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1、Medical 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 function. Medical Genet
2、ics The incidence about 1:3000-4000 individuals in the US. 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 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 Genetics Medical Genetics Threshold effect % of mutant mtDNAs must be above a threshold to produce clinical manifestations % of mutant mtDNAs needed to ca
4、use 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 sons will not pass it on, but daughters will pass it on to all of their children, and s
5、o on. Medical Genetics 3. LHON LHON = Lebers; Hereditary; Optic; Neuropathy 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 n
6、egative family history Large families with maternal inheritance: G11778 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 Pu
7、pillary reactions: May be relatively spared for degree of visual loss Ocular pathology Other features: Some families Cardiac conduction defects; Spastic dystonia; Spastic paraparesis; Dystonia Medical Genetics Medical Genetics Laboratory Muscle pathology No ragged red fibers EOM mitochondria: Diffus
8、e increase in number and size; Disorganized cristae Preservation of myofibrils MRI: Optic nerve may enhance on T2 weighted images Medical Genetics 4. MERRF MERRF=Myoclonic Epilepsy; Ragged Red Fibers Medical Genetics mtDNA point mutations: tRNA Lys : A8344G (Frequent); T8356C; G8363A; G8361A Syndrom
9、es: MERRF or MERRF/MELAS overlap tRNA Ser Syndromes: MERRF/MELAS overlap; Epilepsia Partialis Continua; tRNA Leu Medical Genetics Onset Late adolescence - Early adult Medical Genetics Clinical syndrome: CNS Myoclonus (60%) Epilepsy (45%) Cerebellar dysfunction: Ataxia Dementia Optic atrophy (20%) Po
10、lyneuropathy (20%) Distal sensory loss (large fiber modalities) Hearing loss (40%) Myopathy Short stature (10%) Lipomata (10%) Medical Genetics Medical Genetics Laboratory Lactic acidosis: Variable Pathology of muscle Ragged red fibers Medical Genetics 5. MELAS MELAS=Mitochondrial Encephalomyopathy;
11、 Lactic Acidosis; Stroke 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 Medical Genetics Clinical Syndrome Onset Mean = 10 years; Range = 2 to 40 Encephalopathy: Often episodic Systemic f
12、eatures Myopathy Polyneuropathy More common in patients with myopathy Mean life span with full clinical syndrome 2 to 4 decades Medical Genetics Scattered abnormal, vacuolated fibers with clear rim: H Mother to offspring Medical Genetics mtDNA mutation types Single large mtDNA deletion (2 to 8 kb) M
13、ost 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 Pigmentary degeneration of retin
14、a; Heart block; Mitochondrial myopathy Onset: Distal; Symmetric Occasional fatigue or pain on exertion CNS Hearing loss (95%) Ataxia (90%) Systemic features Medical Genetics Medical Genetics Medical Genetics 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