SCN1A variations and response to multiple antiepileptic drugs.

In the current study, we have used the haplotype-tagging single-nucleotide polymorphisms (SNPs) to determine associations between genetic variants in SCN1A and treatment response in 519 Caucasian patients with known response status for epilepsy treated with antiepileptic drugs (AEDs) with sodium channel blocking effects. Nine SNPs within SCN1A were genotyped in this cohort. The only association observed was for rs10188577. A greater proportion of drug-resistant patients were heterozygous compared with drug responsive patients (48.3% vs 35.4%, P=0.014). After correction for potential confounding factors, the association for rs10188577 was only marginally significant (P=0.049). In light of our findings, it seems unlikely that rs10188577 could be a major determinant of response to AEDs. However, looking at the influence of rs10188577 on the expressed quantitative trait association patterns within the immediate vicinity of SCN1A, we found significant associations with neighbouring sodium channel genes, SCN7A and SCN9A (P<0.025), which warrants further studies.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

A polygenic heterogeneity model for common epilepsies with complex genetics.

Approximately 40% of epilepsy has a complex genetic basis with an unknown number of susceptibility genes. The effect of each susceptibility gene acting alone is insufficient to account for seizure phenotypes, but certain numbers or combinations of variations in susceptibility genes are predicted to raise the level of neuronal hyperexcitability above a seizure threshold for a given individual in a given environment. Identities of susceptibility genes are beginning to be determined, initially by translation of knowledge gained from gene discovery in the monogenic epilepsies. This entrée into idiopathic epilepsies with complex genetics has led to the experimental validation of susceptibility variants in the first few susceptibility genes. The genetic architecture so far emerging from these results is consistent with what we have designated as a polygenic heterogeneity model for the epilepsies with complex genetics.

NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity.

Photosensitive seizures occur most commonly in childhood and adolescence, usually as a manifestation of complex idiopathic generalized epilepsies (IGEs). Molecular mechanisms underlying this condition are yet to be determined because no susceptibility genes have been identified. The NEDD4-2 (Neuronally Expressed Developmentally Downregulated 4) gene encodes a ubiquitin protein ligase proposed to regulate cell surface levels of several ion channels, receptors and transporters involved in regulating neuronal excitability, including voltage-gated sodium channels (VGSCs), the most clinically relevant of the epilepsy genes. The regulation of NEDD4-2 in vivo involves complex interactions with accessory proteins in a cell type specific manner. We screened NEDD4-2 for mutations in a cohort of 253 families with IGEs. We identified three NEDD4-2 missense changes in highly conserved residues; S233L, E271A and H515P in families with photosensitive generalized epilepsy. The NEDD4-2 variants were as effective as wild-type NEDD4-2 in downregulating the VGSC subtype Na(v)1.2 when assessed in the Xenopus oocyte heterologous expression system showing that the direct interaction with the ion channel was not altered by these variants. These data raise the possibility that photosensitive epilepsy may arise from defective interaction of NEDD4-2 with as yet unidentified accessory or target proteins.

Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations.

OBJECTIVE: Two unrelated families were ascertained in which sisters had infantile onset of epilepsy and developmental delay. Mutations in the protocadherin 19 (PCDH19) gene cause epilepsy and mental retardation limited to females (EFMR). Despite both sister pairs having a PCDH19 mutation, neither parent in each family was a heterozygous carrier of the mutation. The possibility of parental mosaicism of PCDH19 mutations was investigated. METHODS: Genomic DNA from peripheral blood was obtained and sequenced for PCDH19 mutations. Parentage was confirmed by markers. RESULTS: Both sister pairs have a mutation in PCDH19. Sister pair 1 has a missense mutation, c.74T>C, L25P, while sequence analysis indicates both of their parents are negative for the mutation. Diagnostic restriction enzyme analysis detected low-level mosaicism of the mutation in their mother. Sister pair 2 are half-sisters who share a mother and each has the missense PCDH19 mutation c.1019 A>G, N340S. The sequence chromatograph of their mother shows reduced signal for the same mutation. These data indicate maternal somatic and gonadal mosaicism of the PCDH19 mutation in both sister pairs. Phenotyping is suggestive of, and PCDH19 mutation detection is diagnostic for, the disorder EFMR in the affected girls. CONCLUSIONS: We show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR. This should be considered when providing genetic counseling for couples who have one affected daughter as they may risk recurrence of affected daughters and having sons at risk of transmitting EFMR.

De novo SCN1A mutations in migrating partial seizures of infancy.

OBJECTIVE: To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI). METHODS: Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations. RESULTS: One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases. CONCLUSION: Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy.

The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies.

Rare GABA(A) receptor gamma2 and alpha1 subunit mutations of pathogenic effect have been described segregating in families with "monogenic" epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABA(A) receptor subunit genes from the one patient cohort. The cohort consists of GEFS(+), FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABA(A) receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations.

Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms.

BACKGROUND: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. METHOD: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. RESULTS: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. CONCLUSIONS: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.