Challenges in Fabry Disease: the Combination of Two Individually Amenable GLA Variants May Be Nonamenable to Migalastat

Abstract

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or absent α-Gal A activity. Migalastat is an oral chaperone therapy for Fabry patients with amenable GLA variants. We previously reported a case of a 60-year-old male patient with a classic phenotype of Fabry disease, presenting with two GLA variants: p.R356Q and p.G360R. Herein, we report that, although these two missense variants are individually classified as amenable to migalastat in the validated in vitro human embryonic kidney-293 cell-based assay, their combination precludes the patient to be treated with this oral chaperone. This case illustrates how therapeutic decisions may be challenging and how a good genotypic characterization of Fabry patients is critical for the selection of the correct therapeutic strategy.

Plain language summary

Fabry disease is a rare genetic disease that is part of a group of conditions called lysosomal storage diseases. It is characterized by an abnormal accumulation of glycosphingolipids, a subclass of glycolipids which are important components of the body’s cell membranes. This accumulation is caused by a reduction in, or absence of, enzyme α-Gal A activity, which normally breaks glycosphingolipids down into smaller units, avoiding their accumulation. The absence or reduction in the α-Gal A enzyme activity is caused by mutations (changes in the normal DNA sequence) in the GLA gene. Migalastat is an oral treatment for Fabry patients with GLA mutations that respond to this treatment. We report a case of a 60-year-old male patient with Fabry disease, presenting with two GLA mutations (p.R356Q and p.G360R). Although these mutations are individually amenable to migalastat, their combination and interaction in the same chromosome precludes response to this treatment. This case illustrates how therapeutic decisions for treating Fabry disease can be challenging depending on the mutations causing the disease and how genetic material is decisive for therapy selection.

Keywords:

• amenable mutations
• Fabry disease
• GLA variants
• migalastat
• nonamenable mutations

Author contributions

RM Fernandes, D Bento, D Carvalho, N Marques and O Azevedo were the writers of this document and revised the entire paper. T Mota, H Costa and ME Santo helped gather the clinical and bibliographic information. I Jesus reviewed the final version of this article.

Acknowledgments

The authors would like to thank A Aguinaga and her team for the support provided.

Financial & competing interests disclosure

O Azevedo has received research grants and/or travel and accommodation support for congresses from Shire Human Genetic Therapies/Takeda, Amicus Therapeutics and Sanofi Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Informed consent disclosure

The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.