Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Charlotte Alston, Dr Langping He, Kate Craig, Dr Andrew Schaefer, Professor Bobby McFarlandORCiD, Professor Rita HorvathORCiD, Professor Patrick Chinnery, Emeritus Professor Doug Turnbull, Professor Robert Taylor, Professor Grainne Gorman

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.


Publication metadata

Author(s): Pitceathly RDS, Smith C, Fratter C, Alston CL, He LP, Craig K, Blakely EL, Evans JC, Taylor J, Shabbir Z, Deschauer M, Pohl U, Roberts ME, Jackson MC, Halfpenny CA, Turnpenny PD, Lunt PW, Hanna MG, Schaefer AM, McFarland R, Horvath R, Chinnery PF, Turnbull DM, Poulton J, Taylor RW, Gorman GS

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2012

Volume: 135

Issue: 11

Pages: 3392-3403

Print publication date: 29/10/2012

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/aws231

DOI: 10.1093/brain/aws231


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
EPSRC
German Federal Ministry of Education and Research (BMBF)
BBSRC
ESRC
Newcastle University Centre for Brain Ageing and Vitality
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
074454/Z/04/ZWellcome Trust
906919Wellcome Trust Centre for Mitochondrial Research
G0601943MRC Centre for Neuromuscular Diseases
G0800674MRC Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK)
G0700718MRC

Share