Developmental And Epileptic Encephalopathy Research Articles

Sensory-Motor Polyneuropathy in an 11-year- old Girl with a Pathogenic Variant in SMC1A: A Case Report.

Pathogenic variants in the SMC1A gene are often dominant-negative and cause an X-linked form of Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features. However, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Here we describe an 11-year-old girl with epilepsy, walking disorder, and neurodevelopmental disorder. A neurophysiological examination of nerve conduction velocity showed a mixed, sensory-motor, chronic 4-limb polyneuropathy. Whole-exome sequencing identified the variant c.3145C > T p.(Arg1049*) in SMC1A (NM_006306.3), which can be classified as pathogenic. To the best of our knowledge, among 79 individuals with SMC1A-related DEE reported in the literature, altered peripheral nerve conduction has never been described. In this article, we propose that severe sensory-motor polyneuropathy could be an expansion of the SMC1A-related phenotype.

Developmental and Epileptic Encephalopathies: Need for Bridging the Gaps Between Clinical Syndromes and Underlying Genetic Etiologies.

Advancement in genetic testing has become increasingly important in diagnosing and managing developmental and epileptic encephalopathies (DEEs), a group of rare neurodevelopmental disorders characterized by early-onset seizures, developmental delay, and electroencephalographic (EEG) abnormalities. These early epileptic encephalopathies are often described as various syndromes as per their clearly defined, relatively uniform, and distinct clinical phenotypes with consistent EEG and/or neuroimaging findings. Finding the underlying molecular mechanisms can cause a definitive change in the management strategy. With the evolving overlapping phenotypes, advent of technologies, and discovery of new genes, it is exceedingly becoming challenging to correctly characterise these disorders and plan subsequent evidence-based management. Cytogenetic microarray (CMA) and next generation sequencing (NGS) with improved data analysis pipe-lines and algorithms have revamped the diagnostic yield dramatically. However, as of now, there is a big lacuna in step-wise evaluation guideline or consensus on integration of genetic testing results with management plan. Understanding the genetic etiologies of such syndromes timely has three major implications: (1) Knowing the outcome of such a syndrome, (2) Therapeutic implications including licensing of drugs for certain forms (e.g. genetic syndromes involving ion channels) and (3) Genetic counseling, prenatal testing and choosing reproductive options in future pregnancies in such families. The focus of this review is to provide an understanding of different types of causative variants and their step-wise genetic testing approach; the most pressing clinical need and to develop an optimal diagnostic pathway for this group of patients.

SLC2A1 variants cause late-onset epilepsy and the genetic-dependent stage feature

BackgroundThe SLC2A1 gene plays a vital role in brain energy metabolism. SLC2A1 variants have been reported to be associated with early-onset refractory seizures. This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.MethodsTrios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies. The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsA total of 14 heterozygous SLC2A1 variants were identified in 16 unrelated families. The variants were evaluated as “pathogenic” or “likely pathogenic” according to the ACMG guidelines. Ten cases (62.5%) presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy (DEE). The other six cases (37.5%) exhibited late-onset seizures and normal development. They were diagnosed with idiopathic partial epilepsy (n = 2) or idiopathic generalized epilepsy (n = 4). Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region, whereas the mild epilepsy-associated variants tended to locate in regions outside the transmembrane region, suggesting a potential molecular sub-regional effect. A total of 15 cases had delayed diagnosis, with the longest delay being 22 years. The SLC2A1 expression stage, which is expressed at relatively high level throughout the whole life span, from the embryonic to adult stages with two peaks at approximately four and 14 years, is generally consistent with the seizure onset age. In addition, patients with early-onset age had variants that were potentially associated with severe damage, suggesting a potential correlation between the age of disease onset and the damaging effects of the variants.ConclusionsSLC2A1 variants are associated with late-onset epilepsy, which is consistent with the genetic-dependent stage feature of SLC2A1. Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).

To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932-943.

