Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations

Abstract

BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation.Case presentationBoth siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries.ConclusionsMutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

Late-onset multiple acyl-CoA dehydrogenase deficiency with breast cancer

“…The vast majority of the mutations (93%) occur in the ETFDH gene [3]. The c.250G>A mutation is the most common mutation (28.1%) in reported cases, followed by c.770A>G (12.9%), c.1227A>C (8.9%), and c.1130 T>C (6.3%) [7]. Most of these cases are reported from Southeast Asia.…”

Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients

“…高 [2,17] 。多项研究报道新生儿期发病患儿 C4~C16 均升高，迟发型患儿多出现 C8~C14 升高 [1,[18][19][20] 。本文 资料中新生儿发病的 2 例患儿 C4~C18:1 均升高，迟发型患儿 C8~C14:1 均升高，以 C8、C10、C12 升 高程度明显，为正常上限 6 倍左右。新生儿发病及死亡患儿 C4 明显升高 [19,[21][22] ,本文资料中新生儿发病患 儿及迟发型出现代谢失调患儿 C4 水平相对较高。Van Rijt 等 [23] 研究发现成纤维细胞中的脂肪酸氧化能力、…”

“…ETFDH 基因突变，大部分为错义突变 [1][2] 。不同国家和地区 ETFDH 基因谱存在差异，土耳其和库尔德人 种的热点突变为 c.1130T＞C，中国南方热点突变为 c.250G＞A [24,[26][27][28] 。MADD 患者的基因型和临床分 型有关，无义突变、框移突变会造成 mRNA 表达及酶活性完全缺失导致最严重的Ⅰ型；剪切突变造成残 留酶活性非常低，导致Ⅱ型；错义突变对 mRNA 表达或 mRNA 稳定性影响较小，残留酶活性较高，导致 发病晚和病情较轻的Ⅲ型 [29][30] 。本文资料中，10 例患儿检查出 ETFDH 突变，除 1 种缺失突变及 1 种剪切 位点突变，其余均为错义突变，最常见突变为 c.250G＞A。研究报道，c.250G＞A 突变常在核黄素反应 性轻型患者中出现，表现为肌无力、胃肠道症状及运动不耐受等症状 [28,31] ，本研究携带该突变的 4 例患儿 除 1 例运动不耐受，其余均无症状。本文资料显示，c.1450C＞T 和 c.1395T＞G 是仅次于 c.250G＞A 的常见突变位点。本组病例中携带 c.1450C＞T 突变的患儿存在死亡和无症状两种结局，与 Fan 等 [19] 报 道一致；Zhu 等 [24] 报道两例 MADD 患者携带 c.1395T＞G 突变，1 例无症状，1 例感觉障碍，而本组 病例中携带该突变的患儿死亡，上述结果表明，ETFDH 基因突变具有临床异质性，基因型和表型的关 系须进一步论证。 MADD 治疗主要是在低脂、高碳水化合物、中等量蛋白质饮食基础上给予维生素 B2、左卡尼汀、辅 酶 Q10 治疗，大部分迟发型患儿的治疗效果明显，及早治疗可避免、减轻及逆转临床症状 [32] 。苯扎贝特 是一种过氧化物酶活性受体激动剂，通过诱导多种参与线粒体脂肪酸氧化酶的转录,降低血清脂质水平，对 于核黄素无反应性患儿有效 [5] 。外源性酮体 3-羟基丁酸是脑、骨骼肌和心脏的重要替代能量，参与胆固醇 合成，促进髓鞘化，具有信号传导功能，激活羧基羧酸受体 2，减少脂肪分解及神经保护作用，3-羟基丁 酸治疗后 70％MADD 患儿的心肌病、脑白质营养不良、肝脏、肌肉和呼吸衰竭症状明显改善 [33] 。 综上所述，MADD 是一种罕见的遗传代谢病，MADD…”

Flavins Act as a Critical Liaison Between Metabolic Homeostasis and Oxidative Stress in the Retina

“…As a vitamin, riboflavin is especially essential for human health due to its vast involvement in the bioenergetics, metabolism, growth, and survival of all cells ( Powers et al, 2012 ; Ashoori and Saedisomeolia, 2014 ; Barile et al, 2016 ; Saedisomeolia and Ashoori, 2018 ; Suwannasom et al, 2020 ). So, the association between low riboflavin levels and various neurodegenerative disorders, metabolic dysfunctions, diabetes mellitus and inborn errors of metabolism, like multiple acyl-CoA dehydrogenation deficiency (MADD) ( Reddi, 1986 ; Barile et al, 2016 ; Marashly and Bohlega, 2017 ; Xin et al, 2017 ; Saedisomeolia and Ashoori, 2018 ; Chen et al, 2019 , 2020 ) is least surprising.…”