Ramaswami Uma, West Michael L, Tylee Karen, Castillon Genaro, Braun Andreas, Ren Megan, Doobaree Indraraj Umesh, Howitt Heena, Nowak Albina
Lysosomal Storage Disorders Unit, Royal Free Hospital NHS Foundation Trust, London, UK; University College London, London, UK.
Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, NS, Canada.
Mol Genet Metab. 2025 Jun;145(2):109110. doi: 10.1016/j.ymgme.2025.109110. Epub 2025 Apr 21.
Fabry disease (FD) is a rare, X-linked lysosomal storage disorder in which a lack of alpha-galactosidase (α-Gal A) enzyme activity leads to intracellular accumulation of deacylated globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), and their analogs. Lyso-Gb3, present in the blood and urine of affected patients, has been extensively investigated as a biomarker for FD. This systematic literature review (SLR) aimed to comprehensively assess the use of lyso-Gb3 as a biomarker for screening, monitoring, and diagnosis of FD in both real-world and clinical trial settings.
An SLR was performed to identify the following outcomes in adult and pediatric patients with FD: lyso-Gb3 testing patterns, lyso-Gb3 levels in subpopulations, performance and accuracy of lyso-Gb3 testing for diagnosis, and lyso-Gb3 testing for monitoring of disease progression or treatment efficacy/effectiveness. Interventional and non-interventional studies published between 1 January 2017 and 3 November 2022 were included. Searches were primarily conducted in MEDLINE and Embase; pragmatic or hand searches were also performed. The methodological quality of included full-text studies was assessed using validated appraisal tools. Extracted data were synthesized qualitatively.
The SLR included 83 eligible publications, comprising 71 observational studies and 12 clinical trials. Differences in lyso-Gb3 levels were identified across subpopulations, with several studies reporting higher levels in males versus females. Lyso-Gb3 demonstrated good diagnostic performance in newborns and high-risk patients when used in combination with other markers (α-Gal A activity or GLA variants) but failed to diagnose females with late-onset FD. Reliability and stability across different methods used to measure lyso-Gb3 was high, with a coefficient of variation <10 % for inter- and intra-assay measurements. Several studies identified moderate to strong correlation between plasma lyso-Gb3 levels and cardiac measures, but association with renal measures needs further investigation.
Lyso-Gb3 testing demonstrated accuracy in screening, diagnosis, and monitoring of FD in certain subpopulations, particularly males, but considering its lower sensitivity in late-onset female patients, it should be used in conjunction with other tools. Given the reliability of the test, it can be considered a feasible method for monitoring disease progression in FD in individual patients. Several gaps in the literature were identified, warranting further investigation.
PROSPERO (CRD42022375141).
法布里病（FD）是一种罕见的X连锁溶酶体贮积症，缺乏α-半乳糖苷酶（α-Gal A）酶活性会导致脱酰基球三糖神经酰胺（Gb3）、球三糖鞘氨醇（溶酶体-Gb3）及其类似物在细胞内蓄积。溶酶体-Gb3存在于受影响患者的血液和尿液中，已被广泛研究作为法布里病的生物标志物。本系统文献综述（SLR）旨在全面评估溶酶体-Gb3作为生物标志物在真实世界和临床试验环境中用于法布里病筛查、监测和诊断的情况。
进行了一项系统文献综述，以确定成年和儿科法布里病患者的以下结果：溶酶体-Gb3检测模式、亚组中的溶酶体-Gb3水平、溶酶体-Gb3检测用于诊断的性能和准确性，以及溶酶体-Gb3检测用于监测疾病进展或治疗疗效/有效性。纳入了2017年1月1日至2022年11月3日期间发表的干预性和非干预性研究。主要在MEDLINE和Embase中进行检索；也进行了实用或手工检索。使用经过验证的评估工具评估纳入的全文研究的方法学质量。对提取的数据进行定性综合。
该系统文献综述纳入了83篇符合条件的出版物，包括71项观察性研究和12项临床试验。在不同亚组中发现了溶酶体-Gb3水平的差异，几项研究报告男性的水平高于女性。当与其他标志物（α-Gal A活性或GLA变体）联合使用时，溶酶体-Gb3在新生儿和高危患者中表现出良好的诊断性能，但未能诊断出晚发型法布里病的女性患者。用于测量溶酶体-Gb3的不同方法之间的可靠性和稳定性很高，批间和批内测量的变异系数<10%。几项研究确定血浆溶酶体-Gb3水平与心脏指标之间存在中度至强相关性，但与肾脏指标的关联需要进一步研究。
溶酶体-Gb3检测在某些亚组，特别是男性中，在法布里病的筛查、诊断和监测中显示出准确性，但考虑到其在晚发型女性患者中的敏感性较低，应与其他工具联合使用。鉴于该检测的可靠性，它可被视为监测个体法布里病患者疾病进展的可行方法。确定了文献中的几个空白，值得进一步研究。
PROSPERO（CRD42022375141）
