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

De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo mutations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drugresistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Hcn1G380D/+ animals had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from HCN1 patients, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the need to tailor effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.

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De Novo Mutations inSLC35A2Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

Human Mutation ◽

10.1002/humu.22446 ◽

2013 ◽

Vol 34 (12) ◽

pp. 1708-1714 ◽

Cited By ~ 59

Author(s):

Hirofumi Kodera ◽

Kazuyuki Nakamura ◽

Hitoshi Osaka ◽

Yoshihiro Maegaki ◽

Kazuhiro Haginoya ◽

...

Keyword(s):

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutations

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Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

Neuropediatrics ◽

10.1055/s-0037-1603977 ◽

2017 ◽

Vol 48 (05) ◽

pp. 371-377 ◽

Cited By ~ 12

Author(s):

Tobias Dietel ◽

Christina Evers ◽

Katrin Hinderhofer ◽

Rudolf Korinthenberg ◽

Daniel Ezzo ◽

...

Keyword(s):

De Novo ◽

Involuntary Movement ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Guanine Nucleotide ◽

Review Of Literature ◽

De Novo Mutations ◽

Guanine Nucleotide Binding Protein ◽

Guanine Nucleotide Binding ◽

Severe Epilepsy

AbstractMutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

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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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Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability

Frontiers in Genetics ◽

10.3389/fgene.2013.00213 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 63

Author(s):

Janelle E. O'Brien ◽

Miriam H. Meisler

Keyword(s):

Intellectual Disability ◽

Sodium Channel ◽

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutations

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Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2-Related Epilepsy

Neuropediatrics ◽

10.1055/s-0037-1606370 ◽

2017 ◽

Vol 49 (01) ◽

pp. 059-062 ◽

Cited By ~ 6

Author(s):

Mirjana Gusic ◽

Roman Günthner ◽

Bader Alhaddad ◽

Reka Kovacs-Nagy ◽

Christine Makowski ◽

...

Keyword(s):

De Novo ◽

Epileptic Seizures ◽

Epileptic Encephalopathy ◽

Genetic Mechanism ◽

Loss Of Function ◽

De Novo Mutations ◽

Functional Studies ◽

Additional Mode ◽

Biallelic Mutations ◽

Mode Of Inheritance

AbstractRecently, heterozygous de novo mutations in SCL1A2 have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in SCL1A2 (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism.

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Cross-Disorder Analysis of De Novo Mutations in Neuropsychiatric Disorders

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-021-05031-7 ◽

2021 ◽

Author(s):

Kuokuo Li ◽

Zhenghuan Fang ◽

Guihu Zhao ◽

Bin Li ◽

Chao Chen ◽

...

Keyword(s):

De Novo ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

Epileptic Encephalopathy ◽

De Novo Mutations ◽

Specific Expression ◽

Functional Pathway ◽

Specific Expression Pattern ◽

Phenotype Similarity ◽

Shared Genetic

AbstractThe clinical similarity among different neuropsychiatric disorders (NPDs) suggested a shared genetic basis. We catalogued 23,109 coding de novo mutations (DNMs) from 6511 patients with autism spectrum disorder (ASD), 4,293 undiagnosed developmental disorder (UDD), 933 epileptic encephalopathy (EE), 1022 intellectual disability (ID), 1094 schizophrenia (SCZ), and 3391 controls. We evaluated that putative functional DNMs contribute to 38.11%, 34.40%, 33.31%, 10.98% and 6.91% of patients with ID, EE, UDD, ASD and SCZ, respectively. Consistent with phenotype similarity and heterogeneity in different NPDs, they show different degree of genetic association. Cross-disorder analysis of DNMs prioritized 321 candidate genes (FDR < 0.05) and showed that genes shared in more disorders were more likely to exhibited specific expression pattern, functional pathway, genetic convergence, and genetic intolerance.

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Syntaxin Binding Protein 1 Related Epilepsies

Journal of Pediatric Neurology ◽

10.1055/s-0041-1727259 ◽

2021 ◽

Author(s):

Alessandra Fontana ◽

Maria Chiara Consentino ◽

Milena Motta ◽

Giuseppe Costanza ◽

Manuela Lo Bianco ◽

...

Keyword(s):

Membrane Trafficking ◽

Early Onset ◽

De Novo ◽

Binding Protein ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Published Data ◽

De Novo Mutations ◽

Ohtahara Syndrome ◽

Protein Receptors

AbstractSyntaxin binding protein 1 (STXBP1), commonly known as MUNC18–1, is a member of SEC1 family membrane trafficking proteins; their function consists in controlling the soluble N-ethylmaleimide-sensitive factor attachment protein receptors complex assembly, making them essentials regulators of vesicle fusion. The precise function and molecular mechanism through which Munc18–1 contributes to neurotransmitter releasing is not entirely understood, but several evidences suggest its probable role in exocytosis. In 2008, heterozygous de novo mutations in neuronal protein Munc18–1 were first referred as a cause of Ohtahara syndrome development. Currently, a wide examination of the published data proved that 3.1% of patients with severe epilepsy carry a pathogenic de novo mutation including STXBP1 and approximately 10.2% of early onset epileptic encephalopathy is due to an aberrant STXBP1 form codified by the mutated gene. STXBP1 mutations can be associated to a wide clinical heterogeneity. All affected individuals show developmental delay and approximately the 95% of cases have seizures and early onset epileptic encephalopathy, characterized by infantile spasms as the main consistent feature. Burst suppression pattern and hypsarrhythmia are the most frequent EEG anomalies. Other neuronal disorders include Rett syndrome and behavioral and movement disorders. Mild dysmorphic features have been detected in a small number of cases. No genotype–phenotype correlation has been reported. Management of STXBP1 encephalopathy requires a multidisciplinary approach, including epilepsy control and neurological rehabilitation. About 25% of patients are refractory to standard therapy. A single or combined antiepileptic drugs may be required. Several studies described vigabatrin, valproic acid, levetiracetam, topiramate, clobazam, and oxcarbazepine as effective in seizure control. Lamotrigine, zonisamide, and phenobarbital are also commonly used. To date, it remains unclear which therapy is the most effective. Severe morbidity and high mortality are inevitable consequences in some of these patients.

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