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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 17 of 34

Secondary stroke prophylaxis with ASA or clopidogrel may be required. Patients with Fabry disease have a
[118]
greatly increased risk of stroke compared with the general population . There is evidence of endothelial
damage, abnormalities in cerebral blood flow velocity, a prothrombotic state, and increased production of
reactive oxygen species that may contribute to the development of stroke in Fabry disease. However, there
are no studies in this patient population of any stroke therapies, so clinicians are left to extrapolate from
data from other larger patient groups. As atrial fibrillation is a common complication of cardiomyopathy in
Fabry disease, it is important to provide appropriate anticoagulation to minimize the risk of subsequent
stroke.

Control of neuropathic pain is very important and a variety of agents are available for use, including
carbamazepine, gabapentin, pregabalin, duloxetine, and others. Narcotic analgesics are to be avoided due to
[119]
their limited effectiveness in treating neuropathic pain and high potential for addiction .
Monitoring
Patients with Fabry nephropathy should be monitored for kidney function (eGFR) and proteinuria (urine
albumin to creatinine ratio (ACR)/PCR/24-h urine), along with other biochemical parameters as per CKD
care standards. Blood pressure control and the presence of edema should be noted at each clinic visit.

Extrarenal complications of Fabry disease should be monitored in adults. An annual highly sensitive
troponin T or I, EKG, echocardiogram, and Holter monitor or loop recorder should be done to detect any
signs of cardiac involvement. N-terminal pro-brain natriuretic peptide is useful for patients with heart
failure. Cardiac MRI done every 2 to 3 years is important to identify fibrosis via late gadolinium
enhancement, which can precede LVH in heterozygotes and males with late-onset cardiac variant disease.
Brain MRI should be done every 2 to 3 years to identify silent infarctions, as well as dolichoectasia and white
matter lesions. Audiograms and pulmonary function tests every 5 years will document the slow loss of
hearing and progression of Fabry pulmonary changes.

Plasma lyso-Gb3 should be monitored in all patients undergoing therapy to ensure a therapeutic response
and to verify drug compliance. As plasma lyso-Gb3 level is now recognized as a risk factor for Fabry disease
complications including decreased eGFR and proteinuria, monitoring these levels at least annually may be
of benefit to help guide therapeutic decisions [68,120] .

Anti-drug antibodies, including neutralizing antibodies, should be done in all males receiving ERT; women
do not need such testing unless they have infusion-associated reactions to ERT or are homozygotes.

Dialysis
Patients with Fabry disease can be managed with either hemodialysis or peritoneal dialysis. ERT can be
given safely during hemodialysis treatments with no appreciable loss of enzyme through the dialyzer
[121]
membrane or due to binding to the plastic tubing . Gb3 is not removed by hemodialysis. It is unknown
whether any Gb3 is removed on peritoneal dialysis, but this could occur due to the loss of peritoneal cells in
the dialysate. Removal of lyso-Gb3 has not been studied during any type of dialysis. Peritoneal dialysis may
have the advantage of better fluid and blood pressure control for Fabry disease patients who often have
severe LVH with diastolic dysfunction due to Fabry cardiac disease. Mignani et al. (2008) noted that some
Fabry patients on hemodialysis suffered a 20% increase in left ventricular mass (LVM) index despite ERT,
while those with a kidney transplant had stable LVM index, suggesting that the increasing LVM index was a
complication of ESRD in Fabry disease patients . Anecdotally, some Fabry patients may show extremely
[122]
rapid progression of LVH with hemodialysis probably in part due to contributions from anemia and