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Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51 Page 5 of 16

Moreover, TIA was described in 20% of males and 17% of females. Lacunar infarcts involving both the
anterior and the posterior circulation were the predominant type of stroke, while only one female suffered a
[60]
hemorrhagic stroke .

[61]
In Australian patients with FD, a prevalence of stroke of 31% in males and 5% in females was reported . A
retrospective analysis of a Dutch cohort of patients with FD from a single center in Amsterdam yielded a
prevalence of stroke or asymptomatic lacunar infarcts detected on magnetic resonance imaging (MRI) of
32% (n = 13, median age: 56 years) in females and 48% (n = 12, median age: 46 years) in males . A
[62]
retrospective Japanese study including 65 patients identified ten subjects (15%, 7 males and 3 females) with
ischemic strokes .
[63]

In 2001, MacDermot et al. analyzed 60 women with FD and identified 4 patients with stroke and 17 with TIA
[64]
(combined prevalence of 21.5%) . In a cross-sectional study, the same authors reported a cohort of
98 males and 60 females, with a respective frequency of stroke of 24% (mean age: 40 years) and 7% (mean
age: 42 years) . In addition, a study comprising only women included 54 participants with a brain MRI; 7%
[65]
of them had lacunar strokes, but it is unclear whether they were symptomatic .
[66]
With the goal of increasing the sample size, several studies used data from collaborative international
registries, such as the Fabry Outcome Survey (FOS) and the Fabry Registry (FR). In 2005, Mehta and
Ginsberg evaluated the prevalence of stroke and TIA among 388 patients in FOS; the prevalence was higher
in females (15.7%) than in males (11.1%) . About half of these patients suffered a stroke or a TIA at an age
[67]
younger than 44 years.

A later study identified that 91 (13.2%) of the 688 patients (330 males, 358 females) registered in FOS by
March 2005 had suffered a stroke or TIA. The prevalence of ischemic strokes among males and females
registered in FOS was 20.1 and 7.8 times higher than expected in a comparable general population,
respectively .
[68]
A more recent FOS study including 1,453 patients identified that cerebrovascular events were almost equally
frequent in males (25%; n = 172/699) and females (21%; n = 159/754) .
[47]
A study analyzing the FR cohort included 2,446 patients. Overall stroke prevalence was 5.6% (n = 138): 6.9%
in males, with a mean age of 39 years, and 4.9% in females, with a mean age of 45 years. The prevalence of
hemorrhagic strokes was 13.2%, whereas the prevalence of ischemic strokes was 86.8%. For ischemic strokes,
up to 70% were lacunar. Moreover, 21.7% of the patients who had a stroke were younger than 30 years old.
Most patients had had a stroke before any cardiac or renal event, or it was their only clinical manifestation.
In addition, 38% of females and 50% of males experienced their first stroke before being diagnosed with FD.
Thus, most patients had either not experienced other major complications or had not been diagnosed with
[69]
FD before their stroke .

Atrial Fibrillation in FD
Atrial fibrillation incidence in FD is variable depending on the choice of diagnostic modality, with 12-lead
ECG and Holter monitoring showing lower detection rates (2.9%-10% per year) compared with higher rates
(19%-31% per year) on continuous rhythm monitoring .
[70]

The worldwide incidence and prevalence of AF is increasing in the general population. Higher rates of AF
were observed due to advancing age, improved survival from co-existing disease, and increasing co-