Huntington's disease (HD) is a progressive neuron-degenerative disorder with an autosomal dominant inheritance and an incidence of 1 in 10,000 [1]. The disease presents at an advanced age (mean age 40 years) with choreic movements, impaired cognition, personality changes, minor motor abnormalities, such as clumsiness, hyperreflexia and eye movement disturbances in the early stage, and bradykinesia, rigidity, dystonia and epilepsy in the terminal stage [2]. Juvenile onset of the disease is seen in about 5-10% of patients, typically manifesting with more severe symptoms, namely rigidity and a more rapid course. About 20% of patients present after 50 years of age.

        The genetic defect causing HD is an expansion of CAG (Gln) trinucleotide repeats in the coding region of exon 1 of the IT15 gene, located on chromosome 4p16.3 [3,4]. The size of the gene is 180 kb, contains 67 exons and codes for a 10.3 kb mRNA product. The gene product, huntingtin, is a 348 kD cytoplasmic protein that consists of 3,144 amino acids and has a role in endocytosis and vesicle trafficking. In the normal population, at least 17 alleles ranging from 6-35 repeats are present, while patients with HD have disease alleles with substantially increased numbers of repeats (more than 36 copies) [5,6]. Elderly asymptomatic individuals with 35-39 CAG repeats (zone of incomplete penetrance of the mutation) have also been reported [5-7]. Less frequently, new mutations, tending to originate from long normal alleles of 29-35 repeats, have also been described [8].

        The neuropathology of HD is similar to the diseases resulting from polyglytamine expansion, such as spino­cerebellar ataxias (SCA), types 1, 2, 3, 6 and 7, spino­bulbar muscular atrophy (SMA) and dentatorubral-pallido­luysian atrophy (DRPLA). They are the product of a gain-of-function mutation, and characterized with aggregate formation of polyglytamine stretches that form cytoplasmic and nuclear inclusions containing huntingtin and ubi­quitin. These inclusions cause neuronal loss in caudate nucleus, putamen and cerebral cortex [1].

        With the advance of DNA methodology, it became possible to perform molecular diagnosis of HD in individuals with signs and symptoms of the disease, to offer predictive testing in asymptomatic individuals with a family history of the disease, and prenatal testing in proven carriers of the disease. In this paper we present our results of the molecular analysis of HD in the Republic of Macedonia.