Background and ObjectivesThe aim of this study was to characterize clinical features, genetic architecture, treatment responses, and neurodevelopmental outcomes in neonatal epilepsy associated with KCNQ2 variants and to delineate genotype-phenotype correlations.MethodsWe conducted a retrospective, two-center study of 30 neonates from 2019 to 2024. All patients underwent whole-exome sequencing with Sanger confirmation and, at last follow-up, were classified, according to International League Against Epilepsy criteria as having self-limited (familial) neonatal epilepsy (SeL[F]NE) or developmental and epileptic encephalopathy (DEE). Primary outcomes were seizure freedom by 6 months and milestone-based three-level neurodevelopment (normal/mild/severe). Clinical/EEG/MRI features and variant class/topology were compared across phenotypes.ResultsMost infants presented in the first week of life (median 3 days), typically with focal tonic seizures. EEG abnormalities were common (90%); burst-suppression/profound discontinuity consistently signaled adverse neurodevelopment. MRI was often normal (53%) or nonspecific. We identified 29 distinct variants (32 occurrences) across 30 patients. Twenty-eight carried a single heterozygous variant, and 2 carried 2 heterozygous variants (phase not determined); missense variants predominated (21/30, 70%). Clear topology-phenotype patterns emerged: transmembrane missense variants-especially S5-pore-S6-were enriched in DEE, whereas C-terminal/nontransmembrane variants were associated with SeL(F)NE and benign outcomes. At the last follow-up, SeL(F)NE accounted for 63% and DEE 37%. Seizure freedom reached 93%. Oxcarbazepine was often associated with seizure control after phenobarbital nonresponse, but this observational signal should not be interpreted as causal. Neurodevelopment was normal in 63%; delays occurred only within the DEE cohort. All 5 single-allele truncating/NMD lesions (CNV deletion, canonical splice-site, 2 nonsense, 1 frameshift) aligned with SeL(F)NE, whereas the 2 individuals with 2 heterozygous variants were classified as DEE with marked impairment; however, phase was not determined and 1 recurrent variant (p.E515D) was classified as likely benign, precluding inference of 2 pathogenic alleles.DiscussionKCNQ2-related neonatal epilepsy shows robust, topology-dependent genotype-phenotype correlations with prognostic utility: early EEG patterns flag risk; transmembrane missense variants are associated with DEE, whereas single-allele truncating/NMD variants are associated with SeL(F)NE. Apparent benefits of oxcarbazepine reflect associations in an observational cohort and should not be interpreted as causal; prospective, phenotype-stratified studies are warranted. Long-term developmental surveillance remains essential, particularly for individuals with DEE and those with severe early EEG patterns or variants in transmembrane/pore regions.

Background and Objectives:The aim of this study was to characterize clinical features, genetic architecture, treatment responses, and neurodevelopmental outcomes in neonatal epilepsy associated with KCNQ2 variants and to delineate genotype-phenotype correlations. Methods:We conducted a retrospective, two-center study of 30 neonates from 2019 to 2024. All patients underwent whole-exome sequencing with Sanger confirmation and, at last follow-up, were classified, according to International League Against Epilepsy criteria as having self-limited (familial) neonatal epilepsy (SeL[F]NE) or developmental and epileptic encephalopathy (DEE). Primary outcomes were seizure freedom by 6 months and milestone-based three-level neurodevelopment (normal/mild/severe). Clinical/EEG/MRI features and variant class/topology were compared across phenotypes. Results:Most infants presented in the first week of life (median 3 days), typically with focal tonic seizures. EEG abnormalities were common (90%); burst-suppression/profound discontinuity consistently signaled adverse neurodevelopment. MRI was often normal (53%) or nonspecific. We identified 29 distinct variants (32 occurrences) across 30 patients. Twenty-eight carried a single heterozygous variant, and 2 carried 2 heterozygous variants (phase not determined); missense variants predominated (21/30, 70%). Clear topology-phenotype patterns emerged: transmembrane missense variants-especially S5-pore-S6-were enriched in DEE, whereas C-terminal/nontransmembrane variants were associated with SeL(F)NE and benign outcomes. At the last follow-up, SeL(F)NE accounted for 63% and DEE 37%. Seizure freedom reached 93%. Oxcarbazepine was often associated with seizure control after phenobarbital nonresponse, but this observational signal should not be interpreted as causal. Neurodevelopment was normal in 63%; delays occurred only within the DEE cohort. All 5 single-allele truncating/NMD lesions (CNV deletion, canonical splice-site, 2 nonsense, 1 frameshift) aligned with SeL(F)NE, whereas the 2 individuals with 2 heterozygous variants were classified as DEE with marked impairment; however, phase was not determined and 1 recurrent variant (p.E515D) was classified as likely benign, precluding inference of 2 pathogenic alleles. Discussion:KCNQ2-related neonatal epilepsy shows robust, topology-dependent genotype-phenotype correlations with prognostic utility: early EEG patterns flag risk; transmembrane missense variants are associated with DEE, whereas single-allele truncating/NMD variants are associated with SeL(F)NE. Apparent benefits of oxcarbazepine reflect associations in an observational cohort and should not be interpreted as causal; prospective, phenotype-stratified studies are warranted. Long-term developmental surveillance remains essential, particularly for individuals with DEE and those with severe early EEG patterns or variants in transmembrane/pore regions.

