Dataset Information

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.

ABSTRACT: OBJECTIVE:To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase gamma (POLG2) and a mutation in the OPA1 gene. DESIGN:Clinical examination and morphological, biochemical, and molecular analyses. SETTING:Tertiary care university hospitals and molecular genetics and scientific computing laboratory. PATIENT:A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal. RESULTS:A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase gamma gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). CONCLUSION:Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.

SUBMITTER: Ferraris S

PROVIDER: S-EPMC2364721 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.

Ferraris Silvio S Clark Susanna S Garelli Emanuela E Davidzon Guido G Moore Steven A SA Kardon Randy H RH Bienstock Rachelle J RJ Longley Matthew J MJ Mancuso Michelangelo M Gutiérrez Ríos Purificación P Hirano Michio M Copeland William C WC DiMauro Salvatore S

Archives of neurology 20080101 1

<h4>Objective</h4>To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase gamma (POLG2) and a mutation in the OPA1 gene.<h4>Design</h4>Clinical examination and morphological, biochemical, and molecular analyses.<h4>Setting</h4>Tertiary care university hospitals and molecular genetics and scientific computing laboratory.<h4>Patient</h4>A 42-year-old man experienced hea ...[more]

PMID: 18195150

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Project description: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.

Dataset Information

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.

Publications

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.

Similar Datasets

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