Objective:To explore the clinical manifestations and genetic characteristics of a child with Leukoencephalopathy with ataxia (LKPAT) caused by a CLCN2 gene variant. Methods:A retrospective analysis was conducted on the clinical data of a child admitted to Hunan Children′s Hospital in June 2024 due to " intermittent convulsions for 13 days" . Peripheral blood samples were collected from the child and his parents for whole exome sequencing, followed by Sanger sequencing validation and pathogenicity analysis of candidate variants. Literature searches were performed using the keywords " CLCN2 gene" "chloride channel-2" "leukoencephalopathy with ataxia/LKPAT" "leukoencephalopathy" in both Chinese and English on CNKI, Wanfang, and PubMed databases. The search time was set from the establishment of the databases to July 31, 2024. Childhood-onset LKPAT literature was screened and analyzed. This study was approved by the Medical Ethics Committee of Hunan Children′s Hospital (Ethics No. HCHLL-2024-351). Results:① The child was a 7-month-and-26-day-old male infant born to consanguineous parents, presenting with epileptic seizures and borderline development. Cranial MRI revealed symmetrical long T 2 signal shadows in the posterior limb of the internal capsule, cerebral peduncle, pons, and middle peduncle of the cerebellum. Video electroencephalogram (EEG) showed an abnormal childhood EEG with one focal seizure. ② Whole exome sequencing revealed a homozygous c. 2201dup (p.Glu735Ter) variant in the CLCN2 gene of the child. Sanger sequencing confirmed that the variant was inherited from both parents. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), this variant was classified as pathogenic (PVS1+ PM3_Supporting+ PM2_Supporting). ③ A total of 8 relevant literature were retrieved, together with the present case, 16 childhood-onset LKPAT patients were cumulatively reported, which consisted of 9 males and 7 females. Twelve CLCN2 gene variants were involved, including 2 nonsense variants, 3 missense variants, 7 frameshifting variants, 2 c. 61dup variants, and 5 c.1709G>A variants. The initial symptoms of the 16 patients included headache, ataxia, epileptic seizures, spasticity, developmental delay, lower back pain, hearing impairment, and intention tremor. Three patients had the onset of the disease before the age of one, of which two had epileptic seizures as the initial symptom. Conclusion:The homozygous variant CLCN2: c. 2201dup (p.Glu735Ter) is considered the pathogenic cause of LKPAT in this child, marking the first childhood-onset case reported in China. Genetic testing has facilitated the diagnosis of childhood-onset LKPAT and expanded the spectrum of CLCN2 gene mutations.

OBJECTIVE: To explore the clinical manifestations and genetic characteristics of a child with Leukoencephalopathy with ataxia (LKPAT) caused by a CLCN2 gene variant. METHODS: A retrospective analysis was conducted on the clinical data of a child admitted to Hunan Children's Hospital in June 2024 due to "intermittent convulsions for 13 days". Peripheral blood samples were collected from the child and his parents for whole exome sequencing, followed by Sanger sequencing validation and pathogenicity analysis of candidate variants. Literature searches were performed using the keywords "CLCN2 gene" "chloride channel-2" "leukoencephalopathy with ataxia/LKPAT" "leukoencephalopathy" in both Chinese and English on CNKI, Wanfang, and PubMed databases. The search time was set from the establishment of the databases to July 31, 2024. Childhood-onset LKPAT literature was screened and analyzed. This study was approved by the Medical Ethics Committee of Hunan Children's Hospital (Ethics No. HCHLL-2024-351). RESULTS: The child was a 7-month-and-26-day-old male infant born to consanguineous parents, presenting with epileptic seizures and borderline development. Cranial MRI revealed symmetrical long T₂ signal shadows in the posterior limb of the internal capsule, cerebral peduncle, pons, and middle peduncle of the cerebellum. Video electroencephalogram (EEG) showed an abnormal childhood EEG with one focal seizure. Whole exome sequencing revealed a homozygous c.2201dup (p.Glu735Ter) variant in the CLCN2 gene of the child. Sanger sequencing confirmed that the variant was inherited from both parents. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), this variant was classified as pathogenic (PVS1+PM3_Supporting+PM2_Supporting). A total of 8 relevant literature were retrieved, together with the present case, 16 childhood-onset LKPAT patients were cumulatively reported, which consisted of 9 males and 7 females. Twelve CLCN2 gene variants were involved, including 2 nonsense variants, 3 missense variants, 7 frameshifting variants, 2 c.61dup variants, and 5 c.1709G>A variants. The initial symptoms of the 16 patients included headache, ataxia, epileptic seizures, spasticity, developmental delay, lower back pain, hearing impairment, and intention tremor. Three patients had onset of the disease before the age of one, of which 2 had epileptic seizures as the initial symptom. CONCLUSION The homozygous variant CLCN2: c.2201dup (p.Glu735Ter) is considered the pathogenic cause of LKPAT in this child, marking the first childhood-onset case reported in China. Genetic testing has facilitated the diagnosis of childhood-onset LKPAT and expanded the spectrum of CLCN2 gene mutations.
Humans ; Chloride Channels/genetics* ; Male ; CLC-2 Chloride Channels ; Leukoencephalopathies/genetics* ; Infant ; Ataxia/genetics* ; Homozygote ; Mutation ; Retrospective Studies ; Exome Sequencing ; Genetic Testing ; Female

Objective:To summarize the clinical manifestations, genetic characteristics and diagnosis and treatment processes of ATP1A2 gene-related childhood neurological diseases presenting with hemiplegic migraine (HM) or epilepsy, and enhance the understanding of clinicians on the diseases related to this gene. Methods:A retrospective study was performed; data of 5 children with ATP1A2 gene variations admitted to Department of Neurology, Hunan Children's Hospital from April 2015 to June 2024 were collected, and their clinical characteristics were summarized. ATP1A2 gene variations were confirmed by whole exome sequencing on these 5 children's families using next-generation sequencing (NGS), and then, further validated by Sanger sequencing. A comprehensive literature search was performed through PubMed, CNKI, and Wanfang databases to summarize the disease spectrum associated with this gene. Results:Among the 5 pediatric patients, 3 exhibited HM phenotype (all presented with neurological symptoms of epilepsy/febrile seizures within the first year of life, followed by HM onset after intervals ranging from 3 years and 3 months to 7 years); 2 pediatric patients aligned with epilepsy phenotype, including one instance of drug-resistant focal-onset epileptic encephalopathy. These 5 pediatric patients carried de novo missense variants in the ATP1A2 gene, encompassing 5 distinct mutation sites. Notably, the c.1023C>G (p.Cys341Trp) and c.2458G>A (p.Ala820Thr) variants were not documented in ClinVar or HGMD databases, and were classified as likely pathogenic according to American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines. Literature review revealed that all reported ATP1A2 mutations in Chinese pediatric patients were missense variants, with c.2143G>C (p.Gly715Arg) being the most commonly prevalent (8/29, 27.6%). The predominant clinical manifestation was HM (22/29), characterized by hemiplegia, aphasia, fever, impaired consciousness, and convulsions (early transient neurological symptoms frequently manifested as febrile seizures [12/22, 54.4%]); additionally, alternating hemiplegia of childhood was noted in 4 pediatric patients and epilepsy in 3 pediatric patients. Conclusion:ATP1A2 gene variants can lead to neurological disorders such as HM and epilepsy, with varied severity at same phenotype; the missense variants c.1023C>G and c.2458G>A in the ATP1A2 gene expand the spectrum of ATP1A2 gene variants and may serve as genetic causes of epilepsy.

