Molecular diagnosis of Huntington disease in Portugal: implications for genetic counselling and clinical practice

Abstract

Huntington disease (HD) is a neurodegenerative, autosomal dominant disorder of late-onset, caused by the expansion of a CAG repeat in the coding region of the gene. Ours is the reference laboratory for genetic testing in HD, in Portugal, since 1998; 90.1% of all 158 families known were identified for the first time, including patients with unusual presentation or without family history. A total of 338 genetic tests were performed: 234 for diagnosis, 96 for presymptomatic and four for prenatal testing (four were done for family studies). Most referring physicians were neurologists (90.6%); 82.8% of all clinical diagnosis were confirmed, while 83.1% of those sent for exclusion were in fact excluded. In presymptomatic testing, an excess of female subjects (59.4%) was again verified; 37.5% of the consultands were found to be carriers. None of the foetuses, in four prenatal tests, were mutation carriers. One juvenile case was inherited from her mother. Our patient population is very similar to others described so far, namely in terms of mean age at onset and (CAG) n distribution, except perhaps for a higher frequency of large normal (class 2) alleles (3.7%). We also identify cases posing particular problems for genetic counselling, such as, 'homozygosity' that can pose a serious ethical dilemma, carriers of large normal alleles, and 'homoallelism' for a normal gene, which will demand further procedures and may delay results in presymptomatic and prenatal testing.

The CAG repeat at the Huntington disease gene in the Portuguese population: insights into its dynamics and to the origin of the mutation

“…The presence of these two mutated alleles in a randomly selected sample of 1,000 individuals from our population could correspond to a higher prevalence of HD in the Portuguese population than described elsewhere. In a previous report, we had predicted it to be at least 2-5:10,0000 (Costa et al 2003), i.e. similar to that of other European countries.…”

“…In addition, haplotype analyses in HD families of different ethnic populations has suggested that multiple mutation events underlie this disorder, and that a specific group of normal unstable alleles within a particular haplotype may be more prone to expansion leading to fully penetrant HD alleles, thus constituting a pool for the generation of new HD genes (Goldberg et al 1993;Squitieri et al 1994;Almqvist et al 1995). Previously, from our routine genetic testing in Portugal, we observed that normal unstable alleles (class 2) had a relatively high frequency, accounting for 3.7% of the ''normal'' chromosomes (Costa et al 2003).…”

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype

“…As we have previously reported (Costa et al 2003), among our series of cases for HD diagnosis, we found a high number of HD mutation-negative patients who had both a family history and typical HD clinical features. Here, we describe a series of 107 HDL patients of Portuguese origin, who do not present (CAG) n expansions in the HD gene.…”

Huntington disease and Huntington disease‐like in a case series from Brazil

“…HD was diagnosed in 93% of 618 French and Moroccan (13), 82.8% of 169 Portuguese (14), 57% of 66 Brazilian (15) and 50% of 11 South African black (16) patients with a HDlike phenotype. A review of the literature might suggest a gradient of frequency, where HTT expansions are much more prevalent among North-Europeans, than in other populations.…”