The clinical and genetical heterogeneity of riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency
SUN Yi-ming1, CAO Ji-qing2, LI Jing2, LI Huan2, ZHANG Cheng2
1 Department of Health, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China;
2 Department of Neurology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
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.
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.
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. Chinese Journal of Contemporary Neurology and Neurosurgery, 2020, 20(6): 534-540.
Vattemi G, Gellera C, Tomelleri G. Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency:delayed hypersensitivity reaction and efficacy of low-dose intermittent supplementation[J]. Eur J Neurol, 2017, 24:e41-42.
[2]
Yamada K, Kobayashi H, Bo R, Takahashi T, Purevsuren J, Hasegawa Y, Taketani T, Fukuda S, Ohkubo T, Yokota T, Watanabe M, Tsunemi T, Mizusawa H, Takuma H, Shioya A, Ishii A, Tamaoka A, Shigematsu Y, Sugie H, Yamaguchi S. Clinical, biochemical and molecular investigation of adult-onset glutaric acidemia type Ⅱ:characteristics in comparison with pediatric cases[J]. Brain Dev, 2016, 38:293-301.
[3]
van der Westhuizen FH, Smuts I, Honey E, Louw R, Schoonen M, Jonck LM, Dercksen M. A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency[J]. J Neurol Sci, 2018, 384:121-125.
[4]
Carroll JE, Shumate JB, Brooke MH, Hagberg JM. Riboflavin-responsive lipid myopathy and carnitine deficiency[J]. Neurology, 1981, 31:1557-1559.
[5]
Grünert SC. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency[J]. Orphanet J Rare Dis, 2014, 9:117.
[6]
Xi J, Wen B, Lin J, Zhu W, Luo S, Zhao C, Li D, Lin P, Lu J, Yan C. Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J]. J Inherit Metab Dis, 2014, 37:399-404.
[7]
Wang ZQ, Chen XJ, Murong SX, Wang N, Wu ZY. Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G > A[J]. J Mol Med (Berl), 2011, 89:569-576.
[8]
Lan MY, Fu MH, Liu YF, Huang CC, Chang YY, Liu JS, Peng CH, Chen SS. High frequency of ETFDH c.250G > A mutation in Taiwanese patients with late-onset lipid storage myopathy[J]. Clin Genet, 2010, 78:565-569.
[9]
Wang ZQ, Wang N, Wu ZY. Hotspot c.250G > A mutations in electron transfer flavoprotein dehydrogenase gene of late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in Southern China[J]. Zhonghua Shen Jing Ke Za Zhi, 2011, 44:368.[王志强, 王柠, 吴志英. 中国南方晚发型多种酰基辅酶A脱氢酶缺陷的电子转移黄素蛋白脱氢酶基因存在高频热点突变c.250G > A[J]. 中华神经科杂志, 2011, 44:368.]
[10]
Wang Y, Zhao DH, Hong DJ, Wang ZX, Yuan Y. Hot spot mutations in electron transfer flavoprotein dehydrogenase gene of riboflavin responsive lipid storage myopathy in 20 Chinese families[J]. Zhonghua Shen Jing Ke Za Zhi, 2011, 44:309-313.[王韵, 赵丹华, 洪道俊, 王朝霞, 袁云. 核黄素反应性脂质沉积性肌病20个家系的电子转移黄素蛋白脱氢酶基因存在热点突变[J]. 中华神经科杂志, 2011, 44:309-313.]
[11]
Chinese Society of Neurology, Chinese Society of Neuromuscular Disease, Chinese Society of Electromyography and Clinical Neuroelectrophysiology. Expert consensus on diagnosis and treatment of lipid deposition myopathy in China[J]. Zhonghua Shen Jing Ke Za Zhi, 2015, 48:941-945.[中华医学会神经病学分会, 中华医学会神经病学分会神经肌肉病学组, 中华医学会神经病学分会肌电图及临床神经生理学组. 中国脂质沉积性肌病诊治专家共识[J]. 中华神经科杂志, 2015, 48:941-945.]
[12]
Wen B, Dai T, Li W, Zhao Y, Liu S, Zhang C, Li H, Wu J, Li D, Yan C. Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations[J]. J Neurol Neurosurg Psychiatry, 2010, 81:231-236.
[13]
Law LK, Tang NL, Hui J, Fung SL, Ruiter J, Wanders RJ, Fok TF, Lam CW. Novel mutations in ETFDH Gene in Chinese patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency[J]. Clin Chim Acta, 2009, 404:95-99.
[14]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17:405-424.
[15]
Cao JQ, Zhang C, Li YQ, Yang J, Liang YY, Feng SW, Zhang X, Li J, Zhang HL, Zhu YL, Geng J, Yang LQ. Clinical characteristics and gene mutation analysis of riboflavin-responsive lipid storage myopathy:report of 3 cases in 2 families and review of literature[J]. Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi, 2014, 14:479-484.[操基清, 张成, 李亚勤, 杨娟, 梁颖茵, 冯善伟, 张旭, 利婧, 张惠丽, 朱瑜龄, 耿嘉, 杨丽卿. 核黄素反应性脂质沉积性肌病临床特征与基因突变分析:两家系三例报告并文献复习[J]. 中国现代神经疾病杂志, 2014, 14:479-484.]
[16]
Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency[J]. Brain, 2007, 130:2045-2054.
[17]
Zhang J, Frerman FE, Kim JJ. Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool[J]. Proc Natl Acad Sci USA, 2006, 103:16212-16217.
[18]
Muralidhara BK, Rathinakumar R, Wittung-Stafshede P. Folding of Desulfovibrio desulfuricans flflavodoxin is accelerated by cofactor flfly-casting[J]. Arch Biochem Biophys, 2006, 451:51-58.
[19]
Xu J, Li D, Lv J, Xu X, Wen B, Lin P, Liu F, Ji K, Shan J, Li H, Li W, Zhao Y, Zhao D, Pok JY, Yan C. ETFDH Mutations and Flavin Adenine Dinucleotide Homeostasis Disturbance Are Essential for Developing Riboflavin-Responsive Multiple Acyl-Coenzyme A Dehydrogenation Deficiency[J]. Ann Neurol, 2018, 84:659-673.
[20]
Liu XY, Wang ZQ, Wang DN, Lin MT, Wang N. A historical cohort study on the efficacy of glucocorticoids and riboflavin among patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J]. Chin Med J (Engl), 2016, 129:142-146.
[21]
Momosaki K, Kido J, Yoshida S, Sugawara K, Miyamoto T, Inoue T, Okumiya T, Matsumoto S, Endo F, Hirose S, Nakamura K. Newborn Screening for Pompe Disease in Japan:Report and Literature Review of Mutations in the GAA Gene in Japanese and Asian Patients[J]. J Hum Genet, 2019, 64:741-755.