BACKGROUND:Pathogenic variants of IBA57 (OMIM ID: 615330) are usually associated with multiple mitochondrial dysfunction syndrome (MMDS) and hereditary spastic paraplegia type 74 (SPG74). Here, we present a novel compound heterozygous IBA57 mutation in a boy with severe global developmental delay, optic atrophy, spastic paraplegia, and focal epileptic seizures. METHODS:The clinical data of a child diagnosed with MMDS were retrospectively collected. Video electroencephalogram (VEEG), cranial magnetic resonance imaging (MRI), and family whole-exome sequencing (WES) were performed. Suspected mutation sites were further confirmed using Sanger sequencing. The activities of mitochondrial respiratory chain complexes I-IV were determined in peripheral blood mononuclear cells. The phylogenetic conservation of the affected residues was assessed by multiple sequence alignment of IBA57 gene orthologs. Furthermore, we conducted a review of the relevant literature. RESULTS:Whole-exome sequencing identified compound heterozygous variants in the IBA57 gene: c.395_400dup (p.V132_Q133dup) and c.832delC (p.R278Afs*23), inherited from his phenotypically normal father and mother, respectively. Biochemical assays demonstrated selective reduction of complexes I and II activities, with normal complexes III and IV, consistent with impaired 4Fe-4S cluster maturation. Phylogenetic alignment revealed strict conservation of residues V132-Q133 and R278 across vertebrates. These variants had not been previously reported in domestic or international databases. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the former was classified as a variant of uncertain significance (PM4 + PM2), while the latter was classified as likely pathogenic (PVS1 + PM2). CONCLUSION:Diseases associated with IBA57 gene variants are autosomal recessive disorders with a broad clinical phenotypic spectrum. Early genetic testing and family screening are beneficial for the diagnosis, treatment, and prognosis of the disease.

Neurocutaneous syndromes are a group of genetic disorders involving the nervous and cutaneous systems, including Tuberous Sclerosis Complex (TSC), neurofibromatosis type 1 (NF1), and Sturge–Weber syndrome (SWS), and others. The incidence of epilepsy, a core clinical manifestation, is significantly higher than in the general population. The purpose of this narrative review is to provide an updated overview of the genetic mechanisms and recent advances in precise treatment for neurocutaneous syndrome-related epilepsy. We conducted a comprehensive search of the PubMed, Scopus, EMBASE, and Web of Science databases using all MeSH terms related to ‘Neurocutaneous Syndromes’, ‘Epilepsy/genetics’, ‘Signal Transduction’, and ‘Precision Medicine’. Selected papers underwent review and risk of bias (RoB) assessment to evaluate core questions. Somatic or germline mutations dysregulate key signaling pathways (e.g., mTOR, Ras-MAPK, PI3K-AKT), inducing malformations of cortical development (MCD) and neuronal-glial dysfunction that collectively form epileptogenic networks. This constitutes the primary pathogenic mechanism underlying neurocutaneous syndrome-related epilepsy. Precise treatment strategies based on molecular mechanisms have achieved breakthroughs: mTOR inhibitors significantly reduce seizure frequency in TSC patients, and cannabidiol (CBD) demonstrates broad-spectrum antiepileptic efficacy in TSC and Dravet syndrome. Advances in surgical techniques, such as multimodal imaging-guided resection, improve outcomes in refractory epilepsy. However, clinical translation faces challenges including technical limitations in detecting mosaic mutations, insufficient specificity of targeted drugs, and interdisciplinary collaboration gaps. Future directions require integrating multi-omics technologies, developing novel gene therapies (e.g., CRISPR-based approaches), and establishing multicenter databases linking genotype–phenotype-treatment responses to advance personalized precision medicine.

