GEFS+ is not related to the most common mutations of SCN1B,SCN1A and GABRG2 in two Tunisian families

The objective was to investigate whether the described mutations of the SCN1A, SCN1B and GABRG2 genes are associated to generalised epilepsy with febrile seizure plus (GEFS+) in two Tunisian families. We performed a genetic study of two multigenerational Tunisian families with GEFS+ spectrum. The molecular analysis included a PCR amplification of SCN1B, SCN1A and GAGRG2 exons, then a screening of the known SCN1B, SCN1A and GABRG2 gene mutations by direct sequencing. The data excluded the involvement of all known published mutations. However, an insertion of a T nucleotide at a heterozygous state within the intron 12 of the SCN1A gene has been identified in two probands and their parents. Our results corroborate the genetic heterogeneity of GEFS+ predominantly in epilepsy patients of different countries and ethnic groups.     

Variable expressivity of a novel mutation in the SCN1A gene leading to an autosomal dominant seizure disorder

Mutations in the SCN1A gene can cause a variety of dominantly inherited epilepsy syndromes. Severe phenotypes usually result from loss of function mutations, whereas missense mutations cause a milder phenotype by altering the sodium channel activity. We report on a novel missense variant (p.Val1379Leu) in the SCN1A gene segregating in an autosomal dominant pattern in a family exhibiting a variable epilepsy phenotype ranging from generalized epilepsy with febrile seizures during infancy to a well controlled seizure disorder in adulthood. This report supports the importance of SCN1A mutation analysis in families in which seizure disorders segregate in an autosomal dominant fashion.     

Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations

PURPOSE: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations. METHODS: We performed a clinical study of seven families (167 individuals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies. RESULTS: Inheritance was autosomal dominant with 69% penetrance. Forty-one individuals had epilepsy: 29 had a phenotype consistent with GEFS+; seven had idiopathic generalized epilepsy (IGE); in three, the epilepsy type could not be classified; and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare. CONCLUSIONS: The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected individuals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.     

A novel inherited SCN1A mutation associated with GEFS+ in benign and encephalopathic epilepsy

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant condition often caused by mutations in SCN1A that usually first manifests as childhood simple febrile seizures but may progress to a variety of afebrile generalized seizure types. Here, we describe the case of an 8-year-old boy with a novel SCN1A mutation who developed febrile seizures at 10 months of age which eventually advanced to frequent afebrile tonic-clonic seizures. His condition was unresponsive to several antiepileptic drugs and the ketogenic diet, and he experienced gradual cognitive decline. The patient’s father carries the same novel mutation, but he only experienced childhood simple febrile seizures. SCN1A mutations display incomplete penetrance and variable expressivity, and the resulting severity may depend on the location and type of mutation, whether the mutation was spontaneous or inherited, and the effect of modifying alleles. The identification of novel pathogenic SCN1A mutations may eventually advance therapeutic development and prognostic capabilities.     

A catalog of SCN1A variants

Over the past 10 years mutations in voltage-gated sodium channels (Na(v)s) have become closely associated with inheritable forms of epilepsy. One isoform in particular, Na(v)1.1 (gene symbol SCN1A), appears to be a superculprit, registering with more than 330 mutations to date. The associated phenotypes range from benign febrile seizures to extremely serious conditions, such as Dravet's syndrome (SMEI). Despite the wealth of information, mutational analyses are cumbersome, owing to inconsistencies among the Na(v)1.1 sequences to which different research groups refer. Splicing variability is the core problem: Na(v)1.1 co-exists in three isoforms, two of them lack 11 or 28 amino acids compared to full-length Na(v).1.1. This review establishes a standardized nomenclature for Na(v)1.1 variants so as to provide a platform from which future mutation analyses can be started without need for up-front data normalization. An online resource--SCN1A infobase--is introduced.     

Novel de novo splice-site mutation of SCN1A in a patient with partial epilepsy with febrile seizures plus

This report describes a 4-year-old male patient experienced prolonged febrile seizures after 1 year of age, multiple febrile seizures and complex partial seizures with secondary generalization. The gene encoding voltage-gated sodium channel alpha1-subunit: SCN1A analysis revealed a heterozygous de novo one-point mutation (IVS16+2 T>C) at a splice-acceptor site. This mutation was inferred to cause truncation of the alpha1-subunit molecule and, thereby, a loss of channel function. To date, truncation mutation has been found exclusively in patients with severe myoclonic epilepsy in infancy (SMEI), although only missense mutations have been found in generalized epilepsy with febrile seizures plus (GEFS+), partial epilepsy with FS+, FS+, and FS. The patient's phenotype is consistent with that of partial epilepsy with FS+, rather than SMEI, including borderline SMEI (SMEB). We present the first case report of partial epilepsy with FS+ associated with a truncation mutation of SCN1A. The possibility exists for concomitant involvement of multiple genes other than SCN1A for seizure phenotypes.     

