This study delineated the clinical phenotypes of epilepsy patients harboring TUBB2A variants and explored the pathogenesis of novel variants in HEK293T cells. The clinical data of 5 epilepsy patients in our cohort and 23 epilepsy patients from published studies carrying TUBB2A variants were evaluated. TUBB2A-FLAG and TUBB2A-EGFP plasmids were constructed to investigate the functional implications of TUBB2A variants. In 28 patients with epilepsy, the seizure onset age spanned from neonatal period to 8 years old, with 61% experiencing seizures before 1-year-old. The prevalent seizure types were epileptic spasms (32%) and focal seizures (32%). All 28 patients showed varying degrees of developmental delay, and 93% had malformation of cortical development (MCD). All identified TUBB2A variants were missense variants. Three-dimensional structure predictions revealed that 83% of patients diagnosed with pachygyria possessed variants situated near or at the linkage of α-β tubulin. We investigated 4 novel variants and 4 reported variants and found that all 8 variants affected the morphology of spindle apparatus and dynamics of microtubules. Variants located at or near α-β tubulin dimer interface exerted a pronounced influence on the morphology and dynamic of microtubules. Most patients with TUBB2A-related epilepsy experience seizures before 1-year-old. Over 90% of these patients presented with MCDs, and all displayed varying degrees of developmental delay. Patients with TUBB2A variants that perturb tubulin dimer linkage were observed to have a higher proportion of severe phenotypes, such as pachygyria.

Aim To construct a genetic landscape of infantile epileptic spasms syndrome (IESS) and explore the pathogenic mechanisms of IESS-associated genes.Method We conducted a nationwide, multicentre, retrospective study across six centres in China, enrolling patients with genetically confirmed IESS between January 2015 and January 2024. Additionally, we reviewed the existing literature, summarized the genetic landscape of IESS, and used bioinformatics approaches to investigate its pathophysiological features.Results Our cohort included 430 probands with a genetic aetiology of IESS, with 394 of 430 (91.6%) carrying monogenic variants and 36 of 430 (8.4%) carrying copy number variants or chromosome abnormalities. A total of 168 genes were identified in 394 patients (219 males, 175 females; median age at epileptic spasms onset of 5.0 [interquartile range 3.0-7.0] months) with monogenic variants, including 14 genes that are not associated with any phenotypes in the Online Mendelian Inheritance in Man database. We compiled 354 IESS-associated genes from our cohort and the related literature. The functions of these genes are related to membrane potential, synaptic signalling, and several ion channel activities.Interpretation We comprehensively mapped the genetic landscape of IESS and identified candidate pathogenic genes associated with the disorder.

OBJECTIVE:To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene.METHODS:Clinical data of five children (four males and one female) admitted to Linyi People's Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing.RESULTS:All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c.4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored a de novo c.3967G>A variant which was rated as pathogenic (PS1+PS2+PM1+PM2_Supporting+PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor a de novo c.415A>T and a c.4697C>T variant, which were both rated as likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored a de novo c.5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation.CONCLUSION:The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.

Background Pathogenic variants of the IRF2BPL gene have been reported to cause neurodevelopmental disorders; however, studies focused on IRF2BPL in zebrafish are limited. Results We reported three probands diagnosed with developmental delay and epilepsy and investigated the role of IRF2BPL in neurodevelopmental disorders in zebrafish. The clinical and genetic characteristics of three patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS) were collected. Three de novo variants (NM_024496.4: c.1171 C > T, p.Arg391Cys; c.1157 C > T, p.Thr386Met; and c.273_307del, p.Ala92Thrfs*29) were detected and classified as pathogenic or likely pathogenic according to ACMG guidelines. Zebrafish crispants with disruption of the ortholog gene irf2bpl demonstrated a reduced body length and spontaneous ictal-like and interictal-like discharges in an electrophysiology study. After their spasms were controlled, they gain some development improvements. Conclusion We contribute two new pathogenic variants for IRF2BPL related developmental epileptic disorder which provided evidences for genetic counseling. In zebrafish model, we for the first time confirm that disruption of irf2bpl could introduce spontaneous electrographic seizures which mimics key phenotypes in human patients. Our follow-up results suggest that timely cessation of spasmodic seizures can improve the patient’s neurodevelopment.

AbstractObjectiveTo summarize the clinical features and genetic mutation characteristics of Chinese children with KCNQ2‐related epilepsy.MethodsA cohort of children with genetically caused epilepsy was evaluated at Linyi People's Hospital from January 2017 to December 2023. After next‐generation sequencing and pathogenicity analysis, we summarized the medical records and genetic testing data of the children who had KCNQ2 gene mutations.ResultsWe identified 23 KCNQ2 gene mutations. 73.9% (n = 17) of the mutation sites were located in S5–S6 segments and the C‐terminal region. In addition to the common phenotypes, 2 new phenotypes were identified: infantile convulsion with paroxysmal choreoathetosis (ICCA) and febrile seizure plus (FS+). Of all the cases with abnormal video‐electro‐encephalography, three cases with self‐limited familial infantile epilepsy (SeLNE) exhibited a small number of multifocal discharges. Of the patients who have taken a particular antiepileptic drug, the statistics on the number of patients who have responded to the drug are as follows: oxcarbazepine (8/9, 88.9%), levetiracetam (5/7, 71.4%), phenobarbital (9/16, 56.3%), and topiramate (2/5, 40.0%). However, the efficacy of phenobarbital varied widely in treating SeLNE and KCNQ2‐DEE. At the final follow‐up, 1 case with SeLNE had a transient developmental regression and 7 cases with KCNQ2‐DEE had mild to severe developmental backwardness.SignificanceAlthough clinically rare, we report 10 new KCNQ2 mutations and two new phenotypes: ICCA and FS+. This further expands genetic and phenotypic spectrum of KCNQ2‐related epilepsy. The gene mutation sites are mostly located in S5–S6 segments and the C‐terminal region, and the former is usually associated with KCNQ2‐DEE. Sodium channel blockers (including oxcarbazepine and topiramate) and levetiracetam should be prioritized over phenobarbital for KCNQ2‐DEE. Some cases with KCNQ2‐related epilepsy may have transient developmental regression during periods of frequent seizures. Early treatment and early seizure control may be beneficial for willing outcomes in children with KCNQ2‐DEE.Plain Language SummaryThis article reports 23 cases of children with KCNQ2‐related epilepsy, including 10 new mutation sites and 2 new phenotypes. It further expands the genetic and phenotypic spectrum of KCNQ2‐related epilepsy. In addition, the article summarizes the gene mutation characteristics and clinical manifestations of children with KCNQ2‐related epilepsy, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of such patients.

OBJECTIVE:To explore the clinical features and genetic etiology of a child with SPONASTRIME dysplasia (SD).METHODS:A 9-month-old female who had presented at the Linyi People's Hospital in August 2022 for short stature was selected as the study subject. Clinical data of the child were collected, and whole exome sequencing (WES) was carried out. Sanger sequencing was used for validating the candidate variants.RESULTS:The child has manifested short stature, mid-face hypoplasia, joint laxity, internal knee rotation, irregularities in the metaphysis of long bones, and flat and concave lumbar vertebrae. WES revealed that she has harbored compound heterozygous variants of the TONSL gene, namely c.3088G>T (p.Glu1030*) and c.3053G>A (p.Arg1018His), which were inherited from her phenotypically normal parents. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3088G>T variant was classified as likely pathogenic (PVS1+PM2_Supporting), whilst the c.3053G>A was classified as a variant of uncertain significance (PM2_Supporting+PM3+PP3).CONCLUSION:The c.3088G>T and c.3053G>A compound heterozygous variants of the TONSL gene probably underlay the pathogenesis in this patient. Above finding has facilitated the clinical diagnosis and genetic counseling for her family.

Abstract Background Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. Methods This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. Results Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). Conclusions Sirolimus’s long-term administration is not associated with adverse effects on children’s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. Trial registration Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Purpose: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis.Method: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene.Result: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drugcontrolled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele.Conclusion: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Abstract Background Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM‐2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS‐like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura. Methods The patient was an 8‐year‐old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS‐like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole‐exome sequencing (WES). Results WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic. Conclusion At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS‐like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.

OBJECTIVE:To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents.METHODS:A female child who had presented at Linyi People's Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks' gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci.RESULTS:The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+PM2_Supporting+PM4), and c.1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+PM3+PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor.CONCLUSION:The c.1126del (p.H376Tfs*56) and c.1285G>C (p.E429Q) compound heterozygous variants of the PIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.

Objective: To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy. Methods: A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint. Results: There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34 +/- 7.93 months vs. 6.94 +/- 6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/ 168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004]. Conclusion: Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time-and dose-dependent.

