Journal
JAMA NEUROLOGY
Volume 72, Issue 1, Pages 106-111Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2014.1753
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Funding
- UK National Health Service (NHS) Specialised Service for Rare Mitochondrial Diseases of Adults and Children, Newcastle
- National Institute for Health Research (NIHR) Biomedical Research Centre funding scheme based at Newcastle upon Tyne Hospitals NHS Foundation Trust
- Newcastle University
- 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
- Canadian Institutes of Health Research
- EU FP7 TIRCON
- NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
- Medical Research Council [G0800674, MR/K006312/1, G0601943] Funding Source: researchfish
- NIHR Newcastle Biomedical Research Centre [BH111030] Funding Source: researchfish
- MRC [MR/K006312/1, G0601943, G0800674] Funding Source: UKRI
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IMPORTANCE Progressive external ophthalmoplegia (PEO) is a common feature in adults with mitochondrial (mt) DNA maintenance disorders associated with somatic mtDNA deletions in muscle, yet the causal genetic defect in many patients remains undetermined. OBSERVATIONS Whole-exome sequencing identified a novel, heterozygous p.(Gly671Trp) mutation in the AFG3L2 gene encoding anmt protease-previously associated with dominant spinocerebellar ataxia type 28 disease-in a patient with indolent ataxia and PEO. Targeted analysis of a larger, genetically undetermined cohort of patients with PEO with suspected mtDNA maintenance abnormalities identified a second unrelated patient with a similar phenotype and a novel, heterozygous p.(Tyr689His) AFG3L2 mutation. Analysis of patient fibroblasts revealed mt fragmentation and decreased AFG3L2 transcript expression. Western blotting of patient fibroblast and muscle showed decreased AFG3L2 protein levels. CONCLUSIONS AND RELEVANCE Our observations suggest that AFG3L2 mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance.
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