In recent years, there have been major advances in molecular therapeutic options for HD. As a prelude to joining international clinical trials, the detailed characterization of target patient populations is essential, enabling clinicians to predict and better understand differences in therapeutic response [23–25].
Accordingly, in this retrospective study, we aimed to characterise 90 HD cases (male: 45, female: 45), and 34 carriers.
The median age of onset (45 years) was close to the European Huntington’s Disease Network’s data for Central Europe (47 years) but it was lower than those of Northern (50 years) or Southern Europe (49 years) as well as that of the United Kingdom (49 years) [4,6,9].
The ratio of juvenile onset cases (3.3%) was slightly lower than the 5% described in other studies [16,22]. All of these patients had a repeat length above 50 and a positive family history where the affected parent was the father. One patient with juvenile onset presented with the atypical Westphal phenotype [21]. Seven patients with late disease onset were identified, representing 7.8% of all cases, which is well within the range (4.4-25%) previously reported [16,22]. Each of these patients had a repeat length below 46, and evidence of an affected parent was present in only 2 out of 7 cases.
The ratio of pure motor onset (47.6%) was similar to the data of the European Huntington’s Disease Network (48%), while psychiatric (12.2%) and cognitive (2.2) onset was less frequent than reported in the same study (19.6% and 8.4%, respectively). This difference might be partly explained by the higher ratio of mixed onset cases (22.2%) in the present study compared to the report of the European Huntington’s Disease Network (13.2%) [6].
Compared to the previous study from Hungary (median: 43, range: 37-70) and the international literature (median: 42-44, range: 36-121), we found that the pathological repeat lengths of HD patients and asymptomatic carriers was similar [6,7,10,26,27]. Alleles with decreased penetrance were found in 9 carriers (26.5%) and 12 HD patients (13.3%), representing approximately 17.5% of all pathological alleles found in this study, which is higher than the data reported by the European Huntington’s Disease Network (3.1% for all participants, 1.8% for Central, 10% for Northern and 2.2% for Southern Europe) [6]. As expected, the median age of onset (53.5 years) of patients in this range was higher than that of the whole HD group (45 years) [12,28]. The frequency of intermediate alleles, either in the control group alleles (10.5%) or in all non-expanded alleles from the three groups (7%), was higher than those reported from most populations (0.45-6%), the exceptions being the findings of 2 Brazilian cohorts with frequencies of 7-8.7% [11,13,23,29,30]. There are several reports associating intermediate alleles to HD-like clinical and pathological findings, thus the assessment of these alleles is gaining increased attention despite the still controversial data [11,12,30]. In the current study, we identified 8 individuals out of 13 controls with intermediate alleles presenting symptoms similar to that of HD, although lacking further clinical data or pathological confirmation, it is unclear whether there is a causative relationship between these alleles and the presenting symptoms.
The median length of non-expanded CAG repeat alleles (19) was similar to that found in the previous Hungarian study (18) and those reported from other Caucasian populations (17.1-19.3), but higher than in Asian or African ethnic groups (16.2-17.7), [10,23].
The strong inverse correlation between age of onset and pathological repeat size was established in the current study as well (R2 = 0.38; p < 0.001). However, there was no significant association between the age of onset and the length of the non-pathological allele. It has been demonstrated that the expanded allele explains about 66-67.3% of the variance in age of onset, whereas the effect of the non-expanded allele is relatively small (approximately 1%) [3,15]. Furthermore, it was proposed that the effect of the normal allele becomes evident among individuals with large pathological repeat lengths [15], the population of which accounts for only a small proportion of patients in our study (25.6% with repeat sizes above 46 and only 8% exceeding 50).
Although the lack of detailed clinical characterization is a limitation of the study, the symptoms of HD, especially at an early stage, are rather diverse and aspecific, therefore, a diagnosis of HD can only be established in possession of correlating genetic evidence.
In conclusion, the genetic and clinical features of the populations examined in the present study were in accordance with the previous Hungarian study as well as with international literature data, except for the higher frequency of intermediate alleles and individuals with reduced penetrance alleles. The presence of these alleles is gaining importance in light of increasing evidence of disease modifying genetic factors, such as the loss of interruption variants, which have been extensively investigated in the past two years [31,32], owing to developments in analytic technologies. They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods. Additionally, some authors suggest that these variants not only influence the age of onset, but, in individuals carrying reduced penetrance alleles, they might play a major role in the manifestation of the disease [31,32]. These factors have not yet been thoroughly analysed in individuals carrying intermediate alleles and presenting neurological symptoms, which could serve as a target for future studies.