Page 19 - Read Online

Page 2 of 16 Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51

kidneys, and brain. As a consequence, a myriad of progressive signs and symptoms may be present,
including neuropathic pain, hypohidrosis, exercise intolerance, gastrointestinal symptoms, hearing loss,
tinnitus, angiokeratoma, “cornea verticillata”, left ventricular hypertrophy, proteinuria, decreased renal
[1-4]
function, and stroke . Estimates of the prevalence of FD range from approximately 1 in 117,000 to 1 in
37,000 live male births for classic FD and up to 1 in 1,400 in some newborn screening projects when atypical
[5-7]
FD variants are included .
Symptoms usually begin in childhood and adolescence, particularly in the classical Type 1 phenotype, and
are mainly characterized by gastrointestinal symptoms, anhidrosis, and neuropathic pain, and progressively
lead to kidney and heart involvement, as well as stroke. Misdiagnosis is common , with a long delay
[8]
between onset of symptoms and diagnosis . Renal, cardiac, and cerebrovascular involvement are the
[9]
leading complications in early adulthood and are associated with severe morbidity and mortality. By
contrast, patients with the Type 2 later-onset phenotype have residual enzyme activity and, therefore,
present with delayed clinical manifestations. Cardiac or renal involvement may be observed in these
patients after their fourth decade of life and stroke may also occur as an isolated manifestation [10-12] .

Enzyme replacement therapy (ERT) has been available for the treatment of FD since 2001 and is the
standard of care . Two ERT formulations are available currently: agalsidase alfa and agalsidase beta .
[14]
[15]
[13]
Additionally, an α-GAL A pharmacological chaperone, migalastat, can be used to treat certain patients with
an amenable GLA mutation .
[16]
This review will describe the frequency and characteristics of cerebrovascular disease in FD, the complex
pathophysiological mechanisms, the neuroimaging findings, the value of screening studies in young patients
with stroke, and the controversies regarding the beneficial effect of ERT for the prevention of
cerebrovascular disease in FD.

PATHOPHYSIOLOGY OF VASCULAR DAMAGE IN FD
Vasculopathy in FD is the result of overlapping abnormalities in the vessel wall, the blood components, and
the circulation [17,18] .

Vasculopathy and Gb3
Two primary hypotheses have been proposed for the pathogenesis of vasculopathy in FD. The first
underlines the pathologic effects of globotriaosylceramide (Gb3) on the endothelial cells, while the second
stresses the deleterious effect of globotriaosylsphingosine (lyso-Gb3) on the muscular layer of blood vessels
[Figure 1]. Following alpha-GAL A deficiency, Gb3 accumulates within caveolae of endothelial cells,
resulting in endothelial nitric oxide synthase (eNOS) uncoupling and superoxide (O2-) production. Nitric
oxide is consumed to form peroxynitrite (ONOO-), which leads to the formation of 3-nitrotyrosine (3NT).
[19]
Gb3 accumulation is sufficient to account for the dysregulation of eNOS , as demonstrated in alpha-GAL
A knockout mice . Studies on cerebral blood flow have reported either decreased or enhanced flow. These
[20]
seemingly contradictory findings might be due to eNOS uncoupling with secondary oxidative stress [21,22] .

A pro-oxidant state occurs in FD associated with both Gb3 and Lyso-Gb3 accumulation leading to tissue
damage through vasculopathy, endothelial free radical formation, and altered oxidative responses [23,24] .

Vasculopathy and chronic inflammation
Tissue deposition of glycolipids is not considered a sufficient explanation of the pathophysiology of FD.
Gb3 and lyso-Gb3 can also induce a chronic inflammatory state leading to vascular damage, as previously