Phenotypic Evolution in Fabry Disease: Our Experience in Indian Cohort.

The current study aimed to explore phenotypic evolution in Fabry disease according to demographics, genotype, specific enzyme activity and pathogenicity scores. We integrated clinical, biochemical, and genomic data of 88 Fabry cases (23 from our cohort, 65 from other published data on Indians) to achieve this objective. The affected cases showed profound impairment in the alpha galactosidase enzyme activity (0.73 ± 1.38% mean normal) while carriers showed 15.64 ± 3.68% mean normal activity. The mutation spectrum is highly heterogeneous with eight different mutations identified in eight different patients in our cohort, while the total data is representative of 68 mutations in Indians. The mean CADD score for these mutations was 20.63 ± 10.38. Highly conserved mutations are associated with renal involvement ( = 0.005), while neuropathic pain is observed even in mutations in less conserved regions ( = 0.02). The age of onset showed a positive association with the percentage of specific enzyme activity ( = 0.375,  < 0.001), renal disease ( = 0.328,  = 0.005), and cardiac problems ( = 0.278,  = 0.026). Consistent with this, we had a very early onset neonatal Fabry with 0% specific enzyme activity harbouring c.613C > G (p.Pro205Ala) mutation in the gene. This emphasizes that many patients with rare genetic diseases can experience delays in diagnosis due to their infrequent occurrence and nonspecific symptoms, which are not easily recognizable. A holistic approach with a combination of WES and biochemical assays will be helpful in arriving at the early and accurate diagnosis through rigorous phenotypic evaluation.