A New Severity Score For Fabry Disease

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Fabry disease is caused by loss of function mutations in the X-linked GLA gene, which encodes the enzyme alpha-galactosidase (α-GAL). The main symptoms include localized and full body pain (nervous system), which increases over time, kidney disease, heart disease, and skin conditions. 

Diagnosis can be made by measuring α-GAL activity in the blood or genetic testing may be used. Evidence suggests that Fabry disease presents in different forms, however, clinical classification can be difficult, particularly in women due to X-inactivation. Scoring systems to classify the severity of Fabry disease exist but may be challenging to use in daily practice.

Olivier Lidove of Sorbonne Université, Paris, France, and colleagues, attempted to identify simple and objective criteria for scoring Fabry disease severity in adults using unsupervised multivariate statistics on clinical data. This data was obtained from the multicenter cohort French Fabry Biobank and Registry (FFABRY), which included enzymatic and/or genetic diagnosis of Fabry disease determined from December 2014 to May 2017. The proposed new scoring system for Fabry disease was published in the journal PLOS ONE.

In male Fabry patients thirty different GLA gene variants were identified. Using multiple component analysis (MCA) and hierarchical clustering on principal components (HCPC) three groups of male patient were identified:

  • Group 1; nonclassical phenotype
  • Group 2; younger classical phenotype
  • Group 3; older classical phenotype

Considering the data, it was not clear that there were clinical clusters in the female patient cohort.

Based on the clinical characteristics of 104 patients, the FFABRY score was constructed using three variables, a kidney disease score, a heart disease score and a central nervous system score. The overall clinical phenotype was noted but not included in the score composed of a total of the following:

  • Kidney disease: K score from K0 to K5
  • Heart disease: H score from H0 to H4
  • Central nervous system involvement: N score from N0 to N2

The male classical phenotype was associated with higher K and H scores. There was no significant difference in FFABRY score between females.

The study was limited by the inability to cluster female patients into clinical phenotypes. This may be due to the current poor understanding of X-inactivation.

“In the era of evidence-based medicine, severity scores have become mandatory for evaluating therapeutics. With FFABRY, we propose a clinically and statistically objective severity scoring system for [Fabry Disease]. The FFABRY score was developed based on the natural history of [Fabry Disease] and the severe clinically relevant events we observed in our center of expertise for lysosomal diseases,” stated the authors.


  1. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233460