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Couce, M. del Toro, M.C. García-Jiménez, L. Gutierrez-Solana, Á. Hermida-Ameijeiras, M. López-Rodríguez, J. Pérez-López, M.Á. Torralba" "autores" => array:8 [ 0 => array:2 [ "nombre" => "M.L." "apellidos" => "Couce" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "del Toro" ] 2 => array:2 [ "nombre" => "M.C." "apellidos" => "García-Jiménez" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Gutierrez-Solana" ] 4 => array:2 [ "nombre" => "Á." "apellidos" => "Hermida-Ameijeiras" ] 5 => array:2 [ "nombre" => "M." "apellidos" => "López-Rodríguez" ] 6 => array:2 [ "nombre" => "J." "apellidos" => "Pérez-López" ] 7 => array:2 [ "nombre" => "M.Á." 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Olivera-González, C. Josa-Laorden, M.A. Torralba-Cabeza" "autores" => array:3 [ 0 => array:4 [ "nombre" => "S." "apellidos" => "Olivera-González" "email" => array:1 [ 0 => "susana.olivera@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Josa-Laorden" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.A." "apellidos" => "Torralba-Cabeza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Enfermedades Minoritarias, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fisiopatología de la enfermedad de Fabry" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1407 "Ancho" => 3192 "Tamanyo" => 200672 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Degradation pathway for complex lipids.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anderson–Fabry disease (AFD) is an inherited condition caused by lysosomal dysfunction linked to chromosome X and caused by mutations in the GLA gene located in chromosome Xq22.1 and which encodes the alpha-galactosidase A (AGA) enzyme.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> Complete or partial deficiency of this enzyme alters the degradation of glycosphingolipids from cell membranes, producing the intracellular accumulation of globotriaosylceramide (Gb3) and other lipid complexes in the kidneys, nervous system and heart (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">2,3</span></a> AFD is the second most common lysosomal storage disease after Gaucher's disease. Its annual incidence is estimated at 1/40,000–1/117,000 living male newborns<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">4</span></a> but is probably underestimated due to undiagnosed cases. In Spain, a rate of 1/400,000 males has been reported, significantly lower than that of other Mediterranean countries such as Italy, France and Portugal.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">5</span></a> If the clinical variants of AFD with late onset or mild impairment are considered, the prevalence could be as high as 1/3000 individuals.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1,6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Fabry and Anderson simultaneously reported the first patients with angiokeratoma and renal impairment with albuminuria.<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">7,8</span></a> Subsequently, in 1963, the hereditary basis of X-linked AFD was identified.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">9</span></a> However, women can also present AFD with incomplete or intermediate phenotypes, due to the phenomenon of lyonization, which consists of the random activation of the defective X chromosome during mitosis.<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">More than 599 mutations have been identified, the most common of which are produced by a change in the reading pattern, substitution of an amino acid by another or a gene splicing disorder.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> Most mutations are restricted to specific families, with no clear genotype-phenotype relationship.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Unlike other lysosomal diseases, Gb3 accumulates in all cells of the body, although mainly in the vascular endothelium and, to a lesser extent, in the neurons, myocytes and the heart's excito-conduction system.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> The most common manifestations in childhood and adolescence are neuropathic pain, hypohidrosis/anhidrosis, angiokeratoma, cornea verticillata and microalbuminuria. Subsequently, renal impairment progresses and heart disease and cerebrovascular disease appear.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Vascular dysfunction</span><p id="par0025" class="elsevierStylePara elsevierViewall">Vascular dysfunction is the main pathophysiological disorder of AFD, in whose pathogenesis the following factors participate: (1) Gb3 accumulation, (2) structural abnormalities in the vessel walls, (3) activated endothelium and (4) the presence of a prothrombotic state.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">14,15</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Globotriaosylceramide deposition</span><p id="par0030" class="elsevierStylePara elsevierViewall">The origin of the Gb3 accumulation has not been sufficiently established. Firstly, this deposit has been shown to come from endogenous synthesis and the subsequent lysosomal accumulation of the terminal α-galactosyl portion contained in the glycosphingolipids, as well as from autophagocytosis of the cell membranes that contain these lipid complexes.