title: Two novel compound heterozygous mutations inOPA3in two siblings with OPA3-related 3-methylglutaconic aciduria.
abstract: OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in theOPA3gene located at 19q13.2-13.3. Here we describe two siblings with novel compound heterozygous variants inOPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lam
authors.affiliation: Department of Pediatrics, Edward Hospital, Naperville, Illinois, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Gallo
authors.affiliation: Department of Pediatrics, University of Illinois, Chicago, Illinois, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Dineen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Dorward
authors.affiliation: Department of Pediatrics, University of Illinois, Chicago, Illinois, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Hoganson
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wolfe
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
keywords: 3-methyl glutaconic aciduria; Costeff optic atrophy syndrome; OPA3; extrapyramidal dysfunction; mitochondrial pathology; optic atrophy plus syndrome
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