GLA Nonsense Mutation (c.485G>A) in a Three-Generation Family with Fabry’s Disease
Gabriela Sarca
Professor C. Angelescu Hospital, Bucharest, Romania
Cristina Dragomir
Genetic Lab, Bucharest, Romania
Adriana Stan
Genetic Lab, Bucharest, Romania.
Emilia Severin *
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
*Author to whom correspondence should be addressed.
Abstract
Background: GLA nonsense mutations seem to be associated with more severe clinical phenotype.
Aims: Main aims were to identify the disease-causing mutation, to screen high risk family members and to predict the severity of clinical phenotype and age of onset based on genotype-phenotype analysis.
Methods: Seven family members were clinically assessed and enzyme activity levels were evaluated as well. Genomic DNA was isolated from blood samples and analyzed for GLA gene mutation.
Results: The proband, a 34-year-old man, was misdiagnosed for years. At 25 years of age he was diagnosed with Fabry’s disease. He had a less severe phenotype failing to express cardiac, cerebral or renal symptoms. In addition, the patient presented a ventricular septal defect as an incidental finding which has not been reported previously in Fabry’s disease. His maternal uncle had a severe classic form and, in addition, osteonecrosis of femoral head rarely reported as associated findings. All females were heterozygous; 3 of them were asymptomatic and 2 developed milder symptoms, skin and heart predominantly affected. Fabry’s disease was caused by the presence of GLA nonsense mutation c.485G>A. All close relatives of proband had one copy of the mutation.
Conclusion: The family nonsense mutation c.485G>A known to predict the classic phenotype showed a wide range of clinical manifestations from severe to asymptomatic forms both in males and females supporting the intrafamilial phenotypic variability for Fabry’s disease.
Keywords: Fabry’s disease, GLA gene, c.485G>A nonsense mutation, ventricular septal defect, intrafamilial phenotypic variability