13線粒體疾病mitochondrialdisees

1、medical geneticsmedical genetics mutations (changes) in the mitochondrial chromosome are responsible for a number of disorders. 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 functio

2、n. medical genetics the incidence about 1:3000-4000 individuals in the us. medical genetics 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 becau

3、se the sperm carries its mitochondria around a portion of its tail and has only about 100 mitochondria compared to 100,000 in the oocyte. medical geneticsmedical geneticsthreshold effect % of mutant mtdnas must be above a threshold to produce clinical manifestations % of mutant mtdnas needed to caus

4、e 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 medical geneticsmitotic segregation % of mutant mtdnas in daughter cells can

5、 shift at cell division produces rapid changes of genotype that may lead to crossing of threshold medical genetics there are many forms of mitochondrial disease. mitochondrial disease presents very differently from individual to individual. medical genetics mitochondrial disease is inherited in a nu

6、mber of different ways. there may be one individual in a family or many individuals affected over a number of generations. 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 al

7、l of their children, and so on. medical genetics lhon = lebers; hereditary; optic; neuropathymedical geneticsgenetic-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

8、(g11778a) have negative family history large families with maternal inheritance: g11778 & t14484c mutations medical geneticsmutations (general) 3 mutations account for 96% of cases all in complex i genes mutations: g11778a (69%), g3460a (13%), t14484c (14%) medical geneticsclinical features (gen

9、eral) male predominance:no relation to any x-linked genesonset :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 depend

10、s 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; dystoniamedical geneticsmedical geneticslaboratory muscle pathology no ragged red fibers eom mitocho

11、ndria: diffuse increase in number and size; disorganized cristae preservation of myofibrils mri: optic nerve may enhance on t2 weighted images medical geneticsmerrf=myoclonic epilepsy; ragged red fibers medical geneticsmtdna point mutations: trna lys : a8344g (frequent); t8356c; g8363a; g8361a syndr

12、omes: merrf or merrf/melas overlap trna ser syndromes: merrf/melas overlap; epilepsia partialis continua; trna leu medical geneticsonset late adolescence - early adult medical geneticsclinical syndrome: cns myoclonus (60%) epilepsy (45%) cerebellar dysfunction: ataxia dementia optic atrophy (20%) po

13、lyneuropathy (20%) distal sensory loss (large fiber modalities) hearing loss (40%) myopathy short stature (10%) lipomata (10%) medical geneticsmedical geneticslaboratory lactic acidosis: variable pathology of muscle ragged red fibers medical geneticsmelas=mitochondrial encephalomyopathy; lactic acid

14、osis; stroke medical geneticsmtdna point mutations trna leu (common) a3243g mutation: 80% of melas syndromes other melas mutation loci: t3271c has later age of onset; 3291 medical geneticsclinical syndrome onset mean = 10 years; range = 2 to 40 encephalopathy: often episodic systemic features myopat

15、hy polyneuropathy more common in patients with myopathy mean life span with full clinical syndrome 2 to 4 decades medical geneticsscattered abnormal, vacuolated fibers with clear rim: h & e scattered ragged red muscle fibers: gomori trichrome medical geneticsragged red muscle fibers: gomori tric

16、hrome medical geneticsgenetic 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: ra

17、re partial expression in multiple family members: common medical geneticslaboratory 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)

18、 medical geneticsfamily history sporadic: most patients familial cases: rare; mother to offspringmedical geneticsmtdna 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