An Introduction to mitochondrial disease.

Transcription

1 9 th September 2017 An Introduction to mitochondrial disease. Dr Andy Schaefer Consultant Neurologist and Clinical Lead NHS Highly Specialised Rare Mitochondrial Disease Service and Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK

2 Mitochondrial Disease adult Biochemical Single deletion Chronic progressive external ophthalmoplegia (CPEO) MELAS syndrome neonatal paediatrics MERRF Pearson syndrome Clinical Lebers hereditary optic neuropathy MNGIE NARP Genetics Adult Mitochondrial depletion syndrome

3 Photo via Creative Commons Different Diseases

4 Different Inheritance Patterns Maternal Sporadic Dominant X-linked Recessive

5 Different Patterns of organ involvement Respiratory Failure Cardiomyopathy Liver Failure Optic Atrophy or Retinitis Pigmentosa Stroke / Seizures Developmental delay Deafness Short Stature Marrow Failure Peripheral Neuropathy Diabetes Thyroid Disease Muscle weakness

6 Mitochondrial disease is common as a whole Prevalence of nuclear and mtdna mutations related to adult mitochondrial disease: 1 in 4300 UK-MRC Mitochondrial Disease Cohort (n=1395) Chinnery et al. Ann. Neurol Schaefer et al. Ann. Neurol Gorman et al. Ann. Neurol. 2015

7 All have one thing in common Energy Failure

8 Mitochondria turn fuel into energy

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10 This doesn t necessarily mean a global loss of energy this occurs at a cellular level

11 Best thought of like a country s power grid with local shortages affecting some areas more than others

12 This can lead to errors in susceptible organs

13 Multisystem disease % chance

14 How is Mitochondrial Disease Inherited? We ll skip the first part

15 Maternal Inheritance of mtdna Colours reflect inheritance of the same mitochondrial genome

16 mtdna disease normal mtdna mutated mtdna Nucleus containing Chromosomes (99.9% of genetic Information - hair colour blood group etc) Mitochondria (batteries)

17 Nuclear genetic disorders: dominant and recessive inheritance Autosomal dominant Autosomal recessive 1 in 2 chance of affected child 1 in 4 chance of affected child

18 Nuclear DNA influence can create other inheritance patterns Quality control mtdna Nucleus Mitochondria

19 The Quality Control analogy Nuclear apparatus Screens mtdna Corrects Errors

20 When quality control goes wrong Abnormal mitochondrial DNA (and mitochondria) accumulate with time

21 Accumulation of mtdna errors Nucleus containing Chromosomes (99.9% of genetic Information - hair colour blood group etc) Mitochondria (batteries)

22 So things are complicated... Nuclear DNA disease Inheritance: Dominant Recessive X-linked Mt DNA disease Inheritance: Maternal

23 ADULT syndromes LHON MIDD MERRF NARP SANDO CPEO CPEO+ MELAS PAEDIATRIC syndromes Barth syndrome PDH deficiency Alpers syndrome Pearson syndrome Leigh syndrome Kearns-Sayre syndrome MELAS

24 Nuclear DNA disease A/B A/B Recessive e.g. some forms of Leigh Disease B/B A/B A/B A/A Each child has 1 in 4 chance of disease A/B B/B Dominant A/B B/B B/B A/B Each child has 1 in 2 chance of disease disease unaffected Unaffected carrier

25 Mitochondrial DNA disease Not Yes or No? well disease disease well Nuclear: e.g. Dominant inheritance But how much? 94% 56% 22% Mitochondrial: Maternal inheritance

26 Less mitochondria less energy Human Cell (the machine) Nucleus containing Chromosomes (blueprint) Mitochondria (batteries)

27 Average tissue levels can affect age of onset * * * * * early muscle disease * * * late heart disease * no brain disease Good mitochondria * Bad mitochondria

28 Variability associated with mtdna mutation cell-to-cell 90% 20% tissue-to-tissue 90% 70% 65% 5% patient-to-patient

29 Clinical relevance Asymptomatic when daughter presents Deafness age 42 Weakness age 45 Off balance age 48 56% 32% 56% 50% Short stature/thin Deafness Cardiac problems Seizures & stroke like events age 28 83% 22% Asymptomatic when sister presents and until retirement Deafness age 64 Diabetes age 70 82% 68% 84% 18% 22% 18%

30 Short stature/thin Deafness Cardiac problems Seizures & stroke like events age 28 Clinical relevance 83% 22% Asymptomatic when daughter presents Deafness age 42 Weakness age 45 Off balance age 48 Please note these are examples of potential clinical outcomes they should not be used for purposes of genetic counselling 56% as many factors affect prognosis. For personal or patient specific guidance a specialist in mitochondrial 32% 56% 50% disease should be consulted Asymptomatic when sister presents and until retirement Deafness age 64 Diabetes age 70 82% 68% 84% 18% 22% 18%

31 Disability NMDS The effects of mutation loads (heteroplasmy) % MELAS % 73% MIDD 50% Age (years)

32 Not everyone is qualified to give advice...

33 Important things to remember Mitochondrial disease has no cure: - But neither does asthma or diabetes and we look after those just fine. We never used to have cures for pneumonia, congenital heart diseases or leukaemia - But now we do.

34 Empathy Passion Expertise Commitment

35 The future is bright

36 Thank You