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">16</span></a> This mechanism is the most important for accumulation in avascular sites such as the cornea and neurons, which presumably would be protected by the blood–brain barrier from increased circulating levels of Gb3.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Secondly, the exclusively cellular distribution of Gb3, especially in the vascular endothelium and smooth muscle, indicate the presence of intracellular production in close relationship with endocytosis or Gb3 dissemination from the circulation to the interior of the cells, where the concentration is 3–10 times greater than in individuals not affected by AFD. Circulating Gb3 is transported in the low and high-density lipoproteins, at a distribution of 60% and 30%, respectively.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> The finding that Gb3 deposition is scarce in hepatocytes (in contrast to the accumulation in Kupffer cells) supports the theory that Gb3 synthesized in the hepatocytes is associated with lipoproteins and is secreted with the lipoproteins.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">19</span></a> This complex, released into circulation, binds to the vascular endothelial membrane and smooth muscle cells, which have high-affinity receptors for lipoproteins.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> This mechanism would also be involved to a lesser degree with dissemination or fluid-phase (nonadsorptive) endocytosis of globosides or plasma Gb3.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Due to the fact that lysosomes in all cells are deficient in AGA activity, the accumulated glycosphingolipids in the form of multivesicular bodies or in more advanced stages as free intracytoplasmic masses can lead to cellular dysfunction or degeneration.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> Lastly, we know that glycosphingolipids are also synthesized in bone marrow, where they are transformed and incorporated into the membranes of the formed elements of blood. Globosides (complex lipids of the glycosphingolipid family) of the membrane of the aged erythrocytes are thereby released into circulation and catabolized in the spleen, producing Gb3. As a result, erythrocyte turnover and that of other senescent blood cells contribute to the increase in glycosphingolipids.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> The total quantity of accumulated glycosphingolipids in a given tissue is therefore dependent on the time, the accumulation rate of the intracellular and circulatory types, the possibility of excretion and the presence or absence of residual AGA activity.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Vascular structural disorders</span><p id="par0045" class="elsevierStylePara elsevierViewall">AFD produces vascular wall disorders that involve the formation of microaneurysms in the retinal vessels and conjunctiva, as well as telangiectasia and angiokeratoma.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">21</span></a> Vasomotor activity control is also affected, due to the vascular lesion and the Gb3 deposits in the autonomic ganglia and myelin sheaths. There is an initial restriction for vasoconstriction and, in more advanced phases, for vasodilation, which explains the patients’ intolerance to temperature fluctuations.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Activated endothelium</span><p id="par0050" class="elsevierStylePara elsevierViewall">This term is defined by the expression and release of proinflammatory molecules by endothelial cells.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Recent studies have shown that exposure of circulating leukocytes and endothelial cells to low-density lipoproteins and glycosphingolipids increases the expression of the adhesion molecules of leukocytes and integrin Mac-1 (a ligand of a leukocyte adhesion molecule). This process results in increased interaction between the leukocytes and the endothelium, which promotes the activation, production and release of other proinflammatory molecules such as interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α).<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> The increased interaction between leukocytes and the endothelium is partly responsible for the activation of the endothelium, through adhesion of these cells by molecules such as integrin Mac-1. Furthermore, the VCAM-1 molecule intervenes in the adhesion to the endothelial wall, thus determining the activation of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase in the membrane of the endothelial cells. VCAM-1 also activates the matrix metalloproteinases, which, in turn, degrade the extracellular matrix, allowing for the migration of endothelial cells, a phenomenon known as “endothelial activation”, and increases capillary patency.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">22,24–26</span></a> Regardless of the above, NADPH-oxidase activation induces the synthesis of reactive oxygen species (ROS), which perpetuates the interaction of the lymphocytes with the endothelial cells.