目的:Fabry病(FD)患者常通过超声心动图检测左心室肥厚(LVH),有时导致与其他病因的肥厚型心肌病(HCM)混淆。考虑到这个诊断挑战,FD应包括在LVH患者的鉴别诊断列表中。为了解决这一问题,我们在中国进行了一项前瞻性筛查研究,使用干血斑(DBS)测试,评估无法解释的LVH患者。
方法:我们的研究是在全国范围内设计的,多中心前瞻性调查。在2022年9月至2023年12月的研究中,共筛查了来自55个不同中心的1015例通过超声心动图诊断为LVH的患者。人口统计信息,生物化学数据,我们精心收集了所有参与者的超声心动图参数和临床观察结果.DBS方法用于评估男性的α-半乳糖苷酶A(α-GalA)活性以及女性的α-GalA和球形鞘氨醇(lyso-Gb3)水平。
结果:最终筛查人群包括906名患者(589名男性,65%)与LVH,平均最大心肌厚度为14.8±4.6mm,平均年龄为56.9±17.2岁。总的来说,43名患者(38名男性,5名雌性)表现出低α-GalA活性测量值(<2.2μmol/L),而21名患者(10名男性,11名雌性)表现出低的α-GalA活性或升高的lyso-Gb3水平(>1.1ng/mL)。在这些患者中,8个人(7名男性和1名女性)被遗传证实携带致病性GLA突变,导致总患病率为0.88%。与无FD患者相比,FD患者倾向于有蛋白尿(75%vs.21.2%,P=0.001),HCM家族史(37.5%vs.2.3%,P<0.01)和神经性疼痛(37.5%vs.4.4%,P<0.01),但收缩压较低(118.5±12.5vs.143.3±29.3mmHg,P=0.017)。五个突变以前被认为与FD相关,而其余两个,p.Asp313Val(c.938A>T)和c.547+3A>G,被认为是潜在的致病性。随后的家族验证诊断后确定了另外14例确诊病例。
结论:这项开创性的使用DBS测量的中国不明原因LVH患者的FD筛查研究,FD检出率为0.88%。我们的发现证实,lyso-Gb3和α-GalA活性的联合测量有利于LVH患者FD的初步筛查。鉴于有效疗法的可用性和大家庭中级联筛查的价值,在LVH患者中早期发现FD具有重要的临床意义.
OBJECTIVE: Left ventricular hypertrophy (LVH) is frequently detected via echocardiography in individuals with Fabry disease (FD), sometimes leading to confusion with hypertrophic cardiomyopathy (HCM) of other aetiologies. Considering this diagnosis challenge, FD should be included in the list of differential diagnosis for patients presenting with LVH. To address this concern, we conducted a prospective screening study in China, using dried blood spot (DBS) testing, to evaluate patients with unexplained LVH.
METHODS: Our study was designed as a nationwide, multicentre prospective investigation. A total of 1015 patients from 55 different centres who were diagnosed with LVH by echocardiography were screened in the study from September 2022 to December 2023. Demographic information, biochemistry data, echocardiography parameters and clinical observations were meticulously collected from all participants. The DBS method was used to assess α-galactosidase A (α-Gal A) activity in males and both α-Gal A and globotriaosylsphingosine (lyso-Gb3) levels in females.
RESULTS: The final screening population included 906 patients (589 males, 65%) with LVH, characterized by a mean maximal myocardial thickness of 14.8 ± 4.6 mm and an average age of 56.9 ± 17.2 years. In total, 43 patients (38 males, 5 females) exhibited low α-Gal A activity measurement (<2.2 μmol/L), while 21 patients (10 males, 11 females) presented low α-Gal A activity or elevated lyso-Gb3 levels (>1.1 ng/mL). Among these patients, eight individuals (7 males and 1 female) were genetically confirmed to harbour pathogenic GLA mutations, resulting in a total prevalence of 0.88%. Compared with patients without FD, patients with FD tended to have proteinuria (75% vs. 21.2%, P = 0.001), family history of HCM (37.5% vs. 2.3%, P < 0.01) and neuropathic pain (37.5% vs. 4.4%, P < 0.01) but lower systolic blood pressure (118.5 ± 12.5 vs. 143.3 ± 29.3 mmHg, P = 0.017). Five mutations were previously recognized as associated with FD while the remaining two, p.Asp313Val (c.938A>T) and c.547+3A>G, were deemed potentially pathogenic. Subsequent familial validation post-diagnosis identified an additional 14 confirmed cases.
CONCLUSIONS: This pioneering screening study for FD among Chinese patients with unexplained LVH using DBS measurement, revealed an FD detection rate of 0.88%. Our findings confirmed that the combined measurement of lyso-Gb3 and α-Gal A activity is beneficial for primary screening of FD in patients with LVH. Given the availability of efficacious therapies and the value of cascade screening in extended families, early detection of FD in LVH patients is clinically important.