Expanded phenotypic spectrum of the m.8344A>G "MERRF" mutation: data from the German mitoNET registry.

Abstract

The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5years ±10.9 (6-48years) with adult onset in 75% of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63% of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72%). Other common features in our cohort were migraine (52%), psychiatric disorders (54%), respiratory dysfunction (45%), gastrointestinal symptoms (38%), dysarthria (36%), and dysphagia (35%). Brain MRI revealed cerebral and/or cerebellar atrophy in 43% of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.