Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), APHP, INSERM, CRNS, Paris, France.
Reference center for Rare Diseases « Neurogénétique », Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.
Mov Disord. 2023 Jul;38(7):1294-1306. doi: 10.1002/mds.29427. Epub 2023 Jun 8.
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.
To study the phenotype of CAG repeat carriers.
We included 35 patients and premanifest carriers of CAG repeats. We compared clinical and neuropsychological profiles of 11 CAG patients with 11 matched CAG patients. In addition, we analyzed 243 CAG individuals from the ENROLL study to complete the phenotype description.
Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG and typically CAG expanded individuals. Chorea as the first symptom was significantly less frequent for CAG patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG carriers (P = 0.003). The similar cognitive and different motor profile of CAG (n = 243) and CAG (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 (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29).
We showed that small CAG expansion carriers had a similar cognitive profile to those with the more common CAG 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.
HTT 基因中 CAG 重复次数小于 39 的携带者通常与较轻的亨廷顿病相关，但他们的临床特征尚未得到广泛研究。
研究 CAG 重复序列携带者的表型。
我们纳入了 35 名 CAG 重复序列携带者患者和前发病携带者。我们比较了 11 名 CAG 患者和 11 名匹配的 CAG 患者的临床和神经心理学特征。此外，我们分析了来自 ENROLL 研究的 243 名 CAG 个体，以完成表型描述。
在小 CAG 和典型 CAG 扩展个体中，整体认知效率和不同认知子领域的表现相似。尽管首次就诊时总运动评分相似，但 CAG 患者的舞蹈病作为首发症状明显较少（P=0.04）。最后一次就诊时，CAG 携带者的总运动评分明显较低（P=0.003）。在 ENROLL 数据库中，我们还证实了 CAG（n=243）和 CAG（n=4675）携带者的相似认知和不同运动表型。此外，尽管发病年龄相似（P=0.29），但临床医生对诊断亨廷顿病的信心明显较低（P=2.4e-8），而且 CAG 患者的诊断明显较晚（P=2.2e-6）。
我们表明，小 CAG 扩展携带者具有与更常见的 CAG 扩展携带者相似的认知特征。这些个体可能由于缺乏舞蹈病而逃避分子诊断，而不是由于症状的低外显率。这一发现应鼓励神经科医生在没有典型舞蹈病的认知障碍老年患者中考虑亨廷顿病，并预测其后代遗传咨询的后果。
