Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability.

BACKGROUND: The Houge type of X-linked syndromic mental retardation is an X-linked intellectual disability (XLID) recently recorded in the Online Mendelian Inheritance in Man (OMIM) and only 8 cases have been reported in literature thus far. CASE PRESENTATION: We present two brothers with intractable seizures and syndromic intellectual disability with symptoms consisting of delayed development, intellectual disability, and speech and language delay. The mother was a symptomatic carrier with milder clinical phenotype. Whole exome sequencing identified a small fragment deletion spanning four exons, about 9.5 kilobases (kb) in length in the CNKSR2 gene in the patients. The mutation co-segregation revealed that exon deletions occurred de novo in the proband's mother. CONCLUSION: Although large deletions have been reported, no small deletions have yet been identified. In this case report, we identified a small deletion in the CNKSR2 gene. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.

A case of mitochondrial and peroxisome fission deficiency-related encephalopathy caused by DNM1L gene mutation / 中华神经科杂志

Mitochondrial and peroxisome fission deficiency-related encephalopathy caused by DNM1L gene mutation is a rare and fatal epileptic encephalopathy, with clinical phenotype and genetic heterogeneity. The acute stage is drug-resistant epilepsy with poor prognosis and serious neurological sequelae. A case of genetically confirmed encephalopathy related to mitochondrial and peroxisome fission defects is reported, the clinical data, treatment process are summarized, and the previous literature is reviewed to improve the understanding of the rare disease.

Analysis of the clinical presentation and genetic profile of epilepsy-aphasia spectrum due to GRIN2A gene mutations / 中华神经科杂志

Objective:To explore the clinical phenotypic features and genetic variation characteristics of children with epilepsy-aphasia spectrum due to GRIN2A gene variants confirmed by second-generation sequencing. Methods:The clinical data of 5 children with epilepsy-aphasia spectrum with epileptic onset diagnosed in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University, from February 2019 to November 2022 were retrospectively analyzed. Whole-exome genome sequencing of the probands using a second-generation sequencing method confirmed that all 5 cases were children with the GRIN2A gene variant. The characteristics of the GRIN2A gene variants were analyzed. Results:Among the 5 children diagnosed with epileptic aphasia spectrum due to GRIN2A gene variants, the male-to-female ratio was 4∶1, and the age range of onset was 1.5-4.4 years. The clinical phenotype included seizures in all cases, language and intellectual developmental deficits in 4 cases, and attention deficit hyperactivity disorder in 3 cases. The seizures were manifested as focal seizures or secondary generalized seizures, and were effectively controlled with antiepileptic drugs. Among the 5 children, gene variant of case 1 was originated from a paternal heterozygous variant, and cases 2-5 had de novo variants, which were c.2107C>T (p.Gln703 *) nonsense variant, c.2284G>A (p.Gly762Arg) missense variant, c.2197del (p.Ala733Glnfs *3) shifted coding variant, c.2511G>A (p.Trp837 *) nonsense variant, and c.1651+1G>C shear site variant, respectively. None of the 5 loci were reported in the literature. Conclusions:Epilepsy-aphasia spectrum is an epilepsy syndrome with a complex onset, and may have different phenotypes at different genetic variant loci, with focal seizures or secondary generalized seizures, which can be effectively controlled with anti-seizure medication. The GRIN2A gene variant is the genetic etiology of the epileptic aphasia spectrum.

Clinical characteristics and genetic analysis of childhood onset neurodegeneration associated with UBTF gene variation / 中华神经科杂志

Objective:To summarize the clinical phenotype and genetic characteristics of children with neurodegeneration caused by UBTF gene mutations in childhood. Methods:The clinical and genetic data of 3 children with neurodegeneration in childhood diagnosed in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University from February 2020 to January 2023 were retrospectively analyzed. All the 3 probands were found having UBTF gene mutations through the whole exome gene sequencing, and the first generation Sanger sequencing method was used to verify the UBTF gene in their family members. The variation characteristics of the UBTF gene were analyzed, and the treatment and follow-up results of the 3 children were summarized. Results:Among the 3 children with childhood onset neurodegeneration, 2 were male and 1 female, aged 9 months, 4 years and 6 months after birth, respectively. The clinical phenotypes mainly included motor retardation, speech and mental retardation, and dystonia. Among them, case 1 and case 2 had seizures, case 1 had dysphagia, feeding problems, no weight gain and ataxia. Brain MRI plain scan showed that case 1 and case 2 had different degrees of cerebral atrophy, case 1 had hypoplasia of corpus callosum, ventricle expansion and softening focus, and case 3 showed non-specific widening of the subarachnoid space. There were no abnormalities in the chromosome copy number variation and mitochondrial ring gene testing in the 3 children; the whole exon gene testing suggested the de novo missense variant in the UBTF gene [NM_014233.4: c.1414(exon14) G>A (p.Gly472Ser), c.1392(exon14)G>T(p.Lys464Asn)] and the maternal nonsense variant [NM_014233.4:c.520C>T(p.Arg174 *)], which were unreported site variants. In terms of treatment, the 3 children received comprehensive rehabilitation function training, and achieved a certain degree of language and intelligence improvement. Seizure control was effectively managed in case 1 with a single antiepileptic drug. Epileptic seizures were effectively treated and controlled in case 2 using more than 4 types of antiepileptic drugs. Conclusions:Neurodegenerative changes caused by UBTF gene mutations in childhood are relatively rare, and some cases may be accompanied with brain atrophy. De novo missense variation and maternal nonsense variation of the UBTF gene are the genetic etiology of the 3 probands.

