CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.
Humans ; Child ; Female ; Cerebellar Ataxia/diagnosis* ; Talipes Cavus ; Hearing Loss, Sensorineural/diagnosis* ; Optic Atrophy/diagnosis* ; Mutation ; Phenotype ; Sodium-Potassium-Exchanging ATPase/genetics* ; Foot Deformities, Congenital ; Reflex, Abnormal

OBJECTIVE: To explore the genetic basis for a child with optic atrophy and global developmental delay. METHODS: A child who had presented at the Guangzhou Women and Children's Medical Center in January 2022 was selected as the study subject. Clinical data were collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a nine-month-old female, had manifested dysopia and global developmental delay. Genetic testing revealed that she has harbored a de novo c.425G>C (p.Arg142Pro) variant of the NR2F1 gene, which has been associated with Bosch-Boonstra-Schaaf syndrome. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM1+PM2_Supporting+PM5+PP3+PP4). CONCLUSION The c.425G>C (p.Arg142Pro) variant of the NR2F1 gene probably underlay the pathogenesis in this child. Above finding has enriched the genotypic and phenotypic spectrum of the NR2F1 gene.
Female ; Humans ; Infant ; Computational Biology ; COUP Transcription Factor I/genetics* ; Genetic Testing ; Genomics ; Genotype ; Optic Atrophy/genetics*

Objective: To investigate the clinical efficacy of liver transplantation in the treatment of acute liver in children with NBAS gene deficiency disease and their outcome. Methods: This retrospective study enrolled children with NBAS gene deficiency who were admitted to the Children's Hospital of Fudan University for liver transplantation from January 2013 to June 2022. The clinical data were collected and analyzed. Medical literature published before June 2022 was searched with the keywords of "NBAS" "neuroblastoma amplified sequence recurrent" "acute liver failure" "SOPH syndrome" "short stature with optic nerve atrophy" "Pelger-Huët anomaly" in PubMed, China National Knowledge Infrastructure and Wanfang database. Results: Liver transplantation was performed in 3 patients (2 males and 1 female) with NBAS deficiency. All patients presented with fever-triggered recurrent acute liver failure. The genetic detection found compound heterozygous NBAS gene pathogenic variants in them. The total episodes of acute liver failure before liver transplantation were 11, 2, and 4 respectively, and the age at liver transplantation was 3.5, 2.3, and 2.0 years respectively. During liver transplantation, patient 1 was in the convalescent phase of acute liver failure, patient 2 was in the acute phase, presenting with hepatic encephalopathy (grade V) and respiratory failure, and patient 3 was considered to be in the acute phase. After liver transplantation, patient 1 recovered normal liver function within 1 month and had no liver transplantation-related complications. Patient 2 had secondary epilepsy, intellectual disability, movement disorder, and transiently elevated transaminases. Patient 3 died of severe infection within 1 month. There was no literature in Chinese, 6 in English, 8 NBAS-deficient patients who were treated with liver transplantation. Total 11 patients presented with fever-triggered recurrent acute liver failure. Their age at liver transplantation ranged from 0.9 to 5.0 years. Postoperative complications occurred in 3 patients. Until the last visit, they were followed up for 0.7 to 14.0 years. Total 2 patients died and the 9 surviving patients did not develop acute liver failure. Conclusions: Liver transplantation is effective for the treatment of acute liver failure associated with NBAS gene disease. However, postoperative complications of liver transplantation may occur. The timing of liver transplantation still needs further research.
Child ; Male ; Humans ; Female ; Infant ; Child, Preschool ; Retrospective Studies ; Neoplasm Proteins/genetics* ; Optic Atrophy/genetics* ; Pelger-Huet Anomaly/genetics* ; Liver Failure, Acute/complications*