A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures

Generalised (genetic) epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with various phenotypes. The majority of individuals with GEFS+ have generalised seizure types, in addition to febrile seizures (FS) or febrile seizures plus (FS+), defined as either continued FS after 6 years of age or afebrile seizures following FS. A 27‐year‐old man with no history of FS/FS+ experienced intractable generalised convulsive seizures. The patient's father had a history of similar seizures during puberty and the patient's siblings had only FS. No individual in the family had both generalised seizures and FS/FS+, although GEFS+ might be considered to be present in the family. Analysis of SCN1A, a sodium channel gene, revealed a novel mutation (c.3250A>T [S1084C]) in the cytoplasmic loop 2 of SCN1A in both the patient and his father. Most previously reported SCN1A mutations in GEFS+ patients are located in the conserved homologous domains of SCN1A, whereas mutations in the cytoplasmic loops are very rare. SCN1A gene analysis is not commonly performed in subjects with generalised seizures without FS. SCN1A mutation may be a clinically‐useful genetic marker in order to distinguish GEFS+ patients from those with classic idiopathic generalised epilepsy, even if they present an atypical clinical picture.     

SCN1A mutation mosaicism in a family with severe myoclonic epilepsy in infancy

PURPOSE: To investigate the genetic background of familial severe myoclonic epilepsy in infancy (SMEI) cases. METHODS: We performed mutation analyses of the sodium-channel gene SCN1A in two Japanese brothers with clinical features of SMEI and their parents, who had no history of febrile and epileptic seizures. RESULTS: Each patient showed nucleotide changes (c.[730G>T; 735G>T; 736A>T]) in the coding exon 6 of SCN1A that led to a truncation of the channel protein. Their father showed no mutations, but their mother showed the same mutation in a subpopulation of lymphocytes. CONCLUSIONS: The maternal mosaicism explains the identical SCN1A mutations in the two brothers. This highlights the importance of investigating parental mosaicism even in sporadic SMEI cases.     

一个全面性癫痫伴热性惊厥附加症家系的临床表型及SCN1A基因突变筛查

目的观察全面性癫痫伴热性惊厥附加症家系(GEFS+)的临床表型,并分析有无钠通道α1亚单位基因(SCN1A)突变。方法收集先证者及家系成员临床资料及外周血,提取基因组DNA,设计引物,进行PCR扩增,琼脂糖凝胶电泳,选取符合条件的PCR产物进行双向测序。结果该家系临床表型包括热性惊厥(FS)、热性惊厥附加症(FS+)伴失神发作,通过PCR对所有SCN1A的所有外显子进行扩增,所有患者和50例正常对照的测序结果与基因组序列相对比,均未发现碱基改变。结论全面性癫痫伴热性惊厥附加症是一种复杂综合征,具有表型异质性,在本家系中未发现SCN1A基因的突变,表明GEFS+具有遗传异质性。     

A novel SCN2A mutation in family with benign familial infantile seizures

Benign familial infantile seizures (BFIS) is a clinical entity characterized by focal seizures with or without secondary generalization, occurring mostly in clusters, and usually first seen between 4 and 8 months of life. Psychomotor development is normal, and seizures usually resolve within the first year of life. BFIS is a genetically heterogenous condition with loci mapped to chromosomes 19 and 16. Mutations in the voltage-gated sodium channel alpha2 subunit (SCN2A) gene on chromosome 2 were recently identified in families affected by neonatal and infantile seizures (benign familial neonatal-infantile seizures, BFNIS) with typical onset before 4 months of life. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS show overlapping clinical features. We report a pedigree showing three affected individuals over three generations. All subjects experienced clusters of focal seizures with or without secondary generalization and onset between 4 and 12 months of life. Response to antiepileptic drugs and the outcome were good. No subjects had other forms of epilepsy later in the life. Neonatal or febrile seizures did not occur in the family. Genetic study in this family revealed a novel heterozygous mutation c.3003 T>A in the SCN2A gene. Comparative analysis of different sodium channel alpha subunits indicates that the mutated residue is highly conserved throughout the evolution, suggesting an important functional role for this domain. Additional families with the infantile form of benign familial seizures should be investigated to corroborate that BFIS and BFNIS may share the same genetic abnormality.     