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It has also been confirmed that the expression of superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, is reduced in patients with AFD. In this respect, excess accumulation of Gb3 suppresses SOD2 synthesis, which causes an increase in ROS and, in turn, an activation of cAMP-dependent protein kinases (AMPK), causing mitochondrial damage that results in endothelial dysfunction.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Furthermore, the nitric oxide (NO) pathway has been implicated in the activation and endothelial dysfunction of AFD. Classically, it has been postulated that circulating Gb3 is deposited in the intima and media layers of the arteries, promoting the proliferation of smooth muscle cells. This proliferation facilitates the production of angiotensin, with the consequent production of ROS and reduction of NO synthesis by endothelial NO synthase (eNOS).<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> An alternative hypothesis proposes that Gb3 deposition produces reduced eNOS activity, with lower NO production and an increase in ROS.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> When vascular damage is caused by ROS, an increase has been observed in the risk of carotid thrombosis, which is correlated with age and Gb3 deposition.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">29</span></a> Gb3 overload has also been associated with increased transcription of the intercellular adhesion molecule 1 (ICAM-1), VCAM-1 and E-selectin.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> Just as ROS play a fundamental role in the protection of the vascular endothelium in vascular diseases, the hyperpolarized factors of the endothelium simultaneously protect the endothelial cells of the lesion, through a mechanism that depends on the calcium-activated potassium channels (K<span class="elsevierStyleInf">Ca</span>) 3.1 and 2.3.<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30,31</span></a> It has been shown that accumulated Gb3 causes K<span class="elsevierStyleInf">Ca</span> 3.1 channel degradation, through a clathrin-dependent process, which leads to lower vasodilation. Furthermore, it has been documented that recovery of these channels leads to normalization of endothelial dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30–32</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prothrombotic state</span><p id="par0065" class="elsevierStylePara elsevierViewall">The activation of IL-1β, TNFα and other molecules in patients with AFD promotes a prothrombotic state, increasing the risk of ischemic events. It has been observed that levels of various adhesion molecules are high in these patients and that the expression of integrin MAC-1 in monocytes is increased.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> Increased levels of ICAM-1 and Mac-1 in patients with AFD are also indicative of an increase in the interaction between the endothelium and inflammatory cells, which explains the early vascular invasion.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> An increase in plasminogen activator inhibitor levels has also been confirmed, as well as a reduction in thrombomodulin, which favors the thrombolytic action of the endothelium and the procoagulant state in this disease in early stages of life.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> The prevalence of stroke in patients with AFD is 10–15%.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">33,34</span></a> Primary prevention of cardiac and cerebrovascular events, suppression of modifiable risk factors, prevention of potential drug interactions, the early initiation of enzyme replacement therapy (ERT), when indicated, and even the use of angiotensin-converting enzyme inhibitors and antiplatelet agents is therefore especially important for patients with AFD.<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">35,36</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pathophysiology of cardiac involvement</span><p id="par0070" class="elsevierStylePara elsevierViewall">In patients with AFD, coronary flow reserve is severely reduced. These findings correspond to the extensive remodeling of the intramural arterioles.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Glycosphingolipid deposition in the endothelium has been classically considered the cause of the vascular abnormalities in AFD; however, there is no directly proportional relationship between vascular damage and the amount of Gb3 deposition. It has therefore been proposed that other mechanisms could be involved. It is believed that the primary enzymatic defect produces a cascade of events that causes endothelial dysfunction and impaired arterial remodeling, causing occlusive phenomena and thrombosis of small and medium arteries with the corresponding infarction in the medium and long term.<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">37–39</span></a> In AFD, not only are the arteries changed due to endothelial damage but there is also accelerated hypertrophy in the medium-caliber arteries, with increased intima-media thickness, affecting the distensibility of the arteries, due to hypertrophy of the smooth muscle cells.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">24</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Gb3 deposition, microcirculation ischemia and impaired expression of adhesion molecules in myