A newborn screening–enabled therapeutic window in late-onset fabry disease: long-term divergent remodeling trajectories with early-stage treatment
K T Sung, H Y Li, C L Hung, W C Yu, P C Lee, W P Fan, C F Yang, Y J Chen, Y H Lu, D M NiuAbstract
Background
In late-onset Fabry disease, enzyme replacement therapy (ERT) is typically initiated after cardiac involvement becomes clinically evident. However, myocardial remodeling progresses along a biological continuum that may precede overt symptom recognition. Whether treatment timing relative to the underlying stage of myocardial remodeling determines long-term structural durability under ERT remains incompletely defined.
Methods
We retrospectively analyzed adults with the GLA IVS4+919G>A variant treated with ERT between January 1, 2008, and December 31, 2025. Patients were identified through nationwide newborn screening with cascade family screening or were diagnosed after developing Fabry-related cardiac symptoms. At treatment initiation, individuals were classified as minimal stage (left ventricular hypertrophy [LVH] without overt cardiac symptoms) or overt stage (Fabry-related cardiac symptoms). Serial echocardiography and biomarker measurements were obtained during follow-up. The primary endpoint was change in left ventricular mass index (ΔLVMI). Longitudinal structural trajectories were evaluated using linear mixed-effects modeling.
Results
Fifty-six adults (41 men, 15 women; mean age 57.3±8.1 years) were followed for a median of 9.2 years (IQR 8.3–11.9). Overt-stage patients had markedly higher baseline LVMI and biomarker burden. LVMI trajectories diverged significantly according to stage at ERT initiation (time-by-stage interaction p<0.001). In both sexes, minimal-stage patients demonstrated early LVMI regression followed by sustained long-term stabilization. In contrast, overt-stage patients exhibited a biphasic trajectory characterized by transient early reduction at 1 year and subsequent progressive hypertrophy despite continued therapy. NT-proBNP ≤125 pg/mL and hs-TnI ≤14 ng/L identified patients with structural regression, whereas elevations predicted progressive remodeling (median ΔLVMI −2.61 vs 7.16 g/m²·⁷; p=0.002 and −8.68 vs 7.27 g/m²·⁷; p<0.001, respectively). LVMI increased stepwise across late gadolinium enhancement fibrosis categories (p for trend=0.001), and severe fibrosis was associated with accelerated longitudinal progression.
Conclusions
In this genetically homogeneous late-onset Fabry cohort, the biological stage at ERT initiation determined long-term remodeling trajectory. Structural hypertrophy without overt symptoms appears to represent a phase of preserved myocardial plasticity during which durable stabilization is achievable. Once biomarker elevation and advanced fibrosis are present, remodeling becomes progressively less modifiable despite therapy. These findings define a stage-dependent therapeutic window and support screening-enabled early intervention strategies aimed at altering the natural history of Fabry cardiomyopathy.