Analysis of clinical characteristics and genetic variants in a child with Isolated sulfite oxidase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with Isolated sulfite oxidase deficiency (ISOD).@*METHODS@#The child and her parents were subjected to targeted capture and next-generation sequencing. Pathogenicity of candidate variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#The child was found to harbor compound heterozygous variants of the SUOX gene, namely c.1200C>G (p.Tyr400*) and c.1406_1421delCCTGGCAGGTGGCTAA (p.Thr469Serfs*20), which were inherited from her mother and father, respectively. The c.1200C>G was a known pathogenic variant, while the c.1406_1421delCCTGGCAGGTGGCTAA was unreported previously and predicted to be a pathogenic variant (PVS1+PM2_Supporting +PM3) based on the guidelines from the American College of Medical Genetics and Genomics.@*CONCLUSION@#The compound c.1200C>G and c.1406_1421delCCTGGCAGGTGGCTAA variants of the SUOX gene probably underlay the pathogenesis of ISOD in this child. Above finding has expanded the spectrum of SUOX gene variants and provided molecular evidence for the clinical diagnosis and genetic counseling for this pedigree.

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.

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 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.

Clinical and PRRT2 gene variants analysis of three families with benign familial infantile epilepsy / 中华神经科杂志

Objective:To investigate the clinical and gene variant characteristics of benign familial infantile epilepsy in generations of three families.Methods:The clinical data of the three benign familial infantile epilepsy patients with PRRT2 gene variant who were diagnosed and their family members were collected from Children′s Hospital Affiliated to Zhengzhou University between 2018 and 2019. All coding exons from the patients and their parents were screened by targeted next-generation sequencing, and detected variants were verified by Sanger sequencing.Results:In all the patients, a cluster of seizures was observed before one year old,but interictal clinical conditions were normal. The electroencephalograms were all normal in interictal stage. The father of proband 1 presented with convulsion onset at the age of eight months and showed remission before one year old. The grandpa, mother and uncle of proband 2 also presented with convulsion onset in their babyhood of life and showed remission before one year old. The mother of proband 3 presented with convulsion onset in their babyhood of life and showed remission before three years old. Proband 1 carried heterozygous c.937G>C variant in the PRRT2 gene which is inherited from his father. Proband 2 carried c.1075_c.1076insC variant inherited from his mother. A deletion of PRRT2 gene exon 2 was detected in both of proband 3 and her mother. The three variants had not been reported in the Human Gene Mutation Database.Conclusions:Benign familial infantile epilepsy is a kind of inherited epilepsy characterized by early onset of seizure in babyhood with better prognosis, a cluster of focal seizures with or without secondary generalization, and cessation of seizure mostly before two or three years of age. The variants c.937G>C, c.1075_c.1076insC and the deletion of exon 2 in the PRRT2 gene have enriched the gene variant spectrum of benign familial infantile epilepsy.

Analysis of clinical phenotype and genotype of Jansen-de Vries syndrome caused by PPM1D gene mutation / 中华神经科杂志

Objective:To investigate the clinical phenotype of a child with Jansen-de Vries syndrome, to clarify its genetic diagnosis and genetic characteristics, and to improve the understanding of this disease.Methods:Clinical data from a child with Jansen-de Vries syndrome diagnosed in the Children′s Affiliated Hospital of Zhengzhou University in October 2019 were collected, using core family-complete exon genomics detection (Trio-WES) and chromosome copy number variation (CNV) analysis techniques for genetic testing for the child and her parents, generation Sanger sequencing for family member verification for possible pathogenic mutations, and clinical and molecular genetic analysis. The relevant reports of PPM1D gene mutation in patients with mental retardation were reviewed.Results:The proband was a 11-month-old girl, presenting with mental retardation, lagging speech and motor development, autistic behavior, gastrointestinal dysfunction, and short stature, low flat nose bridge, low ear, short finger syndrome.Trio-WES results of the core family of the child suggested that PPM1D was a new transcoding heterozygous mutation, PPM1D (NM-003620): c.1216delA (p.Thr406Profs *3), and the karyotype and CNV analysis of the chromosome were normal. Literature retrieval showed currently a total of 18 cases were reported PPM1D gene mutation of mental disorders, described in the online human Mendel database for developmental disorder associated with gastrointestinal dysfunction and pain threshold increases, the age distribution in the seven months to 21 years of age, clinical manifestation of mental retardation, increased pain threshold, abnormal behavior, feeding difficulties, visual impairment, short finger syndrome, a group of syndromes associated with short stature, fever or vomiting, and congenital deformities. Conclusions:Jansen-de Vries syndrome clinically presents mainly with overall retardation (mental retardation/backward delayed motor development, language development, low muscle tone), abnormal behavior (lonely sample behavior, autism), craniofacial malformations (broad forehead, low ear nose bridge, thin upper lip), short finger syndrome (short feet, pinky stubby), gastrointestinal dysfunction (milk overflow, feeding difficulties, constipation). The child was diagnosed as a newly transcoding heterozygous mutation of the PPM1D gene. The current treatment is mainly rehabilitation training, and growth hormone replacement therapy can be given to part of the short height disease. The PPM1D gene [PPM1D(NM-003620): c.1216delA(p.Thr406Profs *3)] is the genetic cause of the child.

