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Page 4 of 16 Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51

decrease vessel compliance. This inflammatory process, along with oxidative stress, weakens the vessel wall
as it activates protease-mediated extracellular matrix degradation and apoptosis of smooth muscle cells.
Progressive weakening of the vessel wall results in elongation, dilatation, and aneurysm formation [38,40,41]
[Figure 1].

Basilar artery dolichoectasia
Basilar artery diameter is significantly enlarged in FD patients [42-44] . It was postulated that a low sympathetic
innervation of intracranial vessels in the posterior circulation is the reason for the selective involvement of
this vessel. Vertebrobasilar dolichoectasia is an additional risk factor for ischemic brain lesions and small
vessel disease . Brain infarctions in patients with basilar artery dolichoectasia may develop due to major
[45]
distortion and obstruction of perforating arteries, thrombosis, and emboli arising from this dolichoectatic
vessel .
[46]

Cardioembolic stroke
In addition to the previously described mechanisms, stroke in the distribution of large vessels is
predominantly due to cardiac embolism, mainly due to arrhythmias and cardiomyopathy. Cardiac
involvement is the main cause of mortality in FD . Hypertrophic cardiomyopathy is a hallmark of FD and
[47]
[48]
evolves into myocardial replacement fibrosis . With FD progression, a reduction of left ventricular end-
diastolic volume is seen, resulting in a lower cardiac output [49,50] . The severe involvement of the conduction
system is the cause of bradycardia, asystole, episodes of ventricular tachycardia, and intermittent atrial
[51]
fibrillation, all of which markedly increase the risk of sudden death and cardioembolic stroke .

Why are females affected in FD?
[52]
The reason why females with FD are affected has been reviewed and the authors indicated that
symptomatic females primarily secrete the mature 46KDa enzyme, with only small amounts of the mannose
[53]
6-phosphorylated form. Therefore, the capacity for enzyme cross-correction of affected cells is limited .
A second possible explanation is that α-GAL A released by the mixed cellular population of the female
[54]
mosaic is more susceptible to dephosphorylation by plasma phosphatases .

PREVALENCE OF STROKE IN FD
Cerebrovascular manifestations in FD are mainly ischemic stroke and transient ischemic attack (TIA).
Hemorrhagic strokes and microbleeds are less frequent, while cerebral venous thrombosis and
subarachnoid hemorrhages are only occasionally seen [55,56] .

Studies on the prevalence and incidence of stroke in FD yielded variable results , likely reflecting
[57]
differences in genetic variants, sample size, gender, and age of the investigated cohort, as well as in the
imaging methods used in the investigation.

The first published studies regarding stroke prevalence in FD were conducted in the 1990s. Morgan et al.
[58]
analyzed 12 patients with FD and found that three of them had had a stroke (25%) . Grewal identified
eight patients with stroke in a group of 33 patients with FD (24%, age range: 6-64 years). Among these
patients, stroke involved small perforating arteries and was evenly distributed between the anterior and the
posterior circulation .
[59]

A retrospective study of central nervous system involvement in FD, including 43 patients, reported a
prevalence of stroke of 24% in males (mean age: 33 years) and 28% in females (mean age: 53 years).