The clinical phenotype of carriers of intermediate alleles in the huntingtin gene: A scoping review

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Abstract
Background: Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin ( HTT ) gene. Intermediate alleles (IAs, CAG = 27–35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature. Objective: To review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers. Methods: Peer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included. Results: In case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls. Conclusion: Based on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.

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