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Page 6 of 16 Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51

[71]
morbidity . These same drivers are shared in those who have FD, including increasing age, improved
[70]
survival with ERT, but concurrently an increasing number of FD co-morbidities .
SCREENING OF FD IN PATIENTS WITH STROKE
The prevalence of FD in young patients with stroke has been an area of great interest. However, the studies
yielded conflicting results, most likely due to the selection criteria of patients (cryptogenic strokes vs. all
types of strokes or the inclusion of white matter lesions), as well as the genetic data interpretation.

Initially, the number of patients with FD that could be identified among young patients with strokes was
overestimated because benign variants or variants of unclear significance were erroneously interpreted [72,73] .

In a prospective study, Rolfs et al. analyzed 721 patients aged 18 to 55 years with cryptogenic strokes in
Germany. FD was estimated to be the etiological factor in 4.9% of males and 2.4% of females. Nevertheless,
the pathogenic variants were not reported . Multiple investigations followed the study of Rolfs, but none of
[72]
them could reproduce its results.

A meta-analysis included 8,302 patients who participated in nine studies (four about strokes of
undetermined origin and five about strokes of all etiologies). Eight studies limited the age to young patients
(18-55 years old), and the ninth study did not have an age limit. The investigators concluded that FD may
explain approximately 1% of all strokes in the young population, including 3%-5% of cryptogenic strokes .
[73]
The study with no age limit, which included all types of strokes as well as white matter lesions, found no
patients with FD at all . An important limitation of this meta-analysis is that the authors did not critically
[74]
analyze the genetic variants reported in the individual studies, which in many cases corresponded to benign
variants or variants of unclear significance .
[73]
The Stroke in Young Fabry Patients (SIFAP) study is the largest multicentric observational study ever
performed and included 5,023 young patients with stroke (both cryptogenic and non-cryptogenic).
Definitive FD was detected in 0.5% of patients (n = 27). Nevertheless, some of the reported variants are now
[12]
still considered benign or likely benign . None of the patients presented signs and/or symptoms of classical
FD.

In recent years, significant improvement was made in the genotype-phenotype correlation of young patients
with stroke included in screening studies of FD, and as a consequence, a lower prevalence of 0.1%-0.3% was
estimated [75,76] . This prevalence may be higher in young patients with either cryptogenic or recurrent
stroke .
[75]
A prospective, multicentric study of stroke and FD in young adults (18-55 years old) included 311 patients
with either cryptogenic or non-cryptogenic strokes. One female (0.3% of the total group, 1% of the
cryptogenic ischemic strokes) had the pathogenic variant c.888G>A/p.Met296Ile/Exon 6 on the GAL gene.
Her only other manifestation of FD was angiokeratoma .
[75]

An additional systematic review included screening studies published between 1995 and 2017. The aim of
the review was not only to present the prevalence of FD in the mentioned population, but also to reanalyze
the genetic data to exclude benign or likely benign variants, and perform genotype-phenotype correlations.
Data from 3,904 males and 2,074 females were analyzed. In males, the investigators found a pre-analysis
prevalence of 0.67% (n = 26) of patients with FD; among them, 21 had either benign variants or variants of
unknown significance, including p.D313Y, p.A143T, p.E66Q, and g.1136C>T(5’-44C>T). Therefore, the true