Screening for Fabry disease in patients with left ventricular noncompaction

Azevedo, Olga; Marques, Nuno; Craveiro, N; Pereira, Ana Rita; Antunes, Hugo; Reis, Liliana; Guerreiro, Rui Azevedo; Santos, Rui Pontes dos; Miltenberger-Miltényi, Gábriel; Sousa, Nuno; Cunha, Damião

doi:10.1016/j.repc.2019.02.014

Cited by 5 publications

(3 citation statements)

References 41 publications

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“…In a patient with a variant associated with a late-onset form (G395A), the discovery of spongy myocardium at CMR, without LVH, yet not meeting criteria for myocardial non-compaction, is noteworthy. Although a case has been reported in the literature in a female with a LO variant (F113L) [ 45 ], this association has not been confirmed as subsequent extensive screening showed no additional AFD cases among patients with LV non-compaction [ 46 ]. LGE, indicative of advanced AFD stages and consequential macroscopic fibrosis, usually concentrates in the inferolateral basal wall of the left ventricle.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Anderson–Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women

Faro,

Losi,

Rodolico

et al. 2023

Genes

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Anderson–Fabry Disease (AFD) is a rare, systemic lysosomal storage disease triggered by mutations in the GLA gene, leading to α-galactosidase A (α-Gal A) deficiency. The disease’s X-linked inheritance leads to more severe, early-onset presentations in males, while females exhibit variable, often insidious, manifestations, notably impacting cardiac health. This study aims to examine gender-based AFD cardiac manifestations in correlation with the variant type: classical (CL), late-onset (LO), or variants of uncertain significance (VUS). We analyzed data from 72 AFD patients (53 females, 19 males) referred to the “G. Rodolico” University Hospital, employing enzyme activity measurements, genetic analysis, periodic lyso-Gb3 monitoring, comprehensive medical histories, and advanced cardiac imaging techniques. Statistical analysis was performed using SPSS version 26. Our AFD cohort, with an average age of 45 ± 16.1 years, comprised 12 individuals with hypertrophy (AFD-LVH) and 60 without (AFD-N). Women, representing about 75% of the subjects, were generally older than men (47.2 ± 16.2 vs. 38.8 ± 14.6, p = 0.046). In the female group, 17% had CL variants, 43.3% LO, and 39.6% had VUS, compared to 21.1%, 36.8%, and 31.6% in the male group, respectively. Females exhibited significantly higher α-Gal A values (median 7.9 vs. 1.8 nmol/mL/h, p < 0.001) and lower lyso-Gb3 levels (1.5 [IQR 1.1–1.7] vs. 1.9 [1.5–17.3] nmol/L, p = 0.02). Regarding the NYHA class distribution, 70% of women were in class I and 28% in class II, compared to 84% and 16% of men, respectively. Among women, 7.5% exhibited ventricular arrhythmias (10.5% in men), and 9.4% had atrial fibrillation (10.5% in men). Cardiac MRIs revealed fibrosis in 57% of examined women, compared to 87% of men. Even among patients without LVH, significant differences persisted in α-Gal A and lyso-Gb3 levels (p = 0.003 and 0.04), as well as LVMi (61.5 vs. 77.5 g/sqm, p = 0.008) and GLS values (−20% vs. −17%, p = 0.01). The analysis underscored older age, decreased lyso-Gb3 deposition, reduced hypertrophy, and lesser GLS compromise in females, suggesting later disease onset. Severe cardiac patterns were associated with classic variants, while more nuanced manifestations were noted in those with VUS. Early GLS impairment in males, irrespective of hypertrophy, emphasized the role of subclinical damage in AFD.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in Anderson–Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women

Faro,

Losi,

Rodolico

et al. 2023

Genes

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“…We reviewed 23 high-risk screenings for FD in individuals with cardiac manifestations (Table 2), with 20 screenings performed for individuals with either LVH or HCM [40,[80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98]. The other three screenings were performed in individuals with a variety of cardiac symptoms, including coronary artery disorders, conduction disorders, cardiomyopathy, and valvular disease [99], those with conduction disorders requiring a pacemaker [100], and those with left ventricular noncompaction (LVNC) [101]. The frequency of pathogenic variants in the GLA gene detected in these screenings was up to 3.3% (0-3.8% in males and 0-4.2% in females).…”

Section: High-risk Screening For Fd In Individuals With Cardiac Manifestationsmentioning

confidence: 99%

“…Furthermore, five studies had no patients with pathogenic GLA variants. These included screening using urinary Gb3 in individuals with LVH [89], serum α-Gal A activity in males with LVH [85], measurement of α-Gal A activity and/or GLA sequencing in individuals with conduction disorders requiring a pacemaker [100], measurement of α-Gal A activity and/or GLA sequencing in individuals with LVNC [101], and GLA sequencing in individuals with LVH [98].…”

Section: High-risk Screening For Fd In Individuals With Cardiac Manifestationsmentioning

confidence: 99%

High-Risk Screening for Fabry Disease: A Nationwide Study in Japan and Literature Review

et al. 2021

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Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A). FD detection in patients at an early stage is essential to achieve sufficient treatment effects, and high-risk screening may be effective. Here, we performed high-risk screening for FD in Japan and showed that peripheral neurological manifestations are important in young patients with FD. Moreover, we reviewed the literature on high-risk screening in patients with renal, cardiac, and central neurological manifestations. Based on the results of this study and review of research abroad, we believe that FD can be detected more effectively by targeting individuals based on age. In recent years, the methods for high-risk screening have been ameliorated, and high-risk screening studies using GLA next-generation sequencing have been conducted. Considering the cost-effectiveness of screening, GLA sequencing should be performed in individuals with reduced α-Gal A activity and females with certain FD manifestations and/or a family history of FD. The findings suggest that family analysis would likely detect FD patients, although GLA sequencing of asymptomatic family members requires adequate genetic counseling.

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