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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 7 of 34

Dialysis
In a cohort of 250,352 dialysis patients from the USRDS database, 42 untreated Fabry patients were
identified, comprising 37 males and 5 females (12%), with a mean starting age of 42 years. Their survival
rate was found to be intermediate compared to age-matched controls with diabetes mellitus or without
[2]
diabetes mellitus; specifically, the survival rate at 3 years was 63% for the Fabry patients .
Renal cell cancer
There is a single-center report of a marginally reduced rate of all cancers but possibly increased rates of
melanoma, urological malignancies, and meningioma in Fabry disease patients compared with the age-
[37]
[36]
matched general population . In particular, there is an increased association with renal cell carcinoma . A
pathophysiologic link between Gb3 accumulation, oxidative stress, and oncogenesis via the von Hippel-
Lindau/hypoxia-inducible factor 1 pathway has been suggested .
[37]
Extrarenal manifestations
Most patients have multiple organ system involvement in Fabry disease. Common features include cornea
verticillata, clustered angiokeratomas, hypohidrosis, and acroparesthesia which is a sensory peripheral
neuropathy involving the distal limbs with pain, pins and needle sensation and dysesthesia. Strokes and TIA
commonly start in middle age. White matter lesions are frequently observed in brain imaging. Cardiac
involvement can include cardiomyopathy with hypertrophic change, diastolic dysfunction, dysrhythmias,
elevated hsTroponin, EKG abnormalities (resting sinus bradycardia, LVH, short PR interval), and cardiac
MRI with low T1 and late gadolinium enhancement of the left ventricular mesomyocardial area often over
the posterolateral wall. Hearing loss, both acute and chronic, is common, along with chronic tinnitus,
dizziness, fatigue, and obstructive lung disease often misdiagnosed as asthma. Chronic symptoms of
alternating diarrhea and constipation, and abdominal bloating with pain may be misdiagnosed as irritable
[1]
bowel syndrome . See Figure 2.
DIAGNOSIS
The diagnosis of Fabry disease rests on the demonstration of a pathogenic variant in the DNA of the GLA
gene on the X chromosome. All males will show a decrease in α-Gal activity in leukocytes, plasma, or whole
blood, with classical males having a marked reduction (< 5%). Males with late-onset variant disease and all
females will demonstrate a lesser decrease in α-Gal activity and up to a third of females may have normal
enzyme activity due to mosaicism .
[38]
Elevated biomarkers such as Gb3 or its metabolite lyso-Gb3 in urine or plasma are commonly documented
to confirm pathogenicity. For patients with a VUS, pathogenicity must also be supported by demonstrating
glycosphingolipid deposits in tissues, typically through skin, kidney, or cardiac biopsy, in addition to
measurements of α-Gal activity and biomarkers. Some variants are of uncertain pathogenicity as there are
conflicting reports in the literature, e.g., R118C [39,40] and A143T [41,42] . Given the marked heterogeneity of
Fabry disease phenotype with these variants, a diagnosis of Fabry disease can only be made on a case-by-
case basis by demonstrating pathogenicity. This will require further investigations and possibly evaluation
by a medical geneticist and a Fabry specialist at a center of excellence for Fabry disease.

Elevated Gb3 or lyso-Gb3 biomarkers or modestly decreased α-Gal activity by themselves are also
insufficient for the diagnosis of Fabry nephropathy, as these results may be abnormal in some patients with
CKD of other causes. See Table 1. These observations mean that the use of these parameters for diagnosis or
screening may not be accurate in CKD patients unless GLA analysis is included. GLA analysis is also
important for determining phenotype and informing treatment decisions regarding chaperone therapy.