The Identification of a Novel Pathogenic Variant of the GLA Gene Associated with a Classic Phenotype of Anderson-Fabry Disease: A Clinical and Molecular Study

Anderson-Fabry (or Fabry) disease is a rare lysosomal storage disorder caused by a functional deficiency of the enzyme alpha-galactosidase A. The partial or total defect of this lysosomal enzyme, which is caused by variants in the gene, leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide in the lysosomes of different cell types. The clinical presentation of Fabry disease is multisystemic and can vary depending on the specific genetic variants associated with the disease. To date, more than 1000 different variants have been identified in the human gene, including missense and nonsense variants, as well as small and large insertions or deletions. The identification of novel variants in individuals exhibiting symptoms indicative of Fabry disease, expands the molecular comprehension of the gene, providing invaluable insights to physicians in the diagnosis of the disease. In this article, we present the case of two members of the same family, mother and son, in whom a new pathogenic variant was identified. This variant has not been previously described in the literature and is not present in databases. The two family members presented with a number of typical clinical manifestations of the disease, including cornea verticillata, neuropathic pain, left ventricular hypertrophy, angiokeratomas and abdominal pain. The son, but not his mother, showed reduced alpha-galactosidase A activity, while high levels of Lyso-Gb3 in the blood, a specific substrate accumulation biomarker, were found in both. Sequencing of the gene revealed the presence of a variant, c.484delT, which is characterised by the deletion of a single nucleotide, a thymine, in exon 3 of the gene. This results in a frameshift variant, which introduces a premature stop codon, thereby generating a truncated and consequently non-functional protein. Therefore, the clinical and laboratory data indicate that the novel p.W162Gfs*3 variant described herein is associated with the classical form of Fabry disease.