title: Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.
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.
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.forename: Conrad
authors.initials: C
authors.lastname: Smith
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Julie C
authors.initials: JC
authors.lastname: Evans
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.forename: Zarfishan
authors.initials: Z
authors.lastname: Shabbir
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.forename: Ute
authors.initials: U
authors.lastname: Pohl
authors.forename: Mark E
authors.initials: ME
authors.lastname: Roberts
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Jackson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Halfpenny
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lunt
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Gráinne S
authors.initials: GS
authors.lastname: Gorman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001927:Brain Diseases / Q000150:complications / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D015331:Cohort Studies; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000150:complications / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D009468:Neuromuscular Diseases / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D012264:Ribonucleotide Reductases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases