5th National Meeting for Mitochondrial Medicine, Bologna

Epidemiology of Mitochondrial Disease in The UK and The Development of A UK Cohort of Patients

with Mitochondrial Disease

Dr Yi Shiau NgClinical Research Associate

Newcastle University

Content

• Epidemiology of adult mitochondrial disease in the North East England

• Development of the UK Mitochondrial Disease Patient Cohort

• Utilization of cohort data

DiabetesThyroid Disease

Myopathy

Peripheral Neuropathy

Deafness

Stroke/ Epilepsy/

Migraine/ Dementia

Respiratory Failure Ptosis/ PEO/ Optic Atrophy/ Retinitis Pigmentosa

Cardiomyopathy

Conduction defect

Short StatureMarrow Failure

Liver Failure

NEUROLOGICALNON-NEUROLOGICAL

Clinical features

North East England

• Adult patients (>16 years)• Single specialist mitochondrial centre in the North East of

England• Genetic diagnosis: mtDNA mutations, nuclear genes, multiple

deletions (but genetically undetermined)• Family tracing and testing wherever possible• Population (>16 years) = 2.1 millions Population (all age) = 2.6 millions 2011 population census data

NB: previous studies only included patients in their working age, ie. male 16-65; female 16-60

Methods

Inclusion• CPEO• Ataxia• Seizure/ myoclonus• Stroke-like episode• Proximal myopathy• Exercise intolerance• Cardiomyopathy• Optic atrophy• Pigmentary retinopathy• Bilateral Deafness• Diabetes

Exclusion • Myalgia• Fatigue• Migraine• Dysphagia• Gastrointestinal upset• Cataracts

The Definition of Clinically Manifesting Mitochondrial Disease

mtDNA mutations

Disease= 9.6/100,000- m.3243A>G- Three LHON mutations (m.11778G>A, m.3460G>A & m.14484T>C)- Single, large scale deletion- m.8344A>G- 8 other point mutations

At risk= 10.7/100,000* All single deletion cases were sporadic in the cohort

Nuclear genes

Disease= 2.9/100,000- SPG7 (ar)- PEO1 (ad)- OPA1 (ad)- POLG (ar)- RRM2B (ad)- 4 other nuclear genes- Multiple deletions

At risk= 5.9/100,000* Heterogenous nature of inheritance patterns

Total prevalence = (9.6+ 10.7+ 2.9)/100,000 1 in 4300

Content

• Epidemiology of adult mitochondrial disease in the North East England

• Development of the UK Mitochondrial Disease Patient Cohort

• Utilization of cohort data

Unmet Clinical Research Need

1.Lack of natural history data2.No meaningful clinical trials3.No evidence-based guidelines

Why develop a Mitochondrial Disease Patient Cohort?

Three Nationally Commissioned Mitochondrial Service

Dr V Nesbitt

Dr R Pitceathly

Julie Phipps

Mitochondrial Disease Patient Cohort

• Initiated in 2009

• New ethics approval in England (01/2014) and Scotland (03/2014)

• Diagnosis of Mitochondrial Disease– Genetic or Biochemical

• Children and Adults – no age limits– Including those with limited capacity for consent

• Living patients

Inclusion Criteria

• Section I: Current Function (10 questions)

• Section 2: Specific System Involvement (9 questions)

• Section 3: Current Clinical Assessment (10 questions)

• Score 0 to 5 per question based on the severity

• Maximal score is 145

An example of NMDAS question

Section III – Current Clinical Assessment

2. Ptosis0. None.1. Mild ptosis – not obscuring either pupil.2. Unilateral ptosis obscuring <1/3 of pupil.3. Bilateral ptosis obscuring <1/3 or unilateral ptosis obscuring

>1/3 of pupil or prior unilateral surgery.4. Bilateral ptosis obscuring > 1/3 of pupils or prior bilateral

surgery.5. Bilateral ptosis obscuring >2/3 of pupils or >1/3 of pupils despite

prior bilateral surgery

Ptosis

Single, large scale deletion of mtDNA

POLG gene mutation PEO1 (Twinkle) gene mutation

Single, large scale deletion of mtDNA

m.3243A>G mutation(deceased)

m.8344A>G mutation

Geographical Distribution of All Cohort Patients(n=1218)