Objective:To investigate the clinical manifestations，etiology/triggers，treatment，and prognosis of children with cerebral venous sinus thrombosis（CVST）.Methods:A retrospective analysis was conducted on 36 children with CVST hospitalized at the Affiliated Children's Hospital of Xiangya School of Medicine,Central South University（Hunan Children's Hospital）from May 2014 to January 2024.A centralized telephone follow-up was performed in May 2024，and clinical data including symptoms，imaging findings，treatments，and outcomes were collected.According to the prognosis,the children were divided into favorable-prognosis group and poor-prognosis group,and the differences of clinical characteristics between the two groups were compared.The univariate Logistic regression was applied to identify factors associated with prognosis.Results:Among the 36 cases,there were 29 males and 7 females,ranging in age from 1 month to 13 years and 3 months,with a median age of 4.6(1.0,8.3) years.The common clinical manifestations included headache（24/25，96.0%），consciousness disorder（25/36，69.4%），vomiting（22/36，61.1%），seizures（14/36，38.9%），limb dysfunction（11/36，30.6%）.The leading etiologies were infection（14/36，38.9%），head trauma（8/36，22.2%），and tumors/chemotherapy（6/36，16.7%）.All 36 children underwent MRI+MRV examination of the head,and all of them had different degrees of CVST,the most commonly involved site was transverse sinus (28/36,77.8%).The favorable-prognosis group（ n=18）included 16 patients receiving anticoagulation and 2 trauma cases without anticoagulation.The poor-prognosis group（ n=18）comprised 9 anticoagulated and 9 non-anticoagulated patients.There were no significant differences in age,sex,clinical manifestations,etiology/inducement and thrombus site between the two groups ( P>0.05).However,the proportion of anticoagulant therapy in the favorable-prognosis group was higher than that in the poor-prognosis group(88.9% vs 50.0%).Among the 25 children receiving anticoagulant therapy,16 had a good prognosis (64.0%),while among the 11 children receiving no anticoagulant therapy,only 2 had a good prognosis (18.2%).The prognosis of children receiving anticoagulant therapy was better than that of those receiving no anticoagulant therapy.The difference was statistically significant ( P<0.05).Fourteen children were admitted with intracranial hemorrhage,with 8 receiving anticoagulant therapy (7 with good prognosis,accounting for 87.5%) and 6 not receiving anticoagulant therapy (only 1 with good prognosis,accounting for 12.5%).The prognosis of children receiving anticoagulant therapy was better than that of those receiving no anticoagulant therapy,and the difference was statistically significant ( P=0.026),with no increasing in intracranial hemorrhage after anticoagulant therapy.Univariate Logistic regression analysis showed that inducement/etiology,intracranial hemorrhage before treatment and prognosis were not related（ P >0.05），but anticoagulation treatment was associated with favorable outcomes（ OR=0.125，95% CI 0.017-0.614, P=0.009）. Conclusion:Infection is the primary etiology of pediatric CVST，with headache，lethargy，and vomiting as key symptoms.Transverse sinus is the most commonly involved site.Children suspected of CVST should be examined by MRI/MRV as soon as possible,and early anticoagulation therapy should be given after a clear diagnosis,so as to improve the prognosis.

Objective:To investigate the clinical manifestations，etiology/triggers，treatment，and prognosis of children with cerebral venous sinus thrombosis（CVST）.Methods:A retrospective analysis was conducted on 36 children with CVST hospitalized at the Affiliated Children's Hospital of Xiangya School of Medicine,Central South University（Hunan Children's Hospital）from May 2014 to January 2024.A centralized telephone follow-up was performed in May 2024，and clinical data including symptoms，imaging findings，treatments，and outcomes were collected.According to the prognosis,the children were divided into favorable-prognosis group and poor-prognosis group,and the differences of clinical characteristics between the two groups were compared.The univariate Logistic regression was applied to identify factors associated with prognosis.Results:Among the 36 cases,there were 29 males and 7 females,ranging in age from 1 month to 13 years and 3 months,with a median age of 4.6(1.0,8.3) years.The common clinical manifestations included headache（24/25，96.0%），consciousness disorder（25/36，69.4%），vomiting（22/36，61.1%），seizures（14/36，38.9%），limb dysfunction（11/36，30.6%）.The leading etiologies were infection（14/36，38.9%），head trauma（8/36，22.2%），and tumors/chemotherapy（6/36，16.7%）.All 36 children underwent MRI+MRV examination of the head,and all of them had different