MERRF and Kearns-Sayre Overlap Syndrome Due to the Mitochondrial DNA M.3291T>C Mutation (IN7-1.008)

Abstract

Objective: To report a patient with a complex phenotype of myoclonus epilepsy with ragged-red fibers (MERRF) syndrome and Kearns–Sayre syndrome (KSS), who harbored a m.3291T>C mutation in the tRNALeu(UUR) gene. This mutation has never been reported in association with a MERRF/KSS syndrome. Background Individuals who harbor a pathogenic mtDNA mutation can manifest overlapping features of typical mitochondrial syndromes. MERRF is a multisystem disorder characterized by myoclonic seizures, cerebellar ataxia, mitochondrial myopathy, and ragged-red fibers (RRF) on muscle biopsy, commonly caused by the m.8344A>G mutation in the tRNALys gene. KSS is a mitochondrial disorder characterized by onset before 20 years of age of progressive external ophthalmoplegia or pigmentary retinopathy, together with at least one of a triad of cerebellar ataxia, heart block, and elevated cerebrospinal fluid protein. Typically, KSS is due to single, large-scale deletions of mtDNA. Design/Methods: Clinical data were collected. Muscle histochemical and biochemical analysis was performed. Muscle DNA was screened for mtDNA large-scale rearrangements and point mutations. Mutation level was quantified by restriction fragment length polymorphism (RFLP) analysis. Results: A 48-year-old man presented with progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy, and bifascicular heart block. Muscle biopsy demonstrated multiple RRF. Biochemical analysis of respiratory chain enzymes was normal. Genetic tests were negative for the common MERRF mtDNA mutations, and no deletions in mitochondrial DNA were detected. Direct sequencing mtDNA revealed a T-to-C transition at nucleotide position 3291 in the tRNALeu(UUR) gene. PCR RFLP showed 92% mutant genome in muscle. Conclusions: This is the first report associating a m.3291T>C mutation in the tRNALeu(UUR) gene with an adult-onset MERRF/KSS overlap. Our data reinforce the well-established concept that, in mtDNA-related disorders, the same genetic abnormality can be associated with a wide spectrum of phenotypes, and the observation that tRNALeu(UUR) is a hotspot for mtDNA mutations. Supported by: The National Institutes of Health (NIH HD32062) and by the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF). M.H. was supported by NIH grants (R01HD57543, R01HD056103, and RCNS070232) and by the Muscular Dystrophy Association. Disclosure: Dr. Emmanuele has nothing to disclose. Dr. Silvers has nothing to disclose. Dr. Sotiriou has nothing to disclose. Dr. Tanji has nothing to disclose. Dr. DiMauro has nothing to disclose. Dr. Hirano has received personal compensation for activities with Athena Diagnostics as a speaker.Dr. Hirano has received personal compensation in an editorial capacity for Current Neurology and Neuroscience Reports.Dr. Hirano has received research support from Santhera Pharmaceutical and Edison Pharmaceuticals.