OBJECTIVE: To explore the clinical and genetic characteristics of a child featuring developmental delay. METHODS: The child was subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: Whole genome sequencing revealed that the child has carried compound heterozygous variants c.2607-1G>C and c.899 + 2dupT of the RAB3GAP1 gene, which were respectively derived from her mother and father. CONCLUSION A rare case of Warburg micro syndrome type 1 was diagnosed. The phenotype of the child was consistent with the literature, in addition with dysplasia of palatine arch, prominent high palatal arch and tooth dysplasia. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the family.
Abnormalities, Multiple/genetics* ; Adult ; Cataract/genetics* ; Child ; Cornea/abnormalities* ; Female ; Humans ; Hypogonadism/genetics* ; Intellectual Disability/genetics* ; Male ; Microcephaly/genetics* ; Mutation ; Optic Atrophy/genetics* ; Whole Exome Sequencing ; rab3 GTP-Binding Proteins/genetics*

Abnormalities, Multiple ; diagnostic imaging ; genetics ; Cataract ; congenital ; diagnostic imaging ; genetics ; Chromosome Deletion ; Chromosomes, Human, Pair 1 ; genetics ; Cornea ; abnormalities ; diagnostic imaging ; Head ; diagnostic imaging ; Humans ; Hypogonadism ; diagnostic imaging ; genetics ; Infant ; Intellectual Disability ; diagnostic imaging ; genetics ; Male ; Microcephaly ; diagnostic imaging ; genetics ; Optic Atrophy ; diagnostic imaging ; genetics ; Phenotype

Child ; Female ; Hereditary Sensory and Motor Neuropathy ; genetics ; Heterozygote ; Humans ; Mitochondrial Proteins ; genetics ; Mutation ; genetics ; Optic Atrophy ; genetics ; Peptide Termination Factors ; genetics

OBJECTIVETo investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON).

METHODSBiochemical characteristics including the activity of complex Ⅰ, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared.

RESULTSComparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex Ⅰ in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls.

CONCLUSIONThese results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction.

Adenosine Triphosphate ; genetics ; Asian Continental Ancestry Group ; genetics ; Female ; Humans ; Male ; Mitochondria ; genetics ; Mutation ; genetics ; NADH Dehydrogenase ; genetics ; Optic Atrophy, Hereditary, Leber ; genetics ; Pedigree

The Diagnostic Genetics Subcommittee of Korean Association of External Quality Assessment Service conducted two trials in 2015 based on cytogenetics and molecular genetics surveys. A total of 43 laboratories participated in the chromosome surveys, 31 laboratories participated in the fluorescence in situ hybridization surveys, and 133 laboratories participated in the molecular genetics surveys. All except one laboratory showed acceptable results in the cytogenetics surveys. The molecular genetics surveys included the following tests: Mycobacterium tuberculosis detection, hepatitis B and C virus detection and quantification, human papilloma virus genotyping, gene rearrangement tests for leukaemias and lymphomas, genetic tests for JAK2, FMS-like tyrosine kinase 3, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), hearing loss and deafness (GJB2 ), multiple endocrine neoplasia 2 (RET), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke like episodes, myoclonic epilepsy ragged red fibre, Leber hereditary optic neuropathy, Prader-Willi/Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome (FMR1), apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, ABO genotyping, cytochrome P450 2C9 genotyping, cytochrome P450 2C19 genotyping, and DNA sequencing analysis. The molecular genetics surveys showed excellent results for most of the participants. The external quality assessment program for genetics analysis in 2015 proved to be helpful for continuous education and the evaluation of quality improvement.
Achondroplasia ; Acidosis, Lactic ; Apolipoproteins ; Breast ; Cytochrome P-450 Enzyme System ; Cytogenetics ; Deafness ; Education ; Epilepsies, Myoclonic ; Fluorescence ; fms-Like Tyrosine Kinase 3 ; Fragile X Syndrome ; Gene Rearrangement ; Genetics* ; Hearing Loss ; Hepatitis B ; Hepatolenticular Degeneration ; Humans ; Huntington Disease ; In Situ Hybridization ; Korea* ; Li-Fraumeni Syndrome ; Lymphoma ; Methylenetetrahydrofolate Reductase (NADPH2) ; Molecular Biology ; Multiple Endocrine Neoplasia ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic ; Muscular Dystrophy, Duchenne ; Mycobacterium tuberculosis ; Optic Atrophy, Hereditary, Leber ; Ovarian Neoplasms ; Papilloma ; Quality Improvement ; Sequence Analysis, DNA ; Spinocerebellar Ataxias ; Stroke

OBJECTIVETo explore the application value of next generation sequencing (NGS) in the diagnosis of mitochondrial disorders.

