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Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences., Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms., Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments., Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Introduction: A large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome sequencing in consanguineous families. Disease-associated variants in TRAPPC9 were reported in eight multiplex consanguineous sibships from different ethnic backgrounds, and led to the delineation of the phenotype. Affected patients have microcephaly, obesity, normal motor development, severe ID, and language impairment and brain anomalies., Patients: We report six new patients recruited through a national collaborative network., Results: In the two patients heterozygous for a copy-number variation (CNV), the phenotype was clinically relevant with regard to the literature, which prompted to sequence the second allele, leading to identification of disease-associated variants in both. The third patient was homozygote for an intragenic TRAPPC9 CNV. The phenotype of the patients reported was concordant with the literature. Recent reports emphasized the role of CNVs in the etiology of rare recessive disorders., Conclusion: This study demonstrates that CNVs significantly contribute to the mutational spectrum of TRAPPC9 gene, and also confirms the interest of combining WES with CNV analysis to provide a molecular diagnosis to patients with rare Mendelian disorders.

Objective: To obtain perspective on epilepsy in patients referred to tertiary centers in France, and describe etiology, epilepsy syndromes, and identify factors of drug resistance and comorbidities., Methods: We performed a cross-sectional analysis of the characteristics of 5,794 pediatric and adult patients with epilepsy included in a collaborative database in France between 2007 and 2013. Comparisons between groups used Student's t-test or Fisher's exact test for binary or categorical variables. Factors associated with drug resistance and intellectual disability were evaluated in multi-adjusted logistic regression models., Results: Mean age at inclusion was 17.9 years; children accounted for 67%. Epilepsy was unclassified in 20% of patients, and etiology was unknown in 65%, including those with idiopathic epilepsies. Etiologies differed significantly in adult- when compared to pediatric-onset epilepsy; however, among focal structural epilepsies, mesial temporal lobe epilepsy with hippocampal sclerosis began as often in the pediatric as in adult age range. Drug resistance concerned 53% of 4,210 patients evaluable for seizure control and was highest in progressive myoclonic epilepsy (89%), metabolic diseases (84%), focal cortical dysplasia (70%), other cortical malformations (69%), and mesial temporal lobe epilepsy with hippocampal sclerosis (67%). Fifty-nine percent of patients with focal structural epilepsy and 69% with epileptic encephalopathies were drug resistant; however, 40-50% of patients with West syndrome and epileptic encephalopathy with continuous spike-and-waves during sleep were seizure-free. Ages at onset in infancy and in young adults shared the highest risk of drug resistance. Epilepsy onset in infancy comprised the highest risk of intellectual disability, whereas specific cognitive impairment affected 36% of children with idiopathic focal epilepsy., Significance: Our study provides a snapshot on epilepsy in patients referred to tertiary centers and discloses needs for diagnosis and treatment. Large databases help identify patients with rare conditions that could benefit from specific prospective studies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking., Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8)., Results and Conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5-30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28-30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.

Objective: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations., Results: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia., Conclusions: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.

We report the case of a female suffering from resistant partial seizures, which were related to 'cryptogenic' epilepsy, as the cerebral cortex was considered normal on the initial MRI images. As her son is mentally retarded and has a pachygyria, the doublecortin gene, usually involved in band heterotopia or lissencephaly, was screened for mutations. A missense mutation was identified, shared by both the son and his mother, and a subtle discontinuous subcortical heterotopia was subsequently detected on the mother's MRI. The pathophysiology of epilepsy in this woman is discussed in the light of the role of doublecortin, not only in neuronal migration, but also in axonal growth and dendritic connectivity., (Copyright 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.)

