Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.

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Case Reports | Journal Article | Review

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Magistrati M, Zupin L, Lamantea E, Baruffini E, Ghezzi D, Legati A, Celsi F, Murru FM, Capaci V, Pinamonti M, ... Show all

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