Kremer B, Goldberg P, Andrew S E, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
N Engl J Med. 1994 May 19;330(20):1401-6. doi: 10.1056/NEJM199405193302001.
Huntington's disease is associated with an expanded sequence of CAG repeats in a gene on chromosome 4p16.3. However, neither the sensitivity of expanded CAG repeats in affected persons of different ethnic origins nor the specificity of such repeats for Huntington's disease as compared with other neuropsychiatric disorders has been determined.
We studied 1007 patients with diagnosed Huntington's disease from 565 families and 43 national and ethnic groups. In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2). The number of CAG repeats was also assessed in 1595 control chromosomes, with the size of adjacent polymorphic CCG trinucleotide repeats taken into account.
Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent). There were no significant differences among national and ethnic groups in the number of repeats. No CAG expansion was found in the 110 control subjects with other neuropsychiatric disorders (specificity, 100 percent; 95 percent confidence interval, 95.2 to 100 percent). In 1581 of the 1595 control chromosomes (99.1 percent), the number of CAG repeats ranged from 10 to 29 (median, 18). In 12 control chromosomes (0.75 percent), intermediate-sized CAG sequences with 30 to 35 repeats were found, and 2 normal chromosomes unexpectedly had expanded CAG sequences, of 39 and 37 repeats.
CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.
亨廷顿舞蹈症与4号染色体p16.3区域一个基因中CAG重复序列的扩增有关。然而，不同种族的亨廷顿舞蹈症患者中CAG重复序列扩增的敏感性，以及与其他神经精神疾病相比，此类重复序列对亨廷顿舞蹈症的特异性均未得到确定。
我们研究了来自565个家庭、43个民族的1007例确诊为亨廷顿舞蹈症的患者。此外，还测定了113名有阿尔茨海默病家族史（44例患者）、精神分裂症家族史（39例）、重度抑郁症家族史（16例）、老年舞蹈症家族史（5例）、良性遗传性舞蹈症家族史（5例）、神经棘红细胞增多症家族史（2例）以及齿状核红核苍白球路易体萎缩家族史（2例）的对照受试者的CAG重复序列长度。同时，在考虑相邻多态性CCG三核苷酸重复序列大小的情况下，对1595条对照染色体中的CAG重复序列数量进行了评估。
在1007例有符合亨廷顿舞蹈症诊断的体征和症状的患者中，995例有CAG重复序列扩增，重复次数在36至121次之间（中位数为44次）（敏感性为98.8%；95%置信区间为97.7%至99.4%）。不同民族之间的重复次数无显著差异。在110例患有其他神经精神疾病的对照受试者中未发现CAG扩增（特异性为100%；95%置信区间为95.2%至100%）。在1595条对照染色体中的1581条（99.1%）中，CAG重复序列数量在10至29次之间（中位数为18次）。在12条对照染色体（0.75%）中，发现了重复次数为30至35次的中等大小CAG序列，另外有2条正常染色体意外出现了CAG序列扩增，重复次数分别为39次和37次。
CAG三核苷酸扩增是全球范围内亨廷顿舞蹈症的分子基础，是该疾病突变遗传的高度敏感和特异的标志物。
