Familial temporal lobe epilepsy as a presenting feature of choreoacanthocytosis.

PURPOSE: Choreoacanthocytosis (ChAc) is an autosomal recessive disorder caused by mutations in VPS13A on chromosome 9q21 and characterized by neurodegeneration and red cell acanthocytosis. Seizures are not uncommon in ChAc but have not been well characterized in the literature. We report two ChAc families in which patients presented with temporal lobe epilepsy. METHODS: Detailed medical and family histories were obtained. EEG, video-telemetry, brain magnetic resonance imaging (MRI) with volumetric studies of amygdala and hippocampus, as well as neuropsychological testing were performed. Blood smears were examined for acanthocytosis. Mutation analysis of VPS13A was carried out in five patients. RESULTS: Six patients in three sibships were initially seen with seizures. Age at seizure onset ranged from 22 to 38 years. Seizures preceded other clinical manifestations of ChAc by < or = 15 years. The epileptic aura consisted of a sensation of déjà-vu, fear, hallucinations, palpitations, or vertigo. EEG with video-telemetry showed epileptiform discharges originating either from one or both temporal lobes. Epilepsy was generally well controlled, but some patients had periods of increased seizure frequency requiring treatment with multiple antiepileptic drugs (AEDs). Both families shared a deletion of exons 70-73 of VPS13A, extending to exons 6-7 of GNA14. CONCLUSIONS: Temporal lobe epilepsy may be the presenting feature of ChAc and may delay its diagnosis. Epilepsy in ChAc patients represents a challenge, because seizures may at times be difficult to control, and some AEDs may worsen the involuntary movements. Mutations in VPS13A or GNA14 or both may be associated with clinical features of temporal lobe epilepsy.

Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.

Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.

Sodium-channel defects in benign familial neonatal-infantile seizures.

Ion-channel gene defects are associated with a range of paroxysmal disorders, including several monogenic epilepsy syndromes. Two autosomal dominant disorders present in the first year of life: benign familial neonatal seizures, which is associated with potassium-channel gene defects; and benign familial infantile seizures, for which no genes have been identified. Here, we describe a clinically intermediate variant, benign familial neonatal-infantile seizures, with mutations in the sodium-channel subunit gene SCN2A. This clinico-molecular correlation defines a new benign familial epilepsy syndrome beginning in early infancy, an age at which seizure disorders frequently have a sombre prognosis.