Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in KCNQ2 and KCNQ3 genes are responsible for benign familial neonatal seizures and epileptic encephalopathies. Some of these mutations have been shown to alter the binding of calmodulin (CaM) to specific C-terminal motifs of KCNQ subunits, known as the A and B helices. Here, we show that the mutation I342A in the A helix of KCNQ3 abolishes CaM interaction and strongly decreases the heteromeric association with KCNQ2. The assembly of KCNQ2 with KCNQ3 is essential for their expression at the axon initial segment (AIS). We find that the I342A mutation alters the targeting of KCNQ2/3 subunits at the AIS. However, the traffic of the mutant channels was rescued by provision of exogenous CaM. We show that CaM enhances the heteromeric association of KCNQ2/KCNQ3-I342A subunits by binding to their B helices in a calcium-dependent manner. To further assert the implication of CaM in channel assembly, we inserted a mutation in the second coil-coil domain of KCNQ2 (KCNQ2-L638P) to prevent its heteromerization with KCNQ3. We observe that the expression of a Ca(2+)-insensitive form of CaM favours the assembly of KCNQ3 with KCNQ2-L638P. Our data thus indicate that both apoCaM and Ca(2+)/CaM bind to the C-terminal domains of KCNQ2 and KCNQ3 subunits, and regulate their heteromeric assembly. Hence, CaM may control the composition and distribution of KCNQ channels in neurons.
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PMID:Calmodulin orchestrates the heteromeric assembly and the trafficking of KCNQ2/3 (Kv7.2/3) channels in neurons. 2433 8

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.(3,4) We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.
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PMID:KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. 2437 3

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
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PMID:Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. 2437 29

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
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PMID:Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. 2446 83

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.
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PMID:Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings. 2481 76

Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families with clinical descriptions that included childhood-onset epilepsy or seizures not part of a recognizable syndrome or an early-onset encephalopathy where standard-of-care investigations were unrevealing. Nine families met these criteria and a diagnosis was made in seven, and potentially eight, of the families. In the eight families we identified mutations in genes associated with known neurological and epilepsy disorders: ASAH1, FOLR1, GRIN2A (two families), SCN8A, SYNGAP1 and SYNJ1. A novel and rare mutation was identified in KCNQ2 and was likely responsible for the benign seizures segregating in the family though additional evidence would be required to be definitive. In retrospect, the clinical presentation of four of the patients was considered atypical, thereby broadening the phenotypic spectrum of these conditions. Given the extensive clinical and genetic heterogeneity associated with epilepsy, our findings suggest that WES may be considered when a specific gene is not immediately suspected as causal.
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PMID:Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study. 2504 40

Mutations in KCNQ2 and KCNQ3 were originally described in infants with benign familial neonatal seizures (BFNS). Recently, KCNQ2 mutations have also been shown to cause epileptic encephalopathy. This report describes three infants carrying abnormalities of KCNQ2 and one infant with a KCNQ3 mutation. The different KCNQ2 abnormalities led to different phenotypes and included a novel intragenic duplication, c.419_430dup, in an infant with BFNS, a 0.761Mb 20q13.3 contiguous gene deletion in an infant with seizures at 3 months, and a recurrent de novo missense mutation c.881C>T in a neonate with "KCNQ2-encephalopathy." The mutation in KCNQ3, c.989G>A, was novel and occurred in an infant with BFNS. KCNQ-related seizures often present with tonic/clonic manifestations, cyanosis, or apnea. Certain genotype-phenotype correlations help predict outcome. Similarly affected family members suggests benign familial "KCNQ-related" epilepsy, whereas neonatal seizures with unexplained multifocal epileptiform discharges or burst suppression on electroencephalography, and acute abnormalities of the basal ganglia/thalami are suggestive of KCNQ2-encephalopathy, which is often sporadic. 20q13.33 contiguous gene deletion encompassing KCNQ2 may harbor atypical features depending on deletion size. Although the phenotype often guides direct targeted gene testing in these conditions, array CGH should also be considered in suspected sporadic or atypical familial cases to diagnose 20q13.33 deletion.
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PMID:The variable phenotypes of KCNQ-related epilepsy. 2505 58

Several potassium channel genes have been implicated in different neurological disorders including genetic and acquired epilepsy. Among them, KCNQ2 and KCNQ3, coding for KV7.2 and KV7.3 voltage-gated potassium channels, present an example how genetic dissection of an epileptic disorder can lead not only to a better understanding of disease mechanisms but also broaden our knowledge about the physiological function of the affected proteins and enable novel approaches in the antiepileptic therapy design. In this chapter, we focus on the neuronal KV7 channels and associated genetic disorders-channelopathies, in particular benign familial neonatal seizures, epileptic encephalopathy, and peripheral nerve hyperexcitability (neuromyotonia, myokymia) caused by KCNQ2 or KCNQ3 mutations. Furthermore, strategies using KV7 channels as targets or tools for the treatment of epileptic diseases caused by neuronal hyperexcitability are being addressed.
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PMID:Potassium channel genes and benign familial neonatal epilepsy. 2519 82

Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.
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PMID:A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. 2552 73

Benign familial neonatal seizures (BFNS) is an autosomal dominant disorder associated with heterozygous mutations of either the KCNQ2 or KCNQ3 gene. Most cases have mutations of the KCNQ2 gene. A handful of cases with KCNQ2 and CHRNA4 deletions have been identified with different phenotypic presentations. Only two cases presented with typical BFNS features. Benign familial neonatal seizures is associated with normal exam and work-up, and seizure remission is seen in the first month of life. We report three unrelated individuals with KCNQ2 and CHRNA4 deletions, presenting with neonatal seizures and developmental delay. Their seizures started within one week after birth; all required antiepileptic drugs. Each had normal brain magnetic resonance imaging and at least two electroencephalograms with either normal or abnormal findings. All were developmentally delayed. None presented with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype associated with CHRNA4 mutation. This study supports reports of KCNQ2 and CHRNA4 deletions associated with phenotypes different from typical BFNS.
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PMID:Contiguous deletion of KCNQ2 and CHRNA4 may cause a different disorder from benign familial neonatal seizures. 2566 22


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