Purpose: To analyze the results of callosotomy in 17 children with symptomatic generalized epilepsy after West syndrome, according to the different seizure types and surgical procedures, to define selection criteria for candidates to callosotomy., Methods: Callosotomy was performed in two successive stages. Partial callosotomy, anterior in 13 and posterior in three, was followed by completion in 14 cases in all but four patients (complete callosotomy in one stage in one, no completion in three). All patients had clinical, video-EEG, and neuropsychological evaluation before and after each stage of callosotomy, with a mean final follow-up of 4 years., Results: Seizure frequency improved in only two of 13 patients after anterior callosotomy, in none of three after posterior callosotomy, but in nine of 14 after complete callosotomy. After complete callosotomy, spasms disappeared in 80% of the cases, and drop attacks, the most severe ictal event, completely stopped or were dramatically reduced in 90% of the children. One patient no longer had episodes of status epilepticus, and another one acquired the ability to walk after complete callosotomy. From the cognitive viewpoint, nine patients with improved seizure frequency after complete callosotomy also had improved behavior and cognitive functions, but two others experienced speech deterioration after posterior callosotomy at age 11 years and completion of callosotomy at age 16 years., Conclusions: As in other severe generalized epilepsies in childhood, drop attacks provide the best indication for complete callosotomy in patients with previous West syndrome. Because drop attacks can be identifiable by falls only, the previous acquisition of walking should be considered as a key feature for any benefit to be obtained.

X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/ LIS) is an intriguing disorder of cortical development, which causes classical lissencephaly with severe mental retardation and epilepsy in hemizygous males, and subcortical laminar heterotopia (SCLH) associated with milder mental retardation and epilepsy in heterozygous females. Here we report an exclusion mapping study carried out in three unrelated previously described families in which males are affected with lissencephaly and females with SCLH, using 38 microsatellite markers evenly distributed on the X chromosome. Most of the X chromosome was excluded and potential intervals of assignment in Xq22.3-q23 or in Xq27 are reported. Although the number of informative meioses did not allow a decision between these two loci, it is worth noting that the former interval is compatible with the mapping of a breakpoint involved in a de novo X;autosomal balanced translocation 46,XX,t(X;2)(q22;p25) previously described in a female with classical lissencephaly. In addition, haplotype inheritance in two families showed a grandpaternal origin of the mutation and suggested in one family the presence of mosaicism in germline cells of normal transmitting males.

Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy.

Hypsarrhythmia and spasms of West syndrome have been postulated by some investigators to have a brainstem origin. Cortical involvement is also postulated because of the frequent association with cortical lesions. Cortical discharges have been proposed to stimulate subcortical structures (i.e., brainstem) and hypsarrhythmia is a secondarily generalized phenomenon produced by the brainstem. Two children with cryptogenic West syndrome refractory for several years to steroids and conventional antiepileptic drugs underwent total callosotomy. Hypsarrhythmia that was bilateral before operation became unilateral after the procedure and spasms became asymmetrical, suggesting that a corticocortical pathway through the corpus callosum is important in the generalization of hypsarrhythmia.

Clinical, neuroradiological data and outcome of epilepsy of 32 patients with symptomatic infantile spasms caused by perinatal insults are reported. Neuroradiological investigations showed focal as well as diffuse cerebral lesions. Fifteen children had a porencephalic lesion, 12 had periventricular leukomalacia and five had diffuse bilateral cerebral atrophy, associated with status marmoratus in one child and bilateral ulegyria in another. Eight patients (25%) had epilepsy following West syndrome. In the group of 15 children with porencephalic cysts, the lesion was always unilateral, but topography and extension varied. Eight children had circumscribed cysts involving the rolandic or parieto-occipital regions, and the outcome of epilepsy was favorable. Seven patients had large lesions involving the frontal lobe, associated with unilateral hemispheric atrophy in four cases. These four children had an unfavorable epilepsy outcome. In the 12 patients with periventricular leukomalacia, all premature, eleven had no seizure relapse after the spasms; one of these children had epilepsy. In the five full-term patients with bilateral and diffuse cerebral lesions, three children had epilepsy at the last observation. In children with leukomalacia and in patients with localized porencephalic lesions the outcome of epilepsy appears to be better than in patients with diffuse cerebral lesions or in children with extensive porencephalic cysts, particularly those involving the frontal lobe.

We describe a female infant with mental retardation and some of the phenotypic features of Williams-Beuren syndrome. Chromosome analysis showed t(X;21)(q28;q11). Diagnosis, inactivation of the X chromosome, and possible involvement of the translocation breakpoints in the pathogenesis of this syndrome are discussed.