Early mortality in STXBP1-related disorders.

INTRODUCTION: 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. METHODS: Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. RESULTS: 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 13 years (range: 11 months-46 years). 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). CONCLUSION: 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.

A roadmap to cure CHD2-related disorders.

Coalition to Cure CHD2 (CCC) is a patient advocacy group dedicated to improving the lives of those affected by CHD2-related disorders (CHD2-RD) by increasing education, building community, and accelerating research to uncover a cure. CHD2 is a chromatin remodeler that was identified in 2013 as being a genetic cause for developmental and epileptic encephalopathies. Pathogenic changes in CHD2 can cause treatment-resistant epilepsy, intellectual and developmental delays, and autism, and some individuals experience neurodevelopmental regression. There are currently no targeted therapies available for CHD2-related disorders. Haploinsufficiency of CHD2 is a causative mechanism of disease for individuals with pathogenic variants (primarily truncating) in CHD2. Recently, identification of individuals with deletion of nearby gene CHASERR, a regulator of CHD2 gene expression, has established dosage sensitivity in CHD2 and solidified the CHASERR gene as a potential therapeutic target for CHD2 levels. Through collaboration with our community and our scientific advisory board, CCC has created a Roadmap to Cure CHD2 as our guide toward a targeted cure that can benefit our community, with steps including (1) identifying and defining patients, (2) developing models of CHD2, (3) studying models of CHD2, (4) testing therapies, (5) involving patients, and (6) reaching a cure. Despite some of the challenges inherent in CHD2 research including establishing animal and cellular models that recapitulate the CHD2 clinical phenotype, identifying measurable outcomes and reliable biomarkers, or testing emerging therapeutic approaches, CCC continues to engage with our community to support ongoing research that aligns with our priorities. CCC sees new and exciting opportunities for additional research that can move our community toward our common goal of a cure that will improve the lives of individuals and their families now and in the future.

A roadmap to cure disorders caused by the CHD2 and CHASERR genes Coalition to Cure CHD2 (CCC) is a nonprofit founded in October 2020 to fund research towards a cure for individuals with CHD2-related disorders. The CHD2 gene was discovered as a genetic cause for epilepsy in 2013. Individuals with CHD2 typically experience seizures that can be resistant to treatment, intellectual disability, delayed development, autism, and other symptoms. The nearby CHASERR gene has been found to regulate CHD2 and is a possible therapeutic target. Individuals with a deletion of CHASERR have been identified - these individuals have too much CHD2 and more severe symptoms. CCC has created a Roadmap to Cure CHD2 as a guide for their journey towards a targeted cure for CHD2-related disorders. The steps in the roadmap include: (1) identify and define patients, (2) develop models of CHD2, (3) study models of CHD2, (4) test therapies, (5) involve patients, (6) reach a cure. CCC has worked with CHD2 families to identify family-level priorities for therapeutic development (e.g. seizures, behavior, etc), to capture the impact of disease through qualitative research, and to collect patient health data and tissue samples for scientific analysis. The development of CHD2 models, mouse models in particular, has been challenging as the mice do not develop seizures. Additional models are underway including frogs, zebrafish, and patient-derived cells. These models have provided crucial insight into the biology of CHD2 but scientific questions remain unanswered. A variety of therapeutic approaches have been proposed including novel treatments that directly target CHD2 biology as well as the repurposing of existing FDA-approved compounds. Establishing measurable outcomes, including biomarkers, and finding treatments that can reach the brain will be important. By continuing to follow this roadmap, the CCC believes that one day there will be a cure for CHD2-related disorders.

