Clinical analysis of 15 851 children at risk of inherited metabolic diseases / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>In 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.</p><p><b>CONCLUSIONS</b>GC-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.</p>

Mutation analysis of a family with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency / 中华儿科杂志

<p><b>OBJECTIVE</b>The aim of this study was to explore the genetic features of a family with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBDD) which may provide the basis for the diagnosis and genetic counseling.</p><p><b>METHOD</b>Clinical data of the proband was collected, total RNA and genomic DNA were extracted from the peripheral blood. The whole coding region of the ACAT1 gene was amplified by RT-PCR. 5' noncoding region of the ACAT1 gene and all 6 exons and flanking intron regions of the HADH2 gene were amplified by PCR. All amplification products were directly sequenced and compared with the reference sequence.</p><p><b>RESULT</b>(1) The patient was a one-year-old boy who presented with psychomotor retardation and astasia when he was admitted to the hospital. Biochemical test revealed slight hyperlactatemia (3.19 mmol/L) and magnetic resonance imaging showed delayed myelination. 2-Methylacetoacetyl-CoA thiolase deficiency was suggested by gas chromatography-mass spectrometry. (2) There was no mutation in the ACAT1 gene and a hemizygous missense mutation c.388C > T was found in the 4 exon of the HADH2 gene which resulted in p. R130C. Proband's mother was the heterozygote and the father was normal.</p><p><b>CONCLUSION</b>This is the first report on MHBDD patient and HADH2 mutation in China. p.R130C is responsible for the pathogenesis of the disease in the infant.</p>

Analysis of ALDH5A1 gene mutation in a Chinese Han family with succinic semialdehyde dehydrogenase deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation in ALDH5A1 gene for a family affected with succinic semialdehyde dehydrogenase deficiency diagnosed by clinical inspection and urine screening.</p><p><b>METHODS</b>Polymerase chain reaction and direct DNA sequencing were carried out for the affected child and her parents. Suspected ALDH5A1 gene mutations were verified in 100 healthy controls to exclude polymorphisms.</p><p><b>RESULTS</b>The child was found to have carried 2 heterozygous missense mutations in the coding region of ALDH5A1 gene, namely c.527G>A and c.691G>A, for which her mother and father were respectively heterozygotes. The same mutations were not detected in 100 healthy controls. The child was also found to have carried two previously described polymorphisms including a heterozygous c.545C>T(derived from her father) and a homozygous c.538C>T(derived from her mother).</p><p><b>CONCLUSION</b>Missense mutations of c.527G>A and c.691G>A in the ALDH5A1 gene are responsible for the pathogenesis of the disease in this family.</p>

Correlation between genotypes and biochemical phenotypes of phenylalanine hydroxylase in patients with phenylketonuria / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the correlation between genotypes and biochemical phenotypes of phenylalanine hydroxylase (PAH) in patients with phenylketonuria (PKU).</p><p><b>METHODS</b>Thirteen exons and flanking introns of PAH gene in 102 patients with high blood phenylalanine levels (Phe > 120 umol/L) at initial diagnosis were amplified with polymerase chain reaction and analyzed with single strand conformation polymorphism (SSCP), denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. Correlation between genotypes and biochemical phenotypes was analyzed.</p><p><b>RESULTS</b>Biochemical assaying has indicated that 69 patients had classical PKU (Phe> 1200 umol/L), 31 were moderate (Phe 600-1200 umol/L), and 2 were mild (Phe 400-600 umol/L). More than 41 mutations and 75 genotypes have been identified. There were 9 (8.8%) homozygous mutations, which included 3 cases with R111X/R111X, 1 case with IVS4-1G>A/IVS4-1G>A, 3 cases with R243Q/R243Q and 2 cases with V399V/V399V. Among these 8 belonged to classic PKU phenotypes, except for a R243Q/R243Q genotype which has led to a moderate phenotype. In 91 patients carrying compound PAH mutations, 61 were classic, 29 were moderate, and 1 was mild. Patients who were heterozygous for R111X/R243Q and EX6-96A>G(Y204C)/R243Q were found with both classic and moderate PKU phenotypes. Certain individuals who have carried 2 null mutant alleles such as R111X/V399V, EX6-96A>G/Y356X and EX6-96A>G/V399V only showed a moderate phenotype. Individuals with R111X/A165D and R176X/A165D genotypes, on the other hand, respectively presented moderate and classic PKU phenotypes.</p><p><b>CONCLUSION</b>Ninety percent of our patients are compound heterozygotes. Independent assortment of mutant alleles has resulted in a complex genotype-phenotype correlation. Although in most cases a correlation may be found, caution should still be taken upon genetic counseling. The phenomena where similar or even identical genotype may give rise to different biochemical phenotypes have implied that other factors may also influence the phenylalanine metabolism.</p>