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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 5 of 12

Figure 3. (A) Examination of a hemicolectomy specimen from a female Fabry patient as a result of diverticular perforation. Photo
property of Dr. Politei. Published with permission of Dr. Politei. (B) Examination of a colectomy specimen from a male Fabry patient
with diverticular disease. Partial sigmoid resection due to multiple episodes of diverticulitis. Photo property of Dr. Politei. Published with
permission of Dr. Politei.

reduction has led to the suspicion of “intestinal angina”, being the reason for the abdominal cramps after
meals.

All these alterations of intestinal motility predispose to bacterial overgrowth and subsequent sustained
diarrhea, malabsorption, and diverticula formation . Bile salt breath tests for expiration or aspiration of
[24]
[10]
jejunal content confirm this finding. In addition to bacterial overgrowth, new evidence suggests that
[7]
globotriaosylsphingosine (lysoGL-3) directly influences microbiotical growth, potentially culminating in
[30]
dysbiosis and a disproportion of the intestinal microbiota . Dysbiosis is associated with the activation of
proinflammatory immune responses due to an abnormal proliferation of immune cells and increases the
production of proinflammatory compounds such as lipopolysaccharides . Furthermore, gut dysbiosis
[31]
compromises the energy supply to the colonic epithelium and elevates epithelial permeability, resulting in a
“leaky gut” [4,32] . In this context, lysoGL-3 increases the biofilm-forming capacity of several individual
bacteria, including Bacteroides fragilis . LysoGL-3 also alters the bacterial conformation of human gut
[30]
microbiota suspensions, increasing bacterial counts of B. fragilis, and influencing the production of short-
[30]
chain fatty acids, resulting in a notable reduction in butyrate concentration . These results were recently
replicated , where dysbiotic features imply a disruption of colon homeostasis, leading to accelerated
[33]
intestinal transit, visceral hypersensitivity, and impaired communication along the gut-brain axis in the
mouse model.

DIAGNOSIS OF GASTROINTESTINAL INVOLVEMENT IN FABRY DISEASE
Misinterpretation of gastrointestinal manifestations is commonly reported in patients with FD. The most
frequent misdiagnoses are irritable bowel syndrome, chronic inflammatory bowel disease, appendicitis,
autoimmune disorders, Whipple’s disease, dermatomyositis, or somatoform disorder . Exceptionally, FD
[34]
may co-occur with other gastrointestinal diseases such as Crohn’s disease, coeliac disease, or colon
[10]
cancer . Previously, the assessment of gastrointestinal signs and symptoms in Fabry patients relied on
patient interviews and tools designed for other gastrointestinal disorders, including the Gastrointestinal
Symptom Rating Scale (GSRS) and Rome III criteria (now Rome IV) . Evaluating GI symptoms in Fabry
[12]
patients using questionnaires based on the Rome III criteria, it was found that 16 out of 25 adult and 2 out
of 8 pediatric Fabry patients, all experiencing GI symptoms, exhibited a symptom profile resembling that of
functional gastrointestinal disorders . The 24-h and 7-day Fabry disease patient-reported outcome-
[35]
gastrointestinal (FABPRO-GI) assessments represent the first FD-specific Patient-Reported Outcomes
(PROs) designed to evaluate GI signs and symptoms in FD patients . Given the paucity of PROs tailored
[36]
for FD, the 24-h and 7-day FABPRO-GI instruments present an opportunity to gain new insights into Fabry