Could Enzymatic Screening Help Identify Fabry?


Data from the article, “Fabry disease in the Spanish population: oberservational study with detection of 77 patients,” suggests that enzymatic screening for Fabry disease in risk populations assisted in identifying undiagnosed patients.

Could enzymatic screening help doctors diagnose Fabry disease?

According to results from a recently published study in the Orphanet Journal of Rare Diseases, the answer is “yes.”

Data from the article, “Fabry disease in the Spanish population: oberservational study with detection of 77 patients,” suggests that enzymatic screening for Fabry disease in risk populations — defined as 2 or more clinical manifestations or family history of the disease – assisted in identifying undiagnosed patients.1

Fabry disease is an X-linked lysosomal storage disorder, resulting from α-galactosidase A (α-Gal) deficiency which leads to the progressive accumulation of globotriaosylceramide (Gb3) and its derivatives (eg. lyso-Gb3). More than 700 genetic defects have been identified in GLA to date; however, no frequent mutations have been described, creating challenges as it pertains to establishing a genotype-phenotype correlation.

Poor specificity of the Fabry disease phenotype typically results in delayed diagnosis, which is usually established in adulthood, even if symptoms present earlier in life. Avoiding delayed diagnosis is critical for increasing the quality and expectancy of life for patients who may require specific treatment.

In the study, 77 newly diagnosed patients with mutations related to classical Fabry disease were identified, in addition to a pair of subjects with a possible new mutation (c.374A > T; p.His125Leu) that need to be confirmed. Eight other subjects carrying genetic variants potentially linked to late onset Fabry disease (p.Arg118Cys and p.Ala143Thr), 4 cases with polymorphism p.Asp313Tyr and 36 individuals with single nucleotide polymorphisms in intronic regions of GLA, were also detected. Five of the identified mutations (c.431delG; c.1182delA; c.374A > T; c.932 T > C; c.125 T > A; c.778G > A), which were associated with a classical phenotype, have not been previously described.

Further, 3 subjects presenting complex haplotypes comprised of the association of intronic variants exhibited impaired levels of GLA transcripts and Gb3 deposits in skin biopsy.

The goal of this work was to perform an observational study based on biochemical and genetic analyses of subjects who manifest a combination of symptoms and signs suggestive of Fabry disease or have a family history of the disease. The observational study was carried out based on biochemical screening of α-Gal A and GLA sequence in subjects with ages comprised between 1 and 85 years and who presented more than 1 clinical sign or symptom associated to the disease. Eight hundred and five dried blood spot samples were collected from 479 males and 326 females, and relevant clinical symptoms and signs were listed for each patient by the physician responsible for checking boxes in the sample-collecting cards designed for the study.

In addition to the 77 newly confirmed patients and 2 individuals with a possible Fabry disease diagnosis, carrying the newly described variant p.His125Leu, Irene Vietez and colleagues helped to identify 8 subjects with variants related to possible late-onset Fabry disease and 3 other subjects with single nucleotide polymorphisms (SNPs) in the intronic region associated to functional and quantitative deficiency of α-Gal A.

The article confirms that Fabry is still underdiagnosed, and that the true prevalence of the disease is more likely reflected by the values projected in recently conducted newborn screening studies in which a prevalence of GLA variants of 0.04% was reported.

The wide range of clinical symptoms and signs shown by each patient — in addition to the identification of impaired enzyme functionality and pathological signs in subjects with SNPs in GLA – suggest that additional factors could potentially contribute to determining the clinical phenotype of the condition.


  1. Vietez I, Souto-Rodriguez O, et al; Groups go here. Fabry disease in the Spanish population: observational study with detection of 77 patients. Orphanet Journal of Rare Diseases. 2018;13:52. doi: 10.1186/s13023-01800792-8.
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