Pathogenesis and Molecular Mechanisms of Anderson–Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies

Abstract

Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.

A Case Report on the Atypical Presentation of Hypertrophic Cardiomyopathy (HOCM) in a 19-Year-Old Female

“…The latter was a representation of angiokeratoma corporis diffusum in males. AFD is caused by a lack of galactosidase A, which causes an accumulation of Gb3, its metabolite globotriaosylsphingosine (Lyso-Gb-3), and its precursor metabolite Gal-Gal-Cer in the lysosomes [ 11 ]. Currently, the two clinically available therapeutic modalities for the treatment of AFD are enzyme replacement therapy (ERT) and chaperone therapy with other alternatives such as substrate reduction therapy, mRNA-based therapy, and gene therapy in development.…”

Lysosomal positioning diseases: beyond substrate storage

“…Indeed, modifications of the lysosomal-autophagy mechanisms have been ascertained in many other LSDs [ 164 ], including Pompe disease [ 179 ], sphingolipidoses such as Gaucher disease [ 204 ], Fabry disease [ 205 , 206 ], and NPC [ 207 , 208 ], mucolipidosis II [ 135 ] and IV subtypes [ 209 ], Danon disease [ 126 ], and some NCLs [ 164 , 210 ]. In Anderson–Fabry disease, the accumulation of sphingolipid substrates in lysosomes inhibits autophagosome–lysosome fusion and disrupts the mTOR activation/inactivation cycle, interfering with the mTOR-mediated control of mitochondrial metabolism [ 129 ]. Disturbed autophagy and activated microglia have been described in a GM1 gangliosidosis mutant mouse model [ 133 ].…”

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

“…Fabry disease (FD) is an LSD characterized by abnormal globotriaosylceramide (Gb3) storage in the lysosomes. Such abnormality is caused by the deficiency of the enzyme acidic alpha-galactosidase (AGAL) [ 23 , 24 , 25 , 26 ]. This protein, which is encoded by the GLA gene, is synthesized in precursor form, imported into the ER for glycosylation, and then targeted to the lysosomes to catalyze glycosphingolipid hydrolysis [ 27 ].…”