BACKGROUND:O'Donnell-Luria-Rodan (ODLURO) syndrome is a newly described neurodevelopmental disorder caused by a pathogenic KMT2E variant. The primary clinical phenotypes include developmental delay, intellectual disability (ID), and epilepsy. Epilepsy, observed in 29% of affected individuals, has not been thoroughly investigated. In this study, we describe the phenotypes and genetic profiles of patients with ODLURO syndrome and epilepsy. METHODS:We summarized and analyzed data from 30 patients with ODLURO syndrome and epilepsy from the systematic literature and DECIPHER database. Information regarding seizure classification, brain MRI findings, antiseizure medications, and genetics variations was collected and analyzed retrospectively. RESULTS:The risk factors associated with epilepsy in ODLURO syndrome remain unclear, and clinical heterogeneity exists. While focal seizures are most prevalent, various epilepsy classifications are observed. Brain MRI findings indicated that cerebral atrophy and cystic changes were common, though no correlation with epilepsy was established. Among ten individuals with a record of antiseizure medication, approximately 70% required two or more antiseizure medications. CONCLUSIONS:A clear genotype-phenotype correlation remains elusive even among individuals with the same KMT2E variation. The pathogenesis of epilepsy associated with KMT2E variation is complex and necessitates further molecular genetic studies to elucidate the mechanisms underlying these genetic disorders. This research provides essential evidence for specific and individualized treatment approaches.

Objective:To summarize the clinical features and the spectrum of ALDH7A1 gene variants in Chinese children with pyridoxine-dependent epilepsy (PDE). Methods:Clinical data were collected from six pediatric patients with PDE treated at Linyi People's Hospital (2017-2023). Whole-exome sequencing, in conjunction with Sanger sequencing, was used to screen for ALDH7A1 gene variant sites. Bioinformatics methods were applied in combination with clinical phenotype assessment to evaluate the pathogenicity of the variants. Results:In six cases of PDE, the male-to-female ratio was 2:4. Five cases began in the neonatal period, and one in early infancy. Three cases experienced hypoxiaetal distress or respiratory distress. Two cases had a family history of recurrent miscarriages or premature deaths of siblings due to seizures. Seizure types varied among the cases. Three individuals experienced cluster seizures, two were heat-sensitive, and four suffered from status epilepticus. Video EEGs of four children revealed hypsarrhythmia, focal, or multifocal discharges initially, which normalized within 3 days to 8 months following vitamin B6 treatment. All patients initiated regular vitamin B6 therapy between 32 days and 17 months post-onset, with an initial dose ranging from 7.7 to 12.5 mg/(kg·d). During follow-up until the age of 1 to 8 years, the maintenance dose was adjusted to 3.3-7.8 mg/(kg·d). Two patients who began standardized treatment before the age of 3 months experienced normal development. The remaining patients showed mild to moderate developmental delays. Eight variants were identified, including a hotspot in Chinese children: c.1008+1G>A, and two recurrent sites: c.1061A>G and c.1547A>G. Additionally, three variants were novel. Conclusion:Pyridoxine-dependent epilepsy must be distinguished from hypoxic-ischemic encephalopathy and other thermally sensitive epilepsies. The severity of the condition and neurodevelopmental outcomes in affected children vary significantly. Early administration of low-dose pyridoxine can effectively control seizures and reverse EEG abnormalities, potentially improving long-term neurodevelopmental outcomes. c.1061A>G and c.1547A>G may be hotspot variants in Chinese children with PDE.

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.

Introduction Increasing evidence reveals critical roles for CHD2 in children with developmental and epileptic encephalopathy. Objectives The aim was to present clinical analysis results of five cases with CHD2 mutations and 157 reported cases with non-copy number variations (non-CNV) of CHD2. Methods This study recruited pediatric epilepsy patients with CHD2 mutations and clinical data from November 2016 to October 2023 in the Linyi People's Hospital, China. Whole-exome and gene panel sequencing were employed to find mutations. The HGMD and PubMed databases were examined for documented cases that had CHD2 mutations. Results This study reports five cases with CHD2 mutations: c.3543T>A, c.1850A>G, c.2536C>T, c.4233_4236del, c.3782G>C. Three novel mutations (c.3543T>A, c.1850A>G, c.2536C>T) have never been reported. c.4233_4236del has been reported in three cases, indicating that this locus may be a mutation hotspot. c.3782G>C has been reported in one case. All five patients had seizures before the age of four. Three patients had varying degrees of developmental delay, and four patients had varying degrees of intellectual disability. All of them had controlled seizures after Valproic acid (VPA) monotherapy or VPA in combination with other medications. Furthermore, we reviewed 157 reported cases having non-CNV mutations of CHD2. Most mutations of these cases were de novo. Epilepsy, developmental delay, and intellectual disability were the typical clinical phenotypes. We also found a significant clustering of the mutations near the C-terminus of the CHD2 protein (P<0.001). Conclusion This study reports new CHD2 genotypes and analyzes reported CHD2 mutation cases. Given its significance in epileptic encephalopathies, research on the CHD2 gene may provide new insights into epileptogenesis.

