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. 2023 Jul;38(7):1294-1306.
doi: 10.1002/mds.29427. Epub 2023 Jun 8.

Huntington's Disease with Small CAG Repeat Expansions

Anna Heinzmann  1   2 , Sabrina Sayah  2 , François-Xavier Lejeune  1   3 , Valérie Hahn  4 , Marc Teichmann  5 , Marie-Lorraine Monin  6 , Enrica Marchionni  7 , Fleur Gérard  8 , Perrine Charles  1 , Jérémie Pariente  8   9 , Alexandra Durr  1   2
Affiliations

Huntington's Disease with Small CAG Repeat Expansions

Anna Heinzmann et al. Mov Disord. 2023 Jul.

Abstract

Background: Carriers 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.

Objective: To study the phenotype of CAG36-38 repeat carriers.

Methods: We included 35 patients and premanifest carriers of CAG36-38 repeats. We compared clinical and neuropsychological profiles of 11 CAG36-38 patients with 11 matched CAG40-42 patients. In addition, we analyzed 243 CAG36-38 individuals from the ENROLL study to complete the phenotype description.

Results: Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG36-38 and typically CAG40-42 expanded individuals. Chorea as the first symptom was significantly less frequent for CAG36-38 patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG36-38 carriers (P = 0.003). The similar cognitive and different motor profile of CAG36-38 (n = 243) and CAG40-42 (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 CAG36-38 (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29).

Conclusions: We showed that small CAG36-38 expansion carriers had a similar cognitive profile to those with the more common CAG40-42 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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Huntington's disease; chorea; cognitive decline; reduced penetrance; small expansions.

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References

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