Résumé
OBJECTIVES@#To investigate the disease spectrum and pathogenic genes of inherited metabolic disorder (IMD) among neonates in Gansu Province of China.@*METHODS@#A retrospective analysis was conducted on the tandem mass spectrometry data of 286 682 neonates who received IMD screening in Gansu Provincial Maternal and Child Health Hospital from January 2018 to December 2021. A genetic analysis was conducted on the neonates with positive results in tandem mass spectrometry during primary screening and reexamination.@*RESULTS@#A total of 23 types of IMD caused by 28 pathogenic genes were found in the 286 682 neonates, and the overall prevalence rate of IMD was 0.63 (1/1 593), among which phenylketonuria showed the highest prevalence rate of 0.32 (1/3 083), followed by methylmalonic acidemia (0.11, 1/8 959) and tetrahydrobiopterin deficiency (0.06, 1/15 927). In this study, 166 variants were identified in the 28 pathogenic genes, with 13 novel variants found in 9 genes. According to American College of Medical Genetics and Genomics guidelines, 5 novel variants were classified as pathogenic variants, 7 were classified as likely pathogenic variants, and 1 was classified as the variant of uncertain significance.@*CONCLUSIONS@#This study enriches the database of pathogenic gene variants for IMD and provides basic data for establishing an accurate screening and diagnosis system for IMD in this region.
Sujets)
Enfant , Nouveau-né , Humains , Études rétrospectives , Maladies métaboliques/génétique , Aminoacidopathies congénitales/génétique , Chine , Santé de l'enfantRésumé
OBJECTIVE@#To investigate the clinical manifestations, biochemical abnormalities and pathogenic variants among children with Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency detected by neonatal screening.@*METHODS@#A total of 2 730 852 newborns were screened from January 2016 to December 2021 with liquid chromatography tandem mass spectrometry. Suspected SBCAD deficiency patients were diagnosed by urine organic acid analysis and high-throughput gene sequencing analysis. The clinical, biochemical and genetic changes of the confirmed cases were analyzed, in addition with guidance for diet and life management, L-carnitine supplement, and survey of growth and intellectual development.@*RESULTS@#Twelve cases of SBCAD deficiency were diagnosed, which yielded a prevalence of 1/227 571. The lsovaleryl carnitine (C5) of primary screening blood samples was between 0.6 and 2.1 µmol/L, all exceeded the normal range. C5/acety1 carnitine (C2) was between 0.02 and 0.12, with 6 cases exceeding the normal range. C5/propionyl carnitine (C3) was between 0.1 and 1.16, with 5 cases exceeding the normal range. Free carnitine (C0) was between 18.89 and 58.12 µmol, with 1 case exceeding the normal range. Three neonates with abnormal screening results were recommended to have appropriate restriction for protein intake and two were given L-carnitine. During follow-up, their C5 has ranged from 0.22 to 2.32 µmol/L, C5/C2 has ranged from 0.01 to 0.31, C5/C3 has ranged from 0.14 to 1.7. C5 or C5/C2 and C5/C3 were transiently normal in all patients except for case 8 during the neonatal screening and follow-up. C0 was 17.42 ∼ 76.83 µmol/L Urine organic acid analysis was carried out in 9 of the 12 cases, and 2-methylbutyroglycine was elevated in 8 cases. Urine organic acid analysis was carried out in 9 cases, and 2-methylbutyrylglycine was increased in 8 cases. Genetic analysis was carried out for 11 children, and in total 6 ACADSB gene variants were identified, which included 4 missense variants (c.655G>A, c.923G>A, c.461G>A, c.1165A>G), 1 frameshift variant (c.746del) and 1 nonsense variant (c.275C>G). Among these, the C.461G>A variant was unreported previously. The most common variants were c.1165A>G (40.9%) and C.275C>G (22.7%). The patients were followed up for 18 days to 55 months. Only one patient had mental retardation, with the remainders having normal physical and mental development.@*CONCLUSION@#SBCAD deficiency is a rare disease. The detection rate of newborn screening in this study was 1/227 571. Early intervention can be attained in most asymptomatic patients through neonatal screening. In this study, the common gene variants are c.1165A>G and c.275C>G.
Sujets)
Humains , Nouveau-né , Aminoacidopathies congénitales/génétique , Carnitine , Dépistage néonatal/méthodesRésumé
OBJECTIVE@#To explore the genetic basis for a child with Isolated sulfite oxidase deficiency (ISOD).@*METHODS@#The child and her parents were subjected to targeted capture and next-generation sequencing. Pathogenicity of candidate variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#The child was found to harbor compound heterozygous variants of the SUOX gene, namely c.1200C>G (p.Tyr400*) and c.1406_1421delCCTGGCAGGTGGCTAA (p.Thr469Serfs*20), which were inherited from her mother and father, respectively. The c.1200C>G was a known pathogenic variant, while the c.1406_1421delCCTGGCAGGTGGCTAA was unreported previously and predicted to be a pathogenic variant (PVS1+PM2_Supporting +PM3) based on the guidelines from the American College of Medical Genetics and Genomics.@*CONCLUSION@#The compound c.1200C>G and c.1406_1421delCCTGGCAGGTGGCTAA variants of the SUOX gene probably underlay the pathogenesis of ISOD in this child. Above finding has expanded the spectrum of SUOX gene variants and provided molecular evidence for the clinical diagnosis and genetic counseling for this pedigree.