Antisense oligonucleotides as a precision therapy for developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) comprise a complex spectrum of neurological disorders characterized by neurodevelopmental delay and early-onset seizures primarily caused by diverse genetic mutations. Traditional treatments have largely been symptomatic, focusing on seizure control without addressing the underlying genetic causes. The advent of gene therapy, particularly through antisense oligonucleotides (ASOs), offers a promising avenue toward targeted therapeutic interventions. ASOs by virtue of their ability to modulate gene expression at the mRNA level represent a sophisticated approach to counteract the effects of pathogenic mutations. This review delves into the recent advancements in ASO technology, highlighting its application in preclinical and clinical settings for DEEs. We present evidence of the efficacy of ASOs in ameliorating disease phenotypes invitro and invivo, alongside promising outcomes from ongoing clinical trials. The therapeutic landscape for DEEs is on the cusp of significant transformation, underscored by the potential of ASOs to offer precise, personalized, treatments that extend beyond symptomatic relief to potentially rectify the genetic underpinnings of these disorders.

Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.

Developmental and epileptic encephalopathies (DEEs) can result from dominant, gain of function variants of neuronal ion channels. More than 450 de novo missense variants of the sodium channel gene SCN8A have been identified in individuals with DEE. We studied a mouse model carrying the patient Scn8a variant p.Asn1768Asp. An AAV-PHP.eB virus carrying an allele-specific single guide RNA (sgRNA) was administered by intracerebroventricular injection. Cas9 was provided by an inherited transgene. Allele-specific disruption of the reading frame of the pathogenic transcript generated out-of-frame indels in 1/4 to 1/3 of transcripts throughout the brain. This editing efficiency was sufficient to rescue lethality and seizures. Neuronal hyperexcitability was reduced in cells expressing the virus. The data demonstrate efficient allele-specific editing of a dominant missense variant and support the feasibility of allele-specific therapy for DEE epilepsy. ANN NEUROL 2024;96:958-969.

Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ families

Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR=1.39, 95% CI 1.08, 1.80, padj=0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of+0.19 higher than relatives with a milder phenotype (padj=0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj=0.0010), the effect was not significant for SCN1B p.Cys121Trp. We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Two familial cases of infantile epileptic spasms syndrome associated with UDP-glucose-6-dehydrogenase deficiency.

Developmental and epileptic encephalopathies (DEEs) are severe forms of epilepsy characterized by seizure onset in infancy or childhood. The seizures are typically drug-resistant and often accompanied by significant alterations in the electroencephalogram (EEG). DEEs are associated with neurodevelopmental impairment, which can arise from both the epileptic activity itself and the underlying etiology, which is most often genetic in origin. We present the clinical and molecular features of two patients with DEE associated with a pathogenic variant in the UGDH gene. This gene encodes a protein that converts uridine diphosphate (UDP)-glucose into UDP-glucuronate, which plays a crucial role in the biosynthesis of glycosaminoglycans, essential components of the connective tissue and extracellular matrix. Both patients started with epileptic spasms associated with a pattern of hypsarrhythmia in the EEG at 4 months of age. Both developed global developmental delay and the physical examination revealed hypotonia and mildly dysmorphic features. In both families, there was another affected sibling with a similar clinical presentation, although genetic studies were not performed in one of these children. A homozygous pathogenic variant in the UGDH gene, NM_003359.4:c.131C>T - p.(Ala44Val), previously reported to be associated with the described phenotype, was identified.

Voltage-Gated Ion Channel Compensatory Effect in DEE: Implications for Future Therapies.

Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over 100 types of DEEs. In this context, genes encoding voltage-gated ion channels (VGCs) play a significant role, and part of the large phenotypic variability observed in DEE patients carrying VGC mutations could be explained by the presence of genetic modifier alleles that can compensate for these mutations. This review will focus on the current knowledge of the compensatory effect of DEE-associated voltage-gated ion channels and their therapeutic implications in DEE. We will enter into detailed considerations regarding the sodium channels SCN1A, SCN2A, and SCN8A; the potassium channels KCNA1, KCNQ2, and KCNT1; and the calcium channels CACNA1A and CACNA1G.

Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.

SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in excitatory and inhibitory neurons, yet previous studies primarily focus on how SCN8A mutations affect excitatory neurons, with limited studies on the importance of inhibitory interneurons. Parvalbumin (PV) interneurons are a prominent inhibitory interneuron subtype that expresses Nav1.6. To assess PV interneuron function within SCN8A DEE, we used 2 mouse models harboring patient-derived SCN8A gain-of-function variants, Scn8aD/+, where the SCN8A variant N1768D is expressed globally, and Scn8aW/+-PV, where the SCN8A variant R1872W is selectively expressed in PV interneurons. Expression of the R1872W SCN8A variant selectively in PV interneurons led to development of spontaneous seizures and seizure-induced death. Electrophysiology studies showed that Scn8aD/+ and Scn8aW/+-PV interneurons were susceptible to depolarization block and exhibited increased persistent sodium current. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed synaptic transmission deficits in Scn8aD/+ and Scn8aW/+-PV interneurons. Together, our findings indicate that PV interneuron failure via depolarization block along with inhibitory synaptic impairment likely elicits an overall inhibitory reduction in SCN8A DEE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.

Independent Occurrence of Two Cases of Lennox — Gastaut Syndrome and Neurofibromatosis in the Family: A Clinical Observation

Developmental and epileptic encephalopathies (DEE) are the most difficult problem in epileptology. Lennox — Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with onset in childhood, manifested by: frequent polymorphic seizures, including tonic axial ones; severe cognitive impairment; slow activity (with a frequency of <2.5–3.0 Hz) sharp-slow wave in the interictal period on the electroencephalogram, as well as runs of fast activity with a frequency of 10–20 Hz, often associated with tonic seizures; and resistance to therapy. Presumably genetic or forms with an unknown cause account for 20–30 % of cases of LGS, but a family history of epilepsy among patients with LGS is observed in only 2.5 %.The purpose of this work was to describe a familial case of LGS in two siblings.Materials and methods. A retrospective description of the medical history of 3 siblings born in a consanguineous marriage was performed.Results and discussion. There was a similarity in the course of the disease in the two brothers, absolute resistance to drug antiepileptic therapy and temporary effectiveness of hormonal therapy for LGS with a decrease in the duration of the effect from course to course. In addition, the rare parallel existence in this family of another autosomal dominant disease — neurofibromatosis type 1 — is shown.Conclusion. A detailed description of LGS within one family will not only expand doctors’ knowledge of this disease and the difficulties of its treatment, but also improve understanding of the genetic mechanisms of the development of DEE.

Early mortality in STXBP1-related disorders.

Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1-related disorders. Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13years (range: 11months-46years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes (p = 0.018). We found a mortality rate in STXBP1-related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1-related disorders and implement preventative strategies.

Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons

More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons.

More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Uncovering etiologic genes through whole exome sequencing in pediatric epilepsy: A case series from Thailand

Introduction Developmental and epileptic encephalopathy (DEE) is characterized by seizures that are difficult to control for a long time and affect development in children who are previously normal or delayed. Therefore, children with DEE should be diagnosed promptly because certain types of the disease respond well to specific medications. In developing countries with limited universal coverage for whole exome sequencing (WES), identifying key clinical features in this patient group will help us make more accurate selections for investigations. The purpose of this study was to determine the prevalence of WES and its common clinical features in children with epileptic encephalopathy. Methods Ten volunteers aged 0-15 years were diagnosed with epilepsy with two or more symptoms of drug-resistant epilepsy, developmental delays, and abnormal nervous system/or dysmorphic features, and their electroencephalogram (EEG) showed abnormal background or specific patterns of epileptiform discharges. These were subjected to WES for the standard > 400 genes in the epilepsy panel. Results The established diagnosis was 4/10. Two known pathogenic variants, SCN2A and PCDH19. Two novel pathological variants, CHD2 and SCN1A. These are drug-resistant epilepsy, which is initially difficult to control and cannot stop antiseizure medications. Out of the 2/4 had moderate to severe intellectual disability. 3/4 had generalized epileptiform discharge activities. Conclusions This study showed a similar detection rate to that of a previous WES study. All the patients had difficult-to-treat epilepsy. For those who have not found abnormalities with the same clinical symptoms, further examinations using other methods should be conducted.

