Objective:To explore the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Spastic paraplegia type 5A (SPG5A).Methods:A pedigree suspected for Hereditary spastic paraplegia (HSP) at Henan Children′s Hospital on August 15 2022 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples were collected from members of the pedigree. Following extraction of genomic DNA, trio-WGS was carried out, and candidate variant was verified by Sanger sequencing.Results:The child, a 1-year-old boy, had presented with microcephaly, hairy face and dorsal side of distal extremities and trunk, intellectual and motor development delay, increased muscle tone of lower limbs, hyperreflexes of bilateral knee tendons, and positive pathological signs. His parents and sister both had normal phenotypes. Trio-WGS revealed that the child has harbored a homozygous c. 1250G>A (p.Arg417His) variant of the CYP7B1 gene, for which his mother was heterozygous, the father and sister were of the wild type. The variant was determined to have originated from maternal uniparental disomy (UPD). The result of Sanger sequencing was in keeping with the that of trio-WGS. SPG5A due to maternal UPD of chromosome 8 was unreported previously. Conclusion:The child was diagnosed with SPG5A, a complex type of HSP, for which the homozygous c. 1250G>A variant of the CYP7B1 gene derived from maternal UPD may be accountable.

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.

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.

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.

Objective:To summarize the clinical phenotype and genetic characteristics of a case of autosomal dominant mental retardation-42 (MRD42) caused by GNB1 gene mutation. Methods:The clinical and genetic data of a case of MRD42 caused by a GNB1 gene missense mutation diagnosed in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in March 2023 were retrospectively analyzed. The child was followed-up, the child′s data were summarized, and related literature was reviewed. Results:The patient is a 6-month-old female infant, who was admitted to hospital because of "developmental delay for 3 months, intermittent convulsions for 1 month". The clinical manifestations included generalized tonic-clonic seizures, focal seizures, intellectual disability, delayed language and motor development. Long-term video electroencephalogram showed slightly slower background activity, bilateral occipital spike and wave discharges, multispike and wave complexes during sleep. Three focal onset seizures were captured. Cranial magnetic resonance imaging suggested that the subarachnoid space of the bilateral frontotemporal areas was slightly wide. Chromosome karyotype and copy number variation analysis showed no abnormality. The results of whole exon sequencing showed a de novo heterozygous missense mutation in the GNB1 gene [NM_002074:c.155(exon5)G>A;p.Arg52Gln], which had not been reported. The seizure was effectively controlled by function rehabilitation training and anti-epileptic drug therapy. Conclusions:MRD42 is a rare autosomal dominant disorder caused by mutation in the GNB1 gene. The clinical manifestations include infantile-onset seizures, mental retardation, speech and motor development delay, etc. The de novo heterozygous missense mutation in the GNB1 gene c.155G>A(p.Arg52Gln) is the genetic cause of the proband.

Objective:To summarize the clinical and genetic features of children with intellectual developmental disorder with seizures and language delay (IDDSELD) due to 12q24.31 deletion and SETD1B locus variants. Methods:The clinical data of a child with 12q24.31 deletion diagnosed in the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University in September 2022 were retrospectively analyzed. Trio-whole exome sequencing (trio-WES) and copy number variations sequencing (CNV-seq) were used for genetic analysis. The relevant literatures were reviewed to summarize the clinical features of the disease.Results:The proband was a 7 years and 9 month old girl who had clinical features of global developmental delay, epilepsy, hyperactivity, hypertonia, gait disorder, special facial features (high eyebrow arch, big ears, upper lip protrusion), funnel chest, lumbar lordosis. Karyotypic analysis showed 46XX in the proband. CNV-seq showed 12q24.31 (chr12: 121895654-122449092) position had a deletion of about 553.44 kb which contained the SETD1B gene. Trio-WES showed deletion of all exons 1-16 of the SETD1B gene. CNV-seq results of her parents were normal: the SETD1B gene was wild-type. This type has not been reported in China. Four children with IDDSELD caused by 12q24.31 deletion (including the SETD1B gene) were retrieved (totally 5 cases including this case), with male to female ratio of 1∶4, all with de novo mutations, and all with mental retardation, cephalo-facial and skeletal malformations. Three cases had seizures, 2 cases still had developmental backwardness after treatment, and 1 case was seizure controlled. Forty-seven cases of IDDSELD due to point mutation in the SETD1B gene were retrieved: male to female ratio was 31∶16, missense mutations (38/47) were predominant, most were de novo mutations (36/47), and a few were inherited from their fathers/mothers (6/47) or of unknown origin (5/47), with clinical manifestations of speech delay (43/47), growth retardation (43/47), intellectual disability (37/41), behavioral problems (37/47), facial malformations (34/47), skeletal malformations (23/47), obesity (16/47), skin abnormalities (11/47), etc. Thirty-nine cases were combined with seizures, 23 of whom were under control after treatment, and 8 cases were recorded as still having developmental backwardness after treatment. Conclusions:IDDSELD patients are rare at home and abroad, with diverse clinical phenotypes and difficult diagnosis. Symptomatic treatment is the main approach. And the patients can leave behind seizures and varying degrees of developmental backwardness. Among them, patients with 12q24.31 deletion are relatively rare and have not been reported in China, and this type is more common in females, all of whom have de novo mutations, and genetic testing is helpful for the early diagnosis of IDDSELD.

Objective:To summary the clinical phenotype and genotype characteristics of 2 cases of autosomal dominant mental retardation (MRD) caused by TRIO gene variation. Methods:Retrospective study of the clinical data of 2 cases of autosomal dominant MRD caused by TRIO gene mutations diagnosed at the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in April 2019 and January 2023 was conducted. The clinical features were summarized and gene analysis and follow-up were carried out. Results:The 2 patients were 6 years and 5 months old and 5 months old males, respectively. Clinical manifestations included seizures, cognitive and motor disorders, low intelligent development; case 1 had microcephaly, attention deficit disorder, ataxia, and aggressive behavior, and case 2 had macrocephaly. Brain magnetic resonance imaging revealed cerebellar atrophy in case 1, and non-specific dilation of the subarachnoid space and hypoplasia of the corpus callosum in case 2. Analysis of chromosome karyotype and chromosome copy number variation in 2 children showed no abnormalities. Whole exome sequencing revealed novel missense mutations in the TRIO gene in both patients [NM_007118:c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn), respectively]. The application of rehabilitation function training and a variety of anti-seizure medications can not fully and effectively control the seizure. Conclusion:TRIO gene c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn) de novo missense variants were the genetic etiology of the 2 probands,causing rare autosomal dominant MRD type 44 and 63.

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.

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.

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.