystrophic pattern with fatty infiltration

• Anoctamin 5 protein is a complex glycoprotein localized in intracellular

vesicles, and has diverse cellular roles in the early development of the

musculoskeletal system

Features

Myopathy Evaluation

Low specificity

1. Myopathy, unspecified

--Nonspecific clinical,

path and EMG findings

2. Neuromyopathy

--Possible myofibrillar or

mitochondrial disorder

3. Genetic or sporadic

non-inflammatory

myopathy, fixed or

metabolic, with negative

focused and/or panel

DNA studies

Exome or genome

sequencing

Diagnostic Approach

Patient: HC (HSC50115)

• Referring service: neurology

• Referring diagnosis: myopathy


• Complaint:

– Progressive leg weakness for 10 years

– Difficulty performing job as letter carrier for 3 years

– Recent arm and hand weakness

– Occasional muscle aches and cramps

– No sensory symptoms

– No speech, swallowing or breathing difficulties

• Past medical history: negative

History


Pedigree


• General: thin body habitus, hypertelorism, pes

cavus, hammertoes

• Mental status: normal

• Cranial nerve: normal

• Sensory: mildly reduced toe vibration sensation

• Reflexes: absent

Exam


• Motor exam

– Arise from chair: no difficulty

– Stance & base: normal

– Gait: mildly unsteady, steppage-pattern

– Deep knee bend: mild difficulty

– Standing on heels & tiptoes: unable

– Tandem-walking: mild difficulty

– Atrophy: trapezius, deltoid, medial pectoralis, humeral, distal quadriceps,

foreleg, foot muscles

– Mild scapular winging

• Studies

– FVC: 4.02 L (74%)

– CK: 1022 units/L (n<170)

Exam


MRC Score

UE R L LE R L







Finger extensors 5 5 Foot dorsiflexors 2 2






Jamar grip forces (lb.) 54 44 Toe abductors 0 0

NCSs

CNE

Comment: Some areas in proximal limb muscles show increased (early) recruitment of small,

polyphasic MUAPs.

CNE


• CMT axonal DNA panel (15 genes): DNM2 VOUS

• Kennedy disease DNA: negative

• Pompe disease GAA blood spot: negative

• Myofibrillar myopathy DNA panel (6 genes): negative

• LGMD DNA panel (35 genes):

– COL6A2 G555R VOUS

– TTN E25692D VOUS

• mtDNA sequencing: MT-TR VOUS

• WES: POLG E1136K pathogenic variant (heterozygous)

• Diagnosis: mitochondrial neuromyopathy, POLG-related

Diagnostic Odyssey

Documents

Neuromuscular Diagnosis in the Modern Era · Neuromuscular Diagnosis in the Modern Era Kevin J. Felice, D.O. Director, Charles H. Kaman Neuromuscular Center Hospital for Special Care