Fabry disease (FD) is a rare genetic disorder due to mutations in the galactosidase alpha (GLA) gene, leading to partial or complete loss of activity of the encoded α-galactosidase A (α-Gal A). This deficiency inhibits the breakdown of globotriaosylceramide (Gb3), resulting in its accumulation in lysosomes and causing a multiple-system disease (1). Clinically, the presentations of FD patients vary significantly, from asymptotic to classic form, but generally, female patients tend to have less typical presentation compared with male patients (2).

Among the affected systems, more than 60% of FD patients display symptoms of cardiac involvement, which is also the primary cause of death for such patients. FD patients often present with left ventricular hypertrophy, arrhythmia, and heart valvular disease (3–5). Notably, arrhythmias induced by FD exhibit diversity, with commonly prescribed antiarrhythmic medications showing limited effectiveness and even worsening their symptoms (5, 6).

Presently, more than 900 types of GLA gene mutations have been identified as pathogenic or likely pathogenic. Different gene mutation sites determine distinct residual enzyme activities, thereby impacting the age of onset and the progression in individuals with FD (7, 8). Here we report a female FD patient with delayed onset, primarily presented with atrial fibrillation (AF), and rhythm control was used successfully with cryo-ablation. Through SWISS-MODEL analysis, the enzyme protein structure in this patient was compared with wild-type control. This case contributes to the clinical understanding of the c.1072_1074delGAG (p.E358del) mutation, offering insights for treating FD patients presenting with arrhythmia complications.

FD is a rare lysosomal storage disorder caused by mutations in the GLA gene on the X chromosome. Epidemiological study shows that more than 60% of patients with FD have cardiac involvement, among which left ventricular hypertrophy is common (3). Therefore, the phenotype of left ventricular hypertrophy is usually an important clue to proceed the subsequent examination to exclude FD.

In clinical practice, the common cause of left ventricular hypertrophy includes hypertension, aortic valve stenosis, hypertrophic cardiomyopathy, amyloidosis, FD, glycogen storage syndrome, etc (21). In this patient, hypertension and aortic valve stenosis were excluded based on the medical history, ambulatory blood pressure monitoring, and echocardiography. In such a case, hypertrophic cardiomyopathy is usually considered. However, hypertrophic cardiomyopathy mainly characterized by asymmetric hypertrophy of the interventricular septum mostly caused by mutations in the sarcomere gene (22), whereas this patient's left ventricular hypertrophy was symmetrical. Another characteristic of FD is the involvement of the cardiac conduction system, leading to sinus bradycardia or bradycardia-tachycardia syndrome caused by sinus node involvement in the early stages of the disease (23, 24).

AF is the most common arrhythmia with an incidence of nearly 20% in FD (4, 5). Notably, arrhythmias in patients with FD have multiplicity and complexity. In this case, the patient mainly presented with paroxysmal atrial flutter and AF, but the heart rate was slow during sinus rhythm, making the use of antiarrhythmic drugs cautious (25). In addition, literature reports suggest that amiodarone can inhibit lysosomal degradation and induce phospholipid deposition in organs, which may exacerbate the symptoms of FD (6). Therefore, rhythm control with antiarrhythmic drugs for such patients were challenging and ablation is an alternative treatment. Up to now, there have been very scarce reports on the use of ablation for AF in patients with FD. Qian et al (25). reported a case with FD complicated with AF and successfully treated with ablation, but in this study, a traditional radiofrequency ablation was adopted and underwent repeated ablation. In contrast, we used cryo-ablation to treat AF in our case. Although previous studies did not demonstrated the superiority of cryo-ablation to traditional radiofrequency ablation (26), whether cryo-ablation is superior to radiofrequency ablation in patients with FD deserves further study.

Currently, ERT is the main treatment for FD via intravenous administration of exogenous agalsidase alpha/beta every two weeks to replace the function of deficient endogenous α-Gal A (27). ERT has demonstrated efficacy in enhancing the quality of life and mitigating adverse events among FD patients (28). However, ERT treatment has several limitations. For instance, most exogenous enzymes are primarily taken up by the liver, resulting in limited amounts reaching the heart and kidneys (27). Furthermore, postmortem analyses have demonstrated some Gb3 accumulation in the brains in FD patients; however, no exogenous enzyme therapy currently available has been shown to traverse the blood-brain barrier although the clinical significance of Gb3 accumulation in the brain remains unclear (27). Moreover, the autopsy results indicated that FD patients had extensive accumulation of Gb3 in their brains, but currently, there is no exogenous enzyme capable of crossing the blood-brain barrier (27). In addition, approximately 40% of male patients undergoing ERT may develop drug antibodies, which may neutralize the drug's efficacy (28). In this context, novel treatment strategies are being explored. Missense mutations in the GLA gene have been shown to have normal or slightly decreased enzyme activity, but α-Gal A cannot enter lysosome and is degraded by endoplasmic reticulum due to structural abnormalities (29). These mutations are now considered to be more effective through the addition of an oral chaperone therapy regimen (30). In comparison to ERT, oral chaperone therapy does not stimulate antibody production and maintains enzyme levels more closely to physiological states over an extended period (28, 31). In our molecular docking experiments, we demonstrated a notable decrease in docking efficacy with substrates following the c.1072_1074 delGAG mutation. The consistency analysis between the wild-type and E358del mutant revealed variances in the protein structure surrounding W236, S276, D335, E358, and N408 (Figure 3E). This observation aligns with the findings of Seiji et al. (32), who illustrated the significant role of hydrogen bonding between E358 and W236 in maintaining the α-Gal A conformation. However, the roles other amino acids played in E358del mutations require further experimental verification.

Changes in critical sites of enzyme structure significantly influence molecular docking capability (Figure 3H), which aligns with previous reports indicating the limited effectiveness of chaperone therapy for E358del mutation (33). Moreover, some GLA gene mutations are related to specific clinical phenotypes, for instance, mutation at N215S or R112H is commonly referred as “cardiac mutations” (34). Multiple studies targeting heterozygous female FD patients have shown that up to 60%–100% of patients have subjective and/or objective evidence of FD, with approximately 10% exhibiting severe symptoms, suggesting that simply X-linked single-gene inheritance patterns cannot explain the complex phenotype in FD (35).

We searched for c.1072_1074delGAG mutations in the GLA gene in the ClinVar database, and found a total of 9 patients with clinical symptoms and phenotypes reported in 6 articles (36–41). The characteristics of all patients associated with this gene mutation, including the one reported in our study, are summarized in Table 3. Among the affected organs, the heart, kidneys, and nervous system were each involved in 5 cases, followed by the cornea, which was involved in 4 cases.

Despite the patient did not receive ERT treatment, her sinus rhythm remained for more than 2 years following bilateral pulmonary vein cryo-ablation, which indicated, for one hand, cryo-ablation is effective for such patients; for the other hand, cryo-ablation can be served as a temporary symptom-alleviated method even if ERT is not administered. Actually, previous studies have demonstrated the benefit of early rhythm control vs. rate control in patients with AF (42). Although the efficacy of ablation in FD patients is still needed to be confirmed, ablation remains a therapeutic option for FD with symptomatic AF.

For patients with unexplained cardiac hypertrophy, especially middle-aged women, even if there is a lack of multi-system involvement, genetic test should be administered to exclude FD. Cryo-ablation of bilateral pulmonary veins may be an effective way to treat AF secondary to FD.