Impaired axon initial segment structure and function in a model of ARHGEF9 developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies (DEE) are rare but devastating and largely intractable childhood epilepsies. Genetic variants in ARHGEF9, encoding a scaffolding protein important for the organization of the postsynaptic density of inhibitory synapses, are associated with DEE accompanied by complex neurological phenotypes. In a mouse model carrying a patient-derived ARHGEF9 variant associated with severe disease, we observed aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo-axonic synaptic inhibition, disrupted action potential generation, and complex seizure phenotypes consistent with clinical observations. These results illustrate diverse roles of ARHGEF9 that converge on regulation of the structure and function of the AIS, thus revealing a pathological mechanism for ARHGEF9-associated DEE. This unique example of a neuropathological condition associated with multiple AIS dysfunctions may inform strategies for treating neurodevelopmental diseases.

Italian report on RARE epilepsies (i-RARE): A consensus on multidisciplinarity.

Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32-member expert panel, representing diverse regions of Italy, validated these statements through a two-round voting process, with consensus defined as an average score ≥7. Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic-clonic seizures. The importance of early implementation of specific drugs and non-pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non-seizure outcomes in adolescence and adulthood. This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision-making and healthcare policies, ultimately enhancing patients' outcomes. The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high-level epilepsy centers and patients' caregivers were directly involved.

POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic-atonic seizures and ataxia.

POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures. The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants. We used online gene-matching tools to identify 13 patients with de novo POLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas. All 13 patients had novel POLR3B variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic-atonic, atypical absence, or tonic-clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic-atonic seizures (EMAtS) in seven patients and "probable EMAtS" in two more. Seizures were treatment resistant in all cases. Three patients became seizure-free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset. Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5/9) who tried it; rufinamide (2/3); and ketogenic diet (2/3). Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13). POLR3B is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients.

Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy

AbstractObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.

Unveiling the disease progression in developmental and epileptic encephalopathies: Insights from EEG and neuropsychology.

Developmental and epileptic encephalopathies (DEEs) are neurological disorders characterized by developmental impairment and epilepsy. Our study aims to assess disease progression by comparing clinical findings, electroencephalography (EEG), and neuropsychological data from seizure onset to the last follow-up evaluation. We retrospectively reviewed patients with genetic DEEs who were followed-up at the epilepsy unit of Bambino Gesù Children's Hospital, Rome. We collected information regarding gender, family history, genetic variant, age at onset and at last follow-up, neurological examination, type of seizure, drug resistance, occurrence of status epilepticus, and movement and cognitive and behavioral disorders. We compared EEG background activity, epileptiform abnormalities, and cognitive functions between seizure onset and the last follow-up evaluation using the McNemar-Bowker test (α = 5%). A total of 160 patients (94 female) were included. Genetic analysis revealed a spectrum of pathogenic variants, with SCN1A being the most prevalent (25%). The median age at seizure onset and at the last follow-up was 0.37 (interquartile range [IQR]: 0.09-0.75) and 8.54 years (IQR: 4.32-14.55), respectively. We documented a statistically significant difference in EEG background activity (p = .017) and cognitive impairment (p = .01) from seizure onset to the last follow-up evaluation. No significant differences were detected for epileptiform abnormalities (p = .2). In addition, high prevalence rates were observed for drug resistance (81.9%), movement disorders (60.6%), behavioral and autism spectrum disorders (45%), neurological deficits (31.3%), and occurrence of status epilepticus (23.1%). Our study provides evidence that a clinical progression may appear in genetic DEEs, manifesting as development or worsening of cognitive impairment and disruption of EEG background activity. These results highlight the challenging clinical course and the importance of early intervention and personalized care in the management of patients with DEEs.