Browse by author
Lookup NU author(s): Dr Gerald Pfeffer, Professor Grainne Gorman, Dr Helen GriffinORCiD, Dr Marzena Kurzawa-Akanbi, Dr Ian Wilson, Dr Kamil Sitarz, David Moore, Dr Julie Murphy, Dr Charlotte Alston, Dr Angela Pyle, Dr Jonathan Coxhead, Dr Brendan PayneORCiD, Professor Mark BakerORCiD, Dr Stephen Jaiser, Dr Patrick Yu Wai Man, Professor Bobby McFarlandORCiD, Dr Andrew Schaefer, Emeritus Professor Doug Turnbull, Professor Rita HorvathORCiD, Professor Robert Taylor, Professor Patrick Chinnery
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.
Author(s): Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2014
Volume: 137
Issue: 5
Pages: 1323-1336
Print publication date: 01/05/2014
Online publication date: 11/04/2014
Acceptance date: 30/01/2014
Date deposited: 07/07/2015
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/awu060
DOI: 10.1093/brain/awu060
PubMed id: 24727571
Altmetrics provided by Altmetric
