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Page 10 of 16 Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51

A proton magnetic resonance spectroscopy study was performed in FD patients using a multi-voxel
analysis, with the objective of investigating changes in the N-acetylaspartate/creatine (NAA/Cr) ratio
indicating possible neuronal degeneration and loss. FD patients showed a diffuse reduction of the NAA/Cr
ratio, affecting both cortical and subcortical structures. These alterations were independent of the presence
of WMH and were attributed to a possible metabolic dysfunction, secondary to Gb3 neuronal accumulation
[103]
rather than a vascular alteration .
The connectome analysis of brain networks in patients with FD, using diffusion and resting-state functional
MRI data, revealed both a structural disconnection (due to mild but widespread axonal damage) and a
functional reorganization, associated with cognitive performances .
[104]

Future longitudinal studies on volumetric MRI, diffusion tensor imaging, and proton magnetic resonance
spectroscopy are necessary to elucidate the possible presence of brain volume differences, microstructural
changes, and metabolic dysfunction in FD.

COGNITIVE INVOLVEMENT AND PARKINSONISM IN FD
Cognitive involvement, ranging from mild reduced attention and executive dysfunction to full dementia,
was identified in some patients with FD. It predominates in patients with more severe disease and a history
of cerebrovascular disease [105-109] . The studies evaluating this problem have yielded conflicting results; while
several investigations identified cognitive defects with male predominance [110,111] , other investigators failed to
identify cognitive decline in FD [79,111-115] . Moreover, executive dysfunction was identified in patients with FD,
but differences with control population disappeared after controlling for depression [116,117] . Differences in
these results are likely due to the characteristics of the evaluated cohort regarding gender, associated
cerebrovascular disease, and depression, as well as the varied neuropsychological techniques used in each
study. All these variables need to be controlled in future prospective studies of cognition in FD.

Parkinsonism is rarely seen in patients with FD, particularly in the absence of cerebral small vessel disease.
Bradykinesia and impaired fine manual movements have been reported in both males and females with
pathogenic GLA variants .
[118]

Moreover, in autopsies series, the storage of glycosphingolipids was documented in neuronal and glial tissue
including substance nigra .
[119]

Nevertheless, it is still not possible to ascertain whether this PD phenotype is related to Gb3 deposition
versus cerebrovascular lesions in the nigrostriatal network and the simultaneous presence of the two
[120]
mechanisms may be considered .

TREATMENT
Whether ERT is beneficial for the prevention of stroke is still a controversial topic. It was initially
considered that ERT was ineffective in reducing the risk of stroke, as it does not cross the blood-brain
barrier. Nevertheless, autopsies performed in FD patients on ERT treatment indicate an almost complete
clearance of endothelial glycolipids, but persistent storage in smooth muscle vascular cells, in addition to
intimal fibrous thickening and adventitial fibrosis [108,121] . It should be stressed that these patients were
severely affected by their disease, and ERT was started very late, possibly at an irreversible stage of vascular
damage.