HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease

Menéndez-González, Manuel; Clarimón, Jordi; Rosas-Allende, Irene; Blázquez, Marta; Martín, Esther Suaréz San; García-Fernández, Ciara; Lleó, Alberto; Dols‐Icardo, Oriol; Illán-Gala, Ignacio; Morís, Germán; Ribacoba, René; Álvarez, Victoria; Martı́nez, Carmen

doi:10.1016/j.neurobiolaging.2018.11.014

Cited by 22 publications

(20 citation statements)

References 24 publications

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“…Nevertheless, HTT CAG repeats below the disease threshold have been showed to play a vital role in evolution and intelligence [22]. More recently, CAG repeats in the intermediate range have been linked to depression [23][24][25], AD [26], and the non-fluent variant of primary progressive aphasia [27].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, subjects carrying IAs experienced more depressive symptoms compared to control subjects [23][24][25]. Other studies reported a significantly higher frequency of HTT IAs in AD patients [26] and in the non-fluent variant of primary progressive aphasia [27], suggesting a role of the HTT gene in the pathogenesis of these diseases. Whether HTT CAG repeats also influence cognition in preclinical and in prodromic phases of AD has not been explored.…”

Section: Introductionmentioning

confidence: 92%

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The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

et al. 2021

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The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

et al. 2021

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“…Therefore, the IA may well exert more effects than could be deduced from the mere blood test analysis. Interestingly, a recent Spanish study reported an IA prevalence of 2.9% among healthy controls and 3.5% among patients with PD whereas the frequency was 5.3% among patients with frontotemporal lobar degeneration and 6.0% among patients with Alzheimer’s disease (AD) and the difference was statistically significant only between healthy controls and AD patients [22]. They also reported no atypical symptoms or clinical features distinctive of HD among IA carriers, but the analysis appears to primarily have been aimed at finding signs of HD among the carriers whereas the patient reported here was analysed in more depth.…”

Section: Discussionmentioning

confidence: 99%

Parkinsonism with a Hint of Huntington’s from 29 CAG Repeats in HTT

Sipilä

2019

Brain Sciences

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Huntington’s disease is caused by at least 36 cytosine-adenine-guanine (CAG) repeats in an HTT gene allele, but repeat tracts in the intermediate range (27–35 repeats) also display a subtle phenotype. This patient had a slightly elongated CAG repeat tract (29 repeats), a prominent family history of Parkinson’s disease (PD), and a clinical phenotype mostly consistent with PD, but early dystonia and poor levodopa response. Neurophysiological test results were more consistent with Huntington’s disease (HD) than PD. It is suggested that the intermediate allele modulated the clinical phenotype of PD in this patient.

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“…Согласно данным эпидемиологического исследования, частота аллелей в промежуточном диапазоне у жителей России составляет 2,6% [10]. Достаточно высокая частота «промежуточных» аллелей регистрируется и среди больных с другими неврологическими заболеваниями: до 3,5% у пациентов с болезнью Паркинсона, достигая максимальной частоты 6,0% у пациентов с болезнью Альцгеймера [11,12].…”

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Atypical course of Parkinson’s disease with clinical manifestations of Huntington’s disease in a patient with an allele of 27 CAG repeats in the HTT gene

et al. 2021

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Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease. Its molecular cause is a cytosine-adenine-guanine (CAG) trinucleotide repeat dynamic expansion in the huntingtin (HTT) gene. Alleles with 36-39 CAG-repeats are incompletely penetrant, as individuals might develop symptoms but typically with a later age of onset. When repeats are equal or greater than 40, the symptoms of the disease occur. It is considered that CAG-repeats in the "intermediate" alleles (27-35 repeats) also cause the symptoms of the HD.We present here the case of a patient who has clinical phenotype and family history of Parkinson's disease (PD), but 27 CAG-repeats. The feature of this patient is early development of non-motor manifestations such as cognitive impairment, psychotic disorders, early dystonia in a hand, camptocormia and poor response to levodopa. It is believed that the intermediate allele of HTT gene might modify the clinical phenotype of PD in this patient.

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HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease

Cited by 22 publications

References 24 publications

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Parkinsonism with a Hint of Huntington’s from 29 CAG Repeats in HTT

Atypical course of Parkinson’s disease with clinical manifestations of Huntington’s disease in a patient with an allele of 27 CAG repeats in the HTT gene

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