Page 88 - Read Online

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

with classical genotypes. Kermond-Marino et al. (2023) estimated that 1 in 3,225 individuals in the general
[8]
population have undiagnosed Fabry disease, based on an assessment of gnomAD variant pathogenicity .
These observations suggest that the true prevalence likely greatly exceeds earlier estimates.

In Canada, the Canadian Fabry Disease Initiative registry (CFDI) has 671 patients enrolled, with 57 reported
deceased; ascertainment is over 95%, with a female-to-male ratio of 2:1 . There are 30 to 40 new patients
[9]
entered annually into the CFDI, suggesting that there are still many patients yet to be discovered. The
prevalence of Fabry disease in Canada is currently estimated at about 671/38,781,291 or 1 in 57,796. In Nova
Scotia, due to a significant founder effect, the prevalence is higher at 1 in 10,083, with 105 patients in a
1,058,694 population, illustrating the marked geographic variability in the prevalence of this condition.

Cross-sectional estimates of prevalence based on the presence of proteinuria/albuminuria and decreased
estimated glomerular filtration rate (eGFR) will vary based on age and sex distribution as well as the
genotype (classic vs. late-onset variant) of each patient population. Age is the most important factor in this
progressive disease, as younger patients may exhibit no albuminuria or proteinuria and have normal kidney
function. Gender is also important, as female heterozygotes have much less ESRD than male hemizygotes,
with a 1:7 ratio , in contrast with the 2:1 ratio expected in an X-linked condition such as Fabry disease.
[2]
Kidney disease is common in classic males with Fabry disease and those males with variant renal
phenotypes. In a referral population of 105 men with mainly classical genotypes, prior to ERT, 74%
[10]
developed CKD, defined as overt proteinuria or decreased eGFR .

[11]
Ortiz et al. (2008) reported on 1,262 untreated adults with Fabry disease from the Fabry Registry . CKD
stage distribution by gender is presented in Figure 1A and B. Men had twice the percentage in CKD stages
III-V than women (28% vs. 13%). These percentages were higher in patients older than 40 years (yr), at 45%
for men and 20% for women, reflecting CKD progression. The excess of males with advanced CKD relative
to females in this study is probably an overestimate as female enrollment was limited at 48% when 66%
would have been expected for this X-linked disease .
[11]

Patients with late-onset variant genotypes tend to have less and later kidney disease than those with classic
genotypes, but there is considerable variability among the late-onset variant genotypes, especially the N215S
variant. Germain (2018) reported on 59 men and 66 women, mean ages 51.9 and 41, respectively, with the
N215S variant; 17% of men and 3% of women had eGFR < 60 mL/min/1.73 m . During follow-up, 1/125
2
[12]
(0.8%) N215S progressed to ESRD vs. 17/381 (4.4%) classic genotype . Oder (2017) studied 26 N215S
patients, mean age 49 years, 50% males, with Fabry cardiomyopathy. Two men aged 53 and 74 years,
[13]
respectively, had albuminuria > 1 g/g with CKD stage II and III; the rest were normal . Lavalle (2018)
compared N215S patients, 37 men and 47 women, with non-N215S patients . Two men with the N215S
[14]
variant presented with ESRD and two more progressed to ESRD. CKD prevalence at presentation was 9/78
(11.5%) vs. 18/148 (12.2%) in nonN215S patients, although CKD and proteinuria started later in the N215S
group.

Data on renal parameters in patients with the IVS4+919G>A intronic late-onset cardiac variant from
Taiwan are limited. CKD distribution was Stage I 41%, II 41%, III 14%, and IV/V 5% in 22 adults, with
17 males and 5 females and median age 61 years . Microalbuminuria was reported in 25% of men and 18%
[15]
of women with this variant .
[16]
The prevalence of Fabry disease patients on dialysis in the US is reported at 0.02% in the 1995-1998 USRDS
cohort, similar to that in Europe . As there are more known patients with Fabry disease than 25 years ago,
[2]
the prevalence of this disease has likely risen in the dialysis population.