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De novo DNM1L mutation associated with mitochondrial epilepsy syndrome with fever sensitivity

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Emma Ladds, Andrea Whitney, Eszter Dombi, Monika Hofer, Geetha Anand, Victoria Harrison, Carl Fratter, Janet Carver, Ines A. Barbosa, Michael Simpson, Sandeep Jayawant, Joanna Poulton

Original languageEnglish
Article numbere258
JournalNeurology: Genetics
Issue number4
Published1 Aug 2018

King's Authors


Catastrophic epileptic encephalopathy of unclear etiology following a mild metabolic insult generally has a poor outcome. Here, we present 2 such unrelated individuals in whom whole-exome sequencing identified the same de novo recurrent mutation (c.1207C>T p.Arg403Cys) in the gene encoding the guanosine triphosphatase (GTPase) Dynamin-1 like Protein (DNM1L) (reference sequence NM-012062.4). The dynamic fission and fusion of the intracellular mitochondrial network are essential to facilitate mitophagy and thusmitochondrial quality and function.1 Duringmitochondrial division, the GTPase DNM1L forms multimeric collars at specific fission sites, constricting portions of the mitochondrial reticulum and generating fragments for engulfment and degradation.2 DNM1L has been implicated in several presentations of refractory epilepsy.3 Both of our patients exhibited signs of preexisting developmental delay and presented with epilepsy during, or recently following, a febrile illness or exercise. Elevated lactate levels, epilepsia partialis continua, nonspecific imaging, and evidence of lipid storage myopathy all support mitochondrial dysfunction (See table for presentation summary and e-case report for details, links.lww. com/NXG/A63). This evidence supports an etiological role for DNM1L in mitochondrial epilepsy syndrome with fever sensitivity (MEFS).

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