MITOCHONDRIAL DISEASE. Amel Karaa, MD Mitochondrial Disease Program Massachusetts General Hospital

Transcription

1 MITOCHONDRIAL DISEASE Amel Karaa, MD Mitochondrial Disease Program Massachusetts General Hospital

2 Disclosures & Disclaimers United Mitochondrial Disease Foundation Research Grant North American Mitochondrial Disease Consortium (RDCRN/NIH) Advisory Board of: Mitochondrial Medicine Society MitoAction Stealth BioTherapeutics

3 Outline: Overview of the mitochondria Overview of mitochondrial function & genetics Overview of mitochondrial disease: Symptoms Diagnosis Management

4 Overview: the mitochondria 1 to 1000s/cell

5 Overview: The mitochondria Vafai et al. Nature 2013:491,

6 Overview: the mitochondria Modified from Wallace D. Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXVI

7 Overview: the mitochondria The electron transport chain Nat Rev Genet December ; 13(12):

8 Overview: the mitochondria The Mitochondrial Organelle Bi-genomic Input mtdna ndna

9 Overview of mtdna Unique mtdna genetics Maternal inheritance

10 Overview of mtdna Unique mitochondrial genetics Maternal inheritance Double stranded circular DNA } 16,569 bp } Encodes 37 proteins: } 22 trnas } 13 respiratory chain peptides } 2 ribosomal } 5 10 copies/mitochondrion, s/cell } Limited DNA repair ( mutation rate)

11 Overview of mtdna Unique mitochondrial genetics Maternal inheritance Double stranded circular DNA Random segregation Threshold expression and Heteroplasmy

12 Overview of mtdna

13 Overview of mtdna Unique mitochondrial genetics Maternal inheritance Double stranded circular DNA Random segregation, Threshold expression and Heteroplasmy jcb.rupress.org

14 Overview of ndna The EMBO Journal VOL 32 NO

15 Overview of ndna Hundreds of genes Autosomal recessive (most common) Autosomal dominant X-linked Mendelian inheritance patterns Sporadic/De novo

16 Overview of mitochondrial disease Prevalence in children 6.2/100,000*, At least 1 in 4,300 of adults will develop mitochondrial disease * D. Skladal, J. Halliday, D. R. Thorburn, Brain 126, (2003).

17 Overview of mitochondrial disease Any age infancy to adulthood Multi-organ dysfunction Variable severity Progressive Episodic any organ, any symptom, any age

18 Overview of mitochondrial disease Metabolic Stress à normal Episodic Phenotype mild aging OBSERVABLE DYSFUNCTION Organ Failure severe moderate TIME

19 Overview of mitochondrial disease (%) Myopathy Encephalopathy Exercise intolerance Ophthalmoplegia Peripheral neuropathy Ataxia Deafness MERRF/MELAS Myocardiopathy Diabetes Retinopathy Liver disease Kidney disease Intestinal disease Optic atrophy Leigh syndrome Dysmorphy Bone marrow dysfunction Alpers syndrome (%) Adults (n = 390) Children (n = 220) SIMD/NAMA :Courtesy of Dr A Lombes Hopital La SalpétrièreUniversité Paris VI

20 Overview of mitochondrial disease Most common reasons for referral Children Hypotonia Seizures Developmental delay Elevated lactate levels Abnormal MRI images Liver disease Failure to thrive GI dysmotility Adults Fatigue +++ Shortness of breath, air hunger Muscle pain GI dysmotility Dysautonomia/POTS Multiple symptoms in many organ system that do not seem to be related

21 Overview of mitochondrial disease When should I suspect mitochondrial disease? Atypical features Multisystemic involvement Recurrent setbacks or flare-ups occur with stressors

22 Overview of mtdna disease DiMauro S, Schon EA. Am J Med Genet 2001;106(1): 18 26

23 Overview of mtdna disease MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokes MERRF: Myoclonic Epilepsy with Ragged Red Fibers LHON: Leber s Hereditary Optic Neuropathy KSS/PEO: Kearns Sayre syndrome/progressive external ophthalmoplegia.