Newcastle56%

London32%

Oxford 6%

Others5%

Figure. Patient recruitment

Last updated on 6/5/2015

Newcastle Patient Cohort

• 689 patients recruited

• 6.6% = deceased during follow up (n=45)

• 87% of patients >16 years

• 63% = Female (n=404)

9075604530150

90

80

70

60

50

40

30

20

10

0

Age

Fre

quency

Mean 45.30StDev 18.63N 638

Figure. Age of patients from Newcastle cohort

Last updated on 6/5/2015

m.3243A>G32%

m.8344A>G6%

m.8993T>C/G2%

Other mtDNA point mutations11%

Single dele-tion15%

PEO16%

POLG6%

RRM2B3%

OPA13%

Other nuclear genes

5%

Multiple dele-tions6%

Other genetically undetermined6%

Genotypes in Newcastle patient cohort (n=689)

Last updated on 6/5/2015

Clinical Features in Adult Patients

PtosisCPEO

MyopathyCerebellarCognition

SeizureDysphagiaHeadache

NeuropathyEncephalopathyExtrapyramidal

SLEDeafness

Gastrointestinal Diabetes mellitus

Cardiovascular

0% 10% 20% 30% 40% 50% 60%

Disease Burden defined by NMDAS

TWINKLE (PEO1)Single deletionRRM2BPOLG1m.8344A>Gm.3243A>G

100

80

60

40

20

0

Genotype

NM

DA

S s

core

m.3243A>G mutation in MTTL-1

Neuropathy

Stroke-lik

e episode

Cardiac

CPEO

Diabetes

Exerci

se intolerance

Myopathy

Migraine

Deafness GI0%

10%

20%

30%

40%

50%

60%

70%

80%

Evolution of stroke-like episode

16/12/2010 24/04/2012

DWI

01/03/2013

DWI

02/07/2014 02/01/2015

Evolution of pseudo-obstruction

(a)

(c) (d)

(b)

(e)

Figure. Abdominal radiograph(a) and (b) on admission(c) 5 days later(d) 10 days later (e) 20 days later

Disease Progression Documented with Serial NMDAS

Content

• Epidemiology of adult mitochondrial disease in the North East England

• Development of the UK Mitochondrial Disease Patient Cohort

• Utilization of cohort data

Cohort Utilization

Data Mining for Analysis

• 13 projects approved • 1,450+ anonymised data sets

reviewed • Projects include

– Clinical Manifestations and Genetic Features

– Prevalence and Predictive Factors – Progression and Correlation– Clinical Audit – Reproductive Health

Screening for Participation in Clinical Study

• 15 studies approved • 350+ patients enrolled • Studies include

– Exercise Intervention– Physiological– Biomarker analysis (specific

project) – Cognition– Qualitative – Questionnaire

Cardiac Involvement in the Mito Cohort (Newcastle)

• 18% (n=78)

• It is more prevalent in mtDNA mutations than common nuclear genes.

Genotype Prevalence

m.3243A>G 25%

m.8344A>G 26%

Single deletion 15%

POLG 1/21

PEO1 0

RRM2B 1/15

Types of Cardiac Involvement

m.3243A>G

m.8344A>G

Other mtD

NA

Single

deletion

POLG

RRM2BOPA1

Other nucle

ar

MD & others

0

10

20

30

40

50

Cardiomyopathy (including LVH) Conduction defect LV impairment LVH + WPW WPW Other

Grady et al. 2014 Disease progression prediction tool in single deletion

Bates et al. 2013 Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease

Lax et al. 2015 Extensive respiratory chain defects in inhibitoryinterneurones in patients with mitochondrial disease

http://research.ncl.ac.uk/mitoresearch/

Best Practice Guidelines

http://www.newcastle-mitochondria.com/service/patient-care-guidelines/8 guidelines freely available; 2 in progress

Future Direction

• Clinical trial readiness

• International collaboration

Treatment – The Evidence (2012)

Cochrane Database Syst Rev. 2012 Apr 18;4:CD004426. doi: 10.1002/14651858.CD004426.pub3.

GRAZIE MILLE

Faculty of Medical Science, Newcastle University