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Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children. Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed. Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy. Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.

Since its first clinical description (on his son) by William James West (1793–1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as “West syndrome”, new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.

Exome sequencing has found an excess of de novo mutations in the ∼4,000 most intolerant genes in patients with two classical epileptic encephalopathies (infantile spasms and Lennox–Gastaut syndrome); among them are multiple de novo mutations in GABRB3 and ALG13 . Epilepsy-linked mutations revealed An extensive exome sequencing study of patients with two 'classical' epileptic encephalopathies — infantile spasms and Lennox-Gastaut syndrome — has found an excess of de novo mutations in the approximately 4,000 genes that are the most intolerant to functional genetic variation in the human population. Among them are de novo mutations in GABRB3 and ALG13 , both showing statistical evidence of an association with epileptic encephalopathy. As in autism spectrum disorders, these de novo mutations are enriched in genes regulated by fragile X protein. Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown 1 . Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms ( n = 149) and Lennox–Gastaut syndrome ( n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population ( P = 2.9 × 10 −3 ). Among these are GABRB3 , with de novo mutations in four patients, and ALG13 , with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10 −10 and P = 7.8 × 10 −12 , respectively. Other genes with de novo mutations in this cohort include CACNA1A , CHD2 , FLNA , GABRA1 , GRIN1 , GRIN2B , HNRNPU , IQSEC2 , MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein ( P  < 10 −8 ), as has been reported previously for autism spectrum disorders 2 .

Neurodevelopmental disorders can have long-lasting effects, causing not only early pediatric symptoms but also a range of neurological issues throughout adulthood. West syndrome is a severe neurodevelopmental disorder marked by infantile spasms, an early symptom that typically subsides with age. However, many patients progress to other seizure forms, known as seizure evolution, which is closely linked to poor long-term outcomes. Despite its clinical significance, the neurobiological mechanisms behind seizure evolution in West syndrome remain poorly understood. Recent genetic studies have consistently identified the CYFIP2 p.Arg87Cys variant in West syndrome patients, and the Cyfip2 + /R87C mouse model carrying this mutation has been shown to recapitulate key symptoms of the disorder, including infantile spasms. In this study, we aimed to gain deeper insight into seizure evolution by conducting longitudinal deep phenotyping of the Cyfip2 + /R87C mouse model from the neonatal stage to seven months of age. We tracked seizure activity through behavioral and EEG recordings and employed multi-omic analyses, including tissue and single-cell level transcriptomics, ultrastructural analysis, proteomics, and lipidomics, to capture a comprehensive view of molecular and cellular changes. Our results showed that after an initial period of neonatal spasms, Cyfip2 + /R87C mice entered a seizure-free phase, followed by spontaneous recurrent seizures in adulthood, ultimately leading to premature death. This progression was associated with synaptic remodeling, sequential activation of different glial cell types, lipid droplet accumulation in astrocytes, and significant proteomic and lipidomic changes in the brain. These findings suggest that seizure evolution in West syndrome involves complex, time-dependent interactions between neurons and glial cells, along with alterations in lipid metabolism. Our study highlights the potential of longitudinal multi-omic approaches to uncover underlying mechanisms of seizure evolution and suggests that targeting these changes could offer novel therapeutic strategies. Additionally, the dataset generated here may provide valuable insights for other epilepsy and neurodevelopmental disorder models.

Christel Depienne, Eric LeGuern and colleagues report the identification of 5 de novo missense mutations in HCN1 in individuals with early-onset epileptic encephalopathy. Functional studies confirmed the pathogenic nature of these mutations. Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels contribute to cationic I h current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of I h currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms. Mouse models of CDKL5 deficiency disorder (CDD) recapitulate multiple clinical symptoms of CDD, such as intellectual disability and autism. Here, the authors show that selective loss of CDKL5 from GABAergic neurons leads to social deficits and stereotypic behaviors, which can be ameliorated through inhibition of NMDAR signaling.

De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.

This single-center study aims to determine the time, diagnostic procedure, and cost saving potential of early exome sequencing in a cohort of 111 individuals with genetically confirmed neurodevelopmental disorders. We retrospectively collected data regarding diagnostic time points and procedures from the individuals’ medical histories and developed criteria for classifying diagnostic procedures in terms of requirement, followed by a cost allocation. All genetic variants were re-evaluated according to ACMG recommendations and considering the individuals’ phenotype. Individuals who developed first symptoms of their underlying genetic disorder when Next Generation Sequencing (NGS) diagnostics were already available received a diagnosis significantly faster than individuals with first symptoms before this cutoff. The largest amount of potentially dispensable diagnostics was found in genetic, metabolic, and cranial magnetic resonance imaging examinations. Out of 407 performed genetic examinations, 296 (72.7%) were classified as potentially dispensable. The same applied to 36 (27.9%) of 129 cranial magnetic resonance imaging and 111 (31.8%) of 349 metabolic examinations. Dispensable genetic examinations accounted 302,947.07€ (90.2%) of the total 335,837.49€ in potentially savable costs in this cohort. The remaining 32,890.42€ (9.8%) are related to non-required metabolic and cranial magnetic resonance imaging diagnostics. On average, the total potentially savable costs in our study amount to €3,025.56 per individual. Cost savings by first tier exome sequencing lie primarily in genetic, metabolic, and cMRI testing in this German cohort, underscoring the utility of performing exome sequencing at the beginning of the diagnostic pathway and the potential for saving diagnostic costs and time.

Johannes Lemke, Holger Lerche and colleagues report the identification of de novo mutations in the potassium channel gene KCNA2 in patients with epileptic encephalopathies. The authors confirm in vitro that two mutations cause dominant loss of channel function, whereas the other two mutations induce gain-of-function effects, leading to permanently open channels. Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features 1 , 2 , 3 , 4 , 5 , 6 . Using next-generation sequencing, we identified four different de novo mutations in KCNA2 , encoding the potassium channel K V 1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of K V 1.2-expressing neurons.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs ( P  = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant ( P  = 2.04 × 10 −6 ) enrichment of damaging de novo mutations in NF1 , a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders. Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.