Sex-Specific Diagnostic Inequality in Fabry Disease: Lessons Learned from Analysis of Newborn Screening and Cascade...

Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (aGAL) deficiency. Newborn screening (NBS) programs for FD have been implemented in several US states; however, its effectiveness in identifying affected females remains uncertain. We hypothesized that sex-specific inequality of NBS-based detection of FD results in different diagnostic pathways for males and females with FD.

We compared diagnostic approaches for males and females with FD using Tennessee NBS results and Vanderbilt Lysosomal Storage Disorders Database (VLSDD). Sex-specific detection differences were assessed using Fisher's exact test (α = 0.05).

Tennessee NBS identified 25 males but no females with FD from 2017 to 2024. In VLSDD, among 81 individuals with FD, sex distribution was nearly equal (42 males, 39 females). Among males, 26/42 (62%) were diagnosed via NBS, 7/42 (17%) through known family history, and 9/42 (21%) based on clinical symptoms. All 16 males diagnosed through non-NBS were born before its implementation. In contrast, none of the 39 females were diagnosed through NBS (p value <0.05). Of these, 13/39 (33%) were diagnosed through cascade testing following their sons' detection by NBS, with a median age at diagnosis of 28 years (25th-75th percentile: 24.5-34.0). Of the remaining 26 females, 12/26 (46%) were diagnosed after a family member was diagnosed through clinical symptoms and 14/26 (54%) were diagnosed through clinical symptoms.

NBS effectively identifies affected males but fails to detect females with FD, though it can indirectly facilitate diagnosis of older female relatives.