Introduction:
Fabry disease (FD) is a genetic disorder caused by GLA gene variants, leading to a lysosomal deficiency of the α-galactosidase A enzyme (α-Gal A). This results in the accumulation of the substrate globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3) in many tissues, causing a systemic disease that mainly affects the cardiovascular, renal, and nervous systems. Fabry nephropathy is one of the major complications of the disease and usually presents with proteinuria and/or reduced glomerular filtration rate (GFR). Lyso-Gb3, as a plasma biomarker, is associated with significant clinical events and helps monitor the response in patients on enzyme replacement therapy (ERT). The objective of this study is to describe the clinical outcomes in patients with Fabry nephropathy under ERT who normalized plasma Lyso-Gb3.
Methods:
A multicenter, retrospective study from five reference Argentinian centers was carried out (1. NEFRA Medical Care Escobar, Buenos Aires; 2. Fundación SPINE, CABA; 3. Hospital Padilla, Tucumán; 4. Instituto Santa María de la Salud de San Isidro, Buenos Aires; 5. Hospital Dr. Notti, Mendoza). Patients with Fabry nephropathy (confirmed by kidney biopsy) on ERT with agalsidase beta 1 mg/kg every other week (EOW) who normalized plasma Lyso-Gb3 levels were included. The variables analyzed were estimated GFR, albuminuria, neuropathic pain, gastrointestinal involvement (diarrhea/abdominal pain), central nervous system compromise, left ventricular hypertrophy, and cardiac arrhythmia. All statistical analyses were performed using Jamovi Desktop version 2.3.
Results:
Seven classic FD patients were included (one male and six females), with a mean age at treatment initiation of 17.6 ± 13.1 years. Five of seven individuals were classified as pediatric patients (under 18 years). Five different GLA variants were found: L415P (n=2), N34D (n=2), A292T (n=1), c.640-1G>C (n=1), and D170H (n=1). The combination of gastrointestinal manifestations with pathological findings on kidney biopsy was the most frequent criterion for ERT initiation. One patient had a Fogo classification score of 1, four patients had a Fogo score of 2, and two patients had a Fogo score of 3 in renal biopsies at the time of diagnosis. Follow-up examinations, up to four years, revealed significant improvements in FD symptoms (neuropathic pain and gastrointestinal manifestations), and kidney function remained stable (based on protein loss/GFR) among patients treated with agalsidase beta 1 mg/kg EOW who achieved normal levels of plasma Lyso-Gb3.
Conclusions:
Over the past few years, we have learned about the crucial role that early FD detection plays in enabling prompt and specific therapeutic intervention. This retrospective study highlights the potential of plasma Lyso-Gb3 normalization as a marker for positive clinical outcomes and organ function preservation in FD patients on ERT. It also underscores the importance of early intervention, given that most patients in this population began treatment at a young age. Further research with larger cohorts and longer follow-up periods is needed to confirm these findings.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.