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Page 2 of 12 Politei et al. Rare Dis Orphan Drugs J 2024;3:10 https://dx.doi.org/10.20517/rdodj.2023.46

phenotype and are generally symptomatic in early childhood. In contrast, patients with residual α-GalA
[2]
activity exhibit milder clinical manifestations and onset occurs later compared to the classic phenotype .
CLINICAL MANIFESTATIONS
In the classic phenotype, clinical manifestations are multisystemic, including distal neuropathic pain,
acroparesthesia, abdominal cramps, diarrhea, angiokeratoma, anhidrosis, and childhood-onset corneal
opacity. As patients age, there is a progression towards major organ involvement in adulthood, marked by
proteinuria, impaired renal function, cardiomyopathy, and stroke. In contrast, individuals with the later-
onset phenotype retain a notable level of α-GalA activity. However, some male patients may develop either
cardiomyopathy or, less frequently, nephropathy, which can be as severe as in the classic phenotype. In
[1,2]
nearly every instance, females with late-onset disease have relatively minor kidney involvement . Two
decades ago, female heterozygotes were erroneously characterized as “carriers of the defective gene”
presumed to be more or less safeguarded against developing disease manifestations. However, it has been
established that most female heterozygotes do develop symptoms and vital organ involvement including
kidneys, heart, and brain a decade later than males .
[3]

Among classic patients, abdominal pain is the most frequently reported symptom. It manifests as
intermittent pain localized in the mid or lower abdomen, accompanied by bloating, cramping, or
[4,5]
midabdominal discomfort . The aforementioned manifestations may appear during or after meals or may
even be triggered by stress. Therefore, it is plausible that many FD patients are unwilling to consume food,
potentially leading to lower body weight. Diarrhea ranks as the second most common manifestation, often
appearing postprandially and occurring up to a dozen times a day, significantly decreasing the quality of life
of affected patients . Additional manifestations include nausea, vomiting (both more frequent in
[5,6]
children), and constipation, with females experiencing the latter more frequently than males. Mainly in
adult patients, the presence of gastritis, hemorrhoids, chronic intestinal pseudo-obstruction, diverticular
disease, and bowel ischemia has also been reported [7-11] .

The real incidence of gastrointestinal (GI) symptoms among patients with FD is unclear, and
underreporting of these non-specific symptoms is a frequent occurrence. However, there has been a notable
incidence of GI symptoms reported, particularly among children and female patients . Registry data from
[12]
patients enrolled in the Fabry Outcome Survey show that 60% of untreated children reported GI symptoms
upon enrollment to the Registry . Similarly, 50% of adult female patients exhibited such symptoms . In
[14]
[13]
2015, Laney published a systematic retrospective analysis of publications and case reports in the pediatric
[15]
Fabry population symptoms reported before 5 years of age . This group uncovered compelling evidence
indicating that symptoms can manifest during early childhood, with cases reported as early as 2 to 3 years of
age. They concluded that neuropathic pain, heat sensitivity, especially recurrent abdominal pain and
diarrhea, should be monitored during early childhood .
[15]

The prevalence of GI manifestations in FD should be taken with caution. It is important to consider that
these symptoms, which can include recurrent abdominal pain and diarrhea, may not exclusively be
attributed to FD, but may also be associated with common functional disorders such as irritable bowel
syndrome, particularly in cases of late-onset FD. Reports published over two decades ago indicated a high
frequency of GI symptoms in males (69%) and females (58.3%). However, it is crucial to note that the
absence of differentiation between phenotypes in these studies could potentially lead to misinterpretation of
the results [16,17] . In 2020, Di Toro investigated the pathological basis of FD-related gastropathy, comparing
classic and late-onset patients with control cases through gastric endoscopy. All patients experienced long-
standing GI disturbances that were poorly managed with medications. In classic FD phenotype,