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DNM1L-related mitochondrial fission defect presenting as refractory epilepsy
Open accessAbstract
Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.
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“Mutations in DRP1 lead to a severe neurological syndrome with microencephaly, hypotonia, alterations in brain development, and metabolism that cause neonatal lethality due to multi-system damage [201–203].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [203]
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Metadata
- Authors
- Care4Rare Consortium, Vanstone, J. R., Smith, A. M., McBride, S., Naas, T., Holcik, M., Antoun, G., Harper, M.-E., Michaud, J., Sell, E., Chakraborty, P., Tetreault, M., Majewski, J., Baird, S., Boycott, K. M., Dyment, D. A., MacKenzie, A., & Lines, M. A.
- Affiliations
- University of Ottawa (CA)
- McGill University and Génome Québec Innovation Centre (CA)
- Corresponding author
- Lines, Matthew A
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2015-11-25
- Volume
- 24
- Issue
- 7
- Pages
- 1084-1088
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC5070894
- OpenAlex
- W2337169310
- Cited by
- 135
- References
- 18
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 9 · 2023: 5 · 2022: 11 · 2021: 25 · 2020: 17 · 2019: 14 · 2018: 17 · 2017: 12 · 2016: 10
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genome Canada
- Canadian Institutes of Health Research (MOP57810)
- 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
- Drp1, mitochondrial fission, drug-resistant epilepsy, developmental delay, de novo mutations, dominant-negative mechanism, mitochondrial hyperfusion, mitochondrial quality control, dynamin-related GTPase, mitochondrial fusion, mitochondrial encephalopathy
- MeSH terms
- Drug Resistant Epilepsy, Cells, Cultured, Child, Developmental Disabilities, Fibroblasts, Humans, Male, Microtubule-Associated Proteins, Mitochondria, Muscle, Syndrome, Muscle, Skeletal, Mutation, Missense, GTP Phosphohydrolases, Mitochondrial Proteins, Dynamins, Exome, Mitochondrial Dynamics
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