Similarity of Phenotype in Three Male Patients With the c.320A>G Variant in ALG13: Possible Genotype-Phenotype Correlation.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of neurometabolic diseases that result from genetic defects in the glycosylation of proteins and/or lipids. Multiple pathogenic genes contribute to the varying reported phenotypes of individuals with CDG-1 syndromes, most of which are inherited as autosomal recessive traits, although X-linked inheritance has also been reported. Pathogenic variants in the asparagine-linked glycosylation 13 homolog (ALG13) gene have been implicated in the aetiology of developmental and epileptic encephalopathy (DEE) 36 (OMIM:*300776, DEE36). The NM_001099922.3:c.320A>G; p.(Asn107Ser) variant is the most frequently described pathogenic variant in ALG13, with 59 females and 2 males with this variant reported to date. METHODS: We report on a male with a de novo, hemizygous variant in ALG13: c.320A>G; p.(Asn107Ser), whose phenotype resembles that of two previously reported males with the same variant. RESULTS: All three males have a de novo mutation, infantile spasms, DEE, drug-resistant epilepsy, intellectual disability, dysmorphic findings, recurrent infections, skeletal anomalies, brain abnormalities and a movement disorder: a phenotype not consistently reported in males with other pathogenic variants in ALG13. CONCLUSION: The similarity of phenotype in the three males with the c.320A>G variant in ALG13, suggests a possible genotype-phenotype correlation.

Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance.

Neonatal intensive care unit (NICU), particularly in treating developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep understanding of their complex etiologies and treatment responses. After excluding treatable cases such as infectious or autoimmune encephalitis, our focus shifted to a more challenging subgroup of 59 patients for in-depth genetic analysis using exome sequencing (ES). The ES analysis identified 40 genetic abnormalities, significantly including de novo variants. Notably, we found structural variation as duplications in regions 2q24.3, including SCN1A and SCN2A were observed in 7 cases. These genetic variants, impacting ion channels, glucose transport, transcription regulation, and kinases, play a crucial role in determining medication efficacy. More than one-third (34.2%) of patients with DEE had an unfavorable response to anti-seizure medications (ASMs) in the chronic phase. However, since the ketogenic supplementary diet showed a positive effect, more than three-quarters (80%) of these drug-resistant patients improved during a 3-month follow-up. In contrast, the ME had a lower adverse reaction rate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and 10 cases with unidentified genetic etiologies. This study suggests the potential of categorizing drug-resistant variants and that a ketogenic diet could be beneficial in managing DEE and ME. It also opens new perspectives on the mechanisms of the ketogenic diet on the discovered genetic variants.

A Case Series of Novel Monogenic Abnormalities Associated With Developmental Epileptic Encephalopathy With Spike-and-Wave Activation in Sleep.

BACKGROUND: Developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) is a rare neurodevelopmental spectrum of disorders marked by regression associated with spike-and-wave activation in sleep. METHODS: As roughly 10% have a related genetic underpinning, we sought to describe narrative clinical histories of four patients at a single academic medical center with monogenic variants associated with DEE-SWAS. In sharing this case series, we aim to build on recent work investigating genetic DEE-SWAS. RESULTS: Findings from this case series not only aid in accurate diagnosis and prognosis for our patients but also may provide potential targets for future therapeutic interventions. CONCLUSIONS: This natural history case series also highlights the difficulty in differentiating genetic phenotype from the effects of DEE-SWAS.

The small steps that lead to big impact: translating therapeutics from idea to reality for the CDKL5 deficiency disorder community.

Despite the unmet needs of patients living with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and the challenges facing a rare population with small patient numbers, now is a time of unprecedented opportunities to turn scientific breakthroughs into safe and effective treatments for families of CDD patients. New data collected for over a decade and an evolution in genetics technologies have resulted in transformational new treatments currently in development for CDD. This progress is in great part due to the patient advocacy efforts early on to drive development of stakeholder research tools necessary to de-risk industry entry into the CDD space, family participation in longitudinal natural history studies, and a robust caregiver-reported database. Cumulatively, these efforts offered new insights into CDD, specifically patterns in disease progression, helped identify the most burdensome symptoms to patients and caregivers, improved clinical trial design, and reduced financial barriers for therapeutic development for potential industry partners. This paper documents the growth of a small patient community through relationship building and collaboration. The International Foundation for CDKL5 Research is mindful of ongoing challenges namely the long research timelines, high development and production costs, and inequitable access to approved therapies. Therefore, sustaining strong early resources while recognizing opportunities that engagement, advocacy, and funding can accelerate progress remains at the heart of the agile foundation strategy.

