氨基酸补充对线粒体氨基酰基tRNA合成酶致病变异相关白质脑病患者的影响：成人临床试验和文献回顾

IF 3.5 2区生物学 Q2 ENDOCRINOLOGY & METABOLISM

Molecular genetics and metabolism Pub Date : 2025-10-06 DOI:10.1016/j.ymgme.2025.109259

Alessia Catania , Silvia Marchet , Krisztina Einvag , Eleonora Lamantea , Ettore Salsano , Daniele Ghezzi , Costanza Lamperti

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引用次数: 0

摘要

线粒体氨酰基tRNA合成酶（mt-ARS）相关疾病是影响线粒体蛋白质合成效率的广泛异质性疾病。AARS2和DARS2双等位基因突变与以弥漫性白质脑病为显著特征的临床综合征相关，其发病年龄变化很大，从婴儿期早期到成年期不等。对患者成纤维细胞的初步体外实验结果和一些关于mt-ARS相关疾病患者的轶事报道表明，补充缺陷mt-ARS的特定底物氨基酸可能有益。方法：我们招募了6例患有AARS2 （n = 2）和DARS2 （n = 4）相关白质脑病的成年患者，分别开始口服丙氨酸和天冬氨酸，总共持续2年。通过临床检查、标准化量表、功能测试、生活质量（QoL）评分、脑MRI和实验室分析来评估治疗效果和安全性。结果总体而言，该治疗对所有患者都是安全且耐受性良好的，但未达到疗效终点，因为在整体、认知或运动评分方面未观察到显着改善。尽管如此，除了一名患者外，所有患者在临床上都保持稳定。尽管这项关键试验存在固有的局限性，但我们的研究结果表明，补充特定氨基酸是一种安全的干预措施，但不会产生明显的症状益处；然而，我们不能排除在稳定dars2相关疾病成人患者临床状况方面的潜在作用。

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Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature

Background

Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis.

AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood.

Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS.

Methods

We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses.

Results

Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable.

Conclusions

Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.

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来源期刊

Molecular genetics and metabolism 生物-生化与分子生物学

CiteScore

5.90

自引率

7.90%

发文量

621

审稿时长

34 days

期刊介绍： Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.