1. Mitochondrial Disorders Chenjie Xia (PGY-IV) Montreal Neurological Institute Wednesday, Jan. 25 th, 2012

2. Outline Basic mitochondrial molecular biology Clinical implications of mitochondrial genetics Clinical approach to mitochondrial disorders –General features –Visual loss, ophthalmoplegia, peripheral neuropathy, ataxia

3. Basic mitochondrial molecular biology

4. Mitochondrion Basics 4 compartments: –outer mb –inner mb (folds into cristae) –intermembrane space –matrix Larsson and Oldfors, Acta Physiol Scand 2001.

5. Role of mitochondria = energy production Berardo et al. Curr Neurol Neurosci Report, 2010

6. Respiratory Chain http://www.photobiology.info/Hamblin.html

7. Mitochondrion Basics Mitochondrial respiratory chain: –Most “lucrative” step for ATP production –5 enzymes complexes (90 protein subunits) –complexes I, II, III, IV creates proton gradient (pump protons out of matrix) –complex V uses H gradient to generate ATP –Mobile electron carriers: CoQ, cyt c

8. Overview of clinical implications of mitochondrial genetics

9. Mitochondria Genetics mt components activity depend on: –nuclear DNA (nDNA) –mitochondrial DNA (mtDNA) Larsson and Oldfors, Acta Physiol Scand 2001.

10. Mitochondrial Genetics mt genome encodes only 37 genes –13/90 proteins of the RC –2 rRNAs, 22 tRNAs Most mt proteins encoded by nDNA –e.g. complex II, CPTII, PDC –nDNA exerts +++ control on mt DNA & proteins –Concept of intergenomic communication Replication of mtDNA depend on factors encoded by nDNA

11. Mitochondrial Genetics nDNA mutations –Usually manifest in childhood –More severe and diffuse mtDNA mutations –Usually manifest in adulthood –More indolent and mosaic These principles hold less well given recent discoveries showing increasing clinical and genetic heterogeneity of mt disorders

12. Mitochondrial Genetics Concept of heteroplasmy –Mitochondrion contain mix of mutant and wild-type mtDNA –Proportion of mutant mtDNA differs in different tissues or even cells of same tissue Concept of threshold effect –Sx develop only when mutant mtDNA reaches certain threshold (usually high, >90%) –Threshold depends on energy metabolism of tissue Concept of replicative segregation –Mutant mtDNA are “selected out” with repeated mitoses, but accumulate in tissues not undergoing mitoses (e.g. neurons, muscles)

13. Mitochondria Genetics Mitochondrial disorders can be sporadic or inherited If inherited, mainly maternally: –“Bottle-neck” effect in oogenesis –rare case report of paternally inherited Often no clear genotype-phenotype correlation

14. Mitochondrial Genetics THM = phenotypic expression of mt disorders depend on many factors: –Nuclear versus mitochondrial mutation –Pathogenicity of mutation itself –Heteroplasmy –Threshold effect –Mitotic activity of tissue –Energy demand of tissue –Age –Etc…

15. Clinical Approach to Mitochondrial Disorders

16. A few words on mitochondrial disorders in general

17. General features of MID Classic S/Sx: –Neurological: stroke, seizure, dev. delay, dementia, visual impairment, EOMs, deafness, neuropathy, myopathy –Other: DM, hepatopathy, cardiomyopathy, cardiac conduction defects, short stature

18. Clinical Manifestations - Systemic Nardin and Johns. Muscle and Nerve, 2001.

19. General features of MID Key points: –+++ multisystemic –+++ overlap b/w different syndromes –same mutation can cause different phenotypes proportion of 3243tRNA mutation determines CPEO vs MELAS vs Leigh’s –same phenotype can result from different mutations MELAS can result from 3243tRNA, 3271tRNA, 11084 ND4

20. Classification of MIDs 1. Affected structure or pathway w/i mito. –RC subunits, tRNA, mt transport machinery, mt maintenance, etc 2. Mono- vs multi-systemic 3. Syndromic vs non-syndromic –+++ genetic & phenotypic overlap b/w the two –Syndromic better known for acronyms and for understanding of mito medicine –But non-syndromic more common, probably less recognized in clinical practice (atypical & less spectacular presentations)

21. Presenting Phenotypes Visual Loss Ptosis / opthalmoplegia Neuropathy Ataxia (Myopathy) (Seizures) (Stroke)

22. Genetic Defects of MIDs Finsterer, CJNS, 2009

23. Presenting Phenotypes Visual Loss Ptosis / opthalmoplegia Neuropathy Ataxia (Myopathy) (Seizures) (Stroke)

24. Visual Loss – LHON Leber’s Hereditary Optic Neuropathy –Degeneration of retinal ganglion cells –Most common disease caused by mtDNA mutation Clinical presentation –Bilateral sequential acute or subacute visual failure –Central vision lost before peripheral, blue-yellow perception lost early on (red-green more preserved) –Disc swelling and hyperemia followed by atrophy –Predominantly in young men –Little or no recovery (altho visual impairment seldom complete)

25. Visual Loss = LHON When to think of LHON for visual loss: –Young men –no vascular comorbidities (less likely ischemic) –Painless (less likely optic neuritis, either viral or demyelinating) –No toxic or deficiency state (B12, thiamine, tobacco-alcohol amblyopia, sildenafil)

26. Genetic Defects of MIDs Finsterer, CJNS, 2009

27. Visual Loss - RP Retinitis Pigmentosa –All retinal layers affected –Predominance in males –1 st Sx = nyctalopia (impairment of twilight vision) –Usu both eyes affected simultaneously –Perimacular zones affected first  partial to complete ring scotoma –Pigmentary changes spare fovea  eventually pt perceives world as if seeing through tubes

