Enzyme replacement therapy (ERT) in male patients with Fabry disease may not prevent disease progression in the long term. On the plus side, long term ERT may reduce the risk of serious complications associated with Fabry disease. Those are the conclusions drawn from a new study published in Orphanet Journal of Rare Diseases. The prospective study by Rombach et al  examined data available at the Academic Medical Center in Amsterdam that serves as the Dutch Fabry disease referral center. The data was collected from all patients with a confirmed diagnosis of Fabry disease treated with ERT from 1999 to 2010 (n= 75). Thos patients were compared to patients with Fabry disease who did not receive ERT (‘Natural History group’: n = 142).
The first objective of study analyzed long-term follow-up of ERT treated Fabry disease patients on renal, cardiac and cerebrovascular parameters. Of the patients receiving ERT, 57 adult patients (30 males) had long term follow-up (< 6 months) and the data analysis revealed:
- Renal function declined in males (-3.4 ml/min/1.73m2 per year, SE 0.2; p < 0.001) but not in females (-0.8 ml/min/1.73m2 per year, SE 0.3; p = 0.001).
- Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52).
- Cerebral white matter lesions developed in 48% of the adult males (12/25) and 28% of adult females (7/25).
The second objective of the study was to compare the occurrence of major complications between the ERT group and the natural history group. In that regard,
- 15 patients in the ERT group had a major complication [cardiac event (4 males/3 females), end stage renal disease (3 male/1 female), stroke (2 males/1 female) and death (1 male)]
- 19 patients in the non ERT group had a major complication [cardiac event (9 males/4 females), end stage renal disease (1 female) and stroke (3 males/2 females)].
- Risk of complications increased with age but decreased with length of ERT treatment.
While this analysis is of interest, it should be noted that the study design had many limitation and somewhat contradicts a recent health technology assessment by Wyatt et al  that more favorable towards ERT. That analysis looked at data from 499 patients with Fabry disease and in the analysis of 311 patients given ERT, they observed small decreases in left ventricular mass and improved glomerular filtration rate. And all of these changes were over time periods greater than 3 years.
It should also be noted that ERT is not indicated to prevent disease progression. Fabrazyme’s prescription information specifically states that it reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. That reduction hopefully results in reduced clinical manifestations of Fabry disease but that correlation has not been established. And the observatinon in the above study that long term ERT does reduce the risk of complications - which ultimately leads to death - could lead one to conclude that ERT does reduce the clinical manifestations of Fabry disease.
In our research on use of ERT for Fabry disease, we found the data to be inconclusive towards the efficacy of long term ERT. The small number of patients with Fabry plus the large variance in patient characteristics makes long term studies problematic. However, we are optimistic such studies will eventually be available to help clinicians understand which patients may benefit most from long term ERT.
Fabry disease is an X-linked lysosomal storage disorder that leads to excessive deposition of glycosphingolipids throughout the body. Skin, eye, kidney, heart, brain, and peripheral nervous system are highly vulnerable. Fabry disease is often difficult to diagnose since signs and symptoms are often nonspecific. For example, common symptoms may be fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, diarrhea etc.
Symptoms do appear in childhood but often go undiagnosed for several years. As the disease progressive, most patients with Fabry disease die in their fourth or fifth decade due to complications arising from renal or cardiovascular problems.
1.Rombach SM, Smid BE, Bouwman MG, et al. Long term replacement therapy for Fabry disease: effectiveness on kidney, heart, and brain. Orphanet J Rare Dis. 2013;8:47.
2.Wyatt K, Henley W, Anderson L, et al. The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage
disorders. Health Technol Assess. 2012;16(39):1-543.