Zhang Huiqiu, Ma Jing, Su Menghan, Zhao Junsen, Duan Weisong, Wang Juan, Liu Dan, Guo Junhong, Chang Xueli, Zhang Wei, Zhao Rongjuan
Department of Neurology, First Hospital of Shanxi Medical University, No. 85, Jiefang South Street, Taiyuan, 030012, China.
Research Center for Neurological Diseases, Shanxi Medical University, Taiyuan, China.
Orphanet J Rare Dis. 2025 Jun 18;20(1):310. doi: 10.1186/s13023-025-03845-7.
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disease chiefly caused by mutations in ETFDH gene. Mutations in the ETFDH gene lead to abnormal structure, impaired function, and increased degradation of ETFDH protein. However, it is not known why approximately 10% of patients carry single heterozygous variants in ETFDH. We speculate that different variation types (e.g., null variants and missense variants) partially account for the phenomenon.
In this study, six databases were searched up until December 01, 2024. Studies describing late-onset MADD patients carrying ETFDH variations were included. The analyses focused on the differences in variation types, computational pathogenicity scores of missense variants, and clinical characteristics between patients with biallelic and single heterozygous variations (biallelic group vs heterozygous group).
Of the initially screened 3638 studies, 30 met the inclusion criteria, including 498 late-onset MADD patients with biallelic variations and 62 with single heterozygous variations in ETFDH. The relative frequency of patients carrying null variants was lower in the biallelic group (21%, 95% CI [16%-27%]) than that in the heterozygous group (34%, 95% CI [23%-48%]) (P = 0.044). Missense variants in the heterozygous group had stronger pathogenicity than those in the biallelic group, as reflected by the computational prediction tools, SIFT, PolyPhen-2 and metaRNN (P < 0.05). Patients carrying biallelic variations had a younger onset age and a higher level of serum creatine kinase at diagnosis (P < 0.05).
Late-onset MADD patients carrying single heterozygous variations in ETFDH gene have distinct variation profiles and clinical severity compared to those harboring biallelic variations, which highlights the complexity of this disease.
迟发性多种酰基辅酶A脱氢酶缺乏症（MADD）是一种常染色体隐性疾病，主要由ETFDH基因突变引起。ETFDH基因突变导致ETFDH蛋白结构异常、功能受损及降解增加。然而，尚不清楚为何约10%的患者在ETFDH基因中携带单杂合变异。我们推测不同的变异类型（如无效变异和错义变异）部分解释了这一现象。
本研究检索了截至2024年12月1日的六个数据库。纳入描述携带ETFDH变异的迟发性MADD患者的研究。分析重点在于双等位基因变异和单杂合变异患者（双等位基因组与杂合子组）之间变异类型、错义变异的计算致病性评分及临床特征的差异。
在最初筛选的3638项研究中，30项符合纳入标准，包括498例携带双等位基因变异的迟发性MADD患者和62例携带ETFDH单杂合变异的患者。双等位基因组中携带无效变异的患者相对频率（21%，95%CI[16%-27%]）低于杂合子组（34%，95%CI[23%-48%]）（P = 0.044）。计算预测工具SIFT、PolyPhen-2和metaRNN显示，杂合子组中的错义变异比双等位基因组中的错义变异具有更强的致病性（P < 0.05）。携带双等位基因变异的患者发病年龄更小，诊断时血清肌酸激酶水平更高（P < 0.05）。
与携带双等位基因变异的迟发性MADD患者相比，携带ETFDH基因单杂合变异的患者具有不同的变异谱和临床严重程度，这凸显了该疾病的复杂性。