Recognizing inflection points throughout the growth of a patient advocacy group: remaining mission focused while pivoting to achieve foundation goals Effectively operating a rare disease patient advocacy foundation presents obstacles that are difficult to anticipate, yet there is silver lining in learning from opportunities lost to regroup and refocus on our mission. The IFCR initially formed to drive research forward and support families while fostering new scientists to study the disorder. This remains the core objective and the organization has successfully contributed to the development of a robust CDD community and important research assets to facilitated research progress. On the heels of the first approved treatment for CDD, we find ourselves contemplating our future in a much different light, asking propelling questions and making tough decisions. Given the constraints that most rare disease communities face, how can we best use limited resources? How can we partner with others to realize timely progress? What gaps exist that require CDD family thought leadership and engagement along the continuum of drug development? Reflecting on past years, it is remarkable how fast science is moving. Genetic therapies are under early development for CDKL5 Deficiency Disorder. We must prepare for any future we are afforded to trial disease-modifying treatments. Multistakeholder engagement is required pre-clinically, during clinical trials and post approval.

Factors associated with poor sleep in children with drug-resistant epilepsy.

OBJECTIVE: We aimed to investigate sleep in children with drug-resistant epilepsy (DRE), including developmental and epileptic encephalopathies (DEEs). Next, we examined differences in sleep macrostructure and microstructure and questionnaire outcomes between children with well-controlled epilepsy (WCE) and children with DRE. Furthermore, we wanted to identify factors associated with poor sleep outcome in these children, as some factors might be targets to improve epilepsy and neurodevelopmental outcomes. METHODS: A cross-sectional study was conducted in children 4 to 18-years-old. Children without epilepsy, with WCE, and with DRE were included. Overnight electroencephalography (EEG), including chin electromyography and electrooculography, to allow sleep staging, was performed. Parents were asked to fill out a sleep questionnaire. Classical five-stage sleep scoring was performed manually, spindles were automatically counted, and slow wave activity (SWA) in the first and last hour of slow wave sleep was calculated. RESULTS: One hundred eighty-two patients were included: 48 without epilepsy, 75 with WCE, and 59 with DRE. We found that children with DRE have significantly lower sleep efficiency (SE%), less time spent in rapid eye movement (REM) sleep, fewer sleep spindles, and a lower SWA decline over the night compared to children with WCE. Subjectively more severe sleep problems were reported by the caregivers and more daytime sleepiness was present in children with DRE. Least absolute shrinkage and selection operator (LASSO) regression showed that multifocal interictal epileptiform discharges (IEDs), benzodiazepine treatment, and longer duration of epilepsy were associated with lower SE% and lower REM sleep time. The presence of multifocal discharges and cerebral palsy was associated with fewer spindles. Benzodiazepine treatment, drug resistance, seizures during sleep, intellectual disability, and older age were associated with lower SWA decline. SIGNIFICANCE: Both sleep macrostructure and microstructure are severely impacted in children with DRE, including those with DEEs. Epilepsy parameters play a distinct role in the disruption REM sleep, spindle count, and SWA decline.

The long odyssey for the DEE-CDKL5 diagnosis: A call for action.

OBJECTIVES: This study aims to determine the current state of CDD diagnosis and epilepsy treatment in an upper-middle-income country. METHODS: Forty-seven families of the Brazilian CDD Association were invited to participate in an online survey to gather information about the diagnosis and treatment of epilepsy. RESULTS: Forty-three families (91.5%) of unrelated patients with confirmed genetic diagnosis of CDD participated. The median age was 7 years (ranging from 1.3-25 years) and the male: female ratio was 1:6. Early and severe epilepsy started during infancy in 74.4%. Seizures occurred daily in 61.9% and 83.7% had clusters of seizures. The mean age of diagnosis was 3.3 years (ranging from 37 days to 16 years), and younger patients had an earlier diagnosis (p < 0.001). Patients were seen by an average of 4.4 physicians (1-15) before the diagnosis. The most relevant obstacles to genetic testing were cost (55.8%) and late requests by physicians (27.9%). At the moment of the assessment, patients received a mean of 3.6 ASMs/day (ranging from 1 to 5). Thirty-four (79.1%) caregivers reported side effects throughout life, including life-threatening events in 16.3%. SIGNIFICANCE: Based on our findings, a sense of urgency for genetic assessment implementation is evident since the delay in the diagnosis with unnecessary use of resources and excessive polytherapy with serious side effects cause a higher burden to the healthcare system, caregivers, and patients. PLAIN LANGUAGE SUMMARY: In this study, we assessed the diagnosis and treatment of patients with genetically confirmed DEE-CDKL5 from the Brazilian Association of CDD with an online survey. Caregivers reported a long delay in the diagnosis associated with cost and late referral to genetic testing, considered the last resource for one-third of the patients. Patients received a high number of ASM, mainly under polytherapy, with serious side effects. Although it is promising that younger patients received earlier diagnosis, public policies for genetic testing are needed to improve CDD patients' care.