METHODAccording to mitochondrial disease criteria, genomic DNA was extracted using standard procedure from peripheral venous blood of patients with suspected mitochondrial disease collected from neurological department of Beijing Children's Hospital Affiliated to Capital Medical University between October 2012 and February 2014. Targeted NGS to capture and sequence the entire mtDNA and exons of the 1 000 nuclear genes related to mitochondrial structure and function. Clinical data were collected from patients diagnosed at a molecular level, then clinical features and the relationship between genotype and phenotype were analyzed.

RESULTMutation was detected in 21 of 70 patients with suspected mitochondrial disease, in whom 10 harbored mtDNA mutation, while 11 nuclear DNA (nDNA) mutation. In 21 patients, 1 was diagnosed congenital myasthenic syndrome with episodic apnea due to CHAT gene p.I187T homozygous mutation, and 20 were diagnosed mitochondrial disease, in which 10 were Leigh syndrome, 4 were mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes syndrome, 3 were Leber hereditary optic neuropathy (LHON) and LHON plus, 2 were mitochondrial DNA depletion syndrome and 1 was unknown. All the mtDNA mutations were point mutations, which contained A3243G, G3460A, G11778A, T14484C, T14502C and T14487C. Ten mitochondrial disease patients harbored homozygous or compound heterozygous mutations in 5 genes previously shown to cause disease: SURF1, PDHA1, NDUFV1, SUCLA2 and SUCLG1, which had 14 mutations, and 7 of the 14 mutations have not been reported.

CONCLUSIONNGS has a certain application value in the diagnosis of mitochondrial diseases, especially in Leigh syndrome atypical mitochondrial syndrome and rare mitochondrial disorders.

Child ; DNA, Mitochondrial ; genetics ; High-Throughput Nucleotide Sequencing ; Homozygote ; Humans ; Leigh Disease ; Mitochondrial Diseases ; diagnosis ; Mitochondrial Encephalomyopathies ; Mutation ; Optic Atrophy, Hereditary, Leber ; Phenotype ; Point Mutation ; Sequence Analysis, DNA

OBJECTIVETo report on clinical, genetic and molecular characterization of two Chinese families with Leber's hereditary optic neuropathy.

METHODSOphthalmological examinations have revealed variable severity and age at onset of visual loss among the probands and other matrilineal relatives of both families. The entire mitochondrial genome of the two probands was amplified with PCR in 24 overlapping fragments using sets of oligonucleotide primers.

RESULTSThe ophthalmological examinations showed that penetrance was 12.5% and 30.0% respectively in the two families. Sequence analysis of the complete mitochondrial genomes in these pedigrees has identified unreported homoplasmic T8821G mutation in the ATPase 6 gene and distinct sets of polymorphisms belonging to haplogroups M10a. The T8821G mutation has occurred at the extremely conserved nucleotide (conventional position 99) of the ATPase6. Thus, this mutation may alter structural formation of ATPase6, thereby leading to failure in the synthesis of ATP involved in visual impairment.

CONCLUSIONAbove observations have suggested that the ATPase6 T8821G mutation may be involved in the pathogenesis of optic neuropathy in these families.

Adolescent ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; China ; DNA, Mitochondrial ; genetics ; Female ; Humans ; Male ; Mitochondrial Proton-Translocating ATPases ; genetics ; Molecular Sequence Data ; Optic Atrophy, Hereditary, Leber ; enzymology ; genetics ; Pedigree ; Point Mutation ; Young Adult