ObjectiveThis study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine. MethodsThrough a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software. ResultsIn 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam. ConclusionThe clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.

Background: Previously known as the anti-rejection drug, then famous for its efficacy on many mTOR-regulated diseases, sirolimus is now reported as the drug to reverse the process of many age-related diseases, rejuvenate immunity, and extend life span. However, its long-term safety profile for all-age groups is still a concern.Methods: Data were from two 10-year prospective cohort studies (ChiCTR-OOB-15006535，NCT031938), in which patients were diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. Indicators on growth, hematopoietic, liver and renal function, and blood lipid were all primary outcomes. GLM analysis and Chi-square test were used to reveal their changes between the baseline and five follow-up periods (< 6 months, 6 to < 12 months, 1 to < 2 years, 2 to < 4 years, and 4-to-10 years)). Four models with cross-validation were constructed for prediction. Descriptive adverse events and the change of regimens were also recorded (secondary outcomes). Findings: 1738 patients aging from 5 days to 69 years were included. The median follow-up period was 25 (12-43) months, and 380 patients were followed for more than four years. Z scores of height, weight, and BMI increased significantly throughout the follow-up (baseline versus 4-to-10-year follow-up: 0·24 vs 0·69, 0·25 vs 0·56, 0·14 vs 0·29). The dose of sirolimus was the only factor related to all the changes. No negative effects on hematopoietic, liver, and renal function were observed throughout the follow-up. On the contrary, the long-term use of sirolimus showed beneficial effects. The increase of blood lipids was mainly in the first six months. Stomatitis was the most common adverse event (920/1738, 52·9% ), and 48·5% of adult females were with menstrual disorders. The economic burden was the main reason for discontinuing therapy.Interpretation: For the first time, we observed the increase in height and weight brought by sirolimus. Also, the length of follow-up was associated with different safety profiles. Some beneficial effects were observed in a longer follow-up.Clinical Trial Registration Details: The pediatric patients in this study are from the "Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSIPT)" study (Chinese Clinical Trial Registration, http://www.chictr.org.cn, No. ChiCTR-OOB-15006535). The adult patients re from "A National Registry on Chinese Patients with Lymphangioleiomyomatosis" (ClinicalTrials.gov, No. NCT03193892).Funding Information: This work was supported by grants from the National Key Research and Development Program of China (No. 2016YFC1000707，No.2016YFC0901502) and the National Natural Science Foundation of China (No. 81471329).Declaration of Interests: The authors have no conflicts of interest relevant tothis article to disclose.Ethics Approval Statement: The Ethics Committee of Chinese PLA General Hospital approved the pediatric study (No. S2013-028-01). The Ethics Committee of Peking Union Medical College Hospital (PUMCH) approved the adult study(JS-1323).

Objectives To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. Study design The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. Results A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. Conclusions Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

To figure out which diagnosis is more suitable and which antiepileptic drugs are more sensitive to epileptic negative myoclonus (ENM) as the first seizure type in atypical benign epilepsy with centrotemporal spikes.We reviewed the electroencephalogram (EEG) database of Linyi People's Hospital Affiliated to Shandong University and medical records of patients with ENM onset. The characteristics of epileptic seizures, onset age, treatment process, growth and development history, past disease history, family history, degree of mental deterioration, cranial imaging, and video-EEG were studied retrospectively and followed up.There were 4 cases with ENM onset and 1 with continuous ENM, 3 males and 1 female. The onset age was from 2 years 3 months to 8 years 7 months. The cranial magnetic resonance imaging (MRI) and developmental quotient, as well as the family, personal, and past disease history, were normal. Frequent falls and drops were the main clinical manifestations. Five months after the onset of ENM, case 1 had focal seizures in sleep. ENM was the first and only manifestation in all the other 3 children. Discharges of interictal EEG were in bilateral rolandic areas, especially in midline areas (Cz, Pz), electrical status epilepticus in sleep was found in 3 cases. One child was sensitive to levetiracetam, the other 3 were sensitive to clonazepam.ENM can affect the upper or lower extremities. ENM as the first or only symptom was a special phenomenon in benign epilepsy with centrotemporal spikes (BECTS) variants. Ignorance of midline spikes mainly in Cz or Pz in BECTS might lead to missed diagnosis of ENM. Whether benzodiazepines are viable as a choice of BECTS variants with electrical status epilepticus in sleep when ENM is the first symptom still needs a large sample evidence-based observation.

