Mild phenotype in a patient with developmental and epileptic encephalopathy carrying a novel de novo KCNB1 variant

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

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Epileptic Encephalopathy with Recurrent Focal Status Epilepticus and Epilepsia Partialis Continua in Patient with De Novo DNM1L Mutation: Electroclinical Features

Neuropediatrics ◽

10.1055/s-0038-1653929 ◽

2018 ◽

Vol 49 (S 01) ◽

pp. S1-S12 ◽

Cited By ~ 1

Author(s):

E. Musto ◽

M. Gambardella ◽

I. Contaldo ◽

M. Quintiliani ◽

M. Perulli ◽

...

Keyword(s):

Status Epilepticus ◽

De Novo ◽

Epileptic Encephalopathy ◽

Epilepsia Partialis Continua ◽

Focal Status Epilepticus

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Faculty Opinions recommendation of De novo mutations in HCN1 cause early infantile epileptic encephalopathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718356631.793494491 ◽

2014 ◽

Author(s):

Laurent Villard

Keyword(s):

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutations

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Correction to: Perampanel treatment in early-onset epileptic encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-021-05084-7 ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

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Perampanel treatment in Early-onset Epileptic Encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-020-04935-z ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

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Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

Developmental Neuroscience ◽

10.1159/000516143 ◽

2021 ◽

pp. 1-6

Author(s):

Miriam C. Aziz ◽

Patricia N. Schneider ◽

Gemma L. Carvill

Keyword(s):

Alternative Splicing ◽

Rna Binding ◽

De Novo ◽

Rna Binding Proteins ◽

Autism Spectrum ◽

Epileptic Encephalopathy ◽

Nonsense Mediated Decay ◽

Subsequent Degradation ◽

Alternative Splicing Events ◽

Genetic Epilepsies

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

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Dravet syndrome associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

Brain Communications ◽

10.1093/braincomms/fcab033 ◽

2021 ◽

Author(s):

Ciria C Hernandez ◽

XiaoJuan Tian ◽

Ningning Hu ◽

Wangzhen Shen ◽

Mackenzie A Catron ◽

...

Keyword(s):

Gabaa Receptor ◽

De Novo ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

First Year ◽

Genes Encoding ◽

Genetic Landscape ◽

Clonic Seizures ◽

Trafficking Defects ◽

First Year Of Life

Abstract Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p.L215P; c.640C>T, p.R214C; c.859G>A; V287I; c.641G>A, p.R214H) and GABRG2 (c.269C>G, p.T90R; c.1025C>T, p.P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p.F331S; c.542A>T, p.Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p.T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.

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

Neuropediatrics ◽

10.1055/s-0039-1685217 ◽

2019 ◽

Vol 50 (03) ◽

pp. 197-201

Author(s):

S. Schmid ◽

M. Wagner ◽

C. Goetz ◽

C. Makowski ◽

P. Freisinger ◽

...

Keyword(s):

Status Epilepticus ◽

Missense Mutation ◽

De Novo ◽

Mitochondrial Fission ◽

Refractory Status Epilepticus ◽

Sudden Onset ◽

Epileptic Encephalopathy ◽

Neurologic Outcome ◽

Dominant Negative Mutation ◽

Refractory Status

AbstractMitochondrial 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.

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