De novo pathogenic DNM1L variant in a patient diagnosed with atypical hereditary sensory and autonomic neuropathy

Abstract

BackgroundProfiling the entire genome at base pair resolution in a single test offers novel insights into disease by means of dissection of genetic contributors to phenotypic features.MethodsWe performed genome sequencing for a patient who presented with atypical hereditary sensory and autonomic neuropathy, severe epileptic encephalopathy, global developmental delay, and growth hormone deficiency.ResultsAssessment of the variants detected by mapped sequencing reads followed by Sanger confirmation revealed that the proband is a compound heterozygote for rare variants within RETREG1 (FAM134B), a gene associated with a recessive form of hereditary sensory and autonomic neuropathy, but not with epileptic encephalopathy or global developmental delay. Further analysis of the data also revealed a heterozygous missense variant in DNM1L, a gene previously implicated in an autosomal dominant encephalopathy, epilepsy, and global developmental delay and confirmed by Sanger sequencing to be a de novo variant not present in parental genomes.ConclusionsOur findings emphasize the importance of genome‐wide sequencing in patients with a well‐characterized genetic disease with atypical presentation. This approach reduces the potential for misdiagnoses.

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

“…Moreover, our patient's fibroblasts were vulnerable and did not survive multiple passages and freezing, hindering additional experiments. Fibroblasts from our other patient [20], harboring a de novo p.V203M mutation, did not survive culturing. Nevertheless, complementary studies in transformed HFF-1 corroborated the normalization of mitochondrial morphology by bezafibrate, although studies in microtiter wells were not possible due to partial transformation efficiency and decreased viability.…”

“…The clinical phenotypes vary between neonatal hypotonia, microcephaly, apnea, persistent elevation of lactate, focal, progressing into generalized status epilepticus, with devastating impaired neurological outcome, and death early in infancy or childhood. Some other patients had a relatively normal early development then developed severe epileptic encephalopathy with intractable seizures and regression after an intercurrent illness, infection, or vaccination [9][10][11][12][13][14][15][16][17][18][19][20].DNM1L is the human analogue to Drp1, a member of the dynamin superfamily of cytoplasmic GTPases. It is an evolutionarily conserved protein that mediates mitochondrial and peroxisomal division, and it is also involved in apoptotic regulation.…”

Dynamic properties of mitochondria during human corticogenesis

“…In fact, mitochondrial diseases, which are linked to mutations that impair OXPHOS, affect about 1 in 5000 live births ( Schaefer et al, 2004 ). In addition, perturbations in genes involved in the maintenance of mitochondrial morphology and cristae dynamics also have devastating effects on human brain development ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Although animal models have been pivotal for elucidating some phenotypes associated with dysfunctional mitochondria, human psychiatric and neurological conditions have developmental origins that cannot be fully understood using animal models ( Molnár et al, 2019 ; O'Rahilly and Müller, 2008 ).…”

“…Mitochondrial homeostasis is maintained through the concerted execution of mitochondrial dynamics (fusion and fission), cristae dynamics, motility and mitophagy ( Barnhart, 2016 ; Chen and Dorn, 2013 ; Cogliati et al, 2013 ; Frank et al, 2001 ; Giacomello et al, 2020 ; Schwarz, 2013 ; Scorrano et al, 2002 ; Ziviani et al, 2010 ). As evidence of the importance of these dynamic properties in the modulation of brain development, rare mutations in proteins involved in their regulation cause phenotypically heterogeneous and severe neurodevelopmental diseases ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Emerging studies have highlighted the crosstalk between the mitochondrial dynamics machinery, the mitochondrial contact site and the cristae organizing system (MICOS), as well as motility and mitophagy machinery at the mitochondria ( Kageyama et al, 2014 ; Morciano et al, 2016 ; Fu et al, 2019 ; Picard et al, 2016 ).…”

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

“…Biochemical investigations revealed reduced activity of mitochondrial respiratory chain in muscle and elevated serum lactate in less than half of the described patients. In all cultured fibroblasts examined, mitochondria, and in some cases, peroxisomes appear elongated and hyperfused [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Although muscle biopsies of patients have been poorly investigated from a histological point of view, recently, our group reported five patients with mutations in DNM1L displaying histological muscle anomalies consisting of abnormal distribution of mitochondria in muscle fibers not associated with mitochondrial DNA instability, and these abnormalities seem to be specific for the DMN1L-related epileptic encephalopathy [ 119 ].…”