An isolated nucleic acid molecule encoding a mutant alpha subunit of a mammalian voltagegated sodium channel, wherein a mutation event selected from the group consisting of point mutations. Interneuron dysfunction in a new knockin mouse model of scn1a. Dravet syndrome is associated with a mutation in the scn1a gene in 8090% of cases rosander 2015. Mechanisms for variable expressivity of inherited scn1a. Genedx is a world leader in genomics with an acknowledged expertise in rare and ultrarare genetic disorders, as well as an unparalleled comprehensive genetic testing menu. Detects exonic deletions in the scn1a gene typical presentation. The scn1a gene belongs to a family of genes that provide instructions for making sodium channels. Febrile seizures, which are often prolonged or focal, and afebrile hemiclonic or generalized seizures in the first year of life.
We evaluated the range of rare cnvs found in 80 welsh patients with id or developmental delay dd, and childhoodonset epilepsy. This scn 1a mutation database aims to provide a practical tool for rapidly checking and comparing information on scn 1a mutations. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta1 subunit modulates the kinetics of channel inactivation. Aug 26, 2009 scn1b homozygous mutation found in dravet syndrome. Mice carrying this mutation develop hallmarks of eiee, but it remains unclear. Mutations in three voltagegated sodium channel genes, scn1a, scn2a, and. Role of scn1a and scn2a gene polymorphisms in epilepsy. The excel file provided for download on this page provides a userfriendly interface that allows the. No more options scn1a mutation epilepsy foundation. Scn1a this is what you need to know in 2014 beyond the. Mechanisms for variable expressivity of inherited scn1a mutations. Dec 06, 2015 the authors focus on a specific aberration in scn8a known as missense mutation p. There is a fivefold enrichment of rare scn9a variants in patients with dravet syndrome. Voltagegated sodium channels nav play a crucial role in development and propagation of action potentials in neurons and muscle cells.
Animal studies have revealed new insights into the mechanisms by which mutations in this gene, encoding the type i voltagegated sodium channel na v 1. Influence of common scn1a promoter variants on the severity of. Dravet syndrome omim 607208 is an epileptic encephalopathy with typical clinical features, including seizure onset at infancy, prolonged convulsive seizures usually triggered by fever, later occurrence of polymorphic afebrile seizures, ataxia, cognitive decline, and medical intractability. The mutation results in a change of arginine r at position 125 to cysteine c in the amino acid sequence. Alekov a, rahman mm, mitrovic n, lehmannhorn f, lerche h.
Mutations of scn1a, encoding a neuronal sodium channel. Two new cases of truncating or nonsense scn1a mutations without the severe outcome of dravet syndrome were described takaori, et. Apr 26, 2016 copy number variants cnvs have been linked to neurodevelopmental disorders such as intellectual disability id, autism, epilepsy and psychiatric disease. As information on the epilepsies caused by scn1a mutations are amongst our most frequently read posts, we thought that a quick update on the stateofthe art regarding scn1a. Our mission is to improve the lives of those affected by scn2a related disorders through research, public awareness, family support and patient advocacy. Scn1a is one of the most clinically relevant sodium channel genes because its mutations are known to be associated with a series of common central nervous system disorders, such as epilepsy, autism, and migraines weiss et al. Distinct mutations in sodium channel trigger autism, epilepsy. They identified mutations in the scn9a gene in 9 8% of 109 patients with dravet syndrome, including 6 with scn1a mutation and 3 without scn1a mutation. These channels, which transport positively charged sodium atoms sodium ions into cells, play a key role in a cells ability to generate and transmit electrical signals. Dravet syndrome ds is a childhood disorder associated with lossoffunction mutations in scn1a and is characterized by frequent seizures and severe cognitive impairment. These mutations identify a new disease gene for human inherited epilepsy. Scn1a mutation screening in adult patients with lennox. Our mission is to make clinical genetic testing available to patients and their families.
Gefs, dravet syndrome, genetics, knockin mice, knockout mice. Dravet syndrome or severe myoclonic epilepsy of infancy smei is a baleful epileptic. One, an 11year old with approximately one seizure per year on two antiepileptic medications, showed moderate mental retardation. A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. Smei borderline, which also included intractable childhood epilepsy with generalized tonicclonic seizures icegtc and incomplete dravet syndrome ids. Scn1a genomic organization and splicing variability nav1. Improved genetic testing including duplication, deletion, and mosaicism identification continues to. Scn1a this is what you need to know beyond the ion channel. We are an organization created by parents of children diagnosed with rare forms of epilepsy and autism as a result of a change in the scn2a gene our vision is to find effective. The other, a 4year old whose only seizures were febrile, showed a borderline developmental quotient. Dravet syndrome and rare variants in scn9a beyond the ion. The m1500v mutation was absent in a group of 62 controls, as well as in the exac database. A special section is on functional studies, which may be helpful in evaluating pathogenicity of scn 1a mutations and further management of patients.
However, the location is not associated with the phenotype in children with gefs. Vilin yy, ruben pc 2001 slow inactivation in voltagegated. Mutations in sodium channel gene scn9a and the pain. Summary mutations in a number of genes encoding voltage. What is the nucleic acid basis for a mutation that has only been reported at the amino acid level. About 22% of dravet syndrome patients are mutationfree regarding already identified genes. Some of these mutations q1489k, l1649q,i1498m, f1661l and. Scn1a mutational analysis in korean patients with dravet syndrome. Patients usually develop other symptoms after age one, including myoclonic, absences, atonic, and partial seizures. A functional null mutation of scn1b in a patient with dravet. Mutations in scn1a, the gene encoding the brain voltagegated sodium channel. Around 78% of dravet syndrome patients have a genetic mutation that appears to cause the associated disease.
