In recent years, there have been major advances regarding molecular therapeutic options in HD. As a prelude to joining international clinical trials, the detailed characterization of target patient populations is essential, enabling clinicians to estimate and better understand differences in therapeutic response (21–23).
Accordingly, in this retrospective study, we aimed at the characterization of 90 HD cases (male: 45, female: 45), and 34 carriers. In age of onset, pathological, and non-expanded allele lengths, there was no significant difference between genders in either group. However, regarding late-onset cases, and those with decreased penetrance alleles, there was a marked female dominance (7:1 and 16:5, respectively). This predominance may be related to their higher life expectancy at birth: during the period in question, the life expectancy of women was by approximately 7.7 years (range: 6.5-9 years) higher, according to the data of the Hungarian Central Statistical Office (24).
The median age of onset (45 years) was close to the European Huntington’s Disease Network’s estimates 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 United Kingdom (49 years) (4, 6, 11).
The ratio of juvenile onset cases (3.3%) was slightly lower than the 5% described in other studies (9, 14). 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 (13). 7 patient of late disease onset was identified, representing 7.8% of all cases, which is well within the range (4.4–25%) reported previously (9, 14). 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.
Compared to the previous study from Hungary (median: 43, range: 37–70) and also to the international literature (median: 42–44, range: 36–121), we found that the pathological repeat lengths of the HD patients and asymptomatic carriers was similar (6, 7, 15, 25, 26). 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 compared to that of the whole HD group (45 years) (17, 27). 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% (16, 18, 21, 28, 29), In light of that there are several reports associating intermediate alleles to HD-like clinical and pathological findings, the assessment of these alleles gains increasing attention despite the still controversial data (16, 17, 29). In the current study we identified 8 individuals out of 13 controls with intermediate alleles presenting with symptoms similar to that of HD, although in the lack of 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), (15, 21).
The strong inverse correlation between age of onset and pathological repeat size was established in the current study as well (rs =-0.575; p < 0.0001). 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, 20). Furthermore, it was proposed that the effect of the normal alleles becomes evident among individuals with large pathological repeat lengths (20), which population 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 median age of onset was lower by approximately 6 years and the median repeat size was larger by 3 in cases of paternal transmission, the difference was not statistically significant. However, all cases of juvenile onset were of paternal inheritance. For a more precise assessment of parental transmission and genetic anticipation, the examination of parent-offspring pairs would be advisable as introduced in other studies (3, 8, 15). Unfortunately, the medical records serving as the basis of this study were not sufficient for the reliable assessment of such relations within our patient population.
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 the higher frequency of intermediate alleles and individuals with reduced penetrance alleles.