A Clinical And Genetic Study On Familial Fabry Disease

Part?: Clinical manifestations of a family with Fabry disease and mutation analysis of GLA genePurpose: Fabry disease is a rare X-linked genetic lysosomal storage disorder caused by the mutations of ?-galactosidase A(GLA)gene.The deficient activity of lysosomal ?-Ga1 A results in progressive accumulation of globotriaosylceramide(Gb3)within lysosomes,and the characteristic renal,cardiovascular,cerebrovascular,neurological,cutaneous and gastrointestinal signs of the disease,presenting with various clinical symptoms including small-fiber peripheral neuropathy and limb burning pain.In this study,we reported a Chinese pedigree of Fabry disease with the initial diagnosis of primary erythromelalgiain.Methods: The clinical manifestations and examinations were collected.The direct sequencing of SCN9 A gene was performed.Then the next-generation sequencing was also performed.We determinated the ?-Ga1 A activity assay in leukocytes of the patient and female carriers.Results: Ourdata did not show any pathological mutations in SCN9 A gene;however,a novel missense mutation c.139T>C(p.W47R)of GLA was identified in the male proband as well as two female carriers in this family.Enzyme assay of ?-Ga1 A activity showed deficient enzyme activity in male patient and female carriers,further confirming the diagnosis of Fabry disease.Conclusions: Because Fabry disease and primary erythromelalgia share similar symptoms,it is a good strategy for clinical physicians to perform genetic mutation screenings on both SCN9 A and GLA genes in those patients with limbs burning pain but without a clear inheritant pattern.Part ?: Determination of ?-Gal A activity encoded by the mutant GLA in 293 T cellsPurpose: To confirm whether the novel mutation c.139T> C(p.W47R)of the GLA gene is pathogenic.Methods: We constructed wide-type and mutant GLA plasmids then determinated ?-Gal A activity in 293 T cells.Results: The replacement of the 47 th amino acid tryptophan(W,UGG)with arginine(R,CGG)or glycine(G,GGG)reduced the activity of ?-Gal A in 293 T cells by functional analysis.Conclusions: The mutation c.139T>C of the GLA gene is the cause in this Fabry disease family.