Phenotypic and genetic analysis of a case with hypohidrotic ectodermal dysplasia due to Xq13.1 microdeletion / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical phenotype and genetic characteristics of a patient with hypohidrotic ectodermal dysplasia (HED) due to partial deletion of EDA gene.@*METHODS@#The child has presented with HED complicated with epilepsy. Family trio whole exome sequencing (Trio-WES), copy number variation sequencing (CNV-seq), and karyotype analysis were carried out to explore the underlying genetic etiology.@*RESULTS@#The proband, a 7-year-and-8-month-old boy, presented with thin curly hair, thin and sparse eyebrow, xerosis cutis, susceptibility to hyperthermia from childhood, hypohidrosis, sharp/sparse/absent teeth, saddle nose, prominent forehead, auricle adulation and seizure. He was found to have a normal chromosomal karyotype, and no abnormality was found by Trio-WES. Genome-wide CNV-seq revealed a 341.90 kb deletion at Xq13.1q13.1 (chrX: 68 796 566-69 138 468). As verified by PCR-electrophoresis, the deletion has removed part of the EDA gene. The deletion was derived from his mother with normal hair, mild xerosis cutis, and sparse, decidulated and nail-like teeth. The mother was detected with a heterozygous 242.10 kb deletion at Xq13.1q13.1 (chrX: 68 836 154-69 078 250).@*CONCLUSION@#Both the proband and his mother have carried a Xq13.1 microdeletion involving part of the EDA gene. The clinical phenotypes of the mother and the proband were consistent with the clinical characteristics of X-linked recessive HED, for which partial deletion of the EDA gene is probably accountable.

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.

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.

Acute necrotizing encephalopathy in a child caused by human herpesvirus-6 infection / 中华神经科杂志

Objective:To analyze the clinical and imaging characteristics of acute necrotic encephalopathy (ANE) in a child with human herpesvirus-6 (HHV-6) infection.Methods:Retrospective analysis was performed on the clinical data and imaging features of a case of HHV-6 related ANE from Children′s Hospital Affiliated to Zhengzhou University in March 2019.Results:The one year and seven month-old child had acute encephalopathy, recurrent convulsions, consciousness disorders, elevated serum transaminase. The number of cerebrospinal fluid (CSF) cells was normal and the protein increased. High throughput gene testing of CSF showed HHV-6. Cranial magnetic resonance imaging showed multiple symmetry damage in the bilateral thalamus, brainstem, and cerebellum. The symptoms improved after the treatment of glucocorticoids, intravenous immunoglobulin, and plasmapheresis.Conclusions:ANE is a rare severe encephalopathy, the characteristic imaging change of which is symmetry multifocal cerebral damage, especially in the bilateral thalamus. ANE should be considered for patients with frequent convulsions and disturbance of consciousness after virus infection.

Clinical phenotype and genetic analysis of pyridoxine dependent epilepsy induced by aldehyde dehydrogenase 7 family member A1 gene mutation / 中华神经科杂志