28. Visual Loss - RP DDx –Bardet-Biedl syndrome, Laurence-Moon syndrome, Freidreich’s ataxia, Refsum, Cockayne syndrome, Bassen-Kornzweig disease –Kearn-Sayre syndrome

29. Presenting Phenotypes Visual Loss Ptosis / opthalmoplegia Neuropathy Ataxia (Myopathy) (Seizures) (Stroke)

30. Ophthalmoplegia – KSS Kearns-Sayre syndrome –Obligatory triad: onset before 20, pigmentary retinopathy, progressive external opthalmoplegia –Other features: cardiac conduction abnormalities, can also have high  CSF protein, cerebellar ataxia, seizures, sensorineural deafness, pyramidal signs

31. Genetic Defects of MIDs Finsterer, CJNS, 2009

32. Ophthalmoplegia – CPEO Chronic progressive external ophthalmoplegia Clinical manifestations –Ptosis, can be asym.; ophthalmoplegia, more symm. (rare diplopia, transient if occurs) –Long durat’n of Sx before presentation (mean 26 years) –majority presents for ptosis (1/2 have less than 10% of ocular motility fxn!!!) –Sx may worsen in the evening –Often no FMHx

33. Genetic Defects of MIDs Finsterer, CJNS, 2009

34. Ophthalmoplegia – CPEO DDx –KSS (ECG, age of onset, severity) –MG (anti-AchR, response to Mestinon) –OPMD (muscle biopsy)

35. Presenting Phenotypes Visual Loss Ptosis / opthalmoplegia Neuropathy Ataxia (Myopathy) (Seizures) (Stroke)

36. Classification of MIDs causing PNP Finsterer, Journal of Neurological Sciences, 2011

37. PNP in MIDs – Leigh syndrome Clinical manifestations –Dev. delay, seizures –Ophthalmoparesis, nystamus –cerebellar ataxia, chorea, dystonia –Spasticity, muscle weakness –Brainstem involvement: respiratory insufficiency, dysphagia, recurrent vomiting, abnormal thermoregulation –Non-neurological: short stature, cardiomyopathy, anemia, RF, vomiting, diarrhea

38. Ataxia in MIDs – Leigh syndrome Other features –Most frequent childhood MID –Wide variety of abnormalities (from severe to absence of neurological problems) –Wide genetic heterogeneity Features of peripheral neuropathy (collateral) –Sensori-motor, demyelinating –Can be confused with GBS (due to severe demyelination)

39. Genetic Defects of MIDs Finsterer, CJNS, 2009

40. Saneto et al. Mitochondrion, 2008 Boy with LS: 7 mos Boy with LS: 19 mos

41. PNP in MIDs – MNGIE Mitochondrial neuro-gastrointestinal encephalopathy –Severe gastrointestinal dysmotility (nausea, postprandial emesis, early satiety, dysphagia, reflux, abdo pain, diarrhea, cachexia) –Others: confusion, PEO, deafness, dysarthria, short stature Features of peripheral neuropathy (collateral) –Sensori-motor, with distal weakness, predominantly affects lower limbs (may be confused with CIDP) –Mixed axonal and demyelinating on NCS

42. Genetic Defects of MIDs Finsterer, CJNS, 2009

43. Presenting Phenotypes Visual Loss Ptosis / opthalmoplegia Neuropathy Ataxia (Myopathy) (Seizures) (Stroke)

44. Finsterer, CJNS, 2009

45. PNP in MIDs – NARP Neurogenic weakness with ataxia and retinitis pigmentosa Clinical manifestations –Proximal muscle weakness due to PNP –Ataxia due to cerebellar atrophy –Visual impairment (optic atrophy, salt&pepper retinopathy, bull’s eye maculopathy, or RP) –Others: short stature, opthalmoplegia, learning difficulties, dementia, seizures, cardiac arrhythmias

46. Genetic Defects of MIDs Finsterer, CJNS, 2009

47. Ataxia in MID – AHS Alpers-Huttenlocher Syndrome –Severe hepatocerebral syndrome Clinical manifestations –Starts in first years of life, early death –Neurological: intractable seizures, dev. delay, psychomotor regression, stroke-like episodes, hypotonia, cortical blindness, ataxia –Other: hepatic failure (avoid valproic acid!!), fasting hypoglycemia

48. Genetic Defects of MIDs Finsterer, CJNS, 2009

49. Saneto et al. Mitochondrion, 2008 Young adult woman with Alpers syndrome

50. Take Home Messages Main role of mitochondria = energy production; mitochondrial disorders predominantly affect high metabolism (energy dependent) tissues Both mtDNA and nDNA abnormalities are implicated in mitochondrial disorders Absence of FMHx by no means preclude Dx of mt disorder Syndromic mt disorders are better known, but non- syndromic mt disorders are more common There is no clear genotype-phenotype correlation in mitochondrial disorders Mitochondrial disorders are often multisystemic There is +++ overlap in phenotype b/w different mt disorders

51. References Caballero et al. Chronic progressive exertnal ophthalmoplegia, The Neurologist, 2007, 33-36. Finsterer, Mitochondrial ataxias, CJNS, 2009, 36, 543-553. Finsterer, Inherited mitochondrial neuropathies, Journal of Neurological Sciences, 304, 2011, 9-16 N.-G. Larsson and A. Oldfors. Mitochondrial myopathies, Acta Physiol Scand 2001, 171, 385-393. Rachel Nardin and Donald Johns. Mitochondrial dysfunction and neuromuscular disease. Muscle and Nerve, 2001, 24: 170-191. Saneto et al. Neuroimaging of mitochondrial disease, Mitochondrion, 2008, 396-413. Schapira, Mitochondrial disease, Lancet, 2006, 70-82

52. Finsterer, Journal of Neurological Sciences, 2011 Classification of MID