Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations
Abstract
Introduction 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.Methods and 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.Conclusion 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.
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OPA1 heterozygous missense recessive mutations cause DOA characterized by an aspecific myopathy with mitochondrial features.
“OPA1 heterozygous missense recessive mutations cause DOA characterized by an aspecific myopathy with mitochondrial features [182, 183].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [182]
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- Authors
- Schaaf, C. P., Blazo, M., Lewis, R. A., Tonini, R. E., Takei, H., Wang, J., Wong, L.-J., & Scaglia, F.
- Affiliations
- Baylor College of Medicine (US)
- Baylor Scott & White Medical Center - Temple (US)
- Houston Methodist (US)
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 103
- Issue
- 4
- Pages
- 383-387
- ISSN
- 1096-7192 (ISSN-L)
- OpenAlex
- W2069779268
- Cited by
- 88
- References
- 22
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 6 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 5 · 2014: 7 · 2013: 5 · 2012: 2
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- OPA1, compound heterozygosity, autosomal dominant optic atrophy, ataxia, hypotonia, gastrointestinal motility disorders, dysphagia, mitochondrial fission, osmiophilic bodies, mtDNA maintenance, semidominant inheritance, frameshift deletion, missense mutations, electron transport chain
- MeSH terms
- Ataxia, Child, Child, Preschool, Deglutition Disorders, DNA, Mitochondrial, Heterozygote, Humans, Male, Muscle Hypotonia, Mutation, Neuromuscular Diseases, Optic Atrophy, Pedigree, Phenotype, Age of Onset, GTP Phosphohydrolases
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