[Importance of the number of trinucleotide repeat expansions in the clinical manifestations of Huntington's chorea].

INTRODUCTION

In 1993 the gene responsible for Huntington's disease (IT15) was isolated [5]. It was mapped to the tip of the short arm of chromosome 4 and within its coding sequence, near the 5' end, it contained a certain number of trinicleotide (CAG)n (cytosine-adenine-guanine) repeats (Figure 1). This gene codes for a protein (348 kd) called "huntington" that is widely expressed, and its sequence is not related to any protein [6]. The normal range of (CAG)n repeat numbers within IT15 was reported to be between 6 and 37 [6]. Mutation responsible for Huntington's disease implied expansion of (CAG)n repeats: in patients with Huntington's disease the pathologic range was determined to be between 35 and 121 repeats [7-10].

PATIENTS AND METHODS

In this study we correlated the age at onset, rate of progression and initial symptoms of Huntington's disease with the number of trinucleotide (CAG)n repeats in IT15. DNA was isolated from peripheral blood leukocytes of patients fulfilling clinical criteria for definite and probable Huntington's disease [2]. Genetic verification of Huntington's disease was made by the previously described and modified PRC (polymerase chain reaction) technique [17, 18]. In our laboratory a gene with 40 or more repeats was considered as a marker of Huntington's disease.

RESULTS

The study comprised 26 patients (11 women and 15 men). At the onset of Huntington's disease they were between 19 and 66 years old (36.6 12.8 years), with the duration of the disease between 1 and 15 years (5.8 4.3 years). The number of (CAG)n, repeats in IT15 ranged between 40 and 95 (49.9 14.1). The negative correlation between the (CAG)n, count in the expanded allele and the age at onset of the disease has been confirmed. Regression analysis showed the correlation coefficient of -0.54 (p = 0.012). The effect of trinucleotide (CAG)n, repeats on the initial clinical manifestations and rate of progression of Huntington's disease is only one of the growing group of "CAG-repeat" disorders that also include entities such as spinocerebellar ataxia-type 1 and 3, spinobulbar muscular atrophy and dentato-rubo-pallidoluysian atrophy [6].