Glycogen storage disease type Ia misdiagnosed as multiple acyl-coenzyme A dehydrogenase deficiency by mass spectrometry.

Objective: To report a case of glycogen storage disease (GSD) type Ia misdiagnosed as multiple acyl-coenzyme a dehydrogenase deficiency (MADD) by mass spectrometry. Methods: A 7 months old boy was admitted to our hospital for elevated transaminase levels lasting more than 1 month. His blood biochemistry showed hypoglycemia, metabolic acidosis, hyperlipidemia, elevated lactate and uric acid, elevated alanine amino transferase (ALT), aspartate amino transaminase (AST) and gamma-glutamyl transferase (GGT). Mass spectrometry analysis of blood and urine showed elevated blood acylcarnitines and dicarboxylic aciduria, indicating multiple acyl-coenzyme A dehydrogenase deficiency. Sanger sequencing of all exons of glucose-6-phosphatase (G6Pase) and electronic transfer flavoprotein dehydrogenase (ETFDH) was performed for the patient and his parents. Results: Coding and flanking sequences of the G6Pase gene detected two heterozygous single base substitutions in the boy. One variant was in exon 1 (c.209G > A), Which was also detected in the father. Another was in exon 5 (c.648G > T), which was detected in the mother. Coding and flanking sequences of the ETFDH gene revealed no pathogenic/likely pathogenic variants in the boy. Conclusion: GSD Ia can manifest elevated blood acyl carnitines and dicarboxylic aciduria which were the typical clinical manifestations of MADD. So the patient with clinical manifestations similar to MADD is in need of differential diagnosis for GSD Ia. Genetic testing is helpful to confirming the diagnosis of inherited metabolic diseases.

Maternal periconceptional folate status and infant atopic dermatitis: A prospective cohort study.

BACKGROUND: Maternal folate status is linked with the risk of allergic disorders including atopic dermatitis (AD) in children, but findings remain inconclusive. We aim to assess the relationship between maternal folate status in early gestation and early-onset infant AD, based on a prospective mother-child cohort study. METHODS: Pregnant women were recruited at 12-14 weeks of gestation. Red blood cell folate (RBC folate) and serum folate concentrations were examined at enrollment. Periconceptional folic acid supplementation was investigated through a self-administered questionnaire. The primary outcome was AD incidence before 6 months of age, diagnosed according to Williams' criteria. Multivariate logistic regression was used to evaluate associations of maternal folate status with infant AD by adjusting parental and child covariates. RESULTS: In total, 107 (23.4%) of 458 infants developed AD before 6 months, with more male infants affected (P = .002). Higher maternal RBC folate levels (per 100 ng/mL) were associated with an increased risk of AD (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.04-1.31). An RBC folate level ≥620 ng/mL was associated with increased infant AD by 91% (aOR 1.91, 95% CI 1.09-3.36). However, associations were not observed for maternal serum folate at early gestation or periconceptional folic acid supplement intakes. CONCLUSIONS: We provide the first evidence that higher maternal RBC folate concentrations during early gestation are associated with increased early-onset infant AD. Our findings support the importance of maintaining appropriate folate levels during the periconceptional period to reduce the risk of AD in infants.

Novel NBAS mutations and fever-related recurrent acute liver failure in Chinese children: a retrospective study.

BACKGROUND: Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. We sought to address this by searching for genes mutated in such children. METHODS: Five unrelated Chinese boys presenting between 2012 and 2015 with RALF of unexplained etiology were studied. Results of whole exome sequencing were screened for mutations in candidate genes. Mutations were verified in patients and their family members by Sanger sequencing. All 5 boys underwent liver biopsy. RESULTS: NBAS was the only candidate gene mutated in more than one patient (biallelic mutations, 3 of 5 patients; 5 separate mutations). All NBAS mutations were novel and predictedly pathogenic (frameshift insertion mutation c.6611_6612insCA, missense mutations c.2407G > A and c.3596G > A, nonsense mutation c.586C > T, and splicing-site mutation c.5389 + 1G > T). Of these mutations, 3 lay in distal (C-terminal) regions of NBAS, a novel distribution. Unlike the 2 patients without NBAS mutations, the 3 patients with confirmed NBAS mutations all suffered from a febrile illness before each episode of liver crisis (fever-related RALF), with markedly elevated alanine aminotransferase and aspartate aminotransferase activities 24-72 h after elevation of body temperature, succeeded by severe coagulopathy and mild to moderate jaundice. CONCLUSIONS: As in other countries, so too in China; NBAS disease is a major cause of fever-related RALF in children. The mutation spectrum of NBAS in Chinese children seems different from that described in other populations.

[Mutation analysis of FAH gene in patients with tyrosinemia type 1].

OBJECTIVE: To investigate the clinical features and mutations of the FAH gene. METHOD: Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants. RESULT: Patient 1 was a 5 months and 21 days-old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha-fetoprotein > 1210 µg/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 µmol/L and 83.7 µmol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 µg/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 µmol/L and 27.48 µmol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235). CONCLUSION: Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children.