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. - 2022
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.
[en] Mutations in DNM1L (DRP1), which encode a key player of mitochondrial and peroxisomal fission, have been reported in patients with the variable phenotypic spectrum, ranging from non-syndromic optic atrophy to lethal infantile encephalopathy. Here, we report a case of an adult female patient presenting with a complex neurological phenotype that associates axonal sensory neuropathy, spasticity, optic atrophy, dysarthria, dysphasia, dystonia, and ataxia, worsening with aging. Whole-exome sequencing revealed a heterozygous de novo variant in the GTPase domain of DNM1L [NM_001278464.1: c.176C>A p.(Thr59Asn)] making her the oldest patient suffering from encephalopathy due to defective mitochondrial and peroxisomal fission-1. In silico analysis suggested a protein destabilization effect of the variant Thr59Asn. Unexpectedly, Western blotting disclosed profound decrease of DNM1L expression, probably related to the degradation of DNM1L complexes. A detailed description of mitochondrial and peroxisomal anomalies in transmission electron and 3D fluorescence microscopy studies confirmed the exceptional phenotype of this patient.
Disciplines :
Neurology
Author, co-author :
Lhuissier, Charlène; MitoLab Team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Université d'Angers, Angers, France
Wagner, Bart E; Department of Histopathology, Royal Hallamshire Hospital, Sheffield, United Kingdom
Vincent, Amy; Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Garraux, Gaëtan ; Centre Hospitalier Universitaire de Liège - CHU > > Service de neurologie
HOUGRAND, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Van Coster, Rudy; Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium
Benoit, Valérie ; Université de Liège - ULiège > Département de pharmacie > GIGA-R : Chimie médicale ; Institut de Pathologie et de Génétique, Gosselies, Belgium
Karadurmus, Deniz; Institut de Pathologie et de Génétique, Gosselies, Belgium
Lenaers, Guy; MitoLab Team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Université d'Angers, Angers, France ; Service de Neurologie, Centre Hospitalier Universitaire d'Angers, Angers, France
Gueguen, Naïg; MitoLab Team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Université d'Angers, Angers, France ; Service de Biochimie et Biologie Moléculaire, CHU Angers, Angers, France
Chevrollier, Arnaud; MitoLab Team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Université d'Angers, Angers, France
Maystadt, Isabelle; Institut de Pathologie et de Génétique, Gosselies, Belgium ; Faculté de Médecine, URPhyM, Université de Namur, Namur, Belgium
Language :
English
Title :
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.
This work was supported by “Université d'Angers.” AV is supported by a Henry Wellcome Fellowship (215888/Z/19/Z).We are thankful to the patient and her family for participating in the study. We thank Katharina DULIEU from the Department of Physical and Rehabilitation Medicine, Libramont, Belgium, for the clinical follow-up of the patient. We thank the University of Angers, SCIAM Microscopy Core Facility, SFR ICAT, F-49000 Angers, France.
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