Prevalence and Clinical Correlates of Cerebrovascular Alterations in Fabry Disease: A Cross-Sectional Study

Abstract

Background/Objectives: Fabry disease (FD) is an inborn error of the glycosphingolipid metabolism with variable kidney, heart, and central nervous system (CNS) involvement. CNS-related FD manifestations include early ischemic stroke and white matter lesions (WMLs) related to cerebral small-vessel disease (CSVD), possibly resulting in cognitive impairment. We studied 40 adult FD patients (17 male) to assess: (i) prevalence of cerebrovascular and cognitive manifestations in FD and their correlation with heart and renal involvement; and (ii) the potential value of serum neurofilament light chain (NfL) levels as an indicator of WMLs in FD. Methods: Patients underwent detailed diagnostic assessment related to FD, also including Mainz Severity Score Index (MSSI), neuropsychological tests, brain MRI to assess WMLs by the modified Fazekas score (mFS), and NfL determination by single-molecule array (SiMoA) (n = 22 FD patients vs. 15 healthy controls). Results: Overall, 4 FD patients had a history of ischemic stroke and 13/32 patients (40.6%) had an mFS ≥ 1. Almost two-thirds of FD patients (27/39, 69.2%) showed impairment on at least one cognitive test. On univariate analysis, only a reduction in estimated glomerular filtration rate was associated with an increased likelihood of having WMLs on brain MRI. Serum NfL levels were higher in FD patients vs. controls, with a trend toward significance (p = 0.08). Conclusions: Mild-to-moderate CSVD is a characteristic brain "signature" in FD patients. Both cardiac and renal involvement correlate with WML load, but only renal involvement appears to be predictive of CNS damage. Brain microvascular damage is associated with mild cognitive impairment in FD, and serum NfL might represent a potential biomarker of CSVD in FD.

Keywords: CNS; FD; Fabry disease; NfL; brain MRI; central nervous system; neurofilament light chain; stroke.

Figure 1

Histogram showing, for each neuropsychological test, percentage of FD patients with abnormal values. Abbreviations: acc., accuracy; cat., category; CVF, categorial verbal fluency; DR, delayed recall; DSB, digit span backward; FCR, forced-choice recognition; imm. rec., immediate recall; per. err., perseverative errors; PVF, phonological verbal fluency; RCPM, Raven’s colored progressive matrices; ROCF, Rey–Osterrieth complex figure; SSB, spatial span backward; SSF, spatial span forward.

Figure 2

Box plot showing serum neurofilament light chain (NfL) levels in patients vs controls. Please note that the extreme outlier described in the text with NfL levels >600 pg/mL is not included in the graph to better visualize data on the y axis reference scale. * represent an outlier.