Baslow M H, Resnik T R
Nathan S. Kline Institute for Psychiatric Research, Center for Neurochemistry, Orangeburg, NY 10962, USA.
J Mol Neurosci. 1997 Oct;9(2):109-25. doi: 10.1007/BF02736855.
Canavan disease (CD), a rare recessive autosomal genetic disorder, is characterized by early onset and a progressive spongy degeneration of the brain involving loss of the axon's myelin sheath. After a relatively normal birth, homozygous individuals generally develop clinical symptoms within months, and usually die within several years of the onset of the disease. A biochemical defect associated with this disease results in reduced activity of the enzyme N-acetyl-L-aspartate amidohydrolase (aspartoacylase) and affected individuals have less ability to hydrolyze N-acetyl-L-asparate (NAA) in brain and other tissues. As a result of aspartoacylase deficiency, NAA builds up in extracellular fluids (ECF) and is excreted in urine. From an analysis of the NAA biochemical cycle in various tissues of many vertebrate species, evidence is presented that there may be two distinct NAA circulation patterns related to aspartoacylase activity. These include near-field circulations in the brain and the eye, and a far-field systemic circulation involving the liver and kidney, the purpose of which in each case is apparently to regenerate aspartate (Asp) in order for it to be recycled into NAA as part of the still unknown function of the NAA cycle. Based on the authors' analysis, they have also identified several metabolic outcomes of the genetic biochemical aspartoacylase lesion. First, there is a daily induced Asp deficit in the central nervous system (CNS) that is at least six times the static level of available free Asp. Second, there is up to a 50-fold drop in the intercompartmental NAA gradient, and third, the ability of the brain to perform its normal intercompartmental cycling of NAA to Asp is terminated, and as a result, the only remaining long-term source of Asp for NAA synthesis is via nutritional supplementation of Asp or its metabolic precursors. Finally, the authors identify a potential maternal-fetal interaction that may be responsible for observed normal fetal development in utero, and that provides a rationale for, and suggests how, CD might respond to far-field nutritional, transplantation, or genetic engineering techniques to alter the course of the disease.
卡纳万病（CD）是一种罕见的常染色体隐性遗传疾病，其特征为发病早且大脑进行性海绵状变性，伴有轴突髓鞘的丧失。在相对正常的出生后，纯合个体通常在数月内出现临床症状，且通常在疾病发作后的几年内死亡。与该疾病相关的生化缺陷导致N - 乙酰 - L - 天冬氨酸酰胺水解酶（天冬氨酸酰基转移酶）的活性降低，受影响个体在大脑和其他组织中水解N - 乙酰 - L - 天冬氨酸（NAA）的能力下降。由于天冬氨酸酰基转移酶缺乏，NAA在细胞外液（ECF）中积累并随尿液排出。通过对许多脊椎动物物种各种组织中NAA生化循环的分析，有证据表明可能存在与天冬氨酸酰基转移酶活性相关的两种不同的NAA循环模式。这些包括大脑和眼睛中的近场循环，以及涉及肝脏和肾脏的远场全身循环，在每种情况下其目的显然是再生天冬氨酸（Asp），以便它作为NAA循环的仍未知功能的一部分被再循环回NAA。基于作者的分析，他们还确定了遗传生化天冬氨酸酰基转移酶损伤的几种代谢结果。首先，中枢神经系统（CNS）中每天诱导的Asp缺乏至少是可用游离Asp静态水平的六倍。其次，隔室间NAA梯度下降高达50倍，第三，大脑进行其正常的NAA到Asp隔室间循环的能力终止，因此，NAA合成中唯一剩余的长期Asp来源是通过Asp或其代谢前体的营养补充。最后，作者确定了一种潜在的母婴相互作用，这可能是子宫内观察到的胎儿正常发育的原因，并为CD如何应对远场营养、移植或基因工程技术以改变疾病进程提供了理论依据并提出了建议。
