A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy

Abstract

Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

“…Since the first report of a pathogenic variant in DNM1L [19], several pathogenic variants in DRP1 have been associated with highly variable neurological phenotypes [215][216][217][218][219][220][221][222][223][224][225][226][227], with some resulting in complex phenotypes and early mortality [19,[228][229][230][231]. Meanwhile, a murine model harboring a mutation in DNM1L leads to cardiomyopathy [232], a common type of organ dysfunction in complex mitochondrial syndromes [233].…”

Case Report: A Novel de novo Mutation in DNM1L Presenting With Developmental Delay, Ataxia, and Peripheral Neuropathy

“…Neurons are particularly vulnerable to Drp1 dysfunction caused by DNM1L mutation (2). Mice with constitutive DNM1L knockout have smaller forebrains and white matter hypoplasia (2), and most cases of DNM1L-related mitochondrial fission defects exhibit refractory epilepsy, myoclonus, and severe global developmental delay (GDD) with a devastating clinical course (3)(4)(5)(6)(7)(8). Here, we describe a pediatric case harboring a novel de novo mutation in DNM1L presenting with a phenotype of developmental delay, ataxia, and peripheral neuropathy.…”

Case report: Thirty-year progression of an EMPF1 encephalopathy due to defective mitochondrial and peroxisomal fission caused by a novel de novo heterozygous DNM1L variant

“…The first case of lethal EMPF1 encephalopathy due to defective mitochondrial and peroxisomal fission was described in 2007, in a new-born girl harboring a de novo heterozygous mutation in DRP1 middle domain, and presenting with microcephaly, abnormal brain development, optic atrophy, persistent lactic acidemia, and mildly elevated plasma concentration of very-long-chain fatty acids (19). Additional descriptions of severe lethal forms of EMPF1 associated with de novo heterozygous variants located in DRP1 middle domain were reported (9,11,(20)(21)(22). Outside the DRP1 middle domain, DNM1L variants were also reported in the GTPase domain, initially at a heterozygous state associated with isolated autosomal dominant optic atrophy and at compound heterozygous state associated with autosomal recessive EMPF1 (23).…”