Analysis Of Clinical Phenotype And Gene Mutation Characteristics Of Infants With Methylmalonic Acid

Background:Methylmalonic acidemia(MMA)is a common organic acidosis,and is also an autosomalrecessive genetic disease.The clinical manifestations of the disease are repeated vomiting,feeding difficulties,drowsiness,mental physical development,backward or backward,convulsions,dyspnea and muscle tension abnormalities,hair yellow as the main performance.The main diagnostic basis of MMA are determination of urinary methylmalonic acid by gas chromatography-mass spectrometry and serum acyl carnitine by tandem mass spectrometry.According to the level of homocysteine,it are divided into simple methylmalonic acid and methylmalonic acid with homocysteine,and gene detection is the most reliable basis for clinical classification.Individual different clinical manifestations can be expressed as multi-system involvement,and the disease may exist from the fetal to adult and easy to be misdiagnosed,missed diagnosis.There are few studies on the clinical manifestations,genotypes and their relationship in this disease.Objective:To summarize the clinical manifestations,laboratory tests,skull images and genotype characteristics in children with methylmalonic acid,and to explore their association with each other.Methods:In this study,74 patients with MMA who were dignosed and done by genetic testing in Zhengzhou Children’s Hospital from Sep.2014 to May 2017 were selected as the subjects.The clinical datas and auxiliary examination results were analyzed retrospectively.The MMA and MMA were combined with homocysteine Clinical features of the disease.Serum C3,C3 / C2 and urinary methylmalonic acid were measured by blood tandem mass spectrometry and urine gas chromatography-mass spectrometry.PCR product was detected by Sanger sequencing,and the relationship between the phenotype of MMA and its gene mutation were further explored.Results:1.Clinical features: There were 74 cases in this study included the single MMA 21 cases,MMA combined with homocysteine with 53 cases.Of the 21 patients with simple MMA,14 patients were included in the study.the onset age of MMA was most from l d to 1month.Clinical features had repeated vomiting,poor breast-feeding,weight does not increase,high lactic acid,metabolic acidosis,high blood ammonia,renal dysfunction and so on;and the onset age of MMA with homocysteinemia patients were from 1 month to 1 year old,and clinical features mainly for breastfeeding,convulsions,dyskinesia,bone marrow suppression.The common features of head imageis were subarachnoid widening or ventricular dilatation,and simple type of MMA patients with common basal ganglia damage.2.Mutant gene: 53 cases of MMA combined with homocysteineemia patients were detected MMACHC gene mutation,including 2 cases a mutation,51 cases two mutations,of which 8 cases of homozygous mutation,43 cases of heterozygous mutation.The detection rate of allele mutation was 98.1%(104/106).A total of 20 mutations were detected.C.609G> A was the most common mutation,and the mutation frequency was 30.2%,and followed by c.658-660 del AAG,the mutation frequency was 16.0%,the other mutation frequency was lower,and c.429 + 1G > T,c.667C> A for the new mutation.Mutations were mainly in exon 4,and the mutation frequency was 74%(77/104).They were nonsense mutations and missense mutations.In the 14 cases of simple MMA patients,methyl methoxyl-Co A mutant(MUT)gene mutations were detected,a mutation was detected in 2 cases,and two mutation were detected in 12 cases.Allele mutation detection rate was 92.9%(26/28),of which MUT0 type 3 cases,a total of 22 kinds of mutations were detected,in addition to twins mutation sites,the rest of each mutation were different,and mutation site was diversification.3.The correlation between clinical phenotype and genotype: children with 609G> A mutation gene had earlier onset age,and no 609G> A mutation gene type in children with more late onset age.MUT0 type had early onset age,severe illness,low survival rate.Compared to combined type of children,simple type of children had more vomiting,being easy to merge disturbance of consciousness,severe metabolic acidosis and hyperammonemia,and long-term prognosis was poor,and convulsions was more in combined type than that in simple type.Conclusion:1.In MMA in children,MMA with homocysteinemia is the most common,and simple MMA rare.2.In MMA with homocysteinemia,Cbl C type is the most common,609G> A(W203X)hot spot mutation(30.2%)exists;MUT0 type is the most common in simple MMA.3.Patients with cbl C type with 609G>A mutation were early onset,and the late onset was more common in those with no mutation.MUT0 type had early onset,heavy condition and low survival rate.4.Simple MMA children are of early onset age,and the condition is heavier.The main performance are of repeated vomiting,easy to disturbance of consciousness,severe metabolic acidosis and hyperammonemia,and long-term prognosis is poor.The basal ganglia damage in head image of are more common in simple MMA patients.