Surendran Sankar, Michals-Matalon Kimberlee, Quast Michael J, Tyring Stephen K, Wei Jingna, Ezell Ed L, Matalon Reuben
Department of Pediatrics, Children's Hospital, The University of Texas Medical Branch, Galveston, TX 77555-0359, USA.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):74-80. doi: 10.1016/j.ymgme.2003.08.015.
Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.
卡纳万病（CD）是一种遗传性脑白质营养不良，由天冬氨酸酰基转移酶（ASPA）缺乏以及脑内N - 乙酰天门冬氨酸（NAA）蓄积所致。ASPA基因已被克隆，已描述的突变有40多种，其中在德系犹太人患者中有两个始祖突变。对德系犹太人进行这两种常见突变的筛查显示携带者频率很高，约为1/40，因此目前正在开展携带者检测项目。CD中的酶缺乏会干扰NAA的正常水解，导致髓鞘破坏和脑白质海绵状变性。该病的临床特征为巨头畸形、头后仰、进行性重度智力发育迟缓以及早期出现肌张力减退，后期转变为痉挛状态。已培育出CD基因敲除小鼠，并用于研究CD的病理生理基础。基因敲除小鼠的研究结果表明，这种单基因性状会导致大脑中一系列的基因组相互作用。变化包括谷氨酸和γ - 氨基丁酸（GABA）水平降低。微阵列表达分析显示GABA - A受体（GABRA6）和谷氨酸转运体（EAAT4）表达水平较低。参与细胞凋亡和细胞死亡的Spi2基因表达水平较高。这种基因相互作用的复杂性导致了蛋白质组表型，即小鼠出现脑海绵状变性和神经功能障碍，与人类患者相似。使用腺相关病毒（AAV）作为载体在小鼠脑内进行天冬氨酸酰基转移酶基因转移试验的结果令人鼓舞，显示注射部位及注射部位以外区域的髓鞘形成得到改善，海绵状变性减少。
