Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance

Clin Genet. 2015 Aug;88(2):161-6. doi: 10.1111/cge.12449. Epub 2014 Sep 5.


Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.

Keywords: Fabry disease; cardiac variant; diagnosis; phenotype; renal variant; screening; variant of unknown significance (VUS).

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biopsy
  • Cardiomyopathy, Hypertrophic, Familial / genetics*
  • Fabry Disease / diagnosis*
  • Fabry Disease / genetics*
  • Female
  • Globosides / blood*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Retrospective Studies
  • Young Adult
  • alpha-Galactosidase / genetics*


  • Globosides
  • alpha-Galactosidase
  • alpha-galactosidase A, human