Huntington's Disease with Small CAG Repeat Expansions

BackgroundCarriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied. ObjectiveTo study the phenotype of CAG(36-38) repeat carriers. MethodsWe included 35 patients and premanifest carriers of CAG(36-38) repeats. We compared clinical and neuropsychological profiles of 11 CAG(36-38) patients with 11 matched CAG(40-42) patients. In addition, we analyzed 243 CAG(36-38) individuals from the ENROLL study to complete the phenotype description. ResultsGlobal cognitive efficiency and performance in different cognitive subdomains were similar in small CAG(36-38) and typically CAG(40-42) expanded individuals. Chorea as the first symptom was significantly less frequent for CAG(36-38) patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG(36-38) carriers (P = 0.003). The similar cognitive and different motor profile of CAG(36-38) (n = 243) and CAG(40-42) (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e-8) and diagnosis happened significantly later in CAG(36-38) (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29). ConclusionsWe showed that small CAG(36-38) expansion carriers had a similar cognitive profile to those with the more common CAG(40-42) expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.