Abstract Introduction G elongation factor mitochondrial 1 (GFM1) encodes one of the mitochondrial translation elongation factors. GFM1 variants were reported to be associated with neurological diseases and liver diseases in a few cases. Here, we present a novel composition of two heterozygous mutations of GFM1 in a boy with epilepsy, mental retardation, and other unusual phenotypes. Methods The patient was found to be blind and experienced recurrent convulsive seizures such as nodding and hugging at the age of 3 months. After antiepileptic treatment with topiramate, he had no obvious seizures but still had mental retardation. The patient vomited frequently at 16 months old, sometimes accompanied by epileptic seizures. Hematuria metabolic screening, mutation screening of mitochondrial gene, and mitochondrial nuclear gene were negative. Then, he was analyzed by whole‐exome sequencing (WES). Results Whole‐exome sequencing revealed a novel composition of two heterozygous mutations in GFM1, the maternal c.679G > A (has not been reported) and the paternal c.1765‐1_1765‐2del (previously reported). At present, there is no specific and effective treatment for the disease, and the prognosis is very poor. Conclusion The discovery of new phenotypes and new genotypes will further enrich the diagnosis information of the disease and provide more experiences for clinicians to quickly diagnose the disease and judge the prognosis.

BACKGROUND:Point and copy number variant mutations in the PRRT2 gene have been identified in a variety of paroxysmal disorders and different types of epilepsy. In this study, we analyzed the phenotypes and PRRT2-related mutations in Chinese epilepsy children. METHODS:A total of 492 children with epilepsy were analyzed by whole exome sequencing (WES) and low-coverage massively parallel CNV sequencing (CNV-seq) to find the single nucleotide variants and copy number variations (CNVs). And quantitative polymerase chain reaction was utilized to verify the CNVs. Their clinical information was followed up. RESULTS:We found PRRT2-related mutations in 19 patients (10 males and nine females, six sporadic cases and 13 family cases). Twelve point mutations, four whole gene deletion, and three 16p11.2 deletions were detected. The clinical features of 39 patients in 19 families included one early childhood myoclonic epilepsy (ECME), one febrile seizure (FS), two infantile convulsions with paroxysmal choreoathetosis (ICCA), six paroxysmal kinesigenic dyskinesias (PKD), 12 benign infantile epilepsy (BIE), and 17 benign familial infantile epilepsy (BFIE). All patients had normal brain MRI. Interictal EEG showed only one patient had generalized polyspike wave and five patients had focal transient discharges. Focal seizures originating in the frontal region were recorded in one patient, two from the temporal region, and two from the occipital region. Most patients were treated effectively with VPA or OXC, and the child with myoclonic seizures was not sensitive to antiepileptic drugs. CONCLUSION:PRRT2 mutations can be inherited or de novo, mainly inherited. The clinical spectrum of PRRT2 mutation includes BIE, BFIE, ICCA, PKD, FS, and ECME. The PRRT2-related mutations contained point mutation, whole gene deletion and 16p11.2 deletions, and large microdeletion mutations mostly de novo. It is the first report of PRRT2 mutation found in ECME. Our report expands the mutation and clinical spectrum of PRRT2-related epilepsy.

AbstractBackgroundPCDH19 has become the second most relevant gene in epilepsy after SCN1A. Seizures often provoked by fever.MethodsWe screened 152 children with fever‐sensitive epilepsy for gene detection. Their clinical information was followed up.ResultsWe found eight PCDH19 point mutations (four novel and four reported) and one whole gene deletion in 10 female probands (seven sporadic cases and three family cases) who also had cluster seizures. The common clinical features of 16 patients in 10 families included fever‐sensitive and cluster seizures, mainly focal or tonic‐clonic seizures, and absence of status epilepticus, normal intelligence, or mild‐to‐moderate cognitive impairment, the onset age ranges from 5 months to 20 years. Only four patients had multiple or focal transient discharges in interictal EEG. Focal seizures originating in the frontal region were recorded in four patients, two from the parietal region, and one from the occipital region.ConclusionPCDH19 mutation can be inherited or de novo. The clinical spectrum of PCDH19 mutation includes PCDH19 Girls Clustering Epilepsy with or without mental retardation, psychosis, and asymptomatic male. The onset age of PCDH19 Girls Clustering Epilepsy can range from infancy to adulthood. Sisters in the same family may be sensitive to the same antiepileptic drugs. And our report expands the mutation spectrum of PCDH19 Girls Clustering Epilepsy.