Clinical, Biochemical, and Molecular Analyses of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients.

Zhuwen Gong,Huiwen Zhang,Yu Wang,Wenjun Ji,Jun Ye,Wenjuan Qiu,Lianshu Han,Xuefan Gu,Lili Liang,Ting Chen

doi:10.3389/fgene.2021.577046

Abstract

ObjectiveMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation. The present study aimed to evaluate clinical and biochemical manifestations, and the mutation spectrum of this disorder in a large cohort of Chinese patients.MethodsA total of 24 patients were enrolled, and blood acylcarnitine and urinary organic acid levels were measured by tandem mass spectrometry and gas chromatography–mass spectrometry (GC–MS), respectively. Mutations in the ACADM gene were detected by Sanger or next-generation sequencing. Clinical progression, acylcarnitine spectra, and mutations were analyzed and described in detail.ResultsAmong the 24 patients, six cases were diagnosed because of disease onset with symptoms such as vomiting, diarrhea, convulsion, and hypoglycemia; 18 patients without symptoms were diagnosed by newborn screening (NBS). All patients who accepted treatment after diagnosis developed normal intelligence and physique. The concentrations of octanoylcarnitine, the octanoylcarnitine/decanoylcarnitine ratio, and the octanoylcarnitine/acetylcarnitine ratio in the blood and urinary dicarboxylic acid concentrations were consistently elevated. Blood biomarkers failed to decrease after treatment. DNA sequencing revealed seven known and 17 novel mutations in the ACADM gene of patients. Mutation p.T150Rfs∗4 was most frequent, followed by p.R31C, p.F103Y, p.I223T, p.G362E, and c.387+1delG.ConclusionDespite biochemical abnormalities, medium-chain acyl-CoA dehydrogenase deficiency showed relatively mild clinical phenotypes with low mortality and optimistic prognoses in China. NBS is crucial for early diagnosis, treatment, and prognosis.

Highlights

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD; OMIM 607008) is a rare autosomal, recessively inherited metabolic disease of mitochondrial fatty acid β-oxidation
The other 18 cases were identified by MS/MS-based newborn screening (NBS), among which 11 cases were identified by our NBS center
We found that MCADD produced relatively mild clinical phenotypes, several biochemical abnormalities, low morbidity, and optimistic prognosis

Summary

Introduction

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD; OMIM 607008) is a rare autosomal, recessively inherited metabolic disease of mitochondrial fatty acid β-oxidation. This disorder occurs more frequently in Caucasian populations at an estimated incidence of 1/8,000–1/20,000, with 1/4,900–1/8,500 in Germany and 1:10,000–30,000 in the United States (Grosse et al, 2006; Rhead, 2006). In China, MCADD incidence varies significantly between regions and was reported at 1/80,332–1/282,591 based on newborn screening (NBS) data (Wang et al, 2019; Yan et al, 2019; Yang et al, 2020). The clinical diagnosis of MCADD is based on biochemical parameters including plasma acylcarnitine, blood glucose, liver functioning, creatine kinase (CK), and blood lipids. The diagnosis can be confirmed by sequencing the ACADM gene, whose mutation spectrum varies greatly between ethnicities

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