A range of point mutations or deletions of mitochondrial or nuclear DNA result in dysfunction of the mitochondrial respiratory chain. There are over 70 different polypeptides on the inner mitochondrial membrane which form the respiratory chain, of which 13 are encoded by mitochondrial DNA; defects have been described in all of these. Two classic pheno-types (MERFF and MELAS) occur in which seizures are a common and important symptom, although intermediate and transitional cases are not uncommon. In a third mitochondrial disorder, the Leigh syndrome and NARP continuum, seizures are also common, but not a predominant feature. The full range of the phenotypes of mitochondrially inherited defects is probably not known, and it certainly seems possible that some cryptogenic epilepsies will have mitochondrial defects as yet undetected. The inheritance, of course, is usually maternal. Mitochondrial disease can result in forms of epilepsy other than PME. Other forms of myo-clonus are characteristic and can be either focal or multifocal, but partial seizures and tonic-clonic seizures are also not infrequently encountered. The genetic defects underlying epilepsy are varied as are the syndromes (which can include MERFF, MELAS, Alpers disease (p. 29)or MNGIE (mitochondrial neuro-gastrointestinal encephalopathy syndrome).
The mitochondrial cytopathy that typically causes progressive myoclonic epilepsy is the syndrome of myoclonus epilepsy with ragged red fibres (MERRF). This is a multisystem disorder with a very variable phenotype, in which myoclonic seizures are often the first symptom, followed by generalized epilepsy, myopathy, ataxia and dementia. Other features are short stature, deafness, optic atrophy, retinopathy, ophthalmoparesis and cardiomyopathy with
Wolff-Parkinson-White syndrome. The clinical features are variable, even within families. The EEG shows spike-wave at 2-5 Hz with a slow background. Ragged red fibres are found on muscle biopsy in 80% of cases, and biochemical analysis will show decreased activity in respiratory chain enzymes. MRI may show atrophy, T2 signal change and also basal ganglia calcification. In 90% of cases the genetic defect is an A-to-G transition at nucleotide-8344 in the tRNAlys gene of mtDNA, and some other cases are caused by T8356C or G8363A mutations. Genetic testing is available. Heteroplasmy is responsible for some of the phenotypic variation and can complicate genetic diagnosis.
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