Skip to main content
Journal cover image

A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females.

Publication ,  Journal Article
Stiles, AR; Zhang, H; Dai, J; McCaw, P; Beasley, J; Rehder, C; Koeberl, DD; McDonald, M; Bali, DS; Young, SP
Published in: Mol Genet Metab
July 2020

PURPOSE: Successful diagnosis of Fabry disease is often delayed or missed in patients, especially females, due to clinical heterogeneity and a lack of disease awareness. We present our experience testing for Fabry disease in high risk populations and discuss the relative sensitivities of α-galactosidase A (α-Gal A) enzyme activity in blood, plasma lyso-globotriaosylceramide (lyso-Gb3) biomarker, and GLA gene sequencing as diagnostic tests for Fabry disease in both males and females. METHODS: Patients with a clinical suspicion of Fabry disease were evaluated with enzyme analysis, biomarker analysis, and GLA sequencing. All three assays were performed from a single tube of EDTA blood. α-Gal A activity was determined in dried blood spots using a fluorometric assay, plasma lyso-Gb3 by UPLC-MS/MS, and GLA analysis by Sanger sequencing. RESULTS: Peripheral blood samples were received from 94 males and 200 females, of which 29% of males and 22% of females had a positive family history of Fabry disease. A likely pathogenic or pathogenic variant was identified in 87 (30%) patients (50 males, 37 females), confirming a diagnosis of Fabry disease. Of the remaining patients, 178 (61%) were determined to be unaffected based on normal enzyme activity (males) or normal lyso-Gb3 and negative sequencing results (females). A VUS was identified in 29 (10%) patients. The positive and negative predictive value of plasma lyso-Gb3 was 100% and 97% in males and 100% and 99% in females, respectively. This compares with 84% and 100% in males, and 58% and 50% in females for α-Gal A activity testing, respectively. CONCLUSIONS: Plasma lyso-Gb3 has high sensitivity and specificity for Fabry disease in males and females, and provides supportive diagnostic information when gene sequencing results are negative or inconclusive. α-Gal A activity in dried blood spots (DBS) has high sensitivity, but lower specificity for Fabry disease in males, as not all males with low α-Gal A activities were confirmed to have Fabry disease. Therefore, reflexing to gene sequencing and plasma lyso-Gb3 is useful for disease confirmation in males. For females, we found that first tier testing consisting of GLA sequencing and plasma lyso-Gb3 analysis provided the greatest sensitivity and specificity. Enzyme testing has lower sensitivity in females and is therefore less useful as a first-tier test. Enzyme analysis in females may still be helpful as a second-tier test in cases where molecular testing and plasma lyso-Gb3 analysis are uninformative and in vitro enzyme activity is low. SUMMARY: Sex-specific testing algorithms that prioritize tests with high specificity and sensitivity offer an effective means of identifying individuals with Fabry disease.

Duke Scholars

Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

July 2020

Volume

130

Issue

3

Start / End Page

209 / 214

Location

United States

Related Subject Headings

  • alpha-Galactosidase
  • Sphingolipids
  • Retrospective Studies
  • Mutation
  • Male
  • Infant, Newborn
  • Humans
  • Glycolipids
  • Genetics & Heredity
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Stiles, A. R., Zhang, H., Dai, J., McCaw, P., Beasley, J., Rehder, C., … Young, S. P. (2020). A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab, 130(3), 209–214. https://doi.org/10.1016/j.ymgme.2020.04.006
Stiles, Ashlee R., Haoyue Zhang, Jian Dai, Patricia McCaw, James Beasley, Catherine Rehder, Dwight D. Koeberl, Marie McDonald, Deeksha S. Bali, and Sarah P. Young. “A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females.Mol Genet Metab 130, no. 3 (July 2020): 209–14. https://doi.org/10.1016/j.ymgme.2020.04.006.
Stiles AR, Zhang H, Dai J, McCaw P, Beasley J, Rehder C, et al. A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab. 2020 Jul;130(3):209–14.
Stiles, Ashlee R., et al. “A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females.Mol Genet Metab, vol. 130, no. 3, July 2020, pp. 209–14. Pubmed, doi:10.1016/j.ymgme.2020.04.006.
Stiles AR, Zhang H, Dai J, McCaw P, Beasley J, Rehder C, Koeberl DD, McDonald M, Bali DS, Young SP. A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab. 2020 Jul;130(3):209–214.
Journal cover image

Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

July 2020

Volume

130

Issue

3

Start / End Page

209 / 214

Location

United States

Related Subject Headings

  • alpha-Galactosidase
  • Sphingolipids
  • Retrospective Studies
  • Mutation
  • Male
  • Infant, Newborn
  • Humans
  • Glycolipids
  • Genetics & Heredity
  • Female