Cornea verticillata and acroparesthesia efficiently discriminate clusters of severity in Fabry disease

Abstract

Backgroud: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Fig 1

a: Variable factor map obtained by multiple component analysis using data for 41 males with complete data (AK: angiokeratoma; CV: cornea verticillata; eGFR: estimated glomerular filtration rate in ml/min/1.73 m²; HCM: hypertrophic cardiomyopathy; KT kidney transplantation). b: Ascending hierarchical classification of individuals using the first 5 dimensions of multiple component analysis performed using data for 41 males with complete data. Three clusters were identified. Group 1, characterized by the absence of cornea verticillata (p<10⁻⁷), the absence of angiokeratoma (p<10⁻⁴), the absence of acral pain (p<0.001) and the absence of renal disease, was referred to as the nonclassical cluster. Groups 2 and 3, characterized by the presence of cornea verticillata (p<0.002), were referred to as classical groups with younger (mean age 32.3 +/- 9.9 years) and older (mean age 48.8 +/- 9.5 years) patients, respectively.

Fig 2. Hierarchical clustering on the first 5 dimensions of the multiple component analysis performed on data of the 41 males with complete data.

Fig 3. Ascending hierarchical classification of individuals (using the first 5 dimensions of multiple component analysis performed using data for 36 females with complete data) did not reveal any significant groups.

Fig 4. Renal, cardiac and neurological severe event-free survival curves (black: Classical group males, green: Nonclassical group males, red: Females).

Fig 5. T-score evolution in the classical group compared to the nonclassical group (with associated linear regression curve).