A case of developmental epileptic encephalopathy type 67 caused by CUX2 gene mutation and literature review / 中华神经科杂志

Objective:To summarize the clinical phenotype and CUX2 gene variation characteristics of developmental epileptic encephalopathy type 67 confirmed by whole exome sequencing. Methods:Clinical data of 1 case diagnosed as CUX2 gene mutations related developmental epileptic encephalopathy type 67 in the Children′s Hospital Affiliated to Zhengzhou University in January 2021 were collected, the patient′s clinical characteristics, genetic testing, head imaging, electroencephalogram results and treatment were summarized, and the patient was regularly followed-up every 3 months. At the same time, the domestic and foreign literatures on epileptic encephalopathy caused by CUX2 gene mutation were reviewed. Results:The proband was a 6 years and 4 months old girl. The main clinical manifestations included focal origin progression to bilateral tonic-clonic seizures, retardation of intellectual, language, and motor development, autistic behavior, hyperactivity disorder, and involuntary hand clapping. The video electroencephalogram showed extensive spiny slow wave and multi-spiny slow wave emission in waking and sleeping stages, and spiny slow wave and spiky slow wave emission in bilateral anterior head in sleeping stage. Brain magnetic resonance imaging (MRI) plain scan and T 2-fluid attenuated inversion recovery (T 2-FLAIR) thin layer scan showed that the signal of the left hippocampus was higher than that of the right, and the left hippocampus was slightly swollen. One month later, the brain MRI and T 2-FLAIR were reexamined. The left hippocampal signal was still slightly higher and decreased, and the hippocampal volume was slightly reduced. Whole exome sequencing showed the CUX2 gene with c.1768G>A(p.Glu590Lys) heterozygous missense variant, which was a reported de novo pathogenic variant and both of her parents were wild-type. A total of 10 cases of new heterozygous missense variants in CUX2 gene [c.1768G>A (p.Gelu590Lys)] were reported in 4 literatures. No relevant cases have been reported in China. Conclusions:Developmental epileptic encephalopathy type 67 is relatively rare. The main clinical features are seizures, global developmental delay, movement disorders, athetosis, autism and hyperactivity disorder. The heterozygous missense variant c.1768G>A (Glu590Lys) of CUX2 gene maybe the genetic cause of this case.

A case of glutathione synthetase deficiency due to compound heterozygous variant of glutathione synthase gene / 中华神经科杂志

The clinical data and gene variant characteristics of a patient with glutathione synthetase (GSS) deficiency were summarized. The child was born 15 min prematurely as a male infant with postnatal respiratory distress, metabolic acidosis, severe anemia, hemolysis, hyperbilirubinemia, and motor developmental backwardness. Blood and urine genetic metabolic screening showed a blood glutamate value of 1 343.1 μmol/L and a urine 5-oxoproline value of 1 873.7 nmol/mg creatinine. Cranial magnetic resonance imaging showed nonspecific subarachnoid widening. Whole-exon gene sequencing of the family line suggested that the GSS gene of the preexisting patient originated from paternal and maternal variants, respectively: c.632_633del (p.Gln211Argfs *8), and c.491G>A (p.Arg164Gln). Complex heterozygous variants of the GSS gene were the genetic etiology of the present case.

