OBJECTIVE: To explore the clinical features and genetic basis for a child with early-onset Isolated sulfite oxidase deficiency (ISOD). METHODS: A child with ISOD who was admitted to Weihai Hospital Affiliated to Qingdao University on May 10, 2020 was selected as the study subject. Clinical data of the child was analyzed. The child and her parents were subjected to trio-whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: The female neonate was transferred to the intensive care unit due to "secondary pollution of amniotic fluid and laborious breathing for 11 minutes", and had developed frequent convulsions. Genetic testing revealed that she has harbored c.1200C>G and c.188G>A compound heterozygous variants of the SUOX gene, which were inherited from her mother and father, respectively. The c.1200C>G has been described previously and was rated as pathogenic based on guidelines from the American College of Medical Genetics and Genomics, whilst the c.188G>A variant was unreported previously and rated as variant of unknown significance. CONCLUSION The compound heterozygous variants of the SUOX gene probably underlay the ISOD in this child. Above finding has enriched the spectrum of SUOX gene variants and provided a basis for the clinical diagnosis and genetic counseling.
Female ; Humans ; Infant, Newborn ; Amino Acid Metabolism, Inborn Errors/diagnosis* ; Genetic Counseling ; Genetic Testing ; Mutation ; Oxidoreductases Acting on Sulfur Group Donors/genetics* ; Sulfite Oxidase/genetics*

OBJECTIVE: To detect variants of the MMACHC gene among 110 ethnic Han Chinese pedigrees affected with metabolic deficiency methylmalonic acidemia (MMA) of cobalamin C (cblC). METHODS: Peripheral blood samples were collected from the probands and their parents. Following DNA extraction, the coding regions of the MMACHC gene were subjected to PCR amplification, Sanger sequencing and quantitative PCR assaying. For 48 pedigrees, chorionic villus samples were taken for prenatal genetic diagnosis. RESULTS: Thirty five types of variants were detected among the 110 pedigrees, which included missense, nonsense, frameshifting, splicing variants and exonic deletions. Most variants have occurred in exons 4 (73.18%). The detection rate for c.609G>A (p.Trp203Ter) variant was the highest (33.64%), followed by c.658_660delAAG (12.27%), c.567dupT (9.09%) and c.80A>G (6.82%). Two variants, namely c.57_58insT (p.Gly20Trpfs*14) and c.505_506delAT (p.Ile169Argfs*12), were unreported previously and both were of frameshifting types. For the 48 pedigrees undergoing prenatal diagnosis, 14 fetuses were found to be normal, 24 have carried heterozygous variants, the remaining 10 have carried compound heterozygous or homozygous variants. CONCLUSION The discovery of the two novel variants has expanded the spectrum of the MMACHC gene variants among ethnic Han population. Above finding has provide a basis for the prenatal diagnosis and genetic counseling for the affected pedigrees.
Amino Acid Metabolism, Inborn Errors/genetics* ; China ; DNA ; Female ; Humans ; Mutation ; Oxidoreductases/genetics* ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Vitamin B 12/genetics*

OBJECTIVE: To identify genetic variants among patients with methylmalonic acidemia and provide genetic evidence for prenatal diagnosis. METHODS: Thirty-one probands and their parents were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. RESULTS: 25 probands or their parents were found to harbor previously known pathogenic or likely pathogenic variants, and three probands were found to carry heterozygous MMACHC exonic deletion. The overall diagnostic yield was 90.32%. CONCLUSION NGS can improve the detection rate for methylmalonic acidemia for its accuracy and efficiency, yet the detection of exonic deletion is required to further improve the diagnostic yield. The identification of specific variants provided evidence for prenatal diagnosis.
Amino Acid Metabolism, Inborn Errors/genetics* ; Female ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Oxidoreductases ; Pregnancy ; Prenatal Diagnosis

