Prospective characterization of early symptom onset and progression in young pediatric patients with variants in the GLA gene across 5 years: Longitudinal data from the Fabry MOPPet Study

Purpose: This prospective, longitudinal study was designed to determine the natural history of Fabry disease (FD) in early pediatric patients across the disease spectrum. Methods: In this observational study of children under 5 years of age with variants in the GLA gene, prospective phenotypic and urinary biomarker data were collected annually over 5 years. Results: The study population included 40 participants (35 male, 5 female) with GLA variants including 15 with classic pathogenic variants (CFD), 6 with nonclassic pathogenic variants (NFD), and 19 with a variant of uncertain significance. The most common first symptoms reported were in participants with CFD and included gastrointestinal symptoms (13/15), heat intolerance (13/15), reduced sweating after previously sweating normally (6/15), and neuropathic pain/uncomfortable feet/hands (3/15). Mapping symptom onset and progression reveals a consistent pattern of frequency and severity occurring in the first years of life and beginning at an average age of 23.4 months (range 11-32 months) in males with CFD. Participants with nonclassic pathogenic variants and variant of uncertain significance did not exhibit consistency in symptom onset or progression during the study period. Conclusion: This study highlights the onset and pattern of progression of the earliest Fabry-related symptoms in children with CFD.