Legius syndrome combined with central precocious puberty: a case report and literature review / 中华神经科杂志

Objective:To investigate the clinical phenotype and genotypic characteristics of Legius syndrome.Methods:The clinical data of a child with precocious puberty and scattered café-au-lait macules admitted to Department of Neurology of the Children′s Hospital Affiliated to Zhengzhou University in July 2021 were retrospectively analyzed. Trio-whole exome sequencing (trio-WES) was used for genetic analysis to confirm the molecular diagnosis of the family. The relevant literature was reviewed to summarize the clinical characteristics of the disease.Results:The proband was a 10-year and 9-month-old girl, presenting with more than 5 café-au-lait macules with diameter>5 mm on the face and trunk, freckles in the axillary, without Lisch tubercles of iris and tumor signs of neurofibromatosis type 1, diagnosed as central precocious puberty at the age of 8. trio-WES results of the family revealed a spontaneous heterozygous nonsense mutation c.751(exon7) C>T in SPRED1 gene, causing a nonsense mutation in the amino acid sequence p.Arg251Ter (p. Ter251 *). Literature review showed a total of 88 pathogenic mutations were reported in SPRED1 gene, including frameshift mutations (41/88), nonsense mutations (31/88), splice mutations (7/88), missense mutations (6/88), and others (3/88), and no mutational hotspots were found. Clinical phenotype was as follows:>5 café-au-lait macules accounted for 92.8% (168/181), armpit and inguinal freckles 43.5% (73/168), macrocephaly 21.4% (31/145), learning disability 18.0% (30/166), psychomotor retardation 13.8% (22/159), lipoma (adult) 13.7% (21/153), Noonan facial sign 12.1% (21/173), and tumor phenotype of neurofibromatosis type 1 was not reported. Conclusions:The central precocious puberty phenotype of Legius syndrome was not reported in China. The clinical phenotype of Legius syndrome was mild, with a large variation, but without neurofibromatosis type 1 tumor phenotype. Genetic testing can be beneficial for early diagnosis of Legius syndrome.

Effects of ICG-001 on autistic behaviors and the development of hippocampal dendritic spine morphology in rats / 中华实用儿科临床杂志

Objective:To explore the effects of the compound ICG-001 on autism-like behaviors and the morphological development of dendritic spines in hippocampal pyramidal neurons of rats.Methods:Healthy Wistar rats were mated.The offspring were divided into the saline-treated group, ICG-001 control group, Sodium valproate (VPA) group and ICG-001 treatment group by using the random number table method.Each group had 12 rats.Social interaction, repetitive, compulsive and anxiety-like behaviors in rodents were assessed by three-chambered social approach, marble burying, open-field and elevated plus maze tests.The number of neuronal nuclei (NeuN)-positive neurons in the hippocampal CA1 region was calculated by the immunofluorescence method.Golgi staining was carried out to detect the density and morphological changes of dendritic spines in hippocampal pyramidal neurons of rats.The expression of phosphorylated LIM kinase 1(LIMK1), phosphorylated actin binding protein(Cofilin), fibros actin (F-actin) and developmentally-regulated brain protein A (Drebrin A) was examined by Western blot.The univariate analysis was made to examine whether the difference was statistically significant, and the data between groups were compared by the Tukey method. Results:(1) In the three-chambered social approach test, the rats in the saline-treated group, ICG-001 control group, VPA group and ICG-001 treatment group spent (219.42±5.38) s, (218.67±10.12) s, (126.58±5.02) s, and (218.58±6.63) s in the chamber, respectively.The corresponding preference score of the said 4 groups were 0.43±0.05, 0.43±0.04, 0.22±0.01 and 0.42±0.04, respectively.Compared with the VPA group, the ICG-001 treatment group spent longer time in the chamber and had a higher preference score (all P<0.05). (2) In the marble burying experiment, the number of marbles buried in said 4 groups were 9.13±0.52, 9.08±0.64, 15.13±0.82 and 9.42±0.86, respectively.ICG-001-treated rats buried markedly less marbles than VPA-exposed rats ( P<0.05). (3) In the open-field test, the rats in the said 4 groups spent (82.33±1.83) s, (81.32±4.19) s, (45.51±3.02) s and (81.44±3.19) s in the center area, respectively.Administration of ICG-001 significantly increased the time that VPA-exposed rats spent in the center area ( P<0.05). (4)In the elevated plus maze trial, the rats in the said 4 groups spent (107.75±7.23) s, (106.08±7.50) s, (63.42±1.91) s and (106.67±7.07) s in open arms, respectively.ICG-001 treatment notably increased the time that VPA-exposed rats spent in open arms ( P<0.05). (5) Immunofluorescence analysis results revealed that the number of NeuN-positive cells in the hippocampal CA1 region of said 4 groups was (41.83±1.17)×10 4/μm 2, (41.00±0.77)×10 4/μm 2, (27.17±0.95)×10 4/μm 2 and (40.00±0.90)×10 4/μm 2, respectively.ICG-001 treatment normalized the alteration in the number of NeuN-containing neurons in VPA-exposed rats ( P<0.05). (6) Golgi staining showed that the density of dendritic spines in hippocampal CA1 pyramidal neurons of said 4 groups was (0.74±0.04)/μm, (0.73±0.03)/μm, (0.49±0.03)/μm and (0.70±0.02) /μm, respectively.Of all types of dendritic spines, mushroom spines accounted for (0.49±0.02)%, (0.49±0.02)%, (0.33±0.02)% and (0.43±0.02) % in said 4 groups.Thin spines accounted for (0.27±0.02)%, (0.26±0.02)%, (0.34±0.01)% and (0.26±0.01) % in said 4 groups, respectively.Compared with the VPA group, the ICG-001 treatment group showed a significant increase in the density of dendritic spines in hippocampal CA1 pyramidal neurons ( P<0.05). After ICG-001 treatment, the number of mushroom spines greatly increased and the number of thin spines sharply decreased in VPA-exposed rats (all P<0.05). (7) According to Western blot test results, the phosphorylated LIMK1/LIMK1 ratio of the hippocampus in said 4 groups were 100.33±2.30, 99.34±2.28, 57.76±4.10 and 99.13±1.90, respectively.The phosphorylated Cofilin /Cofilin ratio were 100.18±2.43, 100.18±1.70, 57.12±1.88 and 99.53±1.69, respectively.The F-actin/globular actin(G-actin) ratio were 100.07±0.86, 99.99±1.72, 51.19±1.23 and 99.28±3.17, respectively.The expression level of Drebrin A were 100.79±1.19, 100.12±2.04, 52.86±3.26 and 99.97±2.44, respectively.Administration of ICG-001 effectively prevented the decrease of phosphorylated LIMK1, phosphorylated Cofilin, F-actin and Drebrin A in the hippocampus of VPA-exposed rats (all P<0.05). Conclusions:ICG-001 regulates the LIMK1/Cofilin signaling pathway, promotes the generation of F-actin, increases the expression of Drebrin A, and thereby alleviates autistic-associated symptoms.