OBJECTIVE: To summarize newborn screening for methionine adenosyltransferase I/III (MAT I/III) deficiency in Quanzhou region of Fujian Province. METHODS: A total of 364 545 neonates were screened for inherited metabolic diseases by tandem mass spectrometry. High-throughput next generation sequencing combined with Sanger sequencing was used to detect potential variants in newborns with MAT I/III deficiency. Pathogenicity of suspected variants was predicted by using MutationTaster and HSF software. RESULTS: Three newborns were identified with MAT I/III deficiency by newborn screening, which yielded an incidence rate of 1 in 121 515. Amino acid and acylcarnitine analysis suggested that the serum methionine of the three patients have increased to various extents. All patients showed normal growth and development during follow-up, and were found to carry MAT1A gene variants including two missense variants [c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His)] and a synonymous variant [c.360C>T (p.Cys120Cys)]. Among these, c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His) were known to be pathogenic, whereas c.360C>T (p.Cys120Cys) was a novel variant. Bioinformatics analysis suggested that this variant may alter RNA splicing and affect the structure and function of the MAT1A protein. CONCLUSION A systematic review of newborn screening for MAT I/III deficiency was provided. Discovery of the novel variant has enriched the variant profile of the MAT1A gene and provided a basis for the diagnosis of this disease.
Amino Acid Metabolism, Inborn Errors ; diagnosis ; China ; Genetic Variation ; Humans ; Infant, Newborn ; Methionine Adenosyltransferase ; deficiency ; genetics ; Neonatal Screening

OBJECTIVE: To assess the value of dry blood spot tandem mass spectrometry for the diagnosis of autism spectrum disorder (ASD). METHODS: Peripheral blood samples of 277 autistic children were collected. Their amino acid and carnitine profiles were detected by liquid chromatography tandem mass spectrometry. Urine samples of suspected patients were collected for verification by gas chromatography mass spectrometry. Blood samples were also taken for genetic testing. RESULTS: Of the 277 children with ASD, 19 (6.9%) were suspected to be with inborn error of metabolism (IEM), which included 6 cases with amino acidemia, 9 with organic acidemia and 4 with fatty acidemia. Three cases of phenylketonuria, one case of homocysteinemia, one case of propionemia, one case of methylmalonic acidemia, one case of glutaric acidemia, one case of isovaleric acidemia, one case of argininemia, one case of citrullinemia I and four cases of primary carnitine deficiency were confirmed by genetic testing, which yielded an overall diagnostic rate of 5.1% (14/277). CONCLUSION Our result has provided further evidence for the co-occurrence of ASD and IEM. Tandem mass spectrometry has a great value for the diagnosis and treatment of ASD in childhood.
Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; Autism Spectrum Disorder ; complications ; diagnosis ; Child ; Dried Blood Spot Testing ; Gas Chromatography-Mass Spectrometry ; Humans ; Metabolism, Inborn Errors ; complications ; diagnosis ; Tandem Mass Spectrometry

OBJECTIVE: To detect potential variation in glutaryl-CoA dehydrogenase (GCDH) gene among three Chinese families affected with glutaric acidemia type Ⅰ(GA-1) and correlate the genotypes with phenotypes. METHODS: Genomic DNA was extracted from peripheral blood samples derived from three patients with GA-1 and their family members. The coding regions of the GCDH gene were amplified with PCR and subjected to Sanger sequencing. RESULTS: The clinical manifestation of the patients varied from macrocephaly to severe encephalopathy, with notable phenotypic difference between siblings carrying the same variation. In pedigrees 1 and 2, the probands have carried compound heterozygous variations c.1133C>T(p.Ala378Val) and c.1244-2A>C, which were derived their fathers and mothers, respectively. In pedigree 3, the proband has carried compound heterozygous variation c.339delT (p.Tyr113) and c.406G>T (p.Gly136Cys). Among these, variations c.339delT and c.1133C>T were verified as novel by retrieval of dsSNP, HGMD and 1000 genome database. Bioinformatic analysis suggested that above variations can affect protein function and are probably pathogenic. CONCLUSION Above discovery has expanded the mutation spectrum of the GCDH gene. No correlation was found between the clinical phenotype and genotype of GA-1 patients.
Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; Brain Diseases, Metabolic ; diagnosis ; genetics ; China ; DNA Mutational Analysis ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Mutation

OBJECTIVETo explore the value of urine gas chromatography-mass spectrometry (GC-MS) in the screening of children at risk of inherited metabolic diseases (IMD), and to identify the disease spectrum of IMD and the clinical characteristics of children with IMD.

METHODSThe clinical data of 15 851 children at risk of IMD who underwent urine GC-MS in the Tianjin Children's Hospital between February 2012 and December 2016 were retrospectively analyzed.

RESULTSIn the 15 851 children, 5 793 (36.55%) were detected to have metabolic disorders. A total of 117 (0.74%) children were confirmed to have IMD, including 77 cases of methylmalonic acidemia (65.8%). The clinical manifestations of confirmed cases in the neonatal period mainly included jaundice, metabolic acidosis, abnormal muscular tension, feeding difficulty, poor response, and lethargy or coma. The clinical manifestations of confirmed cases in the non-neonatal period mainly included delayed mental and motor development, metabolic acidosis, convulsion, recurrent vomiting, and anemia.