degrees of CVST,the most commonly involved site was transverse sinus (28/36,77.8%).The favorable-prognosis group（ n=18）included 16 patients receiving anticoagulation and 2 trauma cases without anticoagulation.The poor-prognosis group（ n=18）comprised 9 anticoagulated and 9 non-anticoagulated patients.There were no significant differences in age,sex,clinical manifestations,etiology/inducement and thrombus site between the two groups ( P>0.05).However,the proportion of anticoagulant therapy in the favorable-prognosis group was higher than that in the poor-prognosis group(88.9% vs 50.0%).Among the 25 children receiving anticoagulant therapy,16 had a good prognosis (64.0%),while among the 11 children receiving no anticoagulant therapy,only 2 had a good prognosis (18.2%).The prognosis of children receiving anticoagulant therapy was better than that of those receiving no anticoagulant therapy.The difference was statistically significant ( P<0.05).Fourteen children were admitted with intracranial hemorrhage,with 8 receiving anticoagulant therapy (7 with good prognosis,accounting for 87.5%) and 6 not receiving anticoagulant therapy (only 1 with good prognosis,accounting for 12.5%).The prognosis of children receiving anticoagulant therapy was better than that of those receiving no anticoagulant therapy,and the difference was statistically significant ( P=0.026),with no increasing in intracranial hemorrhage after anticoagulant therapy.Univariate Logistic regression analysis showed that inducement/etiology,intracranial hemorrhage before treatment and prognosis were not related（ P >0.05），but anticoagulation treatment was associated with favorable outcomes（ OR=0.125，95% CI 0.017-0.614, P=0.009）. Conclusion:Infection is the primary etiology of pediatric CVST，with headache，lethargy，and vomiting as key symptoms.Transverse sinus is the most commonly involved site.Children suspected of CVST should be examined by MRI/MRV as soon as possible,and early anticoagulation therapy should be given after a clear diagnosis,so as to improve the prognosis.

Objective:To explore the clinical manifestations and genetic characteristics of a child with Leukoencephalopathy with ataxia (LKPAT) caused by a CLCN2 gene variant. Methods:A retrospective analysis was conducted on the clinical data of a child admitted to Hunan Children′s Hospital in June 2024 due to " intermittent convulsions for 13 days" . Peripheral blood samples were collected from the child and his parents for whole exome sequencing, followed by Sanger sequencing validation and pathogenicity analysis of candidate variants. Literature searches were performed using the keywords " CLCN2 gene" "chloride channel-2" "leukoencephalopathy with ataxia/LKPAT" "leukoencephalopathy" in both Chinese and English on CNKI, Wanfang, and PubMed databases. The search time was set from the establishment of the databases to July 31, 2024. Childhood-onset LKPAT literature was screened and analyzed. This study was approved by the Medical Ethics Committee of Hunan Children′s Hospital (Ethics No. HCHLL-2024-351). Results:① The child was a 7-month-and-26-day-old male infant born to consanguineous parents, presenting with epileptic seizures and borderline development. Cranial MRI revealed symmetrical long T 2 signal shadows in the posterior limb of the internal capsule, cerebral peduncle, pons, and middle peduncle of the cerebellum. Video electroencephalogram (EEG) showed an abnormal childhood EEG with one focal seizure. ② Whole exome sequencing revealed a homozygous c. 2201dup (p.Glu735Ter) variant in the CLCN2 gene of the child. Sanger sequencing confirmed that the variant was inherited from both parents. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), this variant was classified as pathogenic (PVS1+ PM3_Supporting+ PM2_Supporting). ③ A total of 8 relevant literature were retrieved, together with the present case, 16 childhood-onset LKPAT patients were cumulatively reported, which consisted of 9 males and 7 females. Twelve CLCN2 gene variants were involved, including 2 nonsense variants, 3 missense variants, 7 frameshifting variants, 2 c. 61dup variants, and 5 c.1709G>A variants. The initial symptoms of the 16 patients included headache, ataxia, epileptic seizures, spasticity, developmental delay, lower back pain, hearing impairment, and intention tremor. Three patients had the onset of the disease before the age of one, of which two had epileptic seizures as the initial symptom. Conclusion:The homozygous variant CLCN2: c. 2201dup (p.Glu735Ter) is considered the pathogenic cause of LKPAT in this child, marking the first childhood-onset case reported in China. Genetic testing has facilitated the diagnosis of childhood-onset LKPAT and expanded the spectrum of CLCN2 gene mutations.

