Molecular and clinical studies in five index cases with novel mutations in the GLA gene

• FD is confirmed by the absent α-GAL activity in Fabry males and GLA causative mutation.
• The probands with mutations reported here manifested clinical symptomatology of FD.
• Unclear phenotype–genotype correlation is one of the main causes of missed FD diagnoses.
• A proper clinical approach with FD familiarity could reduce the delay between onset and diagnosis.

Fabry disease is a metabolic and lysosomal storage disorder caused by the functional defect of the α-galactosidase A enzyme; this defect is due to mutations in the GLA gene, that is composed of seven exons and is located on the long arm of the X-chromosome (Xq21–22).The enzymatic deficit is responsible for the accumulation of glycosphingolipids in lysosomes of different cellular types, mainly in those ones of vascular endothelium. It consequently causes a cellular and microvascular dysfunction.In this paper, we described five novel mutations in the GLA gene, related to absent enzymatic activity and typical manifestations of Fabry disease. We identified three mutations (c.846_847delTC, p.E341X and p.C382X) that lead to the introduction of a stop codon in positions 297, 341 and 382. Moreover we found a missense mutation (p.R227P) in the exon 5 of the GLA gene and a single point mutation (c.639 + 5 G > T) occurring five base pairs beyond the end of the exon 4. These mutations have never been found in our group of healthy control subjects > 2300.The studied patients presented some clinical manifestations, such as cornea verticillata, hypo-anhidrosis, left ventricular hypertrophy, cerebrovascular disorders and renal failure, that, considering the null enzymatic activity, suggest that the new mutations reported here are related to the classic form of Fabry disease.The identification of novel mutations in patients with symptomatology referable to FD increases the molecular knowledge of the GLA gene and it gives clinicians an important support for the proper diagnosis of the disease.