Fabry disease in Argentina: clinical, biochemical and molecular correlation in all reported GLA variants.

Abstract

Introduction: Fabry disease is an X-linked trait due to pathogenic variants in the GLA gene, causing deficient GLA enzyme activity, and producing a chronic accumulation of globotriaosylceramide and its derivative globotriaosylsphingosine (LysoGb3) in tissues and fluids. Conflicting or discordant results of interpretation of multiple variants in GLA were reported in literature. The aim of this article is to report the spectrum of GLA variants in Argentine population, as well as the revised interpretation of variants classification. Moreover, we intend to find a possible correlation between biochemical parameters, clinical manifestations and genetic variants of adult male Fabry patients that could be of help for interpretation of variants.

Materials and methods: Blood samples from patients with clinical suspicion of Fabry disease were evaluated for specific laboratory tests: alfa-galactosidase A enzyme activity, LysoGb3 and GLA genetic test.

Results: There are 44 males with pathogenic GLA variants which showed deficient enzyme activity. Among them, thirty-two presented the classic phenotype (72%) and twelve the late onset clinical features (28%). Mean percentage of enzyme activity was 0.9% for classical patients and 3.2% for later onset ones. LysoGb3 values were increased in all males, with classic patients showing considerable higher values than that of late onset.

Discussion: Our results showed that the combined analysis of the clinical picture, leukocyte enzyme activity, globotriaosylsphingosine concentration and a detailed exhaustive study of the genetic variant lead to a definite diagnosis in those cases previously interpreted as of unknown significance, together with a revised interpretation of the phenotype.