Clinical characteristics and genetic variant analysis of a child with Snijders Blok-Campeau syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variant of a child with Snijders Blok-Campeau syndrome (SBCS).@*METHODS@#A child who was diagnosed with SBCS in June 2017 at Henan Children's Hospital was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and the extraction of genomic DNA, which was subjected to trio-whole exome sequencing (trio-WES) and genome copy number variation (CNV) analysis. Candidate variant was verified by Sanger sequencing of his pedigree members.@*RESULTS@#The main clinical manifestations of the child have included language delay, intellectual impairment and motor development delay, which were accompanied with facial dysmorphisms (broad forehead, inverted triangular face, sparse eyebrows, widely spaced eyes, narrow palpebral fissures, broad nose bridge, midface hypoplasia, thin upper lip, pointed jaw, low-set ears and posteriorly rotated ears). Trio-WES and Sanger sequencing revealed that the child has harbored a heterozygous splicing variant of the CHD3 gene, namely c.4073-2A>G, for which both of his parents were of wild-type. No pathogenic variant was identified by CNV testing.@*CONCLUSION@#The c.4073-2A>G splicing variant of the CHD3 gene probably underlay the SBCS in this patient.

Late-onset cluster seizures caused by a truncation variation in SMC1A gene: a case report and literature review / 中华神经科杂志

Objective:To summarize the clinical phenotype and genotypic characteristics of children with truncation variation in SMC1A gene. Methods:The clinical data of a child with late-onset cluster seizures caused by truncation variation in SMC1A gene diagnosed in February 2021 in Children′s Hospital Affiliated to Zhengzhou University were collected. The relevant literature was reviewed to summarize the clinical characteristics. Results:The proband was a 5-year-old girl, presenting with first seizure at the age of 5 and cluster seizures. She had poor response to multiple antiepileptic drugs, and had normal neurodevelopment before seizures. Whole exome sequencing results revealed a spontaneous heterozygous nonsense variation c.55C>T in SMC1A gene, causing a nonsense variant in the amino acid sequence p.Gln19Ter(p.Gln19 *), which has not been reported. There were a total of 14 relevant literatures, and there were in total 32 cases with truncation variation in SMC1A gene including this case. All children were female and 30 children had early-onset intractable epilepsy, and first seizure median age was 5 months (range: 4 weeks to 40 months); 78.1% (25/32) of them had cluster seizures; 93.8% (30/32) had mental retardation; Cornelia de Lange syndrome clinical score in 68.8% (22/32) of them was≥4. The truncation variations in SMC1A gene of 31 children were de novo, and there were 16 children with frameshift variation (16/32), 12 children with nonsense variation [12/32; 3 children (9.4%, 3/32) with c.2923C>T], 4 children with splice variation (4/32). Conclusions:This study further expands the clinical phenotype and genotype of cases with truncation variation in SMC1A gene. Case presenting with female late-onset cluster seizures has not been reported in China, and genetic testing can be beneficial for early diagnosis of hereditary epilepsy and precision treatment.

Clinical characteristics and genetic analysis of HPDL biallelic gene related neurodevelopmental disorders with progressive spasm and cerebral white matter abnormalities / 中华神经科杂志

Objective:To summarize the clinical phenotype and genetic characteristics of biallelic variation in HPDL leading to neurodevelopmental disorders with progressive spasticity and cerebral white matter abnormalities. Methods:The clinical and genetic data of 3 cases with neurodevelopmental disorders confirmed in the Department of Neurology of the Affiliated Children′s Hospital of Zhengzhou University from February 2018 to June 2022 were analyzed. The second-generation sequencing method was used to sequence the HPDL gene and the first-generation Sanger sequencing was used to verify the family members, and the characteristics of gene variants were summarized, and the 3 cases were treateds and followed-up. Results:Among the 3 children with neurodevelopmental disorders, 2 were females and 1 was male, and the age of onset was 25 days to 11 years of birth. In the clinical phenotypes, cases 1 and 2 were children with Leigh-like syndrome with infancy onset, with recurrent seizures, intelligent backwardness, language and motor delay, lactic acid increase, acidosis. Cranial magnetic resonance plain scan suggested deepening of the sulcus in the bilateral cerebral hemisphere, abnormal symmetrical signals in the basal ganglia, dorsal thalamus, cerebral peduncles and brainstem, expansion of the supratentorial ventricle, and thinning of the corpus callosum. And cranial magnetic resonance spectroscopy suggested visible lactate peaks in the measurement area of bilateral putamen lesions. Case 3 presented with spastic paraplegia, early motor retardation, and late spastic gait. The plain skull magnetic resonance imaging scan showed no abnormalities. In the 3 cases, the whole exon genome sequencing showed the heterozygous variant c.26_.28delGCC(p.Cys9_His10delinsTyr) and the parent missense heterozygous variant c.788C>T(p.Thr263Met), the paternal truncated variant c.1051C>T(p.Gln351 *) and the parent frameshift variant c.995de1C(p.Thr332Mfs * 9), the parent missense variant c.781C>G (p.Leu261Val) and the parent truncated variant c.721C>T (p.Gln241 *). The c.26_28delGCC(p.Cys9_His10delinsTyr) was an unreported site mutation. No abnormalities were found in chromosomal copy number variation and mitochondria-related genes. Cases 1 and 2 were treated with anti-seizure drugs and cocktail, and the seizure was under effective control; case 3 was treated with comprehensive treatment and rehabilitation function training, and exercise and intelligence were improved. Conclusions:The clinical phenotype of the biallelic variant in HPDL was Leigh-like syndrome and hereditary spastic paraplegia, characterized by compound heterozygous variant, including whole code, missense, frameshift, and truncated variants. Biallelic variation in HPDL was found to be the genetic etiology of the 3 probands.

A case of Poirier-Bienvenu neurodevelopmental syndrome associated with CSNK2B gene shear variation and literature review / 中华神经科杂志

Objective:To summarize the clinical phenotype and genetic characteristics of Poirier-Bienvenu neurodevelopmental syndrome associated with CSNK2B gene variation. Methods:The clinical and genetic data of a child with Poirier-Bienvenu neurodevelopmental syndrome caused by shear variant of CSNK2B gene who was diagnosed in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in March 2022 were collected. Previous relevant literature at home and abroad was reviewed to summarize the clinical characteristics of the disease. Results:The child was a girl aged 13 months, mainly due to "intermittent convulsions for 2 months" for consultation. The clinical manifestations of the girl were normal face, generalized tonic-clonic seizures, low intelligence, language and motor retardation, and there was no abnormality in the long-range video electroencephalography and the head magnetic resonance imaging. No abnormality was found in chromosome karyotype analysis and chromosome coefficient of copy variation analysis. The whole exon gene sequencing test indicated that the child carried de novo heterozygous shear variant of CSNK2B gene c.291+5G>C, which had not been reported in the literature. According to the clinical manifestations and genetic examination results of the child, the diagnosis of Poirier-Bienvenu neurodevelopmental syndrome was clear. The CSNK2B gene of the proband′s parents and the twin sister was wild-type. The application of sodium valproate anti-seizure medication could effectively control the seizures of the child, and by giving rehabilitation function training, the child′s language and gross motor function was improved. Conclusions:The Poirier-Bienvenu neurodevelopmental syndrome is a rare autosomal dominant disorder caused by variants in the CSNK2B gene. The clinical manifestations are infancy-onset seizures, intellectual development disorders, language and motor development disorders, etc, and the video electroencephalogram and skull magnetic resonance are mostly normal. The CSNK2B gene shear variant is the genetic etiology of the proband.

