Journal
BRAIN
Volume 137, Issue -, Pages 1323-1336Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awu060
Keywords
chronic progressive external ophthalmoplegia; hereditary spastic paraplegia; paraplegin; mtDNA maintenance; SPG7
Categories
Funding
- Bisby Fellowship from the Canadian Institutes of Health Research
- Wellcome Trust Centre for Mitochondrial Research [096919Z/11/Z]
- Medical Research Council (UK) Centre for Translational Muscle Disease research [G0601943]
- Medical Research Council (UK) Mitochondrial Disease Patient Cohort [G0800674]
- UK NHS Highly Specialised 'Rare Mitochondrial Disorders of Adults and Children' Service
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
- Newcastle University
- National Institute for Health Research (NIHR) [NIHR-HCS-D12-03-04]
- NIHR
- Wellcome Trust
- Academy of Medical Sciences
- Fight for Sight [1479/80] Funding Source: researchfish
- Medical Research Council [G0800674, G1000848, G0700718B, G1002570, MR/K006312/1, G0601943, G0701386, G0800470, MR/K000608/1] Funding Source: researchfish
- National Institute for Health Research [NIHR-HCS-D12-03-04, CL-2013-01-004] Funding Source: researchfish
- NIHR Newcastle Biomedical Research Centre [BH111030] Funding Source: researchfish
- MRC [G0800674, G1000848, G0800470, MR/K000608/1, G0701386, MR/K006312/1, G1002570, G0601943] Funding Source: UKRI
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Progressive external ophthalmoplegia (PEO) is a canonical feature of mitochondrial disease, but in many patients its genetic basis is unknown. Using exome sequencing, Pfeffer et al. identify mutations in SPG7 as an important cause of PEO associated with spasticity and ataxia, and uncover evidence of disordered mtDNA maintenance in patients.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.
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