BACKGROUND:Peutz-Jeghers syndrome (PJS) is characterized by the presence of hamartomatous polyps in the gastrointestinal tract and mucocutaneous pigmentation on the lips, oral mucosa, nose, fingers, and toes. Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) refers to the occurrence of multifocal mucinous lesions in at least two sites, including the cervix, uterus, fallopian tubes, and ovaries, in the female genital tract. SMMN-FGT and PJS are rare diseases with a very low incidence, especially when occurring simultaneously. CASE PRESENTATION:We report a case in which a woman with a large mass on the left ovary underwent a gynecological surgery and was diagnosed with cervical gastric-type adenocarcinoma and mucinous lesions in the endometrium, bilateral fallopian tubes, and ovary, i.e., SMMN-FGT, by postoperative paraffin pathology. The patient sought medical attention for abdominal distension and enlargement. A gynecological ultrasound revealed a multilocular cystic mass in the pelvis, while serum tumor markers were within normal limits, with mildly elevated carbohydrate antigen 199 and carbohydrate antigen 125 levels. Cervical thin-prep cytology test result was negative. The patient had a family history of PJS with black spots on her skin and mucous membranes since the age of 8 years. She underwent multiple partial small bowel resections and gastrointestinal polypectomy owing to intestinal obstruction and intussusception. She underwent left adnexectomy, hysterectomy, right salpingectomy, greater omental resection, appendectomy and right ovary biopsy, and received six courses of adjuvant chemotherapy with Lopressor plus Carboplatin. Genetic testing revealed a heterozygous serine threonine kinase 11 germline mutation and there were no signs of recurrence during the 18-month follow-up period after treatment. CONCLUSIONS:This is a rare case in which PJS was complicated by SMMN-FGT. Owing to its extreme rarity, there are no guidelines, but reported cases appear to indicate a poor prognosis. We retrospectively reviewed all cases of collisions between PJS and SMMN-FGT and explored the clinical features, pathological characteristics, diagnosis, treatment methods, and prognosis when the two diseases coexisted. The aim is to deepen the clinicians' understanding of this disease for early detection, diagnosis and treatment.

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.

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.

BACKGROUND:Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation.METHODS:The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software.RESULTS:High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.CONCLUSIONS:We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

为了探讨T140通过靶向阻断SDF-1/CXCR4信号通路调节体内关节软骨退变的作用,并为以后的临床研究提供一定的参考,将45只健康的Hartley豚鼠随机分成3组,分别为:T140处理组(n=15)、磷酸盐缓冲盐水对照组(n=15)和未处理对照组(n=15).分别在处理的2周、6周、8周、10周和12周,通过酶联免疫吸附测定法定量血清中的SDF-1.在治疗12周时,收集膝关节胫骨的软骨用于HE和番红-O染色同时进行Mankin分级;使用RT-PCR测量基质金属蛋白酶(MMP-3,MMP-9和MMP-13),聚集蛋白聚糖(ACAN)和胶原蛋白Ⅱ(ColⅡ)的mRNA表达水平;通过蛋白质印迹测量ColⅡ蛋白的表达水平.T140组中的SDF-l含量升高.与对照相比,HE和番红-O染色显示T140处理的动物中的软骨损失较少.T140组软骨中MMP-3、MMP-9和MMP-13的mRNA表达水平明显低于其他组.而T140处理组软骨中ACAN和ColⅡ的mRNA表达水平明显升高,T140组和对照组中的ColⅡ蛋白水平各不相同.T140可以通过在体内阻断SDF-1/CRCR4信号传导途径来下调基质金属酶的表达水平并减轻软骨的变性,为治疗OA的药理学提供了靶标.

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.