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Page 16 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

[199]
typical of a small vessel disease and is similar to the age-related WML . Rare in children with FD, the
[200]
presence and load of WML increase with age, being both genders equally affected . WML load in FD
could be modulated by classical and genetic vascular risk factors and the presence of other organ injury,
[201]
such as cardiomyopathy or nephropathy ; however, a recent meta-analysis only found a significant
correlation between the load of WML and the risk of stroke, but not with the other organs involvement .
[202]
The effect of long-term ERT in WML remains controversial, with few studies showing the progression of
WML during ERT, but a single study with agalsidase β showed a significantly higher proportion of patients
with stabilization or decrease in WML at follow-up in the ERT group in comparison with the placebo
group [203-205] .

Diffusion tensor imaging and perivascular spaces
Diffusion tensor imaging (DTI) is able to detect early white matter abnormalities and could be a potential
marker of disease progression and treatment response, but it needs to be validated in clinical practice; in
FD, DTI showed widespread areas of microstructural white matter disruption in Fabry disease (extending
beyond WML seen on conventional MRI), with strong correlations with cognition, clinical disease severity,
and plasma lyso-Gb3 [206-208] . An increase in perivascular spaces, mainly in the basal ganglia, was also
demonstrated in FD, suggesting that impaired interstitial fluid drainage might be a mechanism of white
matter injury in FD .
[209]
Basilar artery
Significant enlargement (dolichoectasia) and tortuosity of the intracranial arteries, in particular the basilar
artery, are frequently reported in FD patients and distinguish them from controls [210,211] . Furthermore,
vertebrobasilar dolichoectasia could be an early marker of neurovascular involvement, being present in 56%
[212]
of men and 35% of women and identified even in the absence of WML .

Pulvinar sign and hippocampus atrophy
Increased signal intensity in the pulvinar region on T1-weighted MRI scans (the pulvinar sign) has been
described in patients with FD . Although characteristic, it is not pathognomonic of this disease. It is
[213]
frequently found in male patients and usually affects both thalamus, although unilateral presentation has
been reported. It seems to be present in less than 20% of FD and associated with cardiac and renal
dysfunction, but not stroke .
[214]

Hippocampus atrophy is another CNS image surrogate reported in FD patients (mainly in males) and not
associated with ischemic signs, probably reflecting neuronal direct involvement . Moreover, a significant
[215]
decline in hippocampus volumetry is observed over time and does not correlate with increased WML load
or cerebrovascular events .
[216]
Transcranial Doppler
Transcranial Doppler could also detect abnormalities in brain arteries typical of small vessel disease and
abnormal cerebral autoregulation that may be predictive of future neurovascular events in patients with
FD . Of note, a study with functional transcranial Doppler revealed cortical vascular dysfunction in the
[217]
territory of the posterior circulation in asymptomatic patients .
[196]
SUMMARIZING: WHAT SHOULD WE USE IN THE CLINICAL PRACTICE?
In clinical practice, the aforementioned biomarkers should be used for diagnostic purposes, in the
preclinical and clinical evaluation, and to assess treatment response. Figure 2 summarizes the usefulness of
the described biomarkers in clinical practice according to these different objectives.