Combined oxidative phosphorylation deficiency type 4: clinical features and TUFM gene mutation analysis / 中华神经科杂志

Objective:To investigate the clinical characteristics of patients with combined oxidative phosphorylation deficiency type 4 (COXPD4) related to TUFM gene variation, in order to improve clinicians′ understanding of the disease. Methods:A case of COXPD4 with cystic leukodystrophy admitted to the Children′s Hospital of Zhengzhou University in June 2021 was taken as the study subject, and her clinical characteristics and genetic testing results were retrospectively analyzed. The "combined oxidative phosphorylation deficiency type 4" " TUFM gene" "cystic leukodystrophy" "combined oxidative phosphorylation deficiency 4" "COXPD 4" " TUFM" and "cystic leukodystrophy" were used as keywords, and the documents on COXPD4 related to TUFM gene mutations were reviewed from Wanfang Data Knowledge Service Platform, CNKI, PubMed Document Database, and National Center for Biotechnology Information (NCBI) until August 2021. The COXPD4 patients that have been reported internationally were analyzed for clinical features and variant types. Results:The patient was a 2-month-old girl with clinical manifestations of delayed development and progressive aggravation, elevated lactic acid in serum and cerebrospinal fluid, and diffuse white matter dysplasia with multiple cystic lesions in cerebral magnetic resonance imaging (MRI). Whole exome sequencing showed TUFM gene complex heterozygous variants c.684_684+4delGGTGA and c.1105C>T, which had not been reported in the past. A total of 5 cases of COXPD4 were reported in 4 English literatures. Together with 1 case in this study, there were 4 cases with detailed clinical history data, including 1 male and 3 females. The clinical manifestations were severe early-onset lactic acidosis and developmental lag, and 3 cases were accompanied by progressive infantile encephalopathy. Among them, 3 cases underwent head MRI examination, all of which showed diffuse white matter signal with multiple cystic lesions, 2 cases with basal ganglia involvement and multiple cerebellar gyri deformity. Genetic test indicated different types of TUFM gene variation. Conclusions:COXPD4 is a rare hereditary mitochondrial disease. For cases with COXPD4 clinical and imaging features, TUFM gene mutations can be screened first.

Clinical and genetic analysis of children with developmental and epileptic encephalopathy 8 caused by ARHGEF9 gene variants / 中华神经科杂志

Objective:To analyze the clinical characteristics and genetic variation of 2 children with developmental and epileptic encephalopathy 8 (DEE8).Methods:Whole-exome sequencing (WES) was performed to determine the potential variants in the probands. Candidate variants identified by WES were validated by Sanger sequencing and quantitative real-time polymerase chain reaction. X chromosome inactivation (XCI) detection was performed in the proband 1′s mother and proband 2 to detect the allelic expression difference of ARHGEF9. Results:Both of the cases showed global developmental delay. Proband 1 presented with delayed motor and speech development, intellectual disability, and seizures. Electroencephalography of proband 1 showed slow background activity, with spikes, spike and waves in bilateral frontal and midline regions during sleep. While proband 2 showed delay in acquisition of language, motor skills, and cognition, but no seizures. It was identified that proband 1 carried a novel maternally derived heterozygous splicing variant (c.925-2A>T) in ARHGEF9 by WES, which was verified in Sanger sequencing. The XCI in proband 1′s mother was observed, and the expression ratio of mutant ARHGEF9 and wild-type was 0∶100%. A novel exon 3-10 heterozygous deletion of ARHGEF9 was identified in proband 2, and this variant was not found in his unaffected parents. Conclusions:DEE8 disorders are relatively rare. Most of the patients have varying degrees of neurodevelopmental phenotype, but epilepsy is not a specific clinical manifestation. ARHGEF9 gene deletion and splicing variation may be the genetic cause of the 2 probands, and above findings have enriched the spectrum of variation and phenotype of DEE8.

