Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8

Orphanet Journal of Rare Diseases

Qiang Shu¹  Ling Zhu¹  Chi Chen¹  Fan Tong¹  Xiaoxu Zhao¹  Qi-xing Chen¹  Junqi Feng²  Pingping Jiang³  Chenxi Yang⁴  Yuchen Zhang⁴ 

[1] Department of Genetic and Metabolic Disease, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 3333 Binsheng Road, 310052, Hangzhou, China;Department of Genetic and Metabolic Disease, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 3333 Binsheng Road, 310052, Hangzhou, China;Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, 310058, Hangzhou, China;Department of Genetic and Metabolic Disease, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 3333 Binsheng Road, 310052, Hangzhou, China;Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, 310058, Hangzhou, China;Zhejiang Provincial Key Lab of Genetic and Developmental Disorders, 310058, Hangzhou, China;Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, 310058, Hangzhou, China;

关键词: Isobutyryl-CoA dehydrogenase deficiency (IBDD);    ACAD8;    KMT2A;    Genotype;    Phenotype;    Prognosis;   

DOI  :  10.1186/s13023-021-02018-6

来源: Springer

【 摘 要 】

BackgroundIsobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD.MethodsForty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel.ResultsThe incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann–Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3–108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110–2A > T, c.236G > A, c.259G > A, c.381–14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842–1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%).ConclusionThe concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.

【 授权许可】

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