T8893G mutation in the ATPase 6 gene is the commonest mutation. This is heteroplasmic: at 70%, it causes NARP, at > 90%, causes Leigh syndrome.
Abnormal ATPase activity
Low blood citrulline level (surrogate marker)
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
Respiratory chain defects: Defects in complex I or II (nuclear gene)
Deficiency of complex IV
Onset: usually in the first few months of life or during childhood. Leigh’s Syndrome
Mutation of SURF gene (responsible for assembly and maintenance of complex IV).
ATPase 6 mutations with mutation load of >90% is seen in 20% of patients.
MELAS or MERRF mutations
Pyruvate dehydrogenase deficiency
Subacute necrotising encephalomyelopathy.
mtDNA Mutations Secondary to Nuclear Gene Mutations
Two such mutations have been identified.
These cause multiple mtDNA deletions and depletion.
Adenine nucleotide translocator 1 and TWINKLE gene (a DNA helicase) mutations: result in AD inheritance of CPEO, multiple mtDNA deletions or moderate depletion.
POLG mutations: may result in AD or AR CPEO, Alpers syndrome (an AR disorder with epilepsy, cortical blindness, and liver failure), and noted in patients who present with progressive external ophthalmoplegia and develop PD in later life.
Nuclear Gene Mutations Of Respiratory Chain Subunits
Extremely rarely reported.
This may reflect the deleterious nature of such mutations resulting in early abortions.
Manifest in the neonatal period or early infancy, although late-onset patients have been identified.
Varied phenotypes: infantile Leigh syndrome, cardiomyopathy, seizures, liver failure, progressive ataxia (especially in late onset cases).
The association with paragangliomas and pheochromocytomas is very rare.