Clinical phenotype and gene analysis of TSC2/PKD1 adjacency gene syndrome / 中华神经科杂志

Objective:To explore the clinical phenotype and gene characteristics of a case of TSC2/PKD1 adjacency gene syndrome, so as to improve the clinical understanding of the disease.Methods:A case of TSC2/PKD1 adjacency gene syndrome diagnosed in the Department of Neurology of the Children′s Hospital Affiliated to Zhengzhou University was analyzed retrospectively. The clinical data, laboratory examination, imaging characteristics and gene variation characteristics of the child were summarized.Results:The patient was a 17 months old girl, with the main complaint of "intermittent convulsion with 17 months of underdevelopment". The clinical manifestations were epileptic seizures, which were in the form of a series of spastic seizures, absence seizures, focal seizures, and depigmentation spots can be seen in the trunk and neck. Cranial magnetic resonance imaging showed multiple patchy signals in the cortex and subcortical areas of the bilateral cerebral hemispheres, multiple small nodular shadows under the ependyma of the bilateral lateral ventricles, the heart color Doppler ultrasound showed patent foramen ovale and pericardial effusion, and the abdomen color Doppler ultrasound showed polycystic kidney. Ophthalmic color Doppler ultrasound showed that there were localized small swelling lesions around the optic disc of the left eye. The whole exon gene sequencing of the pedigree showed the proband had partial deletion of TSC2 gene (NM_000548) at chromosome position chr16: 2125799-2185690. The real-time quantitative detection system verified that exons 23-42 were deleted, and all exons of PKD1 gene were deleted (NM_001009944), and multiple ligation dependent probe amplification verified that exons 1-46 were deleted, and no downstream gene deletion was found. The overall deletion size was about 60 kb. Both of the girl's father and mother had normal phenotypes and were wild-type.Conclusions:TSC2/PKD1 adjacency gene syndrome is relatively rare. It can have clinical manifestations of tuberous sclerosis/autosomal dominant polycystic kidney disease. Most of the nervous system and kidney are seriously affected, and the prognosis is poor. TSC2/PKD1 gene deletion and variation is the genetic cause of the TSC2/PKD1 adjacency gene syndrome.

Clinical features and gene mutation analysis of a male case of subcortical band heterotopia caused by mosaic mutation of DCX gene / 中华神经科杂志

Objective:To investigate the clinical phenotype and genotype of a male case of subcortical band heterotopia caused by mosaic mutation of DCX gene.Methods:The clinical data and magnetic resonance imaging (MRI) features of a male case of subcortical band heterotopia diagnosed in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in August 2020 were analyzed retrospectively. At the same time, the whole exon sequencing of the families was performed by next generation sequencing method, the suspicious mutation was verified by polymerase chain reaction Sanger sequencing, and their genetic mutation characteristics were analyzed.Results:The proband, one male, aged 5 years and 1 month, was hospitalized in August 2020 with the complaint of intermittent convulsions for 4 years and six months. Clinical features included that limb muscle tension was slightly high, intellectual and motor development was backward, and head circumference was 48 cm. MRI of his head showed diffuse thick subcortical band heterotopia. The detection of whole exon sequencing in his family showed that there was hemizygous mosaic mutation in DCX gene (mosaic ratio 44%), c.148A>G (p.k50E). The mosaic ratios of oral mucosa and urinalysis were 38.2% and 44.8% respectively. His parents were wild-type, The mutation found in this patient has not been reported at home and abroad.Conclusions:The mosaic variation of DCX gene can cause subcortical band heterotopia in males. The variation of DCX gene c.148A>G (p.k50E) may be the possible cause of the proband, which expands the variation spectrum of subcortical band heterotopia.

Childhood onset spinocerebellar ataxia type 2: a family report and literature review / 中华神经科杂志

Objective:To investigate the clinical characteristics, genetic characteristics and diagnosis of spinocerebellar ataxia type 2 (SCA2) patients with childhood onset.Methods:The clinical data of a SCA2 pedigree who diagnosed at Neurogenetic Metabolic Disease Clinic of Children′s Hospital Affiliated to Zhengzhou University in July 2019 were collected, and the reported cases of childhood-onset SCA2 were reviewed. The CAG repeat of ATXN2 gene was detected by polymerase chain reaction, capillary gel electrophoresis and Sanger sequencing techniques.Results:A total of 9 people in 4 generations of the family were affected, showing an autosomal dominant inheritance. The proband was a 3 years and 4 months old boy, who showed abnormal symptoms at 9 months which manifested as developmental retardation. At 1 year old, he developed progressive regression which represented neither to be amused, recognize others, stand and walk alone, nor had language development. Meanwhile, he had difficulty swallowing, long-term constipation, and a history of convulsions. His sister and mother were not yet sick. His grandmother could not walk, had slurred speech accompanied by nystagmus, and magnetic resonance imaging showed cerebellar atrophy. His granduncles and grandaunts had unstable walking and dysarthria. His great-grandfather required wheelchair to walk. This pedigree showed an autosomal dominant inheritance. One of the ATXN2 gene alleles of the proband, his sister, mother and grandmother all showed abnormal amplification with 99, 55, 44, and 43 times respectively and no inserting CAA sequence. A total of 14 literatures reported 20 cases of childhood-onset SCA2 patients who were genetically diagnosed. The majorities had onset in infancy, and few can develop into school age. The main clinical manifestations were developmental delay, dystonia or insufficiency, myoclonus or infantile spasms, motor retardation, abnormal eye movement, retinitis pigmentosa and dysphagia, while the classic cerebellar syndrome was only partially present. Abnormal rhythm was found on electroencephalogram, cerebellar atrophy on magnetic resonance imaging or CT of the head.Conclusions:This case is the youngest genetically-confirmed SCA2 patient reported in China. Reported patients usually have onset in infancy with excessive repeat sequence expansion. Their clinical characteristics are different from the classic patients and could only be diagnosed by dynamic mutation detection.

