Genetics of Mitochondrial disorders

Mitochondrial DNA and Disease

Introduction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

MtDNA: Structure ,[object Object],[object Object],[object Object],[object Object],[object Object]

OXPHOS System ,[object Object],[object Object],[object Object],[object Object]

Respiratory chain and OXPHOS system

MtDNA: Inheritance ,[object Object],[object Object],[object Object],[object Object],[object Object]

MtDNA: Inheritance ,[object Object],[object Object],[object Object],[object Object]

Mitochondrial Diseases: Overview ,[object Object],[object Object],[object Object],[object Object],[object Object]

Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Biochemical assay of respiratory chain function ,[object Object],[object Object],[object Object],EM ,[object Object],[object Object],[object Object],Muscle Biopsy ,[object Object],S. Lactate ,[object Object],EMG ,[object Object],CK Diagnosis of CPEO

CPEO: Genetic analysis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

KSS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

MELAS: Clinical Features ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

MELAS: Diagnosis ,[object Object],[object Object],Genetics Cerebral vessel histology show SDH reactivity indicating angiopathy as a significant component in the pathogenesis of stroke. ,[object Object],[object Object],[object Object],Muscle biopsy ,[object Object],CSF lactate ,[object Object],[object Object],[object Object],[object Object],Imaging

MERRF: Clinical Features ,[object Object],[object Object],Lipomas are an interesting phenomenon. In some patients, this may be the only manifestation of MERRF. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

MERRF: Diagnosis ,[object Object],[object Object],[object Object],Genetics Cerebral vessel histology show SDH reactivity indicating angiopathy as a major component in the pathogenesis. ,[object Object],[object Object],[object Object],Muscle biopsy ,[object Object],Lactate (serum, CSF) ,[object Object],EEG

NARP: Clinical Features Diagnosis ,[object Object],[object Object],Genetics ,[object Object],[object Object],Biochemical ,[object Object],Muscle biopsy Mental retardation Migraine Seizures Dementia R etinitis pigmentosa A taxias M yopathy N eurogenic muscle weakness

Mutations in MtDNA COX gene mutations Myopathy and myoglobinuria mtDNA deletions Recurrent myoglobinuria, exercise intolerance Mutations in mtDNA COX genes Sideroblastic Anemia Mutations in mtDNA COX genes Motor Neuron disease mtDNA mutations Pure Myopathy mtDNA mutations, rRNA mutations Cardiomyopathy (dilated/hypertrophic) Mutation in tRNA for serine Sensorineural hearing loss 1% to 2% of NIDDM is due to A3243G mutation. It may be the only manifestation or may have associated sensorineural deafness. NIDDM Additional Phenotypes

Leber Hereditary Optic Neuropathy ,[object Object],[object Object],[object Object],[object Object],[object Object]

Leber Hereditary Optic Neuropathy ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Onset: adolescence; most patients are dead by 40 yrs of age. Myoneuro-gastrointestinal encephalopathy (MNGIE) ,[object Object],[object Object],[object Object],[object Object],Genetics ,[object Object],MRI ,[object Object],Muscle biopsy Investigations Sensorimotor ,[object Object],Nausea, vomiting, diarrhoea ,[object Object],Diagnostic criteria: Peripheral neuropathy, CPEO, and gastrointestinal dysmotility.

[object Object],[object Object],Biochemical abnormalities ,[object Object],[object Object],Onset: usually in the first few months of life or during childhood. Leigh’s Syndrome ,[object Object],[object Object],[object Object],Genetics ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Subacute necrotising encephalomyelopathy.

mtDNA Mutations Secondary to Nuclear Gene Mutations ,[object Object],[object Object],[object Object],[object Object]

Nuclear Gene Mutations Of Respiratory Chain Subunits ,[object Object],[object Object],[object Object],[object Object],[object Object]

Toxin Induced MtDNA Abnormalities ,[object Object],[object Object],[object Object]

Treatment of Mitochondrial disorders ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Future research focus ,[object Object],[object Object],[object Object],[object Object],[object Object]

Future research focus ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Genetic Counselling ,[object Object],[object Object],[object Object],[object Object],[object Object]

Conclusion ,[object Object],[object Object],[object Object],[object Object]

Genetics of Mitochondrial disorders

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Genetics of Mitochondrial disorders