Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation
Open accessAbstract
Background: Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes. Objective: To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Methods: We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy. Results: Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients’ muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion. Conclusions: We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.
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The first case of a homozygous missense mutation in OPA1 was reported in two sisters who died at 2 and 10 months of age, showing myopathy, encephalopathy, and cardiomyopathy.
“The first case of homozygous missense mutation has been recently reported in two sisters. They died at 2 and 10 months of age, showing myopathy, encephalopathy, and cardiomyopathy [184].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [184]
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“Interestingly, the first case of homozygous missense mutation has been reported in two sisters that died at 2 and 10 months of age showing myopathy, encephalopathy, and cardiomyopathy (Spiegel et al., 2016).”
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- Authors
- Spiegel, R., Saada, A., Flannery, P. J., Burté, F., Soiferman, D., Khayat, M., Eisner, V., Vladovski, E., Taylor, R. W., Bindoff, L. A., Shaag, A., Mandel, H., Schuler-Furman, O., Shalev, S. A., Elpeleg, O., & Yu-Wai-Man, P.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Hebrew University of Jerusalem (IL)
- Wellcome Centre for Mitochondrial Research (GB)
- Pontificia Universidad Católica de Chile (CL)
- Rambam Health Care Campus (IL)
- University of Bergen (NO)
- Department of Microbiology and Molecular Genetics, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
- Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK
- Corresponding author
- Spiegel, Ronen
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2015-11-11
- Volume
- 53
- Issue
- 2
- Pages
- 127-131
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC4752660
- OpenAlex
- W1886736303
- Cited by
- 117
- References
- 25
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 18 · 2020: 15 · 2019: 13 · 2018: 7 · 2017: 10 · 2016: 8
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Medical Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (096919/Z/11/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- OPA1 mutations, hypertrophic cardiomyopathy, optic atrophy, mitochondrial DNA depletion, mitochondrial DNA instability, mitochondrial fusion, mitochondrial biogenesis, mtDNA maintenance, oxidative phosphorylation defects, consanguinity, autosomal recessive inheritance, mitochondrial cristae morphology
- MeSH terms
- Cardiomyopathy, Hypertrophic, Female, Homozygote, Humans, Infant, Mutation, Optic Atrophy, Pregnancy, Mitochondrial Encephalomyopathies, Muscle, Skeletal, GTP Phosphohydrolases
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