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Late-onset and classic phenotypes of Fabry disease in males with the GLA-Thr410Ala mutation

Kati Valtola1, Marja Hedman2,3, Ilkka Kantola4

  • 1Heart Center, Kuopio University Hospital, Kuopio, Finland.

Open Heart
|March 17, 2023
PubMed

Insights

The Thr410Ala mutation in the alpha-galactosidase A gene causes Fabry disease with varied severity. Biomarkers like enzyme activity and lyso-Gb3 levels predict disease phenotype and progression in affected families.

Area of Science:

  • Genetics
  • Biochemistry
  • Cardiology

Background:

  • Fabry disease (FD) is a rare genetic disorder caused by mutations in the alpha-galactosidase A (GLA) gene.
  • The Thr410Ala (T410A) mutation is a rare GLA variant identified during genetic screening for hypertrophic cardiomyopathy.
  • Phenotypic variability in FD can be influenced by specific mutations and genetic background.

Purpose of the Study:

  • To characterize the phenotypic spectrum and key biomarkers associated with the T410A/GLA mutation in a multi-generational family.
  • To investigate the correlation between GLA enzyme activity, lyso-Gb3 levels, and clinical manifestations of Fabry disease.
  • To assess the impact of enzyme replacement therapy (ERT) on disease progression in individuals with the T410A/GLA mutation.

Main Methods:

  • Genetic sequencing to identify the T410A/GLA mutation in affected family members.
  • Assays to measure alpha-galactosidase A (α-Gal A) enzyme activity.
  • Quantification of plasma lyso-Gb3 analogues as biomarkers.
  • Cardiac magnetic resonance imaging (MRI) to evaluate for Fabry cardiomyopathy (FC).
  • Clinical assessment of symptoms including neuropathic pain, gastrointestinal issues, and cardiac abnormalities.

Main Results:

  • The T410A/GLA mutation was identified across multiple generations, exhibiting a wide range of clinical presentations.
  • Enzyme activity varied from 0% to 26.5%, with higher lyso-Gb3 levels correlating with more severe phenotypes.
  • One elder male developed progressive Fabry cardiomyopathy and died suddenly despite ERT; younger males presented with classic FD symptoms.
  • Female carriers showed variable expressivity, including incipient Fabry cardiomyopathy in one individual.

Conclusions:

  • The T410A/GLA mutation leads to a spectrum of Fabry disease phenotypes, from late-onset progressive cardiomyopathy to classic FD.
  • α-Gal A enzyme activity and lyso-Gb3 analogue levels serve as crucial biomarkers for predicting disease severity and guiding treatment.
  • This family study highlights the importance of comprehensive genetic and biochemical evaluation for understanding rare GLA mutations and their clinical impact.
Abstract

Keywords:
BiomarkersCardiomyopathy, HypertrophicMetabolic Diseases

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