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OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.

We applied conversation analysis in an unselected continuous series of 70 patients to discriminate patients with psychogenic nonepileptic seizures (PNES) from patients with epilepsy. Two psychologists examined the patients' recorded reports. Patients were also submitted to an extensive neuropsychological battery in order to verify whether specific cognitive deficits or mental health problems are typical of patients with PNES and whether some cognitive deficits could prevent the correct diagnosis. The results showed a good percentage of correct diagnosis, with a sensitivity of 0.795 and a specificity of 0.83, while no difference in the cognitive profile was found between patients with PNES and patients with epilepsy. The results also suggest that psychologists can apply the conversation analysis as well as linguists, which is an important finding since psychologists are employed in specialized centers, while linguists in general are not part of the team.

HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3'-UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p<0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p=0.02; OR: 2.6, 95% CI: 1.1-6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal-fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings.

Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients.

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

Febrile seizures (FS) affect 5-12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in approximately 7% of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23-24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na(v)1.1 channel alpha-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy.

Positron emission tomography with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) has been used to assess the pattern of cerebral metabolism in different types of epilepsies. However, PET with [18F]FDG has never been used to evaluate drug naive patients with cryptogenic temporal lobe epilepsy, in whom the mechanism of origin and diffusion of the epileptic discharge may differ from that underlying other epilepsies. In a group of patients with cryptogenic temporal lobe epilepsy, never treated with antiepileptic drugs, evidence has been found of significant interictal glucose hypermetabolism in a bilateral neural network including the temporal lobes, thalami, basal ganglia, and cingular cortices. The metabolism in these areas and frontal lateral cortex enables the correct classification of all patients with temporal lobe epilepsy and controls by discriminant function analysis. Other cortical areas--namely, frontal basal and lateral, temporal mesial, and cerebellar cortices--had bilateral increases of glucose metabolism ranging from 10 to 15% of normal controls, although lacking stringent statistical significance. This metabolic pattern could represent a pathophysiological state of hyperactivity predisposing to epileptic discharge generation or diffusion, or else a network of inhibitory circuits activated to prevent the diffusion of the epileptic discharge.

Summary: We conducted an epidemiological survey of epilepsy among males born in 1967 who were called for selection for military service from the Lombardy region in northern Italy. Of 54,520 subjects, 258 had active epilepsy (prevalence, 0.47%). Idiopathic partial epilepsy was most common (29.1%), and generalized idiopathic and/or symptomatic epilepsy was least common (3.8%). In the year preceding the interview, 66.9% of the subjects had been free of generalized tonic‐clonic seizures, 57.6% had been free of minor seizures, and 36.9% were seizure‐free. Case histories revealed a background of febrile convulsions in 18.9% of subjects, status epilepticus in 11.3%, and a family history of epilepsy in 18.9%. Physical and mental development was normal in 75.5% of the subjects. Education level of subjects was lower than a control group, and the unemployment rate was the same as the local rate. Les auteurs ont effectué une enquêtéépidémiologique parmi les sujets mâles nés en 1%7 appelés pour sélection en vue du service militaire dans la région de Lombardie (italie du Nord). Parmi 54,520 sujets, 258 présentaient une épilepsie active (prévalence: 0.47%). L'épilepsie partielle idiopathique représentait la forme la plus féquente (29.1%); l'épilepsie généralisée idiopathique et/ou symptômatique a été la plus rare (3.8%). Pendant l'année précédant l'entrevue, 66.9% des patients n'avient pas présenté de crises généralisées tonico‐cloniques, 57.6% n'‐avaient pas présenté de crises mineures, et 36.9% n'avient présenté aucun type de crises. Les études des cas ont montré l'existence d'antécédents de convulsions fébriles chez 18.9% des sujets, des antécédents d'états de mal épileptiques chez 11.3% et des antécédents famillaux d'épilepsie chez 18.9%. Le développ‐ement physique et mental a été considéré comme normal chez 75.5% seulement des sujects. Le niveau d'éducation des sujets était inférieur à celui d'un groupe contrôle, alors

At the military hospital a moment has been chosen in which the subjects of the 1967 contingent who denounce to have or have had an epilepsy are being examined. Out of this homogeneous population of a well defined territory, we intend to study through a set of questions of 21 items: the prevalence of epilepsy, the clinical characters, the quality of medical intervention, the social peculiarities of population and the possible correlation between the clinical aspects and the various social factors. On a second time the data will be elaborate by a computer.