Diagnosis and treatment of maple syrup disease: A study of 36 patients
Diagnosis and treatment of maple syrup disease: A study of 36 patients
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DOI：
10.1542/peds.109.6.999
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发表时间：
2002-06-01
期刊：
影响因子：
8
通讯作者：
Kelley, RI
中科院分区：
文献类型：
--
作者：
Morton, DH;Strauss, KA;Kelley, RI
目标。探讨枫糖浆病（MSD）的诊断和治疗方法。家族史和支链α -酮酸脱氢酶e1α亚基Y393N突变的分子检测使我们能够确定患有MSD的高危婴儿。研究人员测量了这些12至24小时大的高危婴儿的血液样本中的氨基酸浓度。另有18名患有MSD的婴儿被诊断为4至16日龄的代谢性疾病。MSD的治疗方案旨在1)抑制内源性蛋白质分解代谢，2)维持蛋白质合成，3)预防必需氨基酸的缺乏，4)维持正常的血清渗透压。我们的方案强调蛋白质合成代谢的增强和饮食对血浆氨基酸失衡的纠正，而不是通过透析或血液过滤去除亮氨酸。在急性疾病期间，监测血浆亮氨酸水平的下降率，作为净蛋白合成的指标。急性疾病的治疗方案包括使用甘露醇、速尿和高渗盐水来维持或重建正常的血清钠和细胞外渗透压，从而预防或逆转危及生命的脑水肿。同样的原则也适用于生病和健康的门诊管理，特别是在第一年，当支链氨基酸摄入量与快速变化的生长速率仔细匹配时。在家中经常监测支链酮酸排泄，并在常规门诊就诊时测量支链氨基酸水平，以便立即诊断和治疗代谢紊乱。1)采用滤纸采集血浆或全血进行氨基酸分析，确定12 ~ 24小时龄MSD高危组18例（n=39）。血浆中亮氨酸与丙氨酸的摩尔比为1.3 ~ 12.4，对照组为0.12 ~ 0.53。经我们的治疗方案处理的3天大的婴儿中没有一个在新生儿期发病，18例中有16例没有住院治疗。2)采用我们的治疗方案，又有18名在诊断时生化中毒的婴儿迅速康复。在所有婴儿中，血浆亮氨酸水平下降到219例患者年，这表明，尽管常见感染经常导致代谢控制丧失，但新生儿期后的总体住院率每例患者每年随访仅为0.56天，发育结局一致良好。4例患者因感染引起的代谢性中毒而发生危及生命的脑水肿，但全部恢复。这4例患者均表现出急性血清钠浓度降低和血清渗透压降低与急性脑水肿的快速进展有关。经典的MSD可以使新生儿病程良性，生长发育正常，住院率低。然而，由于常见的感染和损伤引起的代谢性中毒，神经功能在任何年龄都可能迅速恶化。有效管理这种生化紊乱的复杂病理生理需要综合管理一般医疗保健和营养，以及控制影响内源性蛋白质合成代谢和分解代谢、血浆氨基酸浓度和血清渗透压的几个变量。
Objective. To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD).Methods. Family histories and molecular testing for the Y393N mutation of the E1alpha subunit of the branched-chain alpha-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness.A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements.Results. 1) Eighteen neonates with MSD were identified in the high-risk group (n=39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization.2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to 219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses.Conclusions. Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.