A Novel Mutation in The GLA Gene Leading to Fabry Disease - A Case Report from Islamabad, Pakistan

Abstract

Fabry disease (OMIM #301500) is a rare X-linked lysosomal storage disease. Generally, lysosomal storage
disease is identified by inappropriate lipid storage in lysosomes due to specific enzyme deficiencies. In case of
Fabry disease, the defective enzyme is Alpha-Galactosidase A (Enzyme Commission No- 3.2.1.22). Alpha-
Galactosidase A enzyme is involved in the hydrolysis of terminal, non-reducing Alpha-D-galactose residues in
Alpha-D-galactosides, including galactose oligosaccharides, galactomannans, and galacto-lipids. The defect in
the enzyme is usually due to pathogenic variants in the GLA gene, present on Human X chromosome
(chrX:101397803-101407925, hg38). A mutation in the Alpha-Galactosidase A gene results in the accumulation
of globotriaosylceramide and its derivatives throughout lysosomes in the body. A pathogenic, hemizygous
Alpha-Galactosidase A variant identified through genetic testing usually confirms the diagnosis in male
patients. In contrast, the presence of a heterozygous pathogenic variant may establish the diagnosis in female
patients, as heterozygous females may be as severely affected as males or asymptomatic throughout a normal
life span. To our knowledge, Fabry disease has not been reported from Pakistan. We report the first case of
Fabry disease in a 13-year-old boy presenting with bilateral lower limb acroparesthesia and anhidrosis from
Pakistan. At present, he does not have any additional symptoms, including cardiac and renal. Genetic testing
through targeted panel sequencing revealed a novel pathogenic hemizygous mutation in the Alpha-
Galactosidase A gene (c.779G>A, p.Gly260Glu) in this male patient. This variant is present in exon 5 of the
Alpha-Galactosidase A gene, which comprises of 429 amino acids. We advised Injection Agalsidase beta, 1
mg/kg, I/V infusion every 2 weeks, which is a lifelong enzyme replacement therapy.

How to cite this: Malick AA, Hasan MJ, Ahmad A. A Novel Mutation in The GLA Gene Leading to Fabry Disease - A Case Report from Islamabad, Pakistan. Life and Science. 2025; 6(3): 419-423. doi: http://doi.org/10.37185/LnS.1.1.913