Objective:To summarize the clinical manifestations, genetic characteristics and diagnosis and treatment processes of ATP1A2 gene-related childhood neurological diseases presenting with hemiplegic migraine (HM) or epilepsy, and enhance the understanding of clinicians on the diseases related to this gene. Methods:A retrospective study was performed; data of 5 children with ATP1A2 gene variations admitted to Department of Neurology, Hunan Children's Hospital from April 2015 to June 2024 were collected, and their clinical characteristics were summarized. ATP1A2 gene variations were confirmed by whole exome sequencing on these 5 children's families using next-generation sequencing (NGS), and then, further validated by Sanger sequencing. A comprehensive literature search was performed through PubMed, CNKI, and Wanfang databases to summarize the disease spectrum associated with this gene. Results:Among the 5 pediatric patients, 3 exhibited HM phenotype (all presented with neurological symptoms of epilepsy/febrile seizures within the first year of life, followed by HM onset after intervals ranging from 3 years and 3 months to 7 years); 2 pediatric patients aligned with epilepsy phenotype, including one instance of drug-resistant focal-onset epileptic encephalopathy. These 5 pediatric patients carried de novo missense variants in the ATP1A2 gene, encompassing 5 distinct mutation sites. Notably, the c.1023C>G (p.Cys341Trp) and c.2458G>A (p.Ala820Thr) variants were not documented in ClinVar or HGMD databases, and were classified as likely pathogenic according to American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines. Literature review revealed that all reported ATP1A2 mutations in Chinese pediatric patients were missense variants, with c.2143G>C (p.Gly715Arg) being the most commonly prevalent (8/29, 27.6%). The predominant clinical manifestation was HM (22/29), characterized by hemiplegia, aphasia, fever, impaired consciousness, and convulsions (early transient neurological symptoms frequently manifested as febrile seizures [12/22, 54.4%]); additionally, alternating hemiplegia of childhood was noted in 4 pediatric patients and epilepsy in 3 pediatric patients. Conclusion:ATP1A2 gene variants can lead to neurological disorders such as HM and epilepsy, with varied severity at same phenotype; the missense variants c.1023C>G and c.2458G>A in the ATP1A2 gene expand the spectrum of ATP1A2 gene variants and may serve as genetic causes of epilepsy.

Objective:To analyze the clinical phenotype and genotype characteristics of children with pyridoxine-dependent epilepsy (PDE) and provide evidence for diagnosis.Methods:Clinical data of 3 children with PDE enrolled in the Department of Neurology of Hunan Children′s Hospital from July 2016 to December 2020 were collected, and whole-exome sequencing (WES) was used for analysis. Pathogenic variants were analyzed and screened using bioinformatics tools combined with clinical phenotype. Sanger sequencing was used to analyze the source of mutations in children′s core family members.Results:Cases 1 (female) and 2 (male) were siblings, both of whom had convulsions within 24 hours after birth. WES results showed that the siblings carried compound heterozygous mutations of c.796C>T (p.R266 *) and c.1553G>C (p.R518T) in the ALDH7A1 gene, coming from the father and mother of the siblings respectively. Both of the mutations have been reported as pathogenic. Case 3, female, developed convulsions at the age of 1. WES results revealed that she carried compound heterozygous mutations of c.1094-109T>A and c.7C>T (p.R3C) in the ALDH7A1 gene, coming from her father and mother respectively. After searching HGMDPro, PubMed, 1000 Genomes, and dbSNP databases, both of the 2 mutations of c.1094-109T>A and c.7C>T (p.R3C) were not reported. The pathogenicity predictions of the 2 mutations were carried out by different biological information analysis software. The results showed that both of the mutations were harmful. All the 3 children had no epileptic seizures after treatment with increased doses of vitamin B6. Conclusions:When infants have unexplained convulsions, especially in the neonatal stage, PDE caused by ALDH7A1 gene mutation should be considered. Pyridoxine precision treatment has a good effect. The 2 de novo mutations of c.1094-109T>A and c.7C>T (p.R3C) enrich the mutation spectrum in the ALDH7A1 gene. WES has the auxiliary significance in the diagnosis of epilepsy.

