弗里德里希共济失调症患者白细胞端粒长度的异常年龄依赖行为

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-09-05 DOI:10.1002/mds.29976

Daniela Scarabino PhD, Liana Veneziano PhD, Suran Nethisinghe PhD, Elide Mantuano MSc, Alessia Fiore MSc, Giulia Granata MSc, Nita Solanky PhD, Ginevra Zanni MD, PhD, Francesca Cavalcanti MD, Rosa Maria Corbo MD, Paola Giunti MD, PhD

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引用次数: 0

摘要

背景：弗里德里希共济失调症（FRDA）是一种常染色体隐性遗传的神经退行性疾病，由 FXN 基因第一个内含子中的 GAA 重复扩增引起：本研究旨在分析FRDA患者的白细胞端粒长度（LTL），以验证LTL与疾病进展之间可能存在的关系。我们调查了一组 FRDA 双倍拷贝患者（n = 61）、杂合子（n = 29）和年龄匹配的健康受试者（n = 87）的端粒长度：方法：通过实时聚合酶链反应定量分析（qPCR）测量LTL：结果表明：35 岁之前，患者的白细胞端粒比对照组长，而 36 岁以上的患者则相反。有趣的是，在任何年龄段，杂合子患者的端粒长度都比对照组长。这种情况反映了之前在体外观察到的 FRDA 培养成纤维细胞的情况，由于激活了类似端粒替代性延长（ALT）的机制，早期培养的成纤维细胞端粒明显较长，但随着群体倍增，端粒缩短速度加快。GAA1重复长度与LTL呈正相关，与采血年龄呈负相关。此外，还分析了LTL与临床参数（心肌病、糖尿病、轮椅依赖）的关系。白细胞端粒的显著缩短与心肌病的存在有关，但与糖尿病和依赖轮椅无关：总之，本研究表明，FRDA 中的端粒长度分析可能是跟踪疾病阶段的相关生物标志物。© 2024 The Author(s).运动障碍》由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版。

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Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia

Background

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene.

Objective

The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87).

Methods

LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR).

Results

The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair.

Conclusions

Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.