Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease.
Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease.
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DOI：
10.1093/brain/awp024
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Flanagan JM
中科院分区：
文献类型：
--
作者：
Zinnanti WJ;Lazovic J;Griffin K;Skvorak KJ;Paul HS;Homanics GE;Bewley MC;Cheng KC;Lanoue KF;Flanagan JM
枫糖尿病（MSUD）是一种遗传性支链氨基酸代谢疾病，患者表现为危及生命的脑水肿和髓鞘异常。治疗需要终生限制饮食和监测支链氨基酸，以避免脑损伤。尽管经过精心管理，儿童在与非特异性疾病相关的分解代谢应激的情况下通常会出现代谢失代偿。这种失代偿和脑损伤背后的机制尚不清楚。使用最近开发的经典和中度枫糖浆尿病小鼠模型，我们评估了这些小鼠在脑病期间发生的生化、行为和神经病理变化。在这里，我们表明快速的大脑亮氨酸积累取代了其他必需氨基酸，导致神经递质耗竭和正常大脑生长发育的破坏。一种新的方法，给予去甲亮氨酸的杂合母鼠的经典枫糖浆尿病幼崽减少支链氨基酸的积累在牛奶，以及这些幼崽的血液和大脑，以提高生存。同样地，去亮氨酸显著延缓了中度枫糖浆尿病小鼠的脑病，这些小鼠被置于高蛋白饮食中，模仿了导致人类枫糖浆尿病脑病的分解代谢压力。目前的研究结果表明，枫糖尿病脑损伤的两种汇聚机制包括：(i)与支链氨基酸积累相关的神经递质缺乏和生长限制；（ii）与支链酮酸积累相关的克雷布斯循环中断导致的能量剥夺。经典模型和中间模型都有助于研究枫糖浆尿病的脑损伤机制和潜在的治疗策略。去甲亮氨酸作为一种潜在的治疗方法，在分解代谢应激期间预防枫糖尿病患儿脑病，应进一步试验。
Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.
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影响因子：
8
作者：
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通讯作者：
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