Huntington's Disease with Small CAG Repeat Expansions

Anna Heinzmann; Sabrina Sayah; François-Xavier Lejeune; Valérie Hahn; Marc Teichmann; Marie-Lorraine Monin; Enrica Marchionni; Fleur Gérard; Perrine Charles; Jérémie Pariente; Alexandra Durr

doi:10.1002/mds.29427

Huntington's Disease with Small CAG Repeat Expansions

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

Authors

Anna Heinzmann^{1

2}, Sabrina Sayah², François-Xavier Lejeune^{1

3}, Valérie Hahn⁴, Marc Teichmann⁵, Marie-Lorraine Monin⁶, Enrica Marchionni⁷, Fleur Gérard⁸, Perrine Charles¹, Jérémie Pariente^{8

9}, Alexandra Durr^{1

2}

Affiliations

¹ Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), APHP, INSERM, CRNS, Paris, France.
² Reference center for Rare Diseases « Neurogénétique », Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.
³ Paris Brain Institute's Data Analysis Core, Pitié-Salpêtrière Sorbonne University Hospital, Paris, France.
⁴ Department of Neurology of Memory and Language, GHU Paris Psychiatrie and Neurosciences, Hôpital Sainte-Anne, Paris, France.
⁵ Neurology Department, Pitié-Salpêtrière Sorbonne University Hospital, Paris, France.
⁶ Genetic Department, Bordeaux University Hospital, Bordeaux, France.
⁷ Medical Genetics, Tor Vergata University Hospital, Rome, Italy.
⁸ Neurology Department, Hôpital Purpan, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
⁹ Toulouse NeuroImaging Center (ToNIC), INSERM-University of Toulouse Paul Sabatier, Toulouse, France.

PMID: 37288993
DOI: 10.1002/mds.29427

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 CAG_36-38 repeat carriers.

Methods: We 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.

Results: Global 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).

Conclusions: We 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. © 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chorea* / complications
Heterozygote
Humans
Huntington Disease* / diagnosis
Phenotype