Unraveling neuroimaging insights in developmental epileptic encephalopathy type 25: a comprehensive review of reported cases and a novel SLC13A5 variant.

Developmental and epileptic encephalopathy type 25 with amelogenesis imperfecta (DEE25) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous disease-causing variants in the SLC13A5. These variants can disrupt energy production and delay brain development, leading to DEE25. Key symptoms include refractory seizures, often manifesting in neonates or infants, alongside global developmental delay, intellectual disability, progressive microcephaly, ataxia, spasticity, and speech difficulties. Dental anomalies related to amelogenesis imperfecta are common. Previous studies have typically reported normal or minimally altered early-life brain magnetic resonance imaging (MRI) findings in DEE25. However, our investigation identified a homozygous splice donor variant (NM_177550.5: c.1437 + 1G >T) in SLC13A5 through whole-exome sequencing in two affected siblings (P1 and P2). They displayed developmental delay, cerebral hypotonia, speech delay, recurrent seizures, mild but constant microcephaly, and motor impairments. Significantly, P1 exhibited novel findings on brain magnetic resonance imaging at age 5, including previously unreported extensive persistent hypomyelination. Meanwhile, P2 showed substantial loss of cerebral white matter in the frontoparietal region and delayed myelination at 18 months old. These discoveries broaden the DEE25 imaging spectrum and highlight the clinical heterogeneity even within siblings sharing the same variants.

Electroencephalographic Patterns on Follow-Up Visits in Extremely Premature Infants With Periventricular Leukomalacia: An Observational Study.

BACKGROUND: Periventricular leukomalacia (PVL) is a common brain injury in premature infants, and epilepsy remains a significant complication. One concerning electroencephalographic (EEG) pattern found is developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This pattern is associated with persistent neuropsychological and motor deficits, even without a diagnosis of epilepsy. The purpose of this study is to identify the relationships between various PVL grades and EEG patterns in this population on follow-up visits, especially the occurrence of DEE-SWAS pattern on EEG. METHODS: This is a retrospective study of <36 weeks gestational age newborns who were followed in the neurodevelopmental clinic at Corewell Health East/Corewell Health Children's Hospital in Royal Oak, Michigan, between 2020 and 2022. Patients' demographics along with prematurity complications, diagnostic head ultrasound (HUS), and EEG studies were reviewed and graded. EEG studies are usually ordered when seizures were suspected. RESULTS: A total of 155 newborns met the inclusion criteria. Twenty-six patients had PVL. Nine patients had grade 2 to 3 PVL based on HUS review. EEG was performed on 15 patients with PVL at a mean age of 22 months. More severe PVL grades were significantly associated with worse EEG patterns (P = 0.005). Five patients had DEE-SWAS pattern on EEG, all of whom had grade 2 or 3 PVL. Epilepsy was eventually diagnosed in three infants with PVL. CONCLUSIONS: EEG can help identify important abnormal electrographic patterns in premature infants with PVL early in life; this might give a window of opportunity to intervene early and improve long-term developmental outcomes in this population.

The contribution of NaV1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and NaV1.6 gain-of-function (GOF) mouse seizure control.

BACKGROUND AND PURPOSE: Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. EXPERIMENTAL APPROACH: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild-type mice. KEY RESULTS: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. CONCLUSIONS AND IMPLICATIONS: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.

Beyond the Norm: A Report of a Rare Case of Sodium Channel 8 Alpha (SCN8A) Gene-Related Epilepsy Unveiled in a Nine-Year-Old Child.

