ABSTRACT
Objective:To explore the genetic causes of abnormal isovaleryl carnitine (C5) metabolism in newborns.Methods:Retrospective study.The screening and clinical follow-up data of 34 neonates with elevated C5 levels shown by the tandem mass spectrometry test in Children′s Hospital, Zhejiang University School of Medicine from January 2018 to December 2021 were collected.Afterwards, their ethylenediaminetetraacetic acid (EDTA) anticoagulant venous blood was collected to extract genomic DNA.A total of 79 genes related to genetic metabolic diseases, such as ACADSB, IVD and ACADM, were captured by liquid-phase capture technology.High-throughput sequencing and bioinformatics analysis were used to acquire gene variation information and the genes were categorized by American College of Medical Genetics and Genomics classification standard.According to the results of genetic analysis, the newborns with C5 elevation were divided into 3 groups: non-mutation group(11 cases), ACADSB mutation group(16 cases) and IVD mutation group(7 cases). Wilcoxon rank sum test was performed to analyze the difference between these groups. Results:Among 34 neonates, 6 ACADSB variants were detected in 16 cases, and 2 of them [c.461G>A (p.G154E), c.746delC(p.P249Lfs*15)] were novel variants.Eleven IVD variants were detected in 7 cases, and 7 of them [c.118A>G(p.N40D), c.296-10C>G, c.302A>G(p.Y101C), c.537G>A(p.M179I), c.667C>T(p.R223W), c.983A>G(p.K328R), c.1147+ 5G>A] were never reported before.There was no significant difference in the C5 concentration in initial screening among the three groups ( P>0.05). Conclusions:Mutations in ACADSB and IVD genes are the main causes of augmented C5 levels in neonatal screening.For newly discovered genetic variants, functional prediction by multiple bioinformatics analysis software is recommended.And it is also important to carry out clinical follow-up and evaluation.
ABSTRACT
Objective To analyze 4 child patients with 3-methylcrotonyl-coenzyme A carboxylase deficiency (MCCD) identified by neonatal screening and confirmed by urine gas chromatography-mass spectrometry (GC/MS) and genetic analysis.Methods Newborns whose C4DC + CSOH concentration was above 0.6 μmol/L in newborn screening were recalled for rescreening,and the CADC + C5OH concentrations in their mothers were detected.The child patients suspected with MCCD were further confirmed by urine GC/MS and genetic analysis.Results Three child patients were definitely diagnosed as MCCD by genetic analysis,including 1 MCCD,1 maternal MCCD and 1 paternal MCCD.The other 1 child patient suspected with MCCD had only one allele in MCCC1.Conclusion The mother and father of newborns with elevated C4DC + C5OH identified in neonatal screening should routinely perform MS / MS testing.When only one pathogenic locus is found in the suspected MCCD child patients by genetic analysis,they should be followed up regularly.
ABSTRACT
La deficiencia aislada de 3-metilcrotonil-CoA carboxilasa es un desorden autosómico recesivo del catabolismo de leucina con gran variabilidad fenotípica. Es uno de los errores innatos del metabolismo más común, con una incidencia de hasta 1:36.000 neonatos. Mujeres que presentan esta condición han sido identificadas únicamente luego de que las muestras de tamizaje neonatal de sus hijos sanos presentaran resultados anormales. La deficiencia de 3-metilcrotonil-CoA carboxilasa materna debe tomarse en cuenta al evaluar un resultado positivo de 3-OH-isovalerilcarnitina en tamizaje neonatal. Además, se debe valorar si es necesario brindar seguimiento clínico periódico a los niños diagnosticados con déficit de 3-metilcrotonil-CoA carboxilasa en Costa Rica, pues está documentado que la mayoría de estos pacientes permanecen asintomáticos.
Isolated 3-methylcrotonyl-coenzymeA carboxylase deficiency is an autosomal recessive disorder of leucine catabolism with considerable phenotypic heterogeneity. It is one of the most common inborn errors of metabolism with an incidence as high as 1 in 36.000 newborns. Women presenting this deficiency have been identified only by detection of abnormal results in newborn screening samples of their healthy babies. Maternal 3-methylcrotonyl-coenzyme A carboxylase deficiency should be taken into account when assessing a positive newborn screening result for 3-hydroxy-isovaleryl carnitine. The question of whether or not to provide periodic medical examination to children diagnosed with 3-methylcrotonyl-coenzymeA carboxylase deficiency in Costa Rica should also be addressed, since there are clinical studies sustaining that most of these patients remain asymptomatic.