Systemic inflammation in Fabry disease: a longitudinal immuno-genetic analysis based on variant stratification

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Fabry disease is a multisystemic lysosomal disorder linked to GLA gene mutations.
• Traditionally linked to globotriaosylceramide (Gb3) accumulation, emerging evidence highlights sustained systemic inflammation's role in pathogenesis.
• Inflammation appears to be an early driver of disease, even before significant substrate buildup.

Purpose of the Study:

• To characterize inflammatory and immunological profiles in a familial cohort with Fabry disease.
• To explore potential genotype-dependent immune activation patterns.
• To investigate the relationship between inflammation, genotype, and clinical presentation.

Main Methods:

• Retrospective, longitudinal study of 11 patients from three families with distinct pathogenic GLA variants.
• Analysis of inflammatory biomarkers (CRP, ferritin, fibrinogen) and immunological markers (IgG, IgM, IgE, complement C3/C4, anti-ERT antibodies).
• Multivariate correlation and unsupervised clustering to identify immunophenotypic patterns.

Main Results:

• All patients displayed chronic inflammation, irrespective of their specific GLA genotype.
• Distinct inflammatory profiles were observed: c.53dup variant showed humoral activation, IVS4+1G>A variant exhibited complement-mediated activation with cardiorenal impact, and c.845C>T showed mild inflammation.
• Correlations were found between CRP and IgG, and between complement factors and fibrinogen in the splicing variant group.

Conclusions:

• Inflammation is an active and early driver in Fabry disease, beyond just a consequence of substrate accumulation.
• Identifying preliminary inflammatory phenotypes based on immune mechanisms could inform personalized therapeutic strategies.
• Genotype-specific immune activation suggests tailored treatment approaches may be beneficial for Fabry disease patients.