Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A

AbstractEpilepsies can be caused by specific genetic anomalies or by non-genetic factors, but in many cases the underlying cause is unknown.Mutations in the SCN1A and SCN2A genes are reported in childhood epilepsies; in particular SCN1A was found mutated in patients with Dravet syndrome and with generalized epilepsy with febrile seizures plus (GEFS+).In this paper we report a patient presenting with an atypical epileptic syndrome whose phenotype partially overlaps both Dravet syndrome and benign familial neonatal-infantile seizures (BFNIS).Array-CGH analysis suggested the presence of a mosaic duplication (about 12Mb) at the level of chromosome 2q23.3q24.3 involving SCN2A and SCN3A genes. Additional analyses (radiolabeled RFLP and quantitative PCR) confirmed the mosaicism of the duplication.We suggest that the array-CGH analysis is mandatory for children presenting with epilepsy and psycho-motor retardation even without dysmorphisms or other clinical features suggesting a specific genetic/epileptic syndrome. The analysis must nevertheless be performed taking into account the possibility of a mosaicism

Quantitative Characterization of Motor Control during Gait in Dravet Syndrome Using Wearable Sensors: A Preliminary Study

: Dravet syndrome (DS) is a rare and severe form of genetic epilepsy characterized by cognitive and behavioural impairments and progressive gait deterioration. The characterization of gait parameters in DS needs efficient, non-invasive quantification. The aim of the present study is to apply nonlinear indexes calculated from inertial measurements to describe the dynamics of DS gait. Twenty participants (7 M, age 9-33 years) diagnosed with DS were enrolled. Three wearable inertial measurement units (OPAL, Apdm, Portland, OR, USA; Miniwave, Cometa s.r.l., Italy) were attached to the lower back and ankles and 3D acceleration and angular velocity were acquired while participants walked back and forth along a straight path. Segmental kinematics were acquired by means of stereophotogrammetry (SMART, BTS). Community functioning data were collected using the functional independence measure (FIM). Mean velocity and step width were calculated from stereophotogrammetric data; fundamental frequency, harmonic ratio, recurrence quantification analysis, and multiscale entropy (τ = 1...6) indexes along anteroposterior (AP), mediolateral (ML), and vertical (V) axes were calculated from trunk acceleration. Results were compared to a reference age-matched control group (112 subjects, 6-25 years old). All nonlinear indexes show a disruption of the cyclic pattern of the centre of mass in the sagittal plane, quantitatively supporting the clinical observation of ataxic gait. Indexes in the ML direction were less altered, suggesting the efficacy of the compensatory strategy (widening the base of support). Nonlinear indexes correlated significantly with functional scores (i.e., FIM and speed), confirming their effectiveness in capturing clinically meaningful biomarkers of gait

The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant

Sudden Unexpected Deaths and Vaccinations during the First Two Years of Life in Italy: A Case Series Study

Background The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. Methodology/Principal Findings The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. Conclusions The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age

Time perception in childhood absence epilepsy: Findings from a pilot study

With this explorative study, we aimed to examine time perception in children with childhood absence epilepsy (CAE) and to compare those children with a matched control group. The study also investigated the association between the neuropsychological performance of the group with CAE and time judgment. We hypothesize that children with CAE could fail in time perception and that this may be because of a common underlying substrate with executive impairments

Benign nocturnal alternating hemiplegia of childhood: The first clinical report with paroxysmal events home-video recordings.

Benign familial nocturnal alternating hemiplegia of childhood (BNAHC) is a rare disorder characterized by recurrent attacks of hemiplegia, arising from sleep Without progression to neurological or intellectual impairment. It is distinct from the malignant, relatively more common, alternating hemiplegia of childhood (AHC), complicated by developmental deterioration, cognitive impairment, and permanent neurological deficits such as choreoathetosis. The authors add a new case of BNAHC to the pertinent literature and report, for the first time, a video with the typical nocturnal hemiplegic attacks in order to improve knowledge about this disorder among child neurologists and pediatricians and increase the possibility of clarifying its pathogenesis and molecular basis. (C) 2008 Movement Disorder Society

Ring 17 syndrome: First clinical report without intellectual disability

Ring chromosomes are rare abnormalities caused by the fusion of the telomeric regions. Three-ring chromosome syndromes (Cr 20, Cr 17 and Cr 14) cause epilepsy with variable phenotypes. In ring 17 patients with mild phenotype, some authors have shown an epilepsy syndrome similar to that of ring 20. We report the first case of a girl with ring chromosome 17 and a normal neurological and general cognitive profile. She had had, from 9 years old, focal pharmacoresistant epilepsy associated with episodes of non-convulsive status epilepticus with mainly autonomic features. Cytogenetic analysis revealed an abnormal karyotype characterised by the presence of de novo ring chromosome 17 in 19% of metaphases. The array CGH(100 KB) did not show any genetic deletion. The clinical and epilepsy phenotype was, to a certain degree, similar to that of ring 20 syndrome