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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 7 of 16

prevalence of FD dropped to 0.13%. Among the 5 males with pathogenic variants, 3 exhibited the Type 1
phenotype while 2 displayed the Type 2 phenotype. Similarly, a prevalence of 1.11% of patients with FD was
found in females (n = 23), but when the benign variants were excluded, only 3 presented pathogenic variants
[76]
with the Type 1 phenotype and the actual prevalence dropped to 0.14%, similar to that in males . The
authors found that most FD patients identified in stroke clinics had the Classic phenotype and, therefore,
[76]
should have been diagnosed earlier by their pediatricians and family doctors .
Moreover, similar clinical characteristics of stroke patients were identified in the Fabry Registry. When the
most recent available follow-up examination after their first stroke was analyzed, 59.8% of males and 25.5%
of females had stage 3 to 5 chronic kidney disease. Moreover, 66.1% of males and 59.5% of females had left
[69]
ventricular hypertrophy. These data also suggest that most patients had type 1 phenotype .

A recent study evaluated 172 patients with ischemic stroke using an exome-based panel of 349 genes and
identified pathogenic GLA variants in 2 patients (1.2%) with known FD .
[77]

All these studies demonstrate the need for a careful assessment of screening results based on the diagnostic
methods used, a detailed interpretation of genetic data, and recognition of population selection criteria.
Nevertheless, the interpretation of screening results remains a controversial issue, as demonstrated by a
recent meta-analysis indicating that p.D313Y might induce an atypical neurological phenotype in patients
[78]
with FD . In our opinion, the investigation into FD is warranted in young patients with cryptogenic stroke.
NEUROIMAGING FINDINGS IN FD
Stroke and white matter hyperintensities [Figure 2A and B]
Ischemic strokes and TIAs are the most common cerebrovascular manifestations in FD and can be
attributed to either large or, more frequently, small vessel disease, with cortical and subcortical locations,
respectively. Some authors describe that stroke in FD similarly affects both the anterior and the posterior
[79]
circulation [55,59] , while others underline a predominant involvement of the posterior circulation .
Hemorrhagic stroke is a rare complication in FD, accounting for about 10% of stroke events, with a
predilection for male patients and mostly associated with hypertension or end-stage renal failure. On the
[80]
contrary, chronic cerebral microbleeds are more common, affecting 11% to 30% of FD patients
[Figure 2C]. They can be detected in brain MRI using echo gradient-weighted images, T2-weighted and
[81]
susceptibility-weighted imaging . A study of 36 adult patients with FD identified that 44.4% without
dialysis or previous strokes had MRI evidence of small vessel disease, and 11% of them showed cerebral
[82]
microbleeds .

Small vessel disease is commonly seen in patients with FD, manifested as subcortical stroke and white
matter hyperintensities (WMH) [Figure 2A and B]. The latter represents the most frequent brain imaging
[83]
feature of FD and indicates lesions not referable to focal acute cerebrovascular events . WMHs could range
from small, scattered, and punctuate T2-weighted hyperintense foci to bilateral diffuse, patchy, and
confluent lesions. WMH occurrence is similar in males and females, with no predilection for a specific brain
region [81,84] . Autopsies performed in patients with FD revealed that deep WMHs are either lacunar
infarctions or are associated with small arterioles narrowing .
[85]
Marchesoni et al. identified asymptomatic WMHs in 7 children with FD (15.9%), compared with 3 children
(6.5%) in an aged-matched control group (P = 0.01). Brain abnormalities revealed deep gray matter and
infratentorial involvement .
[86]