CONCLUSIONSGC-MS is an effective method for the screening for IMD in children at risk. Methylmalonic acidemia is the most common IMD. The clinical manifestations of IMD are different between the confirmed cases in the neonatal and non-neonatal periods.

Acidosis ; etiology ; Adolescent ; Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; Child ; Child, Preschool ; Developmental Disabilities ; etiology ; Female ; Gas Chromatography-Mass Spectrometry ; Humans ; Infant ; Infant, Newborn ; Male ; Metabolism, Inborn Errors ; complications ; diagnosis ; Retrospective Studies ; Risk

Adult ; Amino Acid Metabolism, Inborn Errors ; blood ; diagnosis ; Bipolar Disorder ; blood ; diagnosis ; Gas Chromatography-Mass Spectrometry ; Humans ; Hyperhomocysteinemia ; blood ; diagnosis ; Male ; Tandem Mass Spectrometry ; Vitamin B 12 ; blood

A 9-day-old male patient was admitted to the hospital because of cough, anhelation, feeding difficulty and lethargy. The diagnostic examinations indicated pulmonary infection, severe metabolic acidosis, hyperglycemia, hyperammonemia and pancytopenia in the patient. Blood and urine screening and isovaleryl-CoA dehydrogenase (IVD) gene detection for inherited metabolic diseases were performed to clarify the etiology. Tandem mass spectrometric screening for blood showed an elevated isovalerylcarnitine (C5) level. The organic acid analysis of urine by gas chromatography-mass spectrometry showed significantly increased levels in isovaleryl glycine and 3-hydroxyisovaleric acid. Homozygous mutations (c.1208A>G, p.Tyr403Cys) in the IVD gene were identified in the patient. His parents were heterozygous carriers. After the treatment with low-leucine diets and L-carnitine for 3 days, the patient showed a significant improvement in symptoms, but he died one week later. It is concluded that the neonates with pneumonia and metabolic decompensation of unknown etiology should be screened for genetic metabolic disease.
Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; Humans ; Infant, Newborn ; Isovaleryl-CoA Dehydrogenase ; deficiency ; genetics ; Male ; Mutation ; Pancytopenia ; etiology

OBJECTIVETo study gene mutations in four pedigrees with methymalonic aciduria, as well as the feasibility of prenatal diagnosis of methymalonic aciduria.

METHODSHigh-throughput sequencing was performed for related genes in the peripheral blood of children or parents who were diagnosed with methymalonic aciduria to identify the loci with mutations. Then amplification primers were designed for each locus, and PCR and direct sequencing were performed to validate the sequencing in the first generation in the four pedigrees. Whether the mutations were pathogenic were determined with reference to literature review and medical history. In the pedigrees 1, 3, and 4, ultrasound-guided chorionic villi biopsy was performed at weeks 11-13 of pregnancy to perform early prenatal diagnosis.

RESULTSIn pedigree 1, c.656A>T and c.729-730insTT heterozygous mutations in the MUT gene were detected in the proband's father and mother, respectively. Early prenatal diagnosis showed c.656A>T and c.729-730insTT double heterozygous mutations in the fetus. The couple decided to terminate pregnancy. In pedigree 2, c.1106G>A and c.755-756insA double heterozygous mutations in the MUT gene were detected in the proband. c.1106G>A came from the father and c.755-756insA came from the mother. In pedigree 3, c.217C>T and c.609G>A double heterozygous mutations in the MMACHC gene were detected in the proband. c.217C>T came from the father and c.609G>A came from the mother. Prenatal diagnosis showed c.609G>A heterozygous mutation in the fetus. The baby was successfully delivered, and the result of umbilical cord blood testing was consistent with the prenatal diagnosis. In pedigree 4, c.609G>A and c.567dupT double heterozygous mutations in the MMACHC gene were detected in the proband. c.609G>A came from the father and c.567dupT came from the mother. Prenatal diagnosis showed c.567dupT heterozygous mutation in the fetus. The baby was successfully delivered, and the result of umbilical cord blood testing was consistent with the prenatal diagnosis.

CONCLUSIONSIdentification of gene mutations helps with prenatal diagnosis in pedigrees with methymalonic aciduria.

Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Male ; Mutation ; Pedigree ; Prenatal Diagnosis