Editors' note: Clinical manifestations of homozygote allele carriers in Huntington disease

In the article “Clinical manifestations of homozygote allele carriers in Huntington disease”, Dr. Cubo et al. examined the phenotypic differences between patients who were homozygous for Huntington disease (HD)—with both alleles carrying ≥36 CAG repeats—and those who were heterozygous with only one allele carrying such repeats, in 10,921 participants with HD in an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). They found that homozygotes were infrequent (0.3%) and that the age at onset, HD phenotype, and disease progression did not differ significantly between homozygotes and heterozygotes. In response, Dr. Da Prat et al. noted a previous study that reported a more severe and rapid progression in homozygotes. They suggest using the term biallelic HD to refer to these patients to acknowledge the differences in the number of repeats that may exist between the 2 expanded alleles and cite a previous abstract from their group that also reported no differences in age at onset, cognition, motor capabilities, or disease evolution between a small sample of 7 patients with biallelic HD and heterozygous patients. Responding to these comments, Drs. Ramos-Arroyo and Cubo highlighted the potential drawbacks of using the term biallelic HD, noting the differences between patients with 2 expanded alleles carrying ≥36 CAG repeats vs those with one intermediate allele (27–35 repeats) who may have later-onset disease (both groups are combined under the biallelic definition), and noting the exclusion of compound heterozygotes with 2 nonfully penetrant repeat expansions from the conventional biallelic definition. They argue that these issues lead to imprecise categorization of patients with HD and potential noise in the analysis of clinical effects. This exchange illustrates the potential challenges that can arise in the interpretation of genotypic-phenotypic correlation studies from the use of what may appear at the first glance to be superficially discrepant definitions.