Correction: SPOUT1 variants associated with autosomal-recessive developmental and epileptic encephalopathy.

Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an assumed causal relationship between epilepsy and developmental delay. Developmental encephalopathies pathogenesis more independent from epilepsy is supported by the identification of several gene variants associated with both developmental encephalopathies and epilepsy, the possibility for gene-associated developmental encephalopathies without epilepsy, and the continued development of developmental encephalopathies even when seizures are controlled. Hence, 'developmental and epileptic encephalopathy' may be a more appropriate term than epileptic encephalopathy. This update considers the best studied 'developmental and epileptic encephalopathy' gene variants for illustrative support for 'developmental and epileptic encephalopathy' over epileptic encephalopathy. Moreover, the interaction between epilepsy and developmental encephalopathies is considered with respect to influence on treatment decisions. Continued research in genetic testing will increase access to clinical tests, earlier diagnosis, better application of current treatments, and potentially provide new molecular-investigated treatments.

SCN1A-related diseases are a heterogeneous group of disorders with an expanding spectrum of phenotypes. Until recently, mutations in this gene were associated with epileptic syndromes and epileptic and developmental encephalopathy – Dravet syndrome, which was contrasted with a new group of early-onset syndromes, non-Dravet developmental and epileptic encephalopathies (DEEs; OMIM: PS308350). The aim of this paper is to review published data on the phenotypic variability of SCN1A-related developmental and epileptic encephalopathies, particularly non-Dravet syndromes. These are disorders with very early onset, polymorphic, drug-resistant epileptic seizures, impaired psychomotor development and intellectual disability, as well as the presence of additional symptoms such as arthrogryposis, osteopenia, and hyperkinetic movement disorders. Unlike Dravet syndrome, epileptic seizures begin in the first few months of life and may have an epileptic spasm or tonic morphology. The ability to quickly recognise the non-Dravet developmental and epileptic encephalopathy is of significant clinical value, because the identification of pathogenic SCN1A variants and their functional evaluation have an impact on both treatment and prognosis. Studies on the aetiology of non-Dravet developmental and epileptic encephalopathies have shown that pathogenic variants of the gain of function (GOF) type are identified in these patients. Therefore, it is possible to treat such patients with medicaments from the group of sodium channel blockers, which were contraindicated in cases of loss of function (LOF) variants, occurring in Dravet syndrome.

Introduction. The problem of early diagnostics of orphan diseases is relevant for most countries of the world. The challenge for healthcare is to prevent new cases of orphan diseases by providing medical genetic testing and counseling at the stage of family planning. Department of psychoneurology of the State Intstitution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine" has been dealing with the problem of orphan diseases since 2012 and has significant experience in their diagnosis and treatment in children.The aim of paper: to develop an algorithm for the genetic diagnosis of epileptic and developmental encephalopathies in children with developmental delay and dimorphic features based on modern data on the application and interpretation of genetic methods. A case which demonstrate the complexity of interpreting the results and algorithms for early diagnosis of patients and the importance of medical and genetic counseling is presentedMaterial and methods: clinical and neurological examination, sleep video-EEG monitoring during night sleep, brain magnetic resonance imaging (3.0T), whole-exome sequencing (WES).Results. The article presents the algorithm of genetic diagnosis of orphan diseases in children with developmental and epileptic encephalopathies, developmental delay, and dimorphic features. A clinical case of a boy with general developmental delay and atonic epileptic seizures is presented. Sleep EEG-monitoring showed epileptiform activity in the stage of slow-wave sleep localized in the central-parietal and left temporal areas in the form of benign childhood epileptiform patterns.Whole-exome sequencing detected a variant of uncertain significance (VUS) c.5887C>T(p.Arg1963Cys) of SON gene in a heterozygous state, which leads to the replacement of arginine to cysteine. Mutations in the SON gene in the heterozygous state have been described in patients with Zhu-Tokita-Takenouchi-Kim syndrome (OMIM: 617140).Conclusions: It is important for pediatricians and neurologists to be aware of orphan diseases in children with developmental and epileptic encephalopaties and developmental delay. Genetic tests are wide available but they require competent interpretation by clinicists. After obtaining the results, it is important to compare the obtained result with the phenotype of patient. In case the phenotype of patient match and the results of genetic test, (detected VUS) this mutation could be etiological factor of the disease. In our case, the clinical signs coincided with those described in 2015 by the authors of the first description of Zhu-Tokita-Takenuchi-Kim syndrome, and therefore genetic testing helped to verify the final diagnosis. Therefore genetic counseling is extremely important for detection of etiology and prognosis of early developmental and epileptic encephalopathies/

ObjectiveTo assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non‐Dravet refractory developmental and epileptic encephalopathies (DREEs).MethodsRetrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non‐Dravet subgroups.ResultsA total of 82 patients (55 Dravet syndrome and 27 non‐Dravet DREE) were included. Median age was 5 years (range 1–59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6–6] months) than non‐Dravet (17.9 [6–42.3], P < 0.001). Median follow‐up time STP was 24.1 months (2 years; range 0.3–164 months) and was longer in the Dravet group (35.9 months; range 0.8–164) than non‐Dravet (17 months range 0.3–62.3, P < 0.001). At 12 months, retention rate, responder rate and seizure free rate was 68.3% (56/82), 65% [48–77%] and 18% [5.7–29%], respectively. There were no statistically significant differences between groups on these seizure outcomes. Adverse events were reported in 46.3% of patients (38/82), without differences between groups.SignificanceIn this population of patients with epileptic and developmental encephalopathies, outcomes with adjunctive STP were similar in patients with non‐Dravet DREE to patients with Dravet syndrome.