Sodium channel 8 alpha (SCN8A) mutations encompass a spectrum of epilepsy phenotypes with diverse clinical manifestations, posing diagnostic challenges. We present a case of a nine-year-old male with SCN8A gene-associated developmental and epileptic encephalopathies (DEEs), characterized by generalized tonic-clonic seizures (GTCS) since infancy. Despite treatment with multiple antiepileptic drugs (AEDs), including phenytoin, valproate, levetiracetam, carbamazepine, and clobazam, seizure control remained elusive, prompting genetic testing. Whole exome sequencing confirmed a heterozygous mutation (p.Phe210Ser) in SCN8A exon 6, indicative of DEE-13. Functional studies revealed a gain-of-function mechanism in SCN8A variants, resulting in heightened ion channel activity and altered voltage dependence of activation. Despite treatment adjustments, the patient's seizures persisted until topiramate was introduced, offering partial relief. SCN8A, encoding Nav1.6 sodium channels, modulates neuronal excitability, with mutations leading to increased persistent currents and hyperexcitability. Early seizure onset and developmental delays are hallmarks of SCN8A-related DEE. This case highlights the significance of genetic testing in refractory epilepsy management, guiding personalized treatment strategies. Sodium channel blockers like phenytoin and carbamazepine are often first-line therapies, while topiramate presents as a potential adjunctive option in SCN8A-related DEE. Overall, this case underscores the diagnostic and therapeutic complexities of managing SCN8A-related epileptic encephalopathy, emphasizing the importance of long-term monitoring and personalized treatment approaches for optimizing outcomes in refractory epilepsy.

Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies.

INTRODUCTION: Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target. AREA COVERED: This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation. EXPERT OPINION: The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin's role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin's mechanisms and potential antiepileptogenic effects.

Successful treatment of epileptic encephalopathy with spike wave activation in sleep with anakinra.

Patients with epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) often display drug-resistant epilepsy. The activation of epileptic activity during sleep is associated temporally with neurocognitive impairment and causes a spectrum of disorders within the epilepsy-aphasia syndrome. The prognosis is dependent on promptness of treatment and etiology. However, there is no clear consensus with regards to the optimal management for patients with EE-SWAS. We queried our Pediatric Epilepsy Outcome-Informatics Project (PEOIP) database for all patients treated with anakinra in our centre. We herein report a case of a female with EE-SWAS, who demonstrated remarkable neurocognitive improvement with anakinra. We suggest that a trial of anakinra may be an option for patients with EE-SWAS due to non-structural and possibly inflammatory etiology.

Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.

BACKGROUND: KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences. METHODS: In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient. RESULTS: A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities. CONCLUSION: Our findings expands the genetic profile of KCNQ2 and enhances the genotype - phenotype link.

Clinical analysis of developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep: A single tertiary care center experience in China.

PURPOSE: To analyze the electroclinical features of patients with developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (DEE/EE-SWAS) and study the efficacy of different therapies on seizure control, electroencephalogram (EEG) improvements of electrical status epilepticus during sleep (ESES), and cognition outcomes. METHODS: Patients with DEE/EE-SWAS who underwent at least one follow-up EEG 3 months after therapy were retrospectively enrolled. The demographic and clinical characteristics of the patients were analyzed. Variables that influenced the outcomes were evaluated using logistic regression models. RESULTS: In total, 87 patients (47 males) were included. The median age at ESES recognition was 81.0 months (IQR 64.0, 96.0). Forty-six patients were diagnosed with self-limited focal epilepsies (SeLFEs) before ESES recognition, 24 with developmental and epileptic encephalopathies with spike-and-wave activation in sleep (DEE-SWAS), and 17 with other epilepsies. Steroids, benzodiazepines, and antiseizure medications (ASMs) were the initial treatment options for ESES. Patients with structural etiologies or slow EEG backgrounds at the time of ESES recognition were less likely to respond to treatment than other patients. However, only children with slow EEG backgrounds had lower odds of response in logistic regression models. Children with clinical or EEG response showed improvements in cognition. CONCLUSION: Steroids, benzodiazepines, and ASMs are effective treatments for patients with DEE/EE-SWAS. Children with structural etiologies or slow EEG backgrounds at the time of ESES recognition may have a poor long-term prognosis. The efficacy of seizure reduction and EEG improvement is associated with cognitive improvement.

Identification of a Novel Homozygous GLS Gene Variant Associated with Developmental and Epileptic Encephalopathy (DEE) Type 71.