Sujets)
Enfant , Femelle , Humains , Aminoacidopathies congénitales/génétique , Conseil génétique , Génomique , Séquençage nucléotidique à haut débit , MutationRésumé
OBJECTIVE@#To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis.@*METHODS@#Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products.@*RESULTS@#The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection.@*CONCLUSION@#Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Sujets)
Humains , Aminoacidopathies congénitales/génétique , Hydrocéphalie , OxidoreductasesRésumé
OBJECTIVE@#To explore the genetic basis for a neonate affected with Glutaric aciduria type I (GA-I).@*METHODS@#Targeted capture and high-throughput sequencing was carried out for the proband and her parents. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The proband was found to harbor compound heterozygous variants of the GCDH gene, namely c.523G>A and c.1190T>C, which was derived from her father and mother, respectively.@*CONCLUSION@#The compound heterozygous variants of the GCDH gene probably underlay the GA-I in the patient.
Sujets)
Enfant , Femelle , Humains , Nouveau-né , Aminoacidopathies congénitales/génétique , Encéphalopathies métaboliques/génétique , Glutaryl-CoA dehydrogenase/génétique , Séquençage nucléotidique à haut débit , MutationRésumé
Isovaleric acidemia is a type of organic acidemia for which the earliest definite diagnosis was attained. It features an autosomal recessive inheritance, with the onset of age varying from newborn to adulthood. The clinical manifestations are complex and variable, which include feeding difficulty, vomiting, lethargy, coma, metabolic acidosis, sweaty feet odor and mental retardation. The mortality and mobility rates of isovaleric acidemia are quite high, and early diagnosis and rational treatment can significantly improve the prognosis. This article has provided a summary for the current understanding and research progress on isovaleric acidemia.
Sujets)
Adulte , Humains , Nouveau-né , Aminoacidopathies congénitales/génétique , Isovaleryl-CoA dehydrogenase/génétiqueRésumé
OBJECTIVE@#To explore the genetic basis for a child with succinate semialdehyde dehydrogenase deficiency.@*METHODS@#Peripheral blood samples of the proband and his parents were collected and subjected to Sanger sequencing. High-throughput sequencing was used to verify the gene variants. Bioinformatic software was used to analyze the pathogenicity of the variant sites.@*RESULTS@#Sanger sequencing showed that the proband carried a homozygous c.1529C>T (p.S510F) variant of the ALDH5A1 gene, for which his mother was a carrier. The same variant was not detected in his father. However, high-throughput sequencing revealed that the child and his father both had a deletion of ALDH5A1 gene fragment (chr6: 24 403 265-24 566 986).@*CONCLUSION@#The c.1529C>T variant of the ALDH5A1 gene and deletion of ALDH5A1 gene fragment probably underlay the disease in the child. High-throughput sequencing can detect site variation as well as deletion of gene fragment, which has enabled genetic diagnosis and counseling for the family.
Sujets)
Enfant , Humains , Nourrisson , Aminoacidopathies congénitales/génétique , Incapacités de développement , Mutation , Succinate-semialdehyde dehydrogenase/génétiqueRésumé
OBJECTIVE@#To carry out genetic analysis for 21 patients with methylmalonic acidemia (MMA) and provide genetic counseling for their families.@*METHODS@#Next generation sequencing (panel) was used to detect the pathogenic variants underlying the disease.@*RESULTS@#In total 29 variant sites of MMUT, MMAA, MMUT were identified in the 21 patients, with common variants including c.323G>A (10%), c.917C>T (10%), c.984delC (10%) of MMUT gene, and c.609G>A (45%), c.80A>G (10%) , c.567dupT (10%) of MMACHC gene. Among these, c.2000A>G of MMUT, c.298G>T of MMACHC and c.734-7A>G of MMAA gene were unreported previously.@*CONCLUSION@#Genetic testing for MMA patients can clarify the cause of the disease and provide a basis for the clinical diagnosis. Discovery of novel variants has enriched the mutational spectrum of MMA.
Sujets)
Humains , Aminoacidopathies congénitales/génétique , Dépistage génétique , Séquençage nucléotidique à haut débit , Mutation , Oxidoreductases/génétiqueRésumé
OBJECTIVE@#To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.@*METHODS@#Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.@*RESULTS@#The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported.@*CONCLUSION@#The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.
