Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2021-03-17 , DOI: 10.1002/jimd.12377 Dina Zand 1 , Jenny Doan 1 , Sojeong Yi 2 , Jie Wang 2 , Lian Ma 2 , Emmanuel Akinshola 1 , Sushanta Chakder 1 , Joette Meyer 1 , Michael Pacanowski 2 , Laura Lee Johnson 3 , Kathleen Donohue 1 , Julie Beitz 1
1 BACKGROUND
Patients diagnosed with LC‐FAOD are unable to utilize long‐chain fats obtained from diet or catabolism to create TCA cycle substrates (also called anaplerotic substrates). Specifically, this group of autosomal recessive disorders is caused by pathogenic defects in the nuclear genes that encode the mitochondrial enzymes necessary for the creation of anaplerotic substrates. The enzymes transport long‐chain fatty acids across the mitochondrial membrane for metabolism into two‐carbon aceto‐acetate for use in the TCA cycle, which is ultimately converted into energy via this process.
In patients diagnosed with LC‐FAOD, partial or incomplete oxidation of fatty acids leads to the accumulation of toxic fatty acid intermediates, a reduction of anaplerotic substrates and impaired gluconeogenesis. Patients who are unable to metabolize long‐chain fatty acids can experience acute life‐threatening metabolic crises during times of increased energy demand, such as growth, infections, and exercise.1, 2 These metabolic crises are the clinical manifestation of catabolism and most commonly present as acute rhabdomyolysis, hypoglycemia, and/or hypertrophic cardiomyopathy. The metabolic crises can be precipitous and life‐threatening with rapid deterioration requiring emergency medical management. Patients may also demonstrate chronic symptoms of subacute rhabdomyolysis and progressive cardiomyopathy. Disease severity is assessed by the frequency and severity of metabolic crises, and dietary sufficiency is usually assessed by multiple factors, including the number of interim metabolic crises since the last assessment, individual patient growth trajectory, and biochemical analyses of macronutrient intake (ie, creatine kinase levels and plasma amino acids).
Currently, the clinical management of LC‐FAOD focuses on dietary modifications that include a low‐fat diet, limiting of ingestion of long‐chain fatty acids, and medium‐chain triglycerides (MCT) Supplementation.3 MCTs are naturally occurring fats that are not impacted by the enzymatic defects that result in LC‐FAOD. MCT oil is a mixture of C6, C8, C10, and C12 triglycerides. Infant formula and specialized formula for patients with inborn errors of metabolism are also often used to supplement dietary MCT oil. As a dietary supplement, MCT oil is not regulated to the same extent as drugs. Therefore, each commercial MCT oil may vary in composition of the specific triglyceride components. Though it is hypothesized that the component most utilized by LC‐FAOD patients is C8, the percentage of C8 identified in commonly available MCT oil formulations can range from 40% to 70%. In addition, patients with LC‐FAOD appear to have different levels of adherence and/or tolerability to MCT oil, regardless of disease severity, compounding any underlying risk for catabolism and metabolic crises.
The approval of Dojolvi (triheptanoin), a medium‐chain triglyceride consisting of three odd‐chain 7‐carbon length fatty acids (heptanoate), provides a source of calories and fatty acids to adult and pediatric patients that can bypass the LC‐FAOD enzyme deficiencies for energy production and replacement.
中文翻译:
监管新闻:Dojolvi(三庚酸甘油酯)作为长链脂肪酸氧化障碍中卡路里和脂肪酸的来源:FDA 批准摘要
1 背景
被诊断为 LC-FAOD 的患者无法利用从饮食或分解代谢中获得的长链脂肪来产生 TCA 循环底物(也称为回补底物)。具体而言,这组常染色体隐性遗传疾病是由编码产生回补底物所必需的线粒体酶的核基因中的致病性缺陷引起的。这些酶将长链脂肪酸运输穿过线粒体膜进行代谢,转化为双碳乙酰乙酸酯,用于 TCA 循环,最终通过该过程转化为能量。
在诊断为 LC-FAOD 的患者中,脂肪酸的部分或不完全氧化会导致有毒脂肪酸中间体的积累、回补底物的减少和糖异生受损。无法代谢长链脂肪酸的患者在能量需求增加期间(如生长、感染和运动)可能会经历危及生命的急性代谢危机。1、2这些代谢危象是分解代谢的临床表现,最常见的表现为急性横纹肌溶解症、低血糖症和/或肥厚性心肌病。代谢危机可能会迅速恶化并危及生命,需要紧急医疗管理。患者也可能表现出亚急性横纹肌溶解症和进行性心肌病的慢性症状。疾病严重程度通过代谢危机的频率和严重程度进行评估,而饮食充足性通常通过多种因素进行评估,包括自上次评估以来发生的中期代谢危机的次数、个体患者的生长轨迹和常量营养素摄入量(即肌酸)的生化分析激酶水平和血浆氨基酸)。
目前,LC-FAOD 的临床管理侧重于饮食调整,包括低脂饮食、限制长链脂肪酸的摄入和中链甘油三酯 (MCT) 补充剂。3MCT 是天然存在的脂肪,不受导致 LC-FAOD 的酶缺陷的影响。MCT 油是 C6、C8、C10 和 C12 甘油三酯的混合物。婴儿配方奶粉和针对先天性代谢障碍患者的专用配方奶粉也常用于补充膳食中的 MCT 油。作为膳食补充剂,MCT 油不像药物那样受到监管。因此,每种商业 MCT 油的特定甘油三酯成分的组成可能不同。尽管假设 LC-FAOD 患者最常使用的成分是 C8,但在常用 MCT 油配方中鉴定出的 C8 百分比可能在 40% 到 70% 之间。此外,无论疾病严重程度如何,LC-FAOD 患者似乎对 MCT 油的依从性和/或耐受性水平不同,
Dojolvi(三庚酸甘油酯)是一种中链甘油三酯,由三个奇数链 7 个碳长的脂肪酸(庚酸酯)组成,获得批准,为成人和儿童患者提供热量和脂肪酸来源,可以绕过 LC-FAOD 酶能源生产和替代的不足。