Pode-Shakked Naomi, Korman Stanley H, Pode-Shakked Ben, Landau Yuval, Kneller Katya, Abraham Smadar, Shaag Avraham, Ulanovsky Igor, Daas Suha, Saraf-Levy Talya, Reznik-Wolf Haike, Vivante Asaf, Pras Elon, Almashanu Shlomo, Anikster Yair
Department of Pediatrics A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Wilf Children's Hospital, Shaare Zedek Medical Center, Jerusalem, Israel.
Eur J Med Genet. 2020 Jun;63(6):103901. doi: 10.1016/j.ejmg.2020.103901. Epub 2020 Mar 6.
Maple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD.
We describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes.
All affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described.
While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis.
枫糖尿症是一种罕见的常染色体隐性氨基酸代谢病，由支链2-酮酸脱氢酶（BCKD）缺乏引起，随后导致支链氨基酸（BCAAs）：亮氨酸、异亮氨酸和缬氨酸的蓄积。虽然大多数枫糖尿症病例为典型病例，但约20%的病例为非典型变异型，分为中间型或间歇型。后一种类型的患者通常发育正常，认知功能完好，无症状时BCAA水平正常。然而，并发的发热性疾病和分解代谢可能导致代谢紊乱，出现危及生命的神经后遗症。因此，对于间歇性枫糖尿症，早期检测和饮食干预是必要的。
我们描述了来自四个无亲缘关系家庭的八名患者，他们被诊断为间歇性枫糖尿症。他们在代谢危机期间出现的症状各不相同，从意识模糊和意识减退到共济失调以及急性精神病。通过对BCKDHA、BCKDHB和DBT基因进行测序来进行枫糖尿症的分子确诊。
所有受影响个体均被发现BCKDHB或DBT基因存在双等位基因致病性变异。在这七个变异中，BCKDHB基因的四个变异（p.G101D、p.V103A、p.A221D、p.Y195C）和DBT基因的一个变异（p.K427E）此前未被描述。
虽然新生儿筛查项目能够早期检测出典型枫糖尿症，但间歇性类型的病例可能未被发现，并在儿童期后期因代谢紊乱出现一系列非特异性症状时才被发现。我们对本文所报告家庭的经验增加了目前关于这种独特的支链氨基酸代谢先天性缺陷的表型和突变谱的知识，并强调了其诊断所需的高度怀疑指数。