Objective:To investigate the clinical features, treatments and prognoses of children with antibody-mediated central nervous system (CNS) autoimmune diseases.Methods:Two hundred and seven children with antibody-mediated CNS autoimmune diseases confirmed by anti-neuronal antibody detection in blood and/or cerebrospinal fluid in Department of Neurology, Children's Hospital of Hunan Province from June 2014 to May 2022 were enrolled. Their clinical features, laboratory and imaging data, treatment regimens and prognoses were retrospectively analyzed.Results:Of the 207 children, 117 were positive for anti- N-methyl- D-aspartate receptor (NMDAR) antibodies, 63 for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, 32 for anti-glial fibrillary acidic protein (GFAP) antibodies, 6 for anti-contactin-associated protein-like 2 (CNTNAP2) antibodies, 3 for anti-aquaporin 4 (AQP4) antibodies, 2 for anti-gamma-aminobutyric acid type B receptor (GABABR) antibodies, and 1 for anti-anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies. Acute disseminated encephalomyelitis (ADEM) was the most common clinical phenotype among the children, followed by optic neuritis (ON). Behavioral abnormalities, seizures, and involuntary movements were the most common clinical presentations of anti-NMDAR encephalitis for these children, while fever, headache, and disturbance of consciousness or vision were the most common symptoms for children with MOG antibody disease or autoimmune GFAP astrocytopathy. The coexistence of multiple anti-neural antibodies was detected in 17 patients, among which 10 had coexistent anti-NMDAR and anti-MOG antibodies (including 1 with anti-GFAP antibody), 3 had coexistent anti-NMDAR and anti-GFAP antibodies, 3 had coexistent anti-MOG and anti-GFAP antibodies, 2 had coexistent anti-NMDAR and anti-CASPR2 antibodies, and 1 had coexistent anti-GABABR and anti-CASPR2 antibodies. In our cohort, of the 202 children examined for cerebrospinal fluid, 154 had cerebrospinal fluid leukocytosis and 27 had elevated protein. Of the 203 children had electroencephalography, 179 was abnormal; abnormal EEG was mainly manifested as focal or global slow waves, and epileptic discharge in some children; 205 patients received immunotherapy. All survivors were followed up for at least 6 months; 164 recovered completely, 40 had varied sequelae, and 3 died; 28 had one or more relapses. Conclusion:Antibody-mediated CNS autoimmune diseases occur in children at all ages; most such pediatric patients have good response to immunotherapy, enjoying low mortality rate; however, some survivors have relapsing risk.

OBJECTIVE: To report on the clinical, metabolic and genetic characteristics of a child with carnitine palmitoyl transferase 1A (CPT1A) deficiency. METHODS: Clinical data and the level of acylcarnitine for a child who initially presented as epilepsy were analyzed. Genomic DNA was extracted from peripheral blood samples of the child and her parents and subjected to next-generation sequencing (NGS). RESULTS: Mass spectrometry of blood acylcarnitine indicated increased carnitine 0 (C0) and significantly increased C0/ (C16+C18). DNA sequencing revealed that the child has carried compound heterozygous variants of the CPT1A gene, namely c.1846G>A and c.2201T>C, which were respectively inherited from her mother and father. CONCLUSION CPT1A presenting initially as epilepsy was unreported previously. Analysis of blood acylcarnitine C0 and C0/ (C16 + C18) ratio and NGS are necessary for the identification and diagnosis of CPT1A deficiency. The c.1846G>A and c.2201T>C variants of the CPT1A gene probably underlay the disease in this child. Above finding has also enriched the spectrum of CPT1A gene variants.
Carnitine/blood* ; Carnitine O-Palmitoyltransferase/genetics* ; Child ; DNA Mutational Analysis ; Female ; Humans ; Hypoglycemia/genetics* ; Lipid Metabolism, Inborn Errors/genetics*