The term "developmental and epileptic encephalopathy" (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non-progressive diseases with cognitive impairment and co-existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term "developmental encephalopathy" (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term "epileptic encephalopathy" (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.

The aim is to analyze neuroimaging changes in the nervous system of children of an early and preschool age with epileptic encephalopathies (EE) according to MR-tractography to improve the diagnosis of these conditions. Materials and methods. 157 children aged 0 to 6 years with EE, epileptiform and developmental encephalopathies (DEE) were examined. The study included MR-tractography using a 3 Tesla MR scanner. Fractional anisotropy (FA) and average diffusion coefficient (ADC) were determined in Broca's and Wernicke's areas, left arcuate tract, both uncinate tracts, corpus callosum and thalamus. The examined children were divided into 3 groups: I - 75 children with EE, with the onset of seizures before 1 year of age; II - 44 children with EE, with the onset of seizures at the age of 1-3 years; III - 38 children with DEE. Differences between groups were assessed using the Kruskal-Wallis test and Pearson's Chi-square (χ²) test. Results. In children with EE from groups I and II, there was a significant decrease in FA and an increase in ADC in the areas of both language centers and the right uncinate tract in comparison with children of group III (p&lt;0.05). In the group I with EE, there was a significant decrease in FA in the left uncinate tract, knee and trunk of the MT in comparison with the groups II and III of children (p&lt;0.05). It was found that more than 60% of children from group I had destruction of the fibers of the arcuate tract and in the area of one of the speech centers, and 70% had hypoplasia and destruction of the left uncinate tract. In the children of group II with EE, hypoplasia of the anterior (63.6%) and posterior (65.9%) parts of the arcuate tract and the right uncinate tract (81.8%) was detected. Among children from group III, more than 60% had an abnormal location of Broca's speech center, and more than 70 % had an abnormal location of Wernicke's center, almost 80 % had an abnormal location of the left uncinate tract. Conclusions. It was found that in children with EE and DEE, according to MR tractography, there is a decrease in FA indicators and an increase in ADC in all studied structures (arcuate and uncinate tract, corpus callosum, thalamus) in comparison with the reference values given in the scientific literature. The detected changes indicate a violation of the structural integrity of the white matter in Broca's and Wernicke's centers and associative pathways, which will lead to the optimization of early diagnosis and prognosis of consequences in children with EE and DEE. The study was carried out in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committees of the institutions indicated in the work. The informed consent of the children's parents was obtained for conducting the research. No conflict of interest was declared by the authors.

Phenotypic and genetic spectrum in Chinese children with SCN8A-related disorders

Developmental and epileptic encephalopathies: Is prognosis related to different epileptic network dysfunctions?

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

KCNT1-Related Epilepsies and Epileptic Encephalopathies: Phenotypic and Mutational Spectrum Bonardi CM, Heyne HO, Fiannacca M, et al. Brain. 2021;144(12): 3635-3650. doi:10.1093/brain/awab219.Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioral/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic–clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype–phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Developmental and epileptic encephalopathy (DEE) is epilepsy related to developmental impairment that may be caused by both the underlying etiology (developmental encephalopathy) and superimposed epileptic activity (epileptic encephalopathy). The origin of DEE and the causes of its variations remain unknown. Owing the lack of clarity regarding the role of genetic variables in DEE, we conducted a scoping review to qualitatively identify the genes most important in the development of DEE to provide an up-to-date review. We searched all published studies related to the genetic factors of DEE. The identified publications were screened and selected by the authors on basis of on inclusion and exclusion criteria and assessed for methodological quality. Eighteen articles were included. The extracted data included age of onset, sex, gene mutations and inheritance (e.g. nucleotide change, protein change, and family testing), clinical manifestation, electroencephalogram, imaging, medication, and outcomes. A total of 18 studies were included in this scoping review. The most frequently reported gene variants were STXBP1 in Ohtahara Syndrome, SLC1A2 in Early Myoclonic Encephalopathy (EME), CDKL5 in West Syndrome, SCN1A in Dravet Syndrome, and KCNT1 in Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Each gene was associated with distinct electroclinical features, including differences in age of onset, seizure type, EEG patterns, and developmental outcomes. While genotype and phenotype associations were heterogeneous, certain variants showed consistent patterns indicative of more severe disease courses. This review identified key gene variants commonly associated with early-onset DEE in infants, particularly STXBP1, SLC1A2, CDKL5, SCN1A, and KCNT1, each linked to unique clinical presentations and outcomes. These findings support the clinical utility of next-generation sequencing (NGS) for early diagnosis and tailored treatment planning in DEE. Understanding genotype-phenotype correlations may enhance prognostication and highlight potential avenues for targeted therapy in future research.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy. CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants. We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10). Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.

ObjectiveTo analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy‐causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype‐phenotype‐physiological correlations.MethodsTen cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole‐exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two‐electrode voltage clamping were used.ResultsSix unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole‐cell current, but no dominant‐negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole‐cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance.InterpretationThese are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.