SP034A NOVEL PATHOGENIC GLA MUTATION REVEALED IN A GREEK FAMILY

Abstract

INTRODUCTION: Fabry disease (FB) is an X-linked lysosomal disorder, caused by various mutations of the α-galactosidase A gene (GLA). The deficient activity of the GLAcauses storage of Gb3 glycosphingolipids in lysosomes of various cell types, mainly in the vascular endothelium, thus leading to cellular and microvascular dysfunction.More than 900 currently known GLAmutations have been identified, which are associated with various clinical manifestations. Although male patients have been associated with more severe phenotypes, heterozygous female patients who preferentially express the mutant GLA allele have a disease course which might be similar to the male disease phenotype (either classic or later-onset), depending on the specific GLA mutation. METHODS: Recently, a novel GLAmutation was identified while screening a long term hemodialysis (HD) 47 year old female patient with an unknown cause of CKD, demonstrating phenotypic traits suggestive for FD. Specifically, the patient displayed severe left ventricular hypertrophy, ophthalmological stigmata of FB, cornea verticillata, whereas brain MRI, ENT and dermatological evaluation revealed normal findings. RESULTS: After a detailed pedigree was constructed, the patient's parents and offspring (25 year old son and 27 year old daughter), underwent genetic testing. A novel -not previously described-, de novo aGal c.953-956delCCATinsGG mutation [p.(Ala318Glyfs∗14)] was identified in our patient as well as her son and daughter. This variation creates a frame shift starting at codon Ala318. The new reading frame ends in a STOP codon 14 positions downstream. α-Gal A activity in the male subject was undetectable. The concentration of the biomarker lyso-Gb3 in dry blood spot (reference <1.8 ng/ml) was pathologically increased in the patient (lysoGb3 12.3 ng/ ml), her son (lysoGb3 97.2 ng/ml) as well her daughter (lysoGb3 4.9 ng/ml). The patient's son and daughter have preserved renal function, with daughter showing proteinuria in the range of 0.7-1 gr/day and a kidney biopsy is pending. Both children displayed cornea verticillata and angiokeratomas with no other manifestations of FB. All patients were started on enzyme replacement therapy according to current recommendations for treatment of FB. Recently our HD patient underwent successful cadaveric kidney transplantation. CONCLUSIONS: Given the pathogenic result of the Gb3 biomarker analysis and the specific clinical manifestations, all of the family members carrying the novel c.953-956delCCATinsGG mutation [p.(Ala318Glyfs∗14)], fulfill the diagnostic criteria of a definite FD diagnosis and evidence of this novel mutation pathogenicity is provided in this presentation.