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Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics

Pitceathly, RD; Smith, C; Fratter, C; Alston, CL; He, L; Craig, K; Blakely, EL; ... Gorman, GS; + view all (2012) Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain , 135 (11) 3392 -3403. 10.1093/brain/aws231. Green open access

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Abstract

Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.

Type: Article
Title: Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/aws231
Publisher version: http://dx.doi.org/10.1093/brain/aws231
Language: English
Additional information: © The Author (2012). Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted, non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3501970
Keywords: Adult, Aged, Aged, 80 and over, Brain diseases, Cell cycle proteins, Cohort studies, Gene deletion, Heterozygote, Humans, Middle aged, Mitochondrial myopathies, Models, Genetic, Muscle, Skeletal, Mutation, Missense, Neuromuscular Diseases, Phenotype, Ribonucleotide reductases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1380635
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