5 th 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 Ng Clinical Research Associate Newcastle University
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
• 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?
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 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
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
Treatment – The Evidence (2012)
Cochrane Database Syst Rev. 2012 Apr 18;4:CD004426. doi: 10.1002/14651858.CD004426.pub3.