The clinical and genetical heterogeneity of riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency

doi:10.3969/j.issn.1672-6731.2020.06.011

Abstract

Abstract:

Objective To explore the diversity of clinical manifestations and gene mutations of riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency (MADD). Methods and Results The clinical, blood biochemical, EMG, muscle biopsy and genetic analysis results of 5 patients with riboflavin-responsive MADD were collected, to analyze and summarize the clinical characteristics of riboflavin-responsive MADD. The onset age of 5 patients was 13-32 years old, with an average age of 20.40 years old. The main manifestation was fluctuating or progressive muscle weakness, involving facial, neck, proximal limb and respiratory muscles and often aggravated after exercise, fatigue, and infection. Serum creatine kinase (CK) increased slightly to moderately in 5 patients, and blood lactic acid increased significantly after exercise in 2 patients. The EMG of 4 patients showed myogenic damage, and the EMG of one patient showed neurogenic damage in the early stage of the disease and mainly myopathic damage in later stage. Muscle biopsy of 2 patients showed a large amount of lipid droplet deposition in muscle fibers positive for oil red O staining. Genetic analysis revealed that 4 patients showed homozygous or compound heterozygous mutations in the ETFDH gene (one patient carried homozygous mutations of G250A; 2 patients carried compound heterozygous mutations of G250A and G524A; one patient carried compound heterozygous mutations of T1211C and C1454G), the remaining one case carried the G1399C heterozygous mutation in ETFDH gene and the C725T heterozygous mutation in ETFB gene. Conclusions In mainland of China, riboflavin-responsive MADD mainly presents as a lipid deposition disease involving skeletal muscle, with a progressive or fluctuating course. It is easily misdiagnosed as several types of muscular dystrophy, mitochondrial myopathy, glycogen storage disease, myasthenia gravis and peripheral neuropathy. The mutation ETFDH gene is its main cause. Since riboflavin-responsive MADD has a good prognosis, the vitamin B² diagnostic treatment should be given when the patients are suspected of riboflavin-responsive MADD, combined with urine organic acid, blood acylcarnitine, muscle biopsy and genetic analysis to confirm the diagnosis.

Key words: Multiple acyl coenzyme A dehydrogenase deficiency, Riboflavin, Genes, Mutation

摘要：

目的探讨核黄素反应性多酰基辅酶A脱氢酶缺乏症（MADD）的临床表现和基因突变的多样性。方法与结果 收集5例核黄素反应性MADD患者的临床特征、血清学指标、肌电图、肌肉组织活检和基因分析结果，对核黄素反应性MADD的临床特点进行回顾分析和总结。5例患者发病年龄为13~32岁，平均20.40岁；临床表现为波动性或进行性肌无力，主要累及面部、颈部、四肢近端和呼吸肌，运动、劳累或感染后症状加重；血清肌酸激酶水平轻至中度升高，其中2例血清乳酸水平于运动后明显升高；4例呈肌源性损害，1例在疾病早期呈神经源性损害、晚期以肌源性损害为主；肌肉组织活检有2例肌纤维内可见大量油红O染色阳性脂肪滴沉积。基因分析显示，4例表现为ETFDH基因纯合或复合杂合突变，分别携带G250A纯合突变（1例）、G250A和G524A复合杂合突变（2例）、T1211C和C1454G复合杂合突变（1例），1例携带ETFDH基因G1399C杂合突变和ETFB基因C725T杂合突变。结论中国大陆核黄素反应性MADD患者主要表现为骨骼肌受累的脂质沉积性疾病，呈进行性或波动性病程，应注意与各种类型的肌营养不良症、线粒体肌病、糖原贮积病、重症肌无力和周围神经病相鉴别；ETFDH基因突变是其主要致病原因。由于核黄素反应性MADD患者预后良好，对于疑似病例可以小剂量维生素B2进行诊断性治疗，同时结合尿有机酸、血酰基肉碱、肌肉组织活检和基因检测以明确诊断。

关键词: 多酰基辅酶A脱氢酶缺乏, 核黄素, 基因, 突变

SUN Yi-ming, CAO Ji-qing, LI Jing, LI Huan, ZHANG Cheng. The clinical and genetical heterogeneity of riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2020, 20(6): 534-540.

孙毅明, 操基清, 利婧, 李欢, 张成. 核黄素反应性多酰基辅酶A脱氢酶缺乏症的临床表现与基因突变多样性[J]. 中国现代神经疾病杂志, 2020, 20(6): 534-540.

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URL: https://journal11.magtechjournal.com/cjcnn/EN/10.3969/j.issn.1672-6731.2020.06.011

https://journal11.magtechjournal.com/cjcnn/EN/Y2020/V20/I6/534

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