A case of Coffin-Siris syndrome type 1 due to 6q25.3 deletion / 中华神经科杂志

Clinical data and genetic mutation characteristics of a patient with Coffin-Siris syndrome by 6q25.3 deletion were summarized. The child was a 7-year and 6-month old girl who had feeding difficulties, repeated infection, language and motor retardation, low intelligence, laryngeal cartilage dysplasia, thick eyebrows, sparse teeth, hairy back, hyperactivity and aggressive behavior, seizures and ataxia. There was no abnormality in chromosomal karyotype analysis by proband; genomic copy number variant sequencing (CNV-seq) indicated approximately 4.27 Mb heterozygous deletion in chromosome 6q25.3 region, with 17 genes including ARID1B gene, father maternal CNV-seq showing no abnormalities. Trio-whole-exome sequencing showed the proband missed all exons 1-20 of the ARID1B gene, with wild-type parents. The proband had severe clinical symptoms and haplodose insufficiency which was the genetic etiology.

Clinical characteristics and genetic analysis of early epileptic encephalopathy caused by YWHAG gene mutation / 中华神经科杂志

Objective:To report a rare case of early onset epileptic encephalopathy caused by YWHAG gene mutation, and discuss the clinical and genetic characteristics as well as the diagnosis, treatment and prognosis of the disease.Methods:Clinical data of the patient with YWHAG gene deficiency from Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University were collected in January 2018. The whole exome sequencing was performed on the core members of the family, and the characteristics of gene mutations were analyzed.Results:The proband is a girl, three years and 10 months old, presented to the outpatient department of neurology with a history of six-month intermittent convulsions, manifested as epilepsy seizures, mental retardation, motor delay and gait instability, ataxia. The brain magnetic resonance imaging showed myelinated dysplasia, and long-term video electroencephalogram (EEG) showed extensive 1.5-3.0 Hz slow spikes, and multiple spikes during sleep. During the monitoring, the children had clinical seizures and abnormal EEG discharges, indicating that myoclonus was accompanied by atypical absence of consciousness. Whole exome sequencing on the proband detected a de novo mutation c.169C>T (p.Arg57Cys) in YWHAG gene. According to American College of Medical Genetics guidelines (2015), the mutation was considered potentially pathogenic.Conclusion:Early epileptic encephalopathy caused by YWHAG gene mutation is very rare, and the variation of YWHAG gene c.169C>T is the possible pathogenic variation of the genetic cause of early onset epileptic encephalopathy in the proband.

A family of neurofibromatosis type Ⅰ: a clinical feature and gene mutation analysis / 中华神经医学杂志

Objective:To summarize the clinical features of a family of neurofibromatosis type I (NF1) and its NF1 gene mutation characteristics. Methods:The clinical data of a family of NF1 admitted to our hospital in May 2020 were collected. The proband was sequenced with NF1/ NF2 panel using second-generation sequencing. Sanger sequencing verification analysis was performed on the family members. The clinical characteristics of the proband and other family members were summarized and their gene mutations were analyzed. Results:The proband (V 2), a 1-year and 2-month old girl, had multiple Café au lait spots on the skin at birth, normal mental and motor development, and focal epileptic seizures in infancy. The father (IV 3), grandmother (III 2), and other 2 family members (II 2, I 2) in the family all had Café au lait spots or neurofibromatous changes without seizures. The mother's phenotype was normal. The proband had a heterozygous mutation in the NF1 gene, and the mutation site C.83-84delAG (P.N29Hfs*8) was a frameshift heterozygous mutation. After verification analysis by Sanger sequencing, the pathogenic genes of the father and grandmother were consistent with the proband, which was in line with the characteristics of heterozygous mutation in NF1 gene, dominant inheritance. Conclusion:NF1 is caused by NF1 gene mutation; the early clinical manifestations mostly include café-au-lait spots, and some have seizures; patients with multiple café-aulait spots with seizures should be diagnosed by genetic analysis as soon as possible.