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Politei et al. Rare Dis Orphan Drugs J 2024;3:10 https://dx.doi.org/10.20517/rdodj.2023.46 Page 3 of 12

immunohistochemical study revealed specific immunostaining to GL-3 in various cell types, including
endothelial and vascular smooth muscle cells (SMC), pericytes, nerve cells, interstitial mesenchymal cells,
and epithelial cells. The ultrastructural study demonstrated the typical lamellar osmiophilic bodies in the
cytoplasm of the SMC of the muscularis mucosae, both vascular and non-vascular SMCs, nerve cells, and
gastric epithelia. On the contrary, gastric biopsies from late-onset FD patients and control cases did not
show GL-3 accumulation. In these patients (both controls and late-onset cases), GI symptoms were
attributable to gastric comorbidities .
[18]

PATHOPHYSIOLOGY
It is known that most of the well-characterized symptoms of FD are the result of the accumulation of GL-3,
[19]
leading to vascular dysfunction and perturbations in the peripheral and autonomic nervous systems . In a
study by Masotti et al., the α‐Gal A (−/0) mouse model of FD was used to characterize distinct anatomical,
[20]
morphological, and molecular features of the colon tract in comparison with the wild type . The authors
did not detect any difference based on macroscopic damage parameters, nor did they observe any
remarkable sign of inflammatory infiltrate at the mucosal level. These findings are in line with the results of
colonoscopies and histological analysis of Fabry patients, which typically exhibit no indications of mucosal
damage or inflammation [8,21] . Structural analysis reported a thickening of the muscular layer and the size of
ganglia of the myenteric plexus in α‐Gal A −/0 colon, by the presence of GL-3 deposits in smooth muscle
and neuronal cells. Additionally, α‐Gal A −/0 mice exhibited a significant reduction in protein gene product
[20]
9.5-positive innervation entering the mucosa, as compared to the control group .
Several mechanisms through which FD causes these manifestations in patients are hypothesized to be the
result of enteric nervous system dysregulation, impacting gut motility, endothelial GL-3 accumulation
leading to vascular compromise, and involvement of visceral hypersensitivity . Autopsy and biopsy studies
[12]
have shown the presence of GL-3 inclusions in both the submucosal (Meissner’s) plexus and the myenteric
(Auerbach’s) plexus. Anatomopathological records show swelling of ganglion cells and surrounding axons,
with intralysosomal GL-3 inclusions characteristic of FD [Figure 1] [8,21-23] . Notably, patients and mice models
with FD have exhibited an increase in the size of ganglion cells, surpassing twice their normal
dimensions [20,21] . The ganglion and axonal autonomic compromise in association with the resulting cellular
degeneration leads to focal hyperactivity and lack of coordination of the myogenic activity . Reports on gut
[7]
motility have reported an overall delay in peristalsis and regional myogenic hyperactivity . It is worth
[24]
noting that the majority of these reports highlight these spastic contractions occurring predominantly
within the small intestine [21,23] . Liquid and solid gastric emptying studies with Tc99 have repeatedly shown
gastric dysmotility [10,21,25] , confirming this hypothesis. Recently, 48 patients with FD and GI manifestations
[26]
were studied using a wireless motility capsule (WMC) to measure pan-gut motility . The WMC testing
showed a significant correlation between constipation severity and the Bristol stool scale with colonic transit
time. The severity of nausea and vomiting displayed an inverse correlation with the motility index of antral
and duodenal contractility, indicating that heightened motor activity in the antro-duodenum is associated
with less severe nausea and vomiting. Nonetheless, in a symptomatic patient cohort, only about 35%
exhibited delayed transit in one section of the gut .
[26]

Colonic dysmotility can lead some patients to pseudo-obstruction syndrome. As a result, colostomy has
been performed in exceptional cases, including children with FD who lack cardiac, renal, or cerebrovascular
complications [7,9,11] . Vascular involvement, both of small arteries and large vessels, largely explains the
pathophysiology of gastrointestinal alteration. Studies utilizing optical and electron microscopy have
demonstrated a narrowing in blood vessel lumen as a result of GL-3 deposits in endothelial cells, pericytes,
and vascular smooth muscle cells [Figure 2] [21-24,27] . The occlusion of mesenteric vessels resulting in intestinal