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Purpose: To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS)., Methods: Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method., Key Findings: A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation., Significance: Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Disorders of creatine synthesis or its transporter resulting in neurological impairment with mental retardation and epilepsy have only been recognized in recent years. To date, the epileptic disorder observed in creatine transporter deficiency (CRTR-D) has been described as a mild phenotype with infrequent seizures and favorable response to common antiepileptic drugs. We report on a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. After extensive investigations, metabolite analysis and brain 1H-MRS suggested CRTR-D, which was confirmed by the detection of a known pathogenic mutation in the SLC6A8 gene (c.1631C>T; p.Pro544Leu).

Introduction: To determine the occurrence of neuroradiological abnormalities and to perform genotype-phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome)., Patients and Methods: Alpha-subunit type A of voltage-gated sodium channel (SCN1A) mutational screening was performed by denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation probe amplification (MLPA). MRI inclusion criteria were: last examination obtained after the age of 4 years on 1.5-T systems; hippocampal cuts acquired perpendicular to the long axis of the hippocampus; qualitative assessment was performed on T(1)-weighted, T(2)-weighted, proton density, and 1-3 mm thick coronal FLAIR images., Results: We collected 58 SMEI patients in whom last MRI was performed at or later than 4 years of age. SCN1A mutations occurred in 35 (60%) cases. Thirteen (22.4%) out of 58 patients showed abnormal MRIs. Eight patients showed cortical brain atrophy of which 3 associated to ventricles abnormalities, 1 to cerebellar atrophy, 1 to white matter hyperintensity; 3 patients had ventricles enlargement only; 1 patient showed hippocampal sclerosis (HS); 1 had focal cortical dysplasia. Genotype-phenotype analysis indicated that abnormal MRIs occurred more frequently in patients without SCN1A mutations (9/23; 39.1%) compared to those carrying SCN1A mutations (4/35; 11.4%) (p=0.02)., Conclusion: Different brain abnormalities may occur in SMEI. Only one case with HS was observed; thus, our study does not support the association between prolonged febrile seizures and HS in SMEI. Abnormal MRIs were significantly more frequent in patients without SCN1A mutations. Prospective MRI studies will assess the etiological role of the changes observed in these patients.

Purpose: The role of the familial background in severe myoclonic epilepsy of infancy (SMEI) has been traditionally emphasized in literature, with 25-70% of the patients having a family history of febrile seizures (FS) or epilepsy. We explored the genetic background of SMEI patients carrying SCN1A mutations to further shed light on the genetics of this disorder., Methods: We analyzed the occurrence of FS and epilepsy among first- and second-degree relatives (N = 867) of 74 SMEI probands with SCN1A mutations (70 de novo, four inherited) and compared data with age-matched and ethnically matched control families. Familial clustering and syndromic concordance within the affected relatives in both groups were investigated., Results: The frequency of FS or epilepsy in relatives of SMEI patients did not significantly differ from that in controls (FS: 13 of 867 vs. 12 of 674, p = 0.66; epilepsy: 15 of 867 vs. six of 674, p = 0.16). Different forms of epilepsy were identified in both relatives of SMEI probands and controls. Twenty-eight relatives with FS and epilepsy were distributed in 20 (27%) of 74 SMEI families; among the controls, 18 affected relatives were clustered in 13 (18.5%) of 70 families. No pedigree showed several affected members, including the four with inherited mutations., Conclusions: A substantial epileptic family background is not present in our SMEI patients with SCN1A mutations. These data do not confirm previous observations and would not support polygenic inheritance in SMEI. The investigation of the family background in additional series of SMEI patients will further shed light on the genetics of this syndrome.

Purpose: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis., Methods: Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models., Results: Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity., Conclusions: Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.