title: Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.
abstract: BACKGROUND
  Pathogenic mutations in the OPA1 gene are the most common identifiable cause of autosomal dominant optic atrophy (DOA), which is characterized by selective retinal ganglion cell loss, a distinctive pattern of temporal pallor of the optic nerve and a typical color vision deficit, with variable effects on visual acuity. Haploinsufficiency has been suggested as the major pathogenic mechanism for DOA. Here we present two siblings with severe ataxia, hypotonia, gastrointestinal dysmotility, dysphagia, and severe, early-onset optic atrophy who were found to be compound heterozygotes for two pathogenic OPA1 mutations. This example expands the clinical phenotype of OPA1-associated disorders and provides additional evidence for semi-dominant inheritance.
  
  
  RESULTS
  Molecular analysis of the OPA1 gene in this family by Sanger sequencing revealed compound heterozygosity for two mutations in trans configuration, a p.I382 M missense mutation and a p.V903GfsX3 frameshift deletion in both affected siblings. Electron microscopy of a skeletal muscle biopsy of the older sibling revealed dense osmiophilic bodies within the mitochondria. Mitochondrial DNA (mtDNA) content was within normal limits, and electron transport chain analysis showed no deficiencies of the mitochondrial respiratory chain enzymes. Multiple mtDNA deletions were not found.
  
  
  CONCLUSIONS
  Compound heterozygosity of pathogenic OPA1 mutations may cause severe neuromuscular phenotypes in addition to early-onset optic atrophy. While a role for OPA1 in mtDNA maintenance has been discussed, compound biallelic pathogenic OPA1 mutations in our patients did not result in altered mtDNA copy number, mtDNA deletions, or deficiencies of the electron transport chain, despite the severe clinical phenotype.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Schaaf
authors.forename: Maria
authors.initials: M
authors.lastname: Blazo
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Ross E
authors.initials: RE
authors.lastname: Tonini
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Takei
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
mesh_terms: D017668:Age of Onset; D001259:Ataxia / Q000150:complications / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D003680:Deglutition Disorders / Q000150:complications / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000150:complications / Q000235:genetics; D009154:Mutation; D009468:Neuromuscular Diseases / Q000150:complications / Q000235:genetics*; D009896:Optic Atrophy / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human