Sujets)
Enfant , Femelle , Humains , Mâle , Aminoacidopathies congénitales/génétique , Hétérozygote , Isovaleryl-CoA dehydrogenase/génétique , MutationRésumé
OBJECTIVE@#To explore the genetic etiology of a child suspected for β-ketothiolase deficiency by neonatal screening.@*METHODS@#All coding exons and flanking sequences of the ACAT1 gene were subjected to targeted capture and high-throughput sequencing. Suspected variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child was found to harbor compound heterozygous variants of the ACAT1 gene, namely c.121-3C>G and c.275G>A (p. Gly92Asp). The c.121-3C>G variant was also detected in his father and two sisters, while the c.275G>A (p. Gly92Asp) was a de novo variant. A c.334+ 172C>G (rs12226047) polymorphism was also detected in his mother and two sisters. Sanger sequencing has verified that the c.275G>A (p. Gly92Asp) and c.334+172C>G (rs12226047) variants are located on the same chromosome. Bioinformatics analysis suggested both c.121-3C>G and c.275G>A (p.G92D) variants to be damaging. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.275G>A variant of the ACAT1 gene was predicted to be pathogenic (PS2+ PM2+ PM3+ PP3+PP4), the c.121-3C>G variant to be likely pathogenic (PM2+ PM3+ PP3+PP4).@*CONCLUSION@#The c.121-3C>G and c.275G>A variants of the ACAT1 gene probably underlay the pathogenesis of the child. Above finding has enriched the variant spectrum of the ACAT1 gene.
Sujets)
Femelle , Humains , Nouveau-né , Mâle , Acetyl-coA C-acetyltransferase/génétique , Acetyl-coA C-acyltransferase/génétique , Aminoacidopathies congénitales/génétique , Séquençage nucléotidique à haut débit , MutationRésumé
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.
Sujets)
Femelle , Humains , Grossesse , Aminoacidopathies congénitales/génétique , Hétérozygote , Séquençage nucléotidique à haut débit , Mutation , Oxidoreductases , Diagnostic prénatalRésumé
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.
Sujets)
Humains , Mâle , Nouveau-né , Aminoacidopathies congénitales/génétique , Glutathione synthase/déficit , Mutation , Acidose/étiologie , Aminoacidopathies congénitales/métabolisme , Acide glutamique/analyse , Glutathione synthase/génétique , Glutathione synthase/métabolisme , 5-Oxoprolinase(ATP-hydrolysing)/déficit , 5-Oxoprolinase(ATP-hydrolysing)/génétique , Analyse de séquence d'ADN/méthodesRésumé
Estudamos seis pacientes com acidúria glutárica tipo I, em quatro famílias. Observamos variaçoes intensas na apresentaçao clínica, mesmo entre elementos da mesma família. Três pacientes evoluiram sem alteraçoes até o início das anomalias neurológicas, que se manifestaram como encefalite-símile, no primeiro ano de vida. Uma criança apresentou atraso precoce do desenvolvimento, sem episódios agudos de descompensaçao. Dois pacientes nao têm alteraçao cognitiva; um deles apresenta leve tremor associado a quadro coreoatetóide desde o primeiro ano de vida, enquanto o outro teve apenas duas crises convulsivas afebris quando lactente. Três crianças apresentam distonia como sequela, nao sendo capazes de sentar ou firmar a cabeça. Os seis pacientes apresentam macrocrania e a neles tomografia computadorizada de crânio demonstra aumento dos espaços liquóricos em regioes fronto-temporais. O estudo dos ácidos orgânicos urinários dos pacientes demonstra elevaçao dos níveis do ácido glutárico.
Sujets)
Femelle , Humains , Adulte , Enfant , Enfant d'âge préscolaire , Aminoacidopathies congénitales/diagnostic , Acides aminés essentiels/métabolisme , Glutarates/urine , Aminoacidopathies congénitales/diétothérapie , Aminoacidopathies congénitales/génétique , PhénotypeRésumé
Metilmalonicacidúria secundária à deficiência da mutase da metilmalonil CoA foi diagnosticada em duas crianças filhas de pais näo consangüíneos. A primeira criança morreu um dia antes que o diagnóstico correto fosse feito. Nesse período, sua mäe estava no terceiro trimestre de gestaçäo. Os níveis urinários de ácido metilmalônico foram medidos ao longo do terceiro trimestre de gestaçäo, mostrando um aumento gradual e indicando a presença de um feto homozigoto para a doença. A presença de metilmalonicacidúria foi confirmada no recém-nascido e o tratamento pode ser começado precocemente. A criança está sendo tratada com uma dieta com pouca proteína, com suplementaçäo de uma mistura de aminoácidos (exceto treonina, metionina, valina e isoleucina), DL-carnitina e bicarbonato. Está no momento fisicamente e mentalmente normal com doze meses de idade