Correlation Between GLA Gene Mutation And Clinical Manifestations Of Fabry Disease

Objective: To explore the correlation between genotype and phenotype through analyzing the clinical manifestation and the gene mutation in the alpha-galactosidase A(GLA) in families with Fabry disease.Methods: In this study, the clinical data of a diagnosed Fabry disease patient and his family members were collected, including general information, blood biochemical index, electrocardiogram, echocardiography,skull magnetic resonance imaging, and so on. After inform consent, the early morning fasting elbow venous blood of subjects were also collected. α-galactosidase A(α-Gal A) activity was measured using dried blood spots on filter paper, the GLA gene was amplified using polymerase chain reaction(PCR), and the amplified products were purified and sequenced. In addition, thirteen healthy individuals living in the same region were examined as controls. The mutations of GLA gene and clinical manifestation of subjects were analyzed.Results: There were 19 people in this Fabry disease pedigrees, 8 people had clinical symptoms, three male and five female. The average age of them is(36.38±19.41) years. The symptoms of male patients more severe than female patients. In hemizygous male the symptoms include angiokeratoma, limb pain and involvement of cardiovascular, cerebrovascular, renal. In heterozygous female the symptoms just is limb pain, hypohidrosis, and so on. In the thirteen healthy controls, there were 5 male and 8 female. The average age of them is(46.85±18.52) years. The α-Gal A activity analysis revealed the α-Gal A activity in patients with Fabry disease was reduced, and the mean of it is(96.96±81.15)10-15mol/day/spot, and there were significant difference with healthy controls(188.31±42.23)10-15mol/day/spot(P<0.05). What’s more, theα-Gal A activity in males with Fabry disease was only 4.6% of that of healthy controls(8.66±2.15 vs188.31±42.23), the difference between them was significant(P<0.05). Whereas the α-Gal A activity in females with Fabry disease was 79.62% of healthy controls(149.93±46.56 vs 188.31±42.23), although there was a tendency to decline, the difference between them was not significant(P>0.05); when compared with hemizygous male patients, there was significant difference(P<0.05).When all seven exons of the GLA gene and the adjacent areas sequencing were analyzed, the proband was found a two nucleotide deletion in exon 5, and the genotype was g.10208-10209 del AA. There were seven people with the same mutation in these Fabry pedigree, including two hemizygote and five heterozygotes. At the same time, in the healthy controls also exist people with GLA gene mutation, 1390 A to G transition in exon 1(1390A>G), while this person with no symptoms.Conclusion: The α-Gal A activity measured with diagnostic limitations in Fabry disease, the enzymatic activity is significant reduced in male patients. Although patients with Fabry disease carrying the same gene phenotype may not present the same clinical manifestations, and there may be non-pathogenic GLA gene mutation.