Automated quantification of skin Gb3 load and white matter lesion assessment in Fabry disease.

backgroundFabry disease (FD) is an X-linked lysosomal storage disorder characterized by cellular accumulation of globotriaosylceramide (Gb3).

methodsWe investigated dermal Gb3 load as a potential surrogate marker for systemic FD manifestations by applying an automated image analysis pipeline to skin punch biopsies from the lower leg of 149 individuals carrying variants in GLA, the gene encoding alpha-galactosidase A. Variants were stratified by pathogenicity: Group 1 (pathogenic), Group 2 (non-pathogenic), and Group 3 (variants of unknown significance). Gb3 was visualized via Shiga toxin subunit B and quantified using CellProfiler (v4.1.3). Results were compared to healthy controls and patients with idiopathic small fiber neuropathy.

resultsDermal Gb3 load was elevated in both men and women with pathogenic GLA variants (Group 1, p < 0.001), excluding those with the N215S variant. Increased Gb3 deposition was associated with pain in men (p < 0.05), but not with overall disease severity, treatment status, or cerebral white matter lesions. Diagnostic sensitivity and specificity to correctly determine FD were 67% and 95% in men, and 78% and 81% in women, respectively.

conclusionOur findings demonstrate the feasibility of automated dermal Gb3 quantification and its capacity to detect cutaneous Gb3 accumulation in pathogenic GLA variant carriers. However, its diagnostic accuracy is moderate, and it does not reliably reflect systemic involvement in FD.