Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency

Background:Very long chain acyl-CoA dehydrogenase deficiency(VLCADD)is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase(VLCAD),and which can present as cardiomyopathy in neonates,as hypoketotic hypoglycemia in infancy,and as myopathy in late-onset patients.Although many ACADVL mutations have been described,no prevalent mutations in the ACADVL gene have been associated with VLCADD.Herein,we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.Methods:Seven Chinese patients,from newborn to 17 years old,were included in this study.Tandem mass spectrometry was performed to screen for VLCAD defi ciency.All exons and fl anking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing.Online analysis tools were used to predict the impact of novel mutations.Results:All cases had elevated serum levels of tetradecanoylcarnitine(C14:1)which is the characteristic biomarker for VLCADD.The phenotype of VLCADD is heterogeneous.Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth.Three patients showed hepatomegaly and hypoglycemia in infancy.The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis.Three of the patients died at the age of 6-8 months.Eleven different mutations in the ACADVL gene in the 7 patients were identified,including seven reported mutations(p.S22X,p.W427X,p.A213T,p.G222R,p.R450H,c.296-297delCA,c.1605+1G>T)and four novel mutations(p.S72F,p.Q100X,p.M437T,p.D466Y).The p.R450H and p.D466Y(14.28%,2/14 alleles)mutations were identifi ed in two alleles respectively.Conclusions:The clinical manifestations were heterogeneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients.R450H may be a relatively common mutation in Asian populations.The genotype and phenotype had a certain correlation in our patients.

QDPR gene mutation and clinical follow-up in Chinese patients with dihydropteridine reductase deficiency

Background:This study aimed to investigate the mutation spectrum of the QDPR gene,to determine the effect of mutations on dihydropteridine reductase(DHPR)structure/function,to discuss the potential genotype-phenotype correlation,and to evaluate the clinical outcome of Chinese patients after treatment.Methods:Nine DHPR-deficient patients were enrolled in this study and seven of them underwent neonatal screening.QDPR gene mutations were analyzed and confi rmed by routine methods.The potential pathogenicity of missense variants was analyzed using Clustal X,PolyPhen program and Swiss-PDB Viewer 4.04_OSX software,respectively.The clinical outcomes of the patients were evaluated after long-term treatment.Results:In 10 mutations of the 9 patients,4 were novel mutations(G20V,V86D,G130S and A175R),4 were reported by us previously,and 2 known mutations were identified.R221X was a hotspot mutation(27.7%)in our patients.Eight missense mutations probably had damage to protein.Six patients in this series were treated with a good control of phenylalanine level.The height and weight of the patients were normal at the age of 4 months to 7.5 years.Four patients,who underwent a neonatal screening and were treated early,showed a normal mental development.In 2 patients diagnosed late,neurological symptoms were signifi cantly improved.Conclusions:The mutation spectrum of the QDPR gene is different in the Chinese population.Most mutations are related to severe phenotype.The determination of DHPR activity should be performed in patients with hyperphenylalaninemia.DHPR-defi cient patients who were treated below the age of 2 months may have a near normal mental development.