Abstract
Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
Highlights
IntroductionFabry disease (FD; OMIM #301 500) is an X-linked lysosomal storage disease caused by an enzymatic defect of the hydrolase alpha-galactosidase A (AGAL-A), resulting in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) and its deacetylated form globotriaosylsphingosine (lysoGb3), the latter being commonly used as a surrogate biomarker [1,2,3]
We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype
Fabry disease (FD; OMIM #301 500) is an X-linked lysosomal storage disease caused by an enzymatic defect of the hydrolase alpha-galactosidase A (AGAL-A), resulting in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) and its deacetylated form globotriaosylsphingosine, the latter being commonly used as a surrogate biomarker [1,2,3]
Summary
Fabry disease (FD; OMIM #301 500) is an X-linked lysosomal storage disease caused by an enzymatic defect of the hydrolase alpha-galactosidase A (AGAL-A), resulting in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) and its deacetylated form globotriaosylsphingosine (lysoGb3), the latter being commonly used as a surrogate biomarker [1,2,3]. The clinical presentation and incidence of FD are changing as the diagnostic approach is moving from clinicobiochemical algorithms to genetic screenings. Since 1990, a nonclassical or late-onset phenotype of FD has been described, with higher residual AGAL-A activity and predominant, if not isolated, cardiac manifestations [11]. The majority of the individuals detected by genetic screenings carry galactosidase A alpha (GLA) variants that are usually associated with this nonclassical phenotype of FD [7,12].
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