In a previous study, an scn1a mutation was also identified in a patient with lennoxgastaut syndrome lgs, and the aim of our study was to investigate the importance of. Mosaic scn1a mutation in familial severe myoclonic epilepsy of. Among the epilepsy genes, the scn1a gene perhaps known to have the. The authors focus on a specific aberration in scn8a known as missense mutation p. Number exonintron nucleotide change protein change location mutation type consequences phenotype inheritance reference. Data were collected and analyzed using the abi dna sequence analysis software. Voltagegated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells.
The generalized epilepsy with febrile seizures plus type 2 mutation w1204r alters voltagedependent gating of na v 1. Aug 25, 20 there is a fivefold enrichment of rare scn9a variants in patients with dravet syndrome. Sequencing of the scn1a gene revealed a novel aspartic acid for glycine. Dravet syndrome nord national organization for rare. Pdf mechanisms for variable expressivity of inherited scn1a. Direct sequencing of scn1a in 29 patients with dravet syndrome revealed the presence of 11 truncating mutations four nonsense and seven short deletion mutations ranging from one to four base pairs.
Dravet syndrome and rare variants in scn9a beyond the. Mice carrying this mutation develop hallmarks of eiee, but it remains unclear how this. Mutations in the scn1a gene have been identified in a variety of epilepsy phenotypes, from severe encephalopathies such as dravet syndrome to milder familial forms such as generalized epilepsy with febrile seizures plus. The excel file provided for download on this page provides a userfriendly interface that allows the researcher to quickly gather a great amount of information nucleic acid as well as amino acid on any mutation in scn1a. In a study published in december, researchers found a mutation in another sodium channel gene, called scn9a, in one individual with autism.
Copy number variants cnvs have been linked to neurodevelopmental disorders such as intellectual disability id, autism, epilepsy and psychiatric disease. It is also possible for a mutation to reduce the number of channels produced by an individual, which leads to the development of dravet syndrome. Scn1a mutations in focal epilepsy with auditory features. We examined the functional properties of five smei mutations by using wholecell patchclamp analysis of heterologously expressed recombinant human scn1a. They identified a mutation in the scn9a gene in 9 8% of 109 patients with dravet syndrome, including 6 with scn1a mutation. Us7709225b2 nucleic acids encoding mutations in sodium. Most experts believe an infant with two or more prolonged generalized tonic clonic or hemiclonic seizures with or without fever before age 12 months should. Mysteries of scn8a mutation in epilepsy unraveled sciencedaily. Scn1arelated seizure disorders is a group of diseases that includes simple febrile seizures, generalized epilepsy with febrile seizures plus, dravet syndrome, migrating partial seizures of infancy, and intractable childhood epilepsy with generalized tonicclonic seizures, as well as some cases of lennoxgastaut syndrome, west syndrome infantile spasms and vaccinerelated encephalopathy and seizures. Scn1a mutational analysis in korean patients with dravet. Using western blot analysis and elisa, thompson et al. Researching clinical description and scn1a gene mutation.
Omim entry 603415 sodium channel, voltagegated, type. Children with mutations in scn1a, a sodium channel that works in neurons that dampen brain activity, have a severe form of epilepsy called dravet syndrome and, sometimes, autism. The scn1a gene variants and epileptic encephalopathies journal. Pathogenic copy number variants and scn1a mutations in. Dravet syndrome also called severe myoclonic epilepsy of infancy is one of the most severe forms of childhood epilepsy. Data is currently coming together, which will reveal whether this relatively bold assumption. Smei borderline, which also included intractable childhood epilepsy with generalized tonicclonic seizures. Lithiumresponsive seizurelike hyperexcitability is. Dravet syndrome nord national organization for rare disorders. The presence of an scn1a mutation can help confirm diagnosis, but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude diagnosis. The scn1a gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6030 nucleotide base pairs bp. All statistical tests were performed in prism 8 graph pad software inc.
The scn1a gene provides instructions for making one part the alpha subunit of a sodium channel called nav1. An epilepsy mutation in the sodium channel scn1a that. Mutations of scn1a have been found in 40 to 100% of smei patients and a. Mutations in sodium channels are responsible for genetic epilepsy. The molecular analysis included a pcr amplification of scn1b, scn1a and gagrg2 exons, then a screening. May 12, 2020 voltagegated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. Most patients have heterozygous mutations in scn1a, encoding. We welcome information on scn 1a mutations from other sources this scn 1a mutation database aims to provide a practical tool for rapidly checking and comparing information on scn 1a. Haploinsufficiency refers to the situation when only a single functional copy of a gene is present, and the gene product of only one copy is insufficient for normal functioning. This suggests that mutation in scn1a may only result in dravet syndrome if occurring on a particular genetic background. These channels are primarily found in the brain, where they control the flow of sodium ions into cells. Epilepsyassociated dysfunction in the voltagegated neuronal.
Distinct mutations in sodium channel trigger autism. Partial and generalized epilepsy with febrile seizures plus and a novel scn1a mutation. Functional effects of two voltagegated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. Some of these mutations q1489k, l1649q,i1498m, f1661l. A functional null mutation of scn1b in a patient with. There are few studies of cnvs in patients with both id and epilepsy. We found out that he has a genetic scn1a mutation, and after videotaping a seizure for our neurologist, he tells us theres nothing medically i can do for him he needs keto, thats the only option but we cant put him back on that for many reason, including financially.