Study On Children’s Delayed Multiple Acyl-CoA Dehydrogenase Deficiency Clinical Data,Mass Spectrometric And Genetics

Objective: To analyze the clinical features,mass spectrometry results and gene characteristics of children with late-onset multiple acyl-Co A dehydrogenase deficiency(MADD).Structural prediction of mutant proteins was performed with Py MOL software.To explore the relationship between clinical phenotypes and genotypes of late-onset MADD in children.Through the correlation study of clinical phenotype and genotype of delayed MADD in children,to predict and prevent the risk of sudden death caused by acute metabolic disorders in children,to help doctors individualize the treatment of children,improve the prognosis,and provide the basis for genetic screening of neonatal inborn errors of metabolism.Methods: In the first part,children who presented to the Department of Inheritance,Metabolism and Endocrinology at Wuhan Children ’s Hospital from January 2014 to December 2022 and were diagnosed with late-onset MADD were selected.The clinical data of the children were analyzed.The gene mutation characteristics of the children were analyzed,and the mutation sites with unknown significance(VUS)were simulated with Py MOL software to draw the wild-type ETFDH protein and the mutant protein structures,respectively,so as to predict the effect of the mutation on the conformation of the ETFDH protein.In the second part,Pub Mud was used to query the literature,summarize and analyze the published MADD cases,and statistically analyze the late-onset MADD cases to summarize the association between genotypes and phenotypes.Results: Part I: All 7 patients treated in our hospital were patients with late-onset MADD,Cases 1,2,3 and 6 presented with myasthenia,manifested as limb weakness,difficulty in walking and raising head;cases 4 and 5 were admitted due to infection,and developed poor mental response and drowsiness after admission,with gradually reduced limb muscle tone;no significant hypoglycemia or metabolic acidosis was detected during the first hospitalization in7 children;cases 1-5 had significantly increased alanine aminotransferase,aspartate aminotransferase,creatine kinase,creatine kinase-MB,lactate dehydrogenase,and lactate dehydrogenase isoenzyme-1;blood tandem mass spectrometry revealed abnormally increased multiple acyl-Co A in 7 patients;urine organic acids revealed increased ethylmalonic acid,glutaric acid,adipic acid,3-hydroxyglutaric acid,octendioic acid,suberic acid,and sunflower acid.In case 1,genetic testing revealed compound heterozygous mutations of c.872 T > G(p.Val291Gly)and c.929 A > G(p.Tyr310Cys)in the ETFDH gene in the patient;Genetic testing in case 2 revealed compound heterozygous mutations of c.1573 C > T(p.Gln513*)and c.911 A > G(p.Tyr310Cys)on the ETFDH gene;genetic testing in case 3 revealed compound heterozygous mutations of c.1348 G > A(p.Asp450Asn)and c.1486 G > A(p.Glu496Lys)on the ETFDH gene;genetic testing in case 4 revealed homozygous mutations of c.82 G > A(p.Gly28Ser)on the ETFB gene in patients;genetic testing in case 5 revealed homozygous mutations of c.524 G > T(p.Arg175Leu)on the ETFDH gene;and genetic testing in case 6revealed c.524 G > T(p.Arg175Leu)and c.1281-1282AA(p.I428Argfs6)mutations in the ETFDH gene.Seven patients treated with oral L-carnitine and vitamin B2 showed significant improvement in clinical symptoms.Part II: Through searching and screening in Pub Mud,50 articles and 120 cases were identified,including 82 cases of late-onset MADD.In the data of120 cases,the number of ETFA gene mutation cases was 18/120;the number of ETFB gene mutation cases was 11/120;and the number of ETFDH gene mutation cases was 91/120.binary logistic regression model study showed that ETFDH gene mutation was a risk factor for muscle weakness symptoms,P < 0.05,with statistical significance.The mean age of onset of 82 children with late-onset MADD was 11.6 years,73.27% and 41.46% developed acute and chronic symptoms,respectively;39.02% died.The number of ETFDH and ETFA gene mutation cases was 70/82,6/82 and 6/82,respectively.binary logistic regression model study showed that ETFDH gene mutation was a risk factor for muscle weakness symptoms,P < 0.05,with statistical significance.Conclusion: 1.Most patients presented with myasthenia;2.ETFDH gene is more likely to have muscle weakness symptoms than ETF gene and is a risk factor for clinical muscle weakness symptoms;3.there was no significant statistical difference in the correlation between clinical symptoms such as hypoglycemia,metabolic acidosis,vomiting,drowsiness,and survival rate and ETFDH and ETF genes.