Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases

Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.

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Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106373 ◽

2019 ◽

Vol 57 (2) ◽

pp. 132-137 ◽

Cited By ~ 9

Author(s):

Edgard Verdura ◽

Carme Fons ◽

Agatha Schlüter ◽

Montserrat Ruiz ◽

Stéphane Fourcade ◽

...

Keyword(s):

De Novo ◽

Epileptic Encephalopathy ◽

Dominant Mode ◽

Wild Type ◽

Adequate Treatment ◽

Cellular Assays ◽

Disease Spectrum ◽

Whole Exome ◽

Pore Domain ◽

Mode Of Inheritance

BackgroundSince 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.MethodsA patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.ResultsWES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.ConclusionThis newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

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Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000199 ◽

2017 ◽

Vol 3 (6) ◽

pp. e199 ◽

Cited By ~ 22

Author(s):

Mohammed Uddin ◽

Marc Woodbury-Smith ◽

Ada Chan ◽

Ledia Brunga ◽

Sylvia Lamoureux ◽

...

Keyword(s):

Brain Tissue ◽

De Novo ◽

Focal Cortical Dysplasia ◽

Autism Spectrum ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Chromosomal Microarray ◽

Published Data ◽

De Novo Mutations ◽

Coding Region

Objective:To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD).Methods:Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.Results:Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.Conclusions:STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy.

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Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder

Brain Sciences ◽

10.3390/brainsci11070931 ◽

2021 ◽

Vol 11 (7) ◽

pp. 931

Author(s):

Siddharth Srivastava ◽

Erica L. Macke ◽

Lindsay C. Swanson ◽

David Coulter ◽

Eric W. Klee ◽

...

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Case Series ◽

Monozygotic Twins ◽

Copy Number Variant ◽

Limited Information ◽

Phenotypic Spectrum ◽

New Variant ◽

Genetic Landscape ◽

Syndrome Protein

In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic landscape of WASF1-related neurodevelopmental disorder (NDD). In this report, we describe detailed clinical characteristics of six individuals with WASF1-related NDD. We demonstrate a broader spectrum of neurodevelopmental impairment including more mildly affected individuals. Further, we report new variant types, including a copy number variant (CNV), resulting in the partial deletion of WASF1 in monozygotic twins, and three missense variants, two of which alter the same residue, p.W161. This report adds further evidence that de novo variants in WASF1 cause an autosomal dominant NDD.

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Not all SCN1A epileptic encephalopathies are Dravet syndrome

Neurology ◽

10.1212/wnl.0000000000004331 ◽

2017 ◽

Vol 89 (10) ◽

pp. 1035-1042 ◽

Cited By ~ 33

Author(s):

Lynette G. Sadleir ◽

Emily I. Mountier ◽

Deepak Gill ◽

Suzanne Davis ◽

Charuta Joshi ◽

...

Keyword(s):

Movement Disorder ◽

Missense Mutation ◽

De Novo ◽

Age At Onset ◽

Case Series ◽

Febrile Seizures ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Developmental Impairment ◽

Hyperkinetic Movement Disorder

Objective:To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.Methods:A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.Results:We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.Conclusions:Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

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RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood

Neurology ◽

10.1212/wnl.0000000000011543 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011543

Author(s):

Sara Zagaglia ◽

Dora Steel ◽

S Krithika ◽

Laura Hernandez-Hernandez ◽

Helena Martins Custodio ◽

...

Keyword(s):

Movement Disorder ◽

De Novo ◽

Gastrointestinal Symptoms ◽

Colour Change ◽

Epileptic Encephalopathy ◽

Seizure Freedom ◽

Retrospective Case ◽

Alternating Hemiplegia Of Childhood ◽

Phenotypic Spectrum ◽

Complex Motor

Objective:To explore the phenotypic spectrum of RHOBTB2-related disorders, and specifically to determine whether patients fulfil criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.Methods:Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist paediatric centre, with additional cases identified through collaboration with other centres internationally. Clinical data was acquired through retrospective case-note review.Results:11 affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in nine cases. All had a complex motor phenotype, including at least two different kinds of movement disorder, e.g. ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements and eight experienced hemiplegic episodes. In contrast to classical AHC, commonly caused by mutations in ATP1A3, these events were only reported later in RHOBTB2-mutation-positive patients, from twenty months of age. Seven patients had epilepsy, but of these, four achieved seizure-freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin colour change and gastrointestinal symptoms, each in four patients.Conclusion:Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy (EIEE64), our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.

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