Objective:To investigate the clinical phenotypes, therapy and genetic features of aldehyde dehydrogenase 7 family member A1 (ALDH7A1) gene mutations in five cases of pyridoxine dependent epilepsy (PDE) with diagnosis confirmed by next generation sequencing.Methods:Retrospective analysis was carried out on clinical data of five cases of PDE children with early epilepsy onset who were treated in the Department of Neurology of Children′s Hospital Affiliated to Zhengzhou University from February 2018 to November 2019. Next generation sequencing approach was used for genetic sequencing of proband ALDH7A1 gene and the first generation Sanger was used for validation of family members. And the characteristics of gene mutations were analyzed.Results:Among the five children diagnosed with PDE, the male to female ratio was 4 ∶ 1 and ages at clinic visit ranged from two months to 10 months old. In clinical phenotypes, all five cases experienced onset in neonatal period, with repeated seizures, manifested as myoclonus, spasms or focal paroxysm. The administration of antiepileptic drugs performed poorly in seizure control while long term oral intake of large dose pyridoxine showed better efficacy. All the five cases of children came from compound heterozygous mutations of father and mother, i.e. slicing homozygous mutation c.247-2(IVS2)A>T, missense mutation c.584A>G (p.N195S) and nonsense mutation c.1003C>T(p.R335 *), missense mutation c.1553G>C(p.R518T) and c.1547A>G(p.Y516C), missense mutation c.1547A>G(p.Y516C) and frameshift mutation c.1566_1568delTAC, missense mutation c.1061A>G(p.Y354C) and nonsense mutation c.841C>T(p.Q281X, 259), among which c.247-2(IVS2)A>T was novel splicing site mutation not reported before. Conclusions:PDE is induced by ALDH7A gene mutation. Early clinical manifestations are mostly onset of refractory epilepsy in neonatal period. Antiepileptic drugs perform poorly in terms of efficacy while pyridoxine can control seizure effectively. Gene analysis should be conducted on such patients for confirmed diagnosis.

Clinical features and gene mutation analysis of CDKL5 gene related early-onset epileptic encephalopathy / 中华神经科杂志

Objective:To investigate the clinical characteristics and gene mutation of seven cases of CDKL5 gene related early-onset epileptic encephalopathy diagnosed by next-generation sequencing.Methods:The clinical data of children with early-onset epileptic encephalopathy from February 2018 to December 2019 in the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University were retrospectively analyzed. The whole exome sequencing method was used to analyze the entire exome of the proband, and seven cases of CDKL5 gene mutation positive were screened out, and Sanger sequencing verification on family members was performed to identify the source and the characteristics of gene mutations were analyzed.Results:Among the seven children diagnosed with CDKL5 gene related early-onset epileptic encephalopathy, the ratio of male to female was 2∶5, and the age of onset was 15 days to five months of birth. The clinical phenotypes all included different degrees of developmental delay and repeated seizures, which were manifested as general seizures, myoclonic seizures, convulsive seizures or focal seizures; the outcome of use of antiepileptic drugs to control seizures was poor, and some applications of ketogenic diet had better effects. CDKL5 gene mutation sites were all denovo mutations, including NM_003159: c.772_776del (p.K258Efs *10) frameshift mutation, NM_003159.2 (exon: 9-15) heterozygous deletion, CDKL5 hemizygous deletion, NM_003159: c.268 (exon5) G>T (p.E90 *, 941) and NM_003159: c.2578C>T (p.Q860 *, 171) nonsense mutation, NM_003159: c.211A>G (p.Asn71Asp) and NM_001323289: c.545T>C (p.L182P) missense mutation. Among them, c.772_776del (p.K258Efs *10), c.268 (exon5)G>T and c.2578C>T (p.Q860 *, 171) have not been reported. Conclusions:CDKL5 gene related early-onset epileptic encephalopathy is an early onset epilepsy, which is more common in women, and has different forms of seizures. The early electroencephalogram is characterized as severe abnormal brain discharge, and the disease progresses in various forms. There are no specific changes in head magnetic resonance imaging. Different gene mutation sites may lead to different phenotypes and prognostic differences. Many anti-epileptic treatments are ineffective, and ketogenic diets are effective for some patients.

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.

Clinical phenotype and genetic characteristics of two families with tuberous sclerosis / 中华神经医学杂志

Objective:To summarize the clinical features and genetic etiology of tuberous sclerosis (TSC).Methods:A retrospective analysis was carried out to identify the clinical features and auxiliary examination reults of TSC patients in 2 pedigrees admitted to our hospital from January 2018 to April 2018. Whole exome sequencing was performed in peripheral blood samples from these patients and the mutations in their parents were validated by Sanger sequencing.Results:The two probands were a one-year and 7-month old girl and a 2-year and 4-month old boy. They were all normal at birth and had epileptic seizures at preschool age. The elder sister, younger sister and mother of the probands showed abnormal skin and no seizures, and the father had normal phenotype. Physical examination showed normal mental and motor development, facial angiofibroma and depigmentation spots on the skin, knots and shark-like spots on part of the skin, and multiple intracranial calcification shadows on head CT; MR imaging revealed multiple abnormal signals under the parenchymal cortex and bilateral lateral ventricles. The proband (1) and her sister carried heterozygous missense mutation c.5024 c >T(p.pro1675leu) in TSC2 gene; ultrasound of heart, liver and kidney showed presence of hamartoma and cystic scotoma in renal parenchyma. The proband (2) and his younger sister carried heterozygosous splicing variation c. 737+1(IVS8)G>A in TSC1 gene, inherited from his mother; the head CT of younger sister was normal, and there was no hamartoma in the younger sister and the mother's internal organs. Conclusions:TSC is characterized by epileptic seizures and abnormal skin changes in preschool age. It may involve multiple hamartomas of skull, heart, liver, kidney, or other internal organs. The mutation frequency of TSC2 gene is higher than that of TSC1 gene, and the clinical phenotype is severe.