A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree.

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.     

De novo SCN1A pathogenic variants in the GEFS+ spectrum: Not always a familial syndrome

Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non‐EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood‐onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.     

Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities

PURPOSE: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations. METHODS: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients. RESULTS: We classified patients as: SMEI/SMEB = 55; GEFS+= 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations. CONCLUSION: We obtained a frequency of 71%SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes.     

Rasmussen encephalitis associated with SCN 1 A mutation

Mutations in the SCN 1 A gene, encoding the neuronal voltage-gated sodium channel alpha1 subunit, cause SMEI, GEFS+, and related epileptic syndromes. We herein report the R1575C-SCN 1 A mutation identified in a patient with Rasmussen encephalitis. R1575C were constructed in a recombinant human SCN 1 A and then heterologously expressed in HEK293 cells along with the human beta1 and beta2 sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties. The R1575C channels exhibited increased channel availability and an increased persistent sodium current in comparison to the wild-type. These defects of electrophysiological properties can result in neuronal hyperexitability. The seizure susceptibility allele may influence the pathogenesis of Rasmussen encephalitis in this case.     

A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation

A boy with a clinical history of pharmacologically resistant Dravet syndrome died suddenly after falling asleep. The autopsy concluded that the cause of death was sudden unexpected death in epilepsy (SUDEP). Postmortem molecular analysis of the SCN1A gene by multiplex ligation‐dependent probe amplification (MLPA), high‐resolution melting curve analysis (HRMCA), and sequencing revealed a frameshift duplication of adenosine at position 504. The incidence of this mutation is discussed as a potential cause of SUDEP.     

SCN8A as a novel candidate gene associated with bipolar disorder in the Han Chinese population

Background

Bipolar disorder (BPD) is a common, severe and recurrent psychiatric disorder. It has been suggested that BPD patients have a higher risk of suicide than patients with any other psychiatric illnesses. A recent study found that suicide attempt was associated with the SCN8A gene, which has been mapped close to one of the BPD susceptibility loci. Thus, SCN8A is likely to be a candidate gene for BPD.

Methods

In this study, three SNPs (rs1601012, rs303810, rs60637) were analyzed in 506 bipolar patients and 507 controls of Han origin.

Results

We found that two individual SNPs showed statistically significant differences between cases and controls in both allele and genotype distribution, but only rs303810 was still significant in allele distribution (p = 0.0164) after correction. No obvious linkage disequilibrium or haplotypes were observed among these SNPs.

Conclusion

Our results indicate that SCN8A may be a potential susceptibility gene for bipolar disorder in the Han Chinese population.     

SCN1A mutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus

Aims. Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. Methods. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant‐negative EAF patients. Results. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. Conclusion. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.     

Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation

PURPOSE: To report in detail the electroclinical features of a large family in which we recently identified a missense mutation (M145T) of a well-conserved amino acid in the first transmembrane segment of domain I of the human SCN1A. We showed that the mutation is associated with a loss of SCN1A function. METHODS: The family originates from southern Italy and contains 35 members spread over four generations. Of the 14 affected individuals, the 13 still living members (7 males, mean age 36.6 +/- 20.4) underwent a complete electroclinical evaluation. RESULTS: All 13 affected family members had febrile seizures (FS) up to the age of 6 years. Age at onset of FS ranged from 5 to 45 months with a mean age of 12.8 +/- 12.9 months. One of the 13 was affected by post-traumatic epilepsy. Three of the 13 later developed temporal lobe epilepsy (TLE) with both simple focal seizures, and also very rare focal complex or nocturnal secondary generalized tonic-clonic seizures. In two of the three patients who later developed TLE, the MRI studies revealed mesial temporal sclerosis. CONCLUSIONS: Our findings illustrate that SCN1A mutations can cause simple FS associated with TLE, which differ from the characteristic clinical spectrum of GEFS+. It is open to conjecture if this unusual phenotype might at least in part be related to the fact that M145T is the first missense mutation found in DIS1 of SCN1A.