MYOINOSITOL ON CEREBELLAR FUNCTION IN PATIENTS WITH ATAXIA TELANGIECTASIA

常染色体隐性遗传疾病共济失调毛细血管扩张症（AT）导致 小脑共济失调免疫缺陷和癌症缺陷基因ATM， 编码一个大的蛋白质，似乎是局限于细胞核， 大多数细胞，并在AT缺陷的DNA修复中发挥作用。的 ATM蛋白产物还含有类似于酶的基序， 磷脂酰肌醇-3-磷酸激酶，催化 磷脂酰肌醇（ptdins）转化为Ptdins-3-P或Ptdins-4，5-p2转化为Ptdins-3， 4，5-P3。因为这些磷酸肌醇在信号传导中起作用， 转导，这表明ATM蛋白是一种新的 核信号转导系统，帮助某些细胞 在复制和体细胞重组过程中调节DNA的校对阅读 以及DNA修复。然而，缺乏证据表明， 这些磷酸肌醇中的任何一种都在来自患有以下疾病的患者的细胞中受到干扰： AT或其前体肌醇。 该项目的目标是： 1)描述不同年龄患者的小脑功能障碍 且ATM基因突变不同; 2)表征患者的T细胞异常; 3)测量肌醇和磷酸肌醇的水平， 细胞; 4)确定是否有任何临床或实验室异常， 通过提供1个月以上的磷酸肌醇来逆转 前体，肌醇，患者作为他们的日常饮食的一部分。这 将通过进行安慰剂对照、双盲 交叉研究，在每个月的开始和结束时， 将进行小脑和T细胞研究以及测量 磷酸肌醇和肌醇。

The autosomal recessive disorder, Ataxia Telangiectasia (AT), results in cerebellar ataxia, immunodeficiency and cancer. The defective gene, ATM, encodes a large protein which appears to be confined to the nucleus of most cells and plays a role in DNA repair which is defective in AT. The ATM protein product also contains a motif which resembles an enzyme, phosphatidylinositol-3-phosphokinase, that catayzes the conversion of phosphatidylinositol (ptdins) to Ptdins-3-P or Ptdins-4, 5-p2 to Ptdins-3, 4, 5-p3. Because these phosphoinositides play a role in signal transduction, it was suggested that the ATM protein is part of a novel nuclear signal transduction system which helps in certain cells to regulate proof reading of DNA during replication and somatic recombination as well as DNA repair. Lacking, however, is evidence that the levels of any of these phosphoinositides are perturbed in cells from patients with AT or that of their precursor, myo-inositol. The goals of this project are to: 1) characterize the cerebellar dysfunction in patients of different ages and with different ATM gene mutations; 2) characterize the T-cell abnormalities in patients; 3) measure the levels of the myo-inositol and the phosphoinositides in cells; 4) determine whether any of the clinical or laboratory abnormalities can be reversed by supplying for 1 month more of the phosphoinositide precursor, myo-inositol, to patients as part of their daily diet. This will be accomplished by performing a placebo controlled, double-blind crossover study in which at the beginning and end of each month the cerebellar and T-cell studies will be performed as well as the measurement of phosphoinositides and myo-inositol in cells.