Developmental and epileptic encephalopathy (DEEs) (OMIM#618,328) is characterized by seizures, hypotonia, and brain abnormalities, often arising from mutations in genes crucial for brain function. Among these genes, GLS stands out due to its vital role in the central nervous system (CNS), with homozygous variants potentially causing DEE type 71. Using Whole Exome Sequencing (WES) on a patient exhibiting symptoms of epileptic encephalopathy, we identified a novel homozygous variant, NM_014905.5:c.1849G > T; p.(Asp617Tyr), in the GLS gene. The 5-year-old patient, born to consanguineous parents, presented with developmental delay, encephalopathy, frequent seizures, and hypotonia. Sanger sequencing further validated the GLS gene variant in both the patient and his family. Furthermore, our bioinformatics analysis indicated that this missense variant could lead to alteration of splicing, resulting in the activation of a cryptic donor site and potentially causing loss of protein function. Our finding highlights the pathogenic significance of the GLS gene, particularly in the context of brain disorders, specifically DEE71.

Identification of a novel KCNT2 variant in a family with developmental and epileptic encephalopathies: a case report and literature review.

Background: Developmental and epileptic encephalopathies (DEEs) are a group of heterogeneous neurodevelopmental diseases characterized mainly by developmental delay/intellectual disability and early-onset epilepsy. Researchers have identified variations in the KCNT2 gene (OMIM* 610044) as the cause of DEE type 57 (MIM# 617771). Case presentation: We report in this study a 46-year-old woman who presented with early-onset epilepsy, intellectual disability, hypertrichosis, coarse facial features, and short stature. Besides, there were four other affected individuals in her family history, including two elder brothers, a younger brother, and their mother. We collected blood samples from the proband, her two affected brothers, and her clinically normal daughter for genetic analysis. Clinical exome sequencing revealed a novel heterozygous variant in the KCNT2 gene (NM_198503: c.188G>A, p.Arg63His) in the proband and her two affected brothers, while her daughter did not carry this variant. Furthermore, we reviewed all 25 patients identified in the literature with KCNT2 variants and compared their phenotypes. Conclusion: Epilepsy and intellectual disability/developmental delay occur in almost all patients with KCNT2 variants. KCNT2-relevant DEEs partially overlap with the clinical phenotypes of KATP channel diseases, particularly in hypertrichosis and distinctive coarse facial features.

Novel CAD gene mutations in a boy with developmental and epileptic encephalopathy 50 with dramatic response to uridine therapy: a case report and a review of the literature.

BACKGROUND: Developmental and epileptic encephalopathy-50 (DEE-50) is a rare clinical condition believed to be caused by a mutation in the CAD gene and is associated with a bleak prognosis. CAD-related diseases have a wide range of clinical manifestations and other symptoms that may be easily overlooked. Like other rare diseases, the clinical manifestations and the treatment of DEE-50 necessitate further investigation. CASE PRESENTATION: A 1-year-old male patient presented with developmental delay, seizures, and anaemia at 3 months of age. He further developed refractory status epilepticus (SE), rapid deterioration of cognitive and motor function, and even became comatose at 5 months of age. Whole-exome sequencing of trios (WES-trios) revealed a compound heterozygous variant in the CAD gene, with one locus inherited from his father (c.1252C>T: p.Q418* nonsense mutation) and one from his mother (c.6628G>A: p.G2210S, missense mutation). This compound heterozygous CAD variant was unreported in the Human Gene Mutation Database. After uridine treatment, his cognitive faculties dramatically improved and he remained seizure-free. Forty two cases with CAD gene mutation reported in the literatures were reviewed. Among them, 90% had onset before 3 years of age, with average of 1.6±1.8 years old. The average age of diagnosis was 7.7 ± 10 years. The mortality rate was approximately 9.5%, with all reported deaths occurring in patients without uridine treatment. The clinical entity could be improved dramatically when the patient treated with uridine. CONCLUSIONS: We present a boy with DEE 50 caused by novel CAD gene mutations and reviewed the clinical features of 42 patients reported previously. DEE 50 has early onset, refractory seizures, even status epilepticus leading to death, with favorable response to treatment with oral uridine. Early uridine treatment is recommended if CAD defect is suspected or genetically diagnosed. This study enhances the knowledge of DEE 50 and expands the spectrum of CAD gene mutations.