Progressive myoclonic epilepsy due to rare mitochondrial ND6 mutation, m.14487T>C

IntroductionMitochondrial diseases exhibit wide phenotypic heterogeneity, and can present as progressive myoclonic epilepsy.SummaryWe report a case of adult-onset drug-resistant epilepsy, cortical myoclonus and bilateral optic neuropathies due to m.14487T>C, a rare mitochondrial gene mutation identified on whole-genome sequencing. This mutation, which affects the NADH dehydrogenase 6 (ND6) subunit of the mitochondrial respiratory chain, is most commonly implicated in cases of infantile-onset Leigh syndrome, although a broader phenotypic spectrum including migraine with aura and progressive myoclonic epilepsy have been described. Serial MRI scans over a 2-year period demonstrated the interval development of bihemispheric stroke-like lesions. Giant somatosensory evoked potentials and short-duration myoclonic jerks with craniocaudal spread on surface electromyography were consistent with cortical myoclonus. Optical coherence tomography showed bilateral symmetric thinning of the nerve fibre layer in the papillomacular bundles.ConclusionWhole-genome sequencing can help to provide a definitive diagnosis for mitochondrial disease and should be considered in situations where clinical suspicion remains high despite normal genetic panels or muscle histopathology. Mitochondrial disease can present as adult-onset progressive myoclonic epilepsy, and bilateral optic neuropathies can be a striking feature of ND6 mitochondrial gene mutations. In our case, severe cortical myoclonus affecting speech and swallowing remained highly drug-resistant, however, symptomatic benefit was derived from targeted onabotulinum toxin A injections.

Glycine receptor antibodies and coeliac disease-related neurological dysfunction

Gluten sensitivity can manifest with a spectrum of neurological dysfunction including ataxia, encephalopathy and neuropathy with or without associated coeliac disease (CD). Gluten sensitivity can also present with central nervous system (CNS) hyperexcitability and cortical myoclonus which is often accompanied with refractory CD. CNS hyperexcitability can also be associated with Glutamic Acid Decarboxylase (GAD) antibodies or much less commonly with Glycine Receptor Antibodies (GlyR-Abs) but the direct pathogenic roles of these antibodies remain debatable. We have previously reported a link between gluten sensitivity and anti-GAD associated ataxia which improves with the adoption of gluten-free diet. It is unclear if a similar link exists between gluten driven CNS hyperexcitability and the presence of GlyR-Abs. We report two cases of CD presenting with CNS hyperexcitability and associated GlyR-Abs. Apart from ataxia and cortical myoclonus, one patient had refractory CD and died from enteropathy-associated T-cell lymphoma. The other patient not only improved with strict gluten-free diet but also showed serological elimination of circulating GlyR-Abs. We conclude that there is an interaction between gluten sensitivity and GlyR-Abs-associated CNS hyperexcitability and in such patients gluten-free diet is an important therapeutic intervention. The elimination of GlyR-Abs by the adoption of gluten free diet suggests that these antibodies may represent an epiphenomenon rather than being directly implicated in the pathogenesis.