Clinical significance of complex intronic haplotype in Fabry disease screening cohort: A prospective cohort study in Korean patients

초록

Introduction: Intronic variants within the GLA gene is known to alter gene expression and enzyme activity in Fabry disease (FD). However, clinical significance of complex intronic haplotype (CIH) in FD remains controversial. Methods: Patients with left ventricular hypertrophy (LVH) assessed by echocardiography or those with family history of FD were included. Serum α-galactosidase A activity and plasma lyso-Gb3 levels were analyzed, and GLA gene sequencing was performed. Results: Overall, 57 of 721 patients (7.9 %) were identified with CIH variants. Patients with CIH variants had mean age of 64.3 ± 13.0 years old, and 56 (98.2 %) were female. In the CIH carriers, mean α-galactosidase A activity was significantly reduced compared to the control (4.7 ± 1.4 vs. 9.7 ± 14.7 nmol/h/mg, p b 0.001). Lyso-Gb3 levels were within normal range in CIH carriers. LVH for voltage criteria was noted in 4 patients (7.0 %) and left ventricular mass index was lower than the controls in sex-matched analysis of females (104.8 ± 23.5 vs. 111.9 ± 31.0 mg/m2 , p = 0.041). Definite conduction abnormality in ECG were found in 3 patients (5.2 %), and there was no clinical manifestations of FD in the CIH group. Conclusions: In patients with CIH, the activity of αgalactosidase A was reduced to similar extent as that of GLA mutation, but pathological features of FD were not present. This finding suggests that CIH may not be pathogenic like FD, and clinical symptoms should be prioritized for evaluation of disease progression.