title: 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 24.5 years ±10.9 (6-48 years) 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.
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany.|Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Altmann
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, München, Germany.
authors.forename: Boriana
authors.initials: B
authors.lastname: Büchner
authors.affiliation: Department of Neurology, University Hospital of Angers, Angers, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nadaj-Pakleza
authors.affiliation: Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schäfer
authors.affiliation: Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Lehmann
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Halle/Saale, Germany.|Department of Neurology, University of Technology München, München, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.affiliation: Institute of Human Genetics, Helmholtz Centre München, München, Germany.|Institute of Human Genetics, Technical University München, München, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.affiliation: Institute for Medical Statistics and Epidemiology, University of Technology München, München, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lautenschläger
authors.affiliation: Institute for Medical Statistics and Epidemiology, University of Technology München, München, Germany.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Kuhn
authors.affiliation: Institute of Clinical Neurogenetics, Department of Neurology and Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Karle
authors.affiliation: Institute of Clinical Neurogenetics, Department of Neurology and Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany.|JARA - Translational Brain Medicine, Aachen, Germany.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Human Genetics, Helmholtz Centre München, München, Germany.|Institute of Human Genetics, Technical University München, München, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany.|Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kornblum
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany. Kristl.Claeys@uzleuven.be.|Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. Kristl.Claeys@uzleuven.be.|Department of Neurology, University Hospitals Leuven and University of Leuven (KU Leuven), Leuven, Belgium. Kristl.Claeys@uzleuven.be.
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, München, Germany.|German Center for Neurodegenerative Diseases (DZNE), München, Germany.|Munich Cluster for Systems Neurology (SyNergy), München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging; D015331:Cohort Studies; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D017243:MERRF Syndrome / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012357:RNA, Transfer, Lys / Q000235:genetics*; D012042:Registries
chemical_list: D000077278:RNA, Mitochondrial; D012357:RNA, Transfer, Lys; D012313:RNA
keywords: Ataxia; Epilepsy; Hearing impairment; Myoclonus; Psychiatric; Ragged-red fibres