24 Overview of mtdna disease MELAS: Symptoms before age 40 Neurosensory hearing loss Migraine headaches Peripheral neuropathy Myopathy Depression and other psychiatric disorders

25 Overview of mtdna disease MELAS: Endocrine Cardiac involvement Kidney dysfunction

26 Overview of mtdna disease MELAS: Polygenetic disorder caused by at least 29 mutations in mtdna A3243G (trna gene): most common mutation (80%) Overlap with MERRF

27 Overview of mtdna disease MELAS: Symmetric signal prolongation in both occipital lobes involving the medial aspects. à IV Arginine Protocol

28 Overview of mtdna disease MERRF: Ataxia, weakness and dementia Sensorineural hearing loss Exercise intolerance, seizures, dystonia Optic atrophy, pigmentary retinopathy, ophthalmoparesis Cardiomyopathy Multiple lipomas

29 Overview of mtdna disease MERRF: The most common mutation (> 80%): m.8344a>g

30 Overview of mtdna disease LHON: Degeneration of retinal ganglion cells and their axons Acute or subacute loss of central vision Affects predominantly young adult males

31 Overview of mtdna disease DNA deletion syndromes/peo:

32 Overview of mtdna disease DNA deletion syndromes/kss: Clinical triad Onset < 20 yrs CPEO Retinal degeneration Other features Cerebellar ataxia Sensorineural deafness Complete heart block Elevated CSF protein (100 mg/dl) Endocrinopathies Nearly always sporadic

33 Overview of ndna The EMBO Journal VOL 32 NO

34 Overview of ndna 2493 cases of progressive ID 112 (69 males, 43 females) with mitochondrial diseases Ages birth to 14 years Median age 12mo Most with non-specific: Developmental delay Hypotonia Failure to thrive Seizures Mortality was high 36% Abnormal CSF lactate 77% Abnormal MRI (increased basal ganglia signal) 60% Clinical Presentation of Mitochondrial Diseases in Children with PIND Christopher M Verity et al.

35 Overview of 2 ry mitochondrial disease Primary mitochondrial disease Vs. Secondary mitochondrial dysfunction Common in cancer, chronic diseases, Parkinson s disease, ALS, Pompe, other neurodegenerative disorders, and normal aging.

36 Overview of 2 ry mitochondrial disease Lancet 2012; 379:

37 Diagnostic Evaluation: The problem Nonspecific symptoms There is no universally accepted diagnostic algorithm for mitochondrial disorders There is no gold standard diagnostic method. Enzyme (ETC) testing may produce false positive and false negative results. Molecular testing is positive in 25-45% of the cases at best.

38 Diagnostic Evaluation Morava et al Neurology 2006

39 Diagnostic Evaluation: Other Annals of Medicine, 2013; 45: 4 16

40 Diagnostic Evaluation IMAGING TESTING Leigh MELAS KSS ETC def MNGIE Bilateral deep gray [putamen, GP, caudate] MERRF Metabolic stroke [non-vascular territory] Diffuse white matter abnormalities Lactate on MRS (abnl choline, NAA) Cerebral and/or cerebellar volume loss E.Grant

41 Diagnostic Evaluation EM Histochemistry RRF COX SDH

42 Diagnostic Evaluation Molecular Testing:? New Gold standard mtdna Screen point mutations Whole genome screen Deletion/duplication analysis Depletion ndna Specific gene selection Screening NGS panel whole exome/whole genome or dual genome analysis

43 Treatment and Management No single treatment. Management is tailored for each individual. Lifestyle changes are very important and can be effective.

44 Treatment and Management Energy balance equation: Minimize energy losses Avoid physical stresses Emotional stresses Adequate rest Optimize energy gains. Sleep Nutrition Exercise

45 Treatment and Management Avoid toxins: Drugs, cigarette smoking, alcohol Mitochondrial cocktail : Variety of vitamin and cofactor supplementation.

46 Treatment and Management Therapy in trials: EPI-743: - Small molecule (Edison Pharmaceuticals) for the treatment of Leigh syndrome, Pearson syndrome and other ETC deficiency. MTP-131 Bendavia: - Peptide (Stealth Biotherapeutics) that targets mitochondria for the treatment of mitochondrial myopathy.

47 Treatment and Management Therapy in trials: RTA- 408: - Small molecule (Reata Pharmaceuticals) for the treatment of mitochondrial myopathy. RP-103: - Cysteamine (Raptor Pharmaceuticles) for children with confirmed mitochondrial disease. Ultragenix: - Triheptanoin

48 Prevention: Mitochondrial Donations Science. 2015, VOL 349 ISSUE 6255

49 Thank you, and any questions? Amel Karaa, MD Adult Mitochondrial Disease Program Massachusetts General Hospital