Clinical manifestations of homozygote allele carriers in Huntington disease

Abstract

Objective Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles ≥36 CAG repeats and heterozygotes with 1 allele ≥36 CAG repeats. Methods This was an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). Baseline and longitudinal total functional capacity, motor, cognitive, and behavioral scores of the Unified Huntington's Disease Rating Scale (UHDRS) were compared between homozygotes and heterozygotes. Four-year follow-up data were analyzed using longitudinal mixed-effects models. To estimate the association of age at onset with the length of the shorter and larger allele in homozygotes and heterozygotes, regression analysis was applied. Results Of 10,921 participants with HD (5,777 female [52.9%] and 5,138 male [47.0%]) with a mean age of 55.1 ± 14.1 years, 28 homozygotes (0.3%) and 10,893 (99.7%) heterozygotes were identified. After correcting for multiple comparisons, homozygotes and heterozygotes had similar age at onset and UHDRS scores and disease progression. In the multivariate linear regression analysis, the longer allele was the most contributing factor to decreased age at HD onset in the homozygotes (p < 0.0001) and heterozygotes (p < 0.0001). Conclusions CAG repeat expansion on both alleles of the HTT gene is infrequent. Age at onset, HD phenotype, and disease progression do not significantly differ between homozygotes and heterozygotes, indicating similar effect on the mutant protein. Classification of evidence This study provides Class II evidence that age at onset, the motor phenotype and rate of motor decline, and symptoms and signs progression is similar in homozygotes compared to heterozygotes.

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

“…Although certainly attractive, this hypothesis fails to explain two groups of data. First, it does not explain why the age of onset of dominant HD is well-predicted by the length of the longer repeat expansion allele in homozygous patients (243,244) or why the age of onset of recessive FRDA is determined solely by the shorter GAA expansion allele JBC REVIEWS: Repeat-mediated genome instability (245)(246)(247). Second, it fails to explain why the age of onset of HD is better predicted by the length of noninterrupted CAG repeats in DNA rather than by the length of the polyQ tract in the protein (128 -130).…”

Analysis of HTT CAG repeat expansion in Italian patients with amyotrophic lateral sclerosis

“…Indeed, HTT alleles with 37 repeats are considered pathogenic with reduced penetrance (37 < CAG < 40). Nevertheless, biallelic HD patients do not display significant differences in disease onset or progression compared to those harboring a single mutated allele, 16 supporting the “complete dominance” of HD.…”

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

“…Huntington’s disease is caused predominantly by an expansion of trinucleotide CAG repeats in the huntingtin gene ( HTT ; OMIM #613004) [92]. Huntington’s disease is a true autosomal dominant condition because the clinical phenotype of a homozygote is indistinguishable from that of a heterozygote [93]. Nonetheless, it is the number of CAG repeats that determines the age of onset of disease, as well as its progression and severity.…”