MFSD8 gene mutation and clinical characteristics of a family with neuronal ceroid lipofuscinosis type 7 / 中华神经科杂志

Objective:To investigate the clinical characteristics and mutation of MFSD8 gene in a family with neuronal ceroid lipofuscinosis type7 (CLN7).Methods:The clinical data of a CLN7 patient and her family from the Children′s Hospital Affiliated to Zhengzhou University in January 2018 were reviewed and analyzed. Whole exome sequencing of second-generation sequencing was used to analyze gene mutation results.Results:The proband, a five years and nine months old girl, admitted to the Children′s Hospital Affiliated to Zhengzhou University with the chief complaint of "intermittent seizures for seven months". She had the first seizure at the age of five years and two months, and different types of generalized tonic-clonic and atypical absence seizures were found. At the age of five years and nine months, she was admitted to the hospital with mild mental deterioration. She had normal motor and physical development. Ophthalmological evaluation revealed macular degeneration. The video electroencephalography revealed multifocal spikes or spike-and-wave, prominent in the anterior fronto-temporal regions. Magnetic resonance imaging (MRI) revealed cerebellar atrophy. Compound heterozygous mutations c.553 (exon 6) G>A and c.1391 (exon 13) C>T were found on her MFSD8 gene, supporting the diagnosis of CLN7. Each of her parent carried one of the mutations, and c.553 (exon 6) G>A was a new mutation. Her elder brother had the first seizure at the age of 6 years, with motor and mental deterioration as well as visual impairment. MRI revealed generalized cerebral atrophy. He had the same compound heterozygous mutations with his sister. No pathogenic mutation was found in her younger brother.Conclusions:CLN7 is a rare neurodegenerative disease, the main clinical features of which are epileptic seizures, progressive motor intelligence regression, visual loss, cranial MRI suggesting brain atrophy, and binocular macular degeneration. MFSD8 gene heterozygous mutations c.553G>A (p.V185I) and c.1391C>T (p.A464V) are the genetic etiology of this proband.

Analysis of the clinical phenotype and tripeptidyl peptidase-1 gene mutation in a family with type 2 neuronal ceroid lipofuscinosis / 中华神经科杂志

Objective:To summarize the clinical phenotype and tripeptidyl peptidase-1 (TPP1) gene mutation characteristics in a family with type 2 neuronal ceroid lipofuscinosis (CLN2) confirmed by second generation sequencing. Methods:The clinical data of a family with CLN2 from the Department of Neurology of the Children′s Hospital Affiliated to Zhengzhou University in June 2018 were collected. The proband was confirmed by using the whole-exome sequencing and the Sanger test of the first generation was used in the family members, and the mutation characteristics of TPP1 gene were analyzed, and the clinical features were summarized.Results:The proband is a three-year- and nine-month-old girl, presented with generalized tonic-clonic seizures, normal mental function, mild backward development of language and movement. The ophthalmic examination showed binocular ametropia, normal visual acuity, and no macular degeneration. Cranial magnetic resonance imaging (MRI) showed widening of the subarachnoid space in the frontotemporal region, deepening of the sulci, and cerebellar atrophy. There were two heterozygous mutations in the TPP1 gene, from her parents with normal phenotypes respectively. The c. 1449-1450insG (p.I484Dfs*7) mutation comes from her father, which is an unreported heterozygous mutation of code-shifting, whereas the c.1417G>A(p.G473R) mutation comes from her mother, which is a known missense mutation, consistent with the characteristic of CLN2 complex heterozygous mutation. The proband′s elder brother, whose first symptom was myoclonic seizure at the age of three, and now he is seven years old with progressive visual impairment and regression of intellectual, motor and cognitive functions. The ophthalmic examination showed retinal degeneration, and the cranial MRI showed whole-brain atrophy with obvious cerebellar atrophy. The pathogenic gene of TPP1 and the complex heterozygous mutation site were consistent with the proband. Now the proband′s younger brother is 2-year- and 10-month-old, whose phenotype is normal, with a single heterozygous mutation of c.1417G>A (p.G473R), which comes from their mother, and the parents of the proband have no clinical phenotype. Conclusions:CLN2 is a rare lysosomal storage disorder that is characterized by seizures, progressive mental and motor deterioration, loss of vision and brain atrophy on MRI, binocular macular degeneration. TPP1 complex heterozygous mutation c. 1449-1450insG(p.I484Dfs*7) and c.1417G>A(p.G473R) is the genetic cause of this case.

Clinical phenotype and genetic analysis of neurofibromatosis type 1 caused by neurofibromatosis type 1 gene mutation / 中华神经科杂志

Objective:To investigate the clinical phenotype and summarize the genetic characteristics of children with neurofibromatosis type 1 (NF1) diagnosed by next-generation sequencing.Methods:The clinical data of 12 children with NF1 who were admitted to the Department of Neurology of the Children's Hospital Affiliated to Zhengzhou University from December 2017 to October 2019 were retrospectively analyzed. The next-generation sequencing method was used to sequence the NF1 gene of the probands and the mutations were verified by PCR-Sanger sequencing.Results:Among the 12 children diagnosed with NF1 (male: female=11: 1), who aged from seven months to 11 years old, the main complaints were seizures and skin with café-au-lait spots. Five children were found with freckles in axillae, and two with cutaneous neurofibroma. Six cases had seizures, two children suffered spastic seizures, two with generalized tonic-clonic seizures, one with typical absence seizure, one with focal seizure, one case had severe headache and vomiting. Fortunately for the children with seizures, anti-epileptic drugs had a good prognosis. There were five mutation types detected in 12 cases, including one case of loss of overall heterozygosity in NF1 gene; three missense mutations: c.7867C>A (p.L2623I), c.7855C>A (p.L2619I) and c.7792C>A(p.L2598I); three frameshift mutations: c.3162delC(p.N1054Nfs *8), c.540dupA (p.Q181Tfs *20) and c.2027dupA(p.V679Pfs *21); three nonsense mutations: c.1467T>A(p.Y489X, 2351), c.1318C>T(p.R440X, 2400) and c.1411C>T(p.K471X, 2369); two splicing mutations: c.2326-2(IVS10)G>C and c.1186-1(IVS10)G>C. Nine children were found with spontaneous mutations, one case was inherited from the father, and two cases were inherited from the mother. c.7867C>A(p.L2623I), c.7855C>A(p.L2619I), c.3162delC(p.N1054Nfs *8), c.1411C>T(p.K471X, 2369), c.2326-2(IVS10)G>C, c.1186-1(IVS10)G>C were unreported mutations in literature. Conclusions:NF1 is caused by NF1 gene mutation. The early clinical manifestations of children with NF1 defect presented with café-au-lait spots, and some suffered seizures. For patients with multiple café-au-lait spots and seizures in the clinic, genetic analysis should be performed as soon as possible to confirm the diagnosis.

Clinical features and TRPM6 mutations of an infant with hypomagnesemia with secondary hypocalcemia / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and mutations of the TRPM6 gene in an infant featuring hypomagnesemia and secondary hypocalcemia.@*METHODS@#Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Targeted exome sequencing was carried out to screen the potential mutations. Suspected mutations were verified by Sanger sequencing.@*RESULTS@#A novel homozygous c.5538delA (p.Q1846Qfs*2) mutation in the TRPM6 gene was identified in the proband, for which both of her parents were heterozygous carriers.@*CONCLUSION@#The homozygous frameshift mutation of TRPM6 gene (c.5538delA) probably underlies the disease in the proband. The finding has expanded the mutation spectrum of TRPM6 gene.

Clinical and aspartoacylase gene mutation analysis of Canavan disease in a child / 中华神经科杂志

Objective To investigate the clinical and aspartoacylase (ASPA) gene mutation characteristics of Canavan disease.Methods The clinical data of a child with Canavan disease diagnosed by gene detection who visited Children's Hospital Affiliated to Zhengzhou University in June 2018 were reviewed and analyzed.Results A one year and five months old girl presented with psychomotor retrogression,hypermyotonia,and tendon hyperreflexia.The urinary N-acetylaspartic acid levels were significantly higher (66.832 7,more than 60 times that of normal individuals).Magnetic resonance imaging of the brain showed a multiple and symmetrical hyperintense signal changes in the cerebral white matter.Two heterozygous mutations c.79_80del (p.Gly27Arg) and c.554G＞T (p.Gly185Val) were screened by targeted next generation sequencing.The results of Sanger sequencing showed the two mutations were compound heterozygous mutation derived from her father and mother,and the mutation c.554G＞T has never been reported.Conclusions The next generation sequencing can accurately detect ASPA gene mutation as the first choice for the diagnosis of Canavan disease.The mutation c.554G＞T enriches the gene mutation spectrum of Canavan disease.