Molecular Pathogenesis of Central and Peripheral Nervous System Complications in Anderson‐Fabry Disease
Authors: Tuttolomondo Antonino , Riolo Renata , Todaro Federica , Baglio Irene , Miceli Salvatore , Simonetta Irene 
Published: August 2023

Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The impairment of the nervous system, in addition to the acroparesthesias, is characterized by hypohidrosis and cerebrovascular accidents.
Gb3-accumulation supports the hypothesis that Gb3 is not solely responsible for disease manifestation. Overloading of lysosomes with Gb3 may simply lead to the rupture of cytoplasma and in consequence to cell death .Secondary effects of Gb3 accumulation which might be responsible for disease pathology include also inflammatory processes. Perturbed leukocyte function in Fabry disease compared to healthy controls and abnormal numbers of different immune cells, including lymphocytes, monocytes, CD8+ cells, B cells and dendritic cells . Noteworthy other studies reported no correlation between CRP-levels as a global inflammatory marker and the Mainz-Severity-Score-Index (MSSI) as a marker for disease severity .
Other authors reported on auto-immunological reactions in α-galactosidase A deficiency. Others researchers found higher expressions of neuronal apoptosis inhibiting protein as a key anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Noteworthy, this upregulation did not change after institution of ERT, whereas apoptosis inducing factor appears to be upregulated under ERT. The authors were not able to explain their observations, but further research has to be directed on this topic. Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. The authors hypothesized that ERT may enhance endothelial damage, allowing to understand continuously occurring strokes in patients on treatment.
Furthermore, Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. Another gateway into alteration of endothelial function may be given by the Nitric-Oxide-Synthase-3-genotypes. Endothelium-derived nitric oxide is a key regulator of vessel wall function and cardiovascular homeostasis.
Thus, neurological complications seem to be linked to different pathogenetic molecular mechanisms.Progressive accumulation of GB3 represent a possible pathogenetic event of peripheral nerve involvement, whereas central nervous involvement in the clinical setting of cerebrovascular ischemic events seem to be due to the endotheliopathy of Anderson-Fabry Disease with lacunar lesions and white matter hyperintensities ( WMHs) .
In this review manuscript we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease.