Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.

中文翻译：

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支链α-酮酸脱氢酶缺乏症（枫糖浆尿病）：治疗，生物标志物和结果。

在过去的三十年中，我们研究了184个个体，这些个体具有174个支链α-酮酸脱氢酶活性的不同分子变体，在这里描述了枫糖浆尿病（MSUD）表型的基本临床和生化特征。我们收集了经典（即严重； n = 176），中度（n = 6）和间歇性（n = 2）MSUD患者的治疗，生存，住院，代谢控制和肝移植方面的数据。总共13,589个氨基酸谱用于分析亮氨酸耐受性，氨基酸稳态，估计的脑氨基酸摄取，对合成代谢疗法的定量反应以及肝移植后的代谢控制。使用标准仪器测量神经精神病学结局。尽管临床护理有所进步，经典的MSUD仍然是一种病态并可能致命的疾病。严格的饮食疗法将代谢变量维持在可接受的范围内，但是实施起来具有挑战性，无法恢复循环氨基酸之间的适当浓度关系，并且不能完全预防认知和精神障碍。肝移植消除了对处方饮食的需要，并保护了患者免受危及生命的新陈代谢危机的影响，但与可预测的发病率相关，并且不会逆转先前存在的神经系统后遗症。迫切需要针对MSUD的安全有效的疾病缓解疗法，该疗法可在生命早期实施。