title: Distal weakness with respiratory insufficiency caused by the m.8344A > G "MERRF" mutation.
abstract: The m.8344A>G mutation in the mt-tRNA(Lys) gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A>G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A>G 'MERRF' mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A>G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A>G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lecky
authors.affiliation: Aintree Chest Centre, University Hospital Aintree, Liverpool L9 7AL, UK.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Chakrabarti
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Falkous
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK. Electronic address: grainne.gorman@ncl.ac.uk.
authors.forename: Grainne S
authors.initials: GS
authors.lastname: Gorman
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial / Q000235:genetics*; D049310:Distal Myopathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D017243:MERRF Syndrome / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D012131:Respiratory Insufficiency / Q000209:etiology / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial
keywords: Distal myopathy; MERRF syndrome; Mitochondria