1. Medical Genetics 13 线粒体疾病 mitochondrial diseases

2. Medical Genetics Mutations (changes) in the mitochondrial chromosome are responsible for a number of disorders.

3. Medical Genetics Mitochondrial disease is a chronic, genetic disorder that occurs when the mitochondria of the cell fails to produce enough energy for cell or organ function.

4. Medical Genetics The incidence about 1:3000-4000 individuals in the US.

5. Medical Genetics Characteristics Unlike nuclear genes, which are inherited from both parents, mitochondrial genes are inherited only from the mother. In mammals, 99.99% of mitochondrial DNA (mtDNA) is inherited from the mother. This is because the sperm carries its mitochondria around a portion of its tail and has only about 100 mitochondria compared to 100,000 in the oocyte.

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7. Threshold effect % of mutant mtDNAs must be above a threshold to produce clinical manifestations % of mutant mtDNAs needed to cause cell dysfunction varies according to tissue oxidative requirements Disease signs especially manifest in –Tissues with a high energy expenditure: Dependent on oxidative metabolism –Specific tissues: Brain, Heart & Muscle

8. Medical Genetics Mitotic segregation –% of mutant mtDNAs in daughter cells can shift at cell division –Produces rapid changes of genotype that may lead to crossing of threshold

9. Medical Genetics There are many forms of mitochondrial disease. Mitochondrial disease presents very differently from individual to individual.

10. Medical Genetics Mitochondrial disease is inherited in a number of different ways. There may be one individual in a family or many individuals affected over a number of generations.

11. Medical Genetics If there is a mutation in a mitochondrial gene, it is passed from a mother to all of her children; sons will not pass it on, but daughters will pass it on to all of their children, and so on.

12. Medical Genetics 3. LHON LHON = Leber's; Hereditary; Optic; Neuropathy

13. Medical Genetics Genetic-Clinical correlations: Maternal Inheritance Recurrence risks: Brother 30%; Sister 8%; Nephew 46%; Niece 10%; Male cousin 31%; Female cousin 6% 40% of patients with commonest mutation (G11778A) have negative family history Large families with maternal inheritance: G11778 & T14484C mutations

14. Medical Genetics Mutations (General) –3 Mutations account for 96% of cases All in Complex I genes Mutations: G11778A (69%), G3460A (13%), T14484C (14%)

15. Medical Genetics Clinical features (General) Male predominance:No relation to any X-linked genes Onset :Midlife: Mean 30 years; Range 1 to 70 Visual loss –Clinical features Painless Visual loss pattern Severity: May deteriorate to 20/200 or less Progression: Mean 4 months; Interval between eyes affected: ~ 2 months Tendency to recover depends on mutation Pupillary reactions: May be relatively spared for degree of visual loss –Ocular pathology Other features: Some families Cardiac conduction defects; Spastic dystonia; Spastic paraparesis; Dystonia

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17. Laboratory Muscle pathology –No ragged red fibers –EOM mitochondria: Diffuse increase in number and size; Disorganized cristae –Preservation of myofibrils MRI: Optic nerve may enhance on T2 weighted images

18. Medical Genetics 4. MERRF MERRF=Myoclonic Epilepsy; Ragged Red Fibers

19. Medical Genetics mtDNA point mutations: tRNA Lys : A8344G (Frequent); T8356C; G8363A; G8361A –Syndromes: MERRF or MERRF/MELAS overlap tRNA Ser –Syndromes: MERRF/MELAS overlap; Epilepsia Partialis Continua; tRNA Leu

20. Medical Genetics Onset Late adolescence - Early adult

21. Medical Genetics Clinical syndrome: CNS –Myoclonus (60%) –Epilepsy (45%) –Cerebellar dysfunction: Ataxia –Dementia –Optic atrophy (20%) Polyneuropathy (20%) –Distal sensory loss (large fiber modalities) Hearing loss (40%) Myopathy Short stature (10%) Lipomata (10%)

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23. Laboratory Lactic acidosis: Variable Pathology of muscle –Ragged red fibers

24. Medical Genetics 5. MELAS MELAS=Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke

25. Medical Genetics mtDNA point mutations –tRNA Leu (common) A3243G mutation: 80% of MELAS syndromes Other MELAS mutation loci: T3271C has later age of onset; 3291

26. Medical Genetics Clinical Syndrome Onset –Mean = 10 years; Range = 2 to 40 Encephalopathy: Often episodic Systemic features Myopathy Polyneuropathy More common in patients with myopathy Mean life span with full clinical syndrome ~ 2 to 4 decades

27. Medical Genetics Scattered abnormal, vacuolated fibers with clear rim: H & E Scattered "ragged red" muscle fibers: Gomori trichrome

28. Medical Genetics Ragged red muscle fibers: Gomori trichrome

29. Medical Genetics Genetic counseling: A3423G mutation % of affected offspring: Increased with higher mutant load in maternal blood Mutant load 1% to 19%: 20% chance of affected offspring Mutant load > 20%: 50% chance of affected offspring Full expression of phenotype in multiple family members: Rare Partial expression in multiple family members: Common

30. Medical Genetics Laboratory Lactic acidosis: Blood & CSF EMG: Mormal or Myopathic Serum CK: Normal to 2x high (32%) MRI: Strokes Biochemistry –Respiratory chain dysfunction –Reduced activity of Complexes I & IV Pathology (A3243G mutation)

31. Medical Genetics 6. Kearns-Sayre Syndrome Family history Sporadic: Most patients Familial cases: Rare; Mother to offspring

32. Medical Genetics mtDNA mutation types Single large mtDNA deletion (2 to 8 kb) –Most common mutation type (80%) –Common deletions Most common: 4977 base pairs from 8488 to 13460; 13 base pair repeat at mutation break point Thai patients: 3558 bp deletion; 10204 to 13761, or 10208 to 13765 –Most deletions preserve Promoters of transcription of heavy & light strands 12S & 16S ribosomal RNA genes Origin of heavy strand replication –Change in number of deletions over time Increased in muscle Reduced in rapidly turning over cells (hematopoetic) Large scale tandem duplication

33. Medical Genetics Clinical features General –Characteristic signs: PEO; Pigmentary degeneration of retina; Heart block; Mitochondrial myopathy Onset: < 20 years; Later onset patients may have only PEO Ocular –External Ophthalmoplegia Dysphagia: 50% of adults symptomatic Myopathy –Weakness (90%): Proximal > Distal; Symmetric –Occasional fatigue or pain on exertion CNS –Hearing loss (95%) –Ataxia (90%) Systemic features

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36. Laboratory Muscle pathology –Ragged red fibers (98%): COX + and COX - –Variation in muscle fiber size Lactic acidosis (80%) Head CT: Basal ganglia calcifications (5%) CSF Protein: High