Tuesday, January 12, 2016

SCN1B mutation

Inspired by a patient with a SCN1B mutation.  This 8 year old boy had a history of prolonged seizures.  After the most recent of these, he had lingering neurological handicaps, leading to an admission for rehabilitation.  Genetic testing was obtained at that time.

Ogiwara I, Nakayama T, Yamagata T, Ohtani H, Mazaki E, Tsuchiya S, Inoue Y,
Yamakawa K. A homozygous mutation of voltage-gated sodium channel β(I) gene SCN1B
in a patient with Dravet syndrome. Epilepsia. 2012 Dec;53(12):e200-3.


Dravet syndrome is a severe form of epileptic encephalopathy characterized by early onset epileptic seizures followed by ataxia and cognitive decline. Approximately 80% of patients with Dravet syndrome have been associated with heterozygous mutations in SCN1A gene encoding voltage-gated sodium channel (VGSC) α(I) subunit, whereas a homozygous mutation (p.Arg125Cys) of SCN1B gene encoding VGSC β(I) subunit was recently described in a patient with Dravet syndrome. To further examine the involvement of homozygous SCN1B mutations in the etiology of Dravet syndrome, we performed mutational analyses on SCN1B in 286 patients with epileptic disorders, including 67 patients with Dravet syndrome who have been negative for SCN1A and SCN2A mutations. In the cohort, we found one additional homozygous mutation (p.Ile106Phe) in a patient with Dravet syndrome. The identified homozygous SCN1B mutations indicate that SCN1B is an etiologic candidate underlying Dravet syndrome.

Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, Saar K,
Reis A, Johnson EW, Sutherland GR, Berkovic SF, Mulley JC. Febrile seizures and
generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit
gene SCN1B. Nat Genet. 1998 Aug;19(4):366-70.


Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.


  1. Sun H, Zhang Y, Liang J, Liu X, Ma X, Wu H, Xu K, Qin J, Qi Y, Wu X. SCN1A,SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. J Hum Genet. 2008;53(8):769-74.


    Generalized epilepsy with febrile seizures plus (GEFS+; MIM#604233) is a familial epilepsy syndrome characterized by phenotypic and genetic heterogeneity. It was associated with mutations in the neuronal voltage-gated sodium channel subunit gene (SCN1A, SCN2A, SCN1B) and ligand-gated gamma aminobutyric acid receptors genes (GABRG2, GABRD). We investigated the roles of SCN1A, SCN1B, and GABRG2 mutations in the etiology of Chinese GEFS+ families. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood lymphocytes of 23 probands and their family members. The sequences of SCN1A, SCN1B, and GABRG2 genes were analyzed by polymerase chain reaction (PCR) and direct sequencing. The major phenotypes of affected members in the 23 GEFS+ families exhibited FS and FS+, whereas rare phenotypes afebrile generalized tonic-clonic seizures (AGTCS), myoclonic-astatic epilepsy (MAE), and partial seizures were also observed. A novel SCN1A mutation, p.N935H, was identified in one family and another novel mutation in GABRG2, p.W390X, in another family. However, no SCN1B mutation was identified. The combined frequency of SCN1A, SCN1B, and GABRG2 mutations was 8.7% (2/23), extending the distribution of SCN1A and GABRG2 mutations to Chinese GEFS+ families. There were still unidentified genes contributing to the pathogenesis of GEFS+.

  2. Kim YO, Dibbens L, Marini C, Suls A, Chemaly N, Mei D, McMahon JM, Iona X,Berkovic SF, De Jonghe P, Guerrini R, Nabbout R, Scheffer IE. Do mutations in SCN1B cause Dravet syndrome? Epilepsy Res. 2013 Jan;103(1):97-100.


    A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied. Genomic DNA was Sanger sequenced for mutations in the 6 exons of SCN1B. In 54 patients with DS recruited from four centres, no SCN1B mutations were identified. SCN1B mutation is not a common cause of DS.

  3. Prior to our patient's third episode of status epilepticus, "He does not have a history of receiving special education services. Mother reported that he was below grade level academically. Parents had consulted with a psychologist due to parental concerns regarding the possibility of ADHD."

    He was hospitalized for 9 days and then transferred for rehabilitation. Initial consultation following transfer: "His hospital course was notable for lack of return to baseline. He was noted to have significant posturing of his arms. There is note of particularly right arm posturing and extensor posturing of his right leg, as well as notation of clonus. He was nonverbal and not following commands."

    MRI: 1) Abnormal pattern of T2 or diffusion hyperintensity involving most of the cerebral gyri, relative sparing of the occipital lobes and perirolandic gyri. Pattern can be seen in the setting of status epilepticus or hypoxemia. However, the patient has not had status epilepticus for at least two weeks. Uncertain as to whether this could be persistent signal abnormality from that event. 2) Mild generalized atrophy. This has occurred in the interval from the head CT scan 13 days earlier, and may be related to the status epilepticus and subsequent brain injury.

    EEG: Diffuse slowing of the background and lack of expected physiological features for age in wakefulness and sleep. Rare brief intermittent right frontocentral temporal slowing is observed in sleep only. No interictal epileptiform activity or electrographic seizures are identified.

    At the conclusion of his 6 weeks rehabilitation hospitalization: "No rocking was noted today in his wheelchair. His affect was pleasant and different from yesterday when he was in a very somber mood. He appears to be trying to engage in reciprocal activity, such as pushing a ball to the other person or pushing a car to the other person although his hand movements consist of coming down from above and hitting the object. Occasionally he will open his fingers and grab the ball, but this is rare. He continues with vocalizations today but no verbal imitation. He is able to stick out his tongue, but not on command. He continues to look at himself in the mirror and will put his hand to his mouth area and he does appear to be attempting to try and use speech, but he cannot use speech to request or label."