MYOINOSITOL ON CEREBELLAR FUNCTION IN PATIENTS WITH ATAXIA TELANGIECTASIA

常染色体隐性遗传病，共济失调毛细血管扩张症(AT)，导致 小脑性共济失调、免疫缺陷和癌症。有缺陷的基因自动取款机， 编码一种似乎仅限于核内的大蛋白 大多数细胞，并在AT缺陷的DNA修复中发挥作用。这个 ATM蛋白产品还包含一个类似酶的基序， 磷脂酰肌醇-3-磷酸肌醇-3-磷酸激酶，催化 磷脂酰肌醇(Ptdins)至Ptdins-3-P或Ptdins-4，5-P2至Ptdins-3， 4、5-P3。因为这些肌醇磷脂在信号传递中起作用 转导，有人认为ATM蛋白是一个新的 核信号转导系统，帮助某些细胞 调控复制和体细胞重组过程中DNA的校对 以及DNA修复。然而，缺乏证据表明， 这些磷脂酰肌醇中的任何一种都会在患者的细胞中受到干扰 肌醇或其前体肌醇。 该项目的目标是： 1)不同年龄段患者小脑功能障碍的特点 且具有不同的ATM基因突变； 2)确定患者T细胞异常的特征； 3)测定血清中肌醇和肌醇的含量 细胞； 4)确定任何临床或实验室异常是否可以 通过多供应1个月的肌醇磷脂而逆转 前体，肌醇，作为患者日常饮食的一部分。这 将通过实施安慰剂对照、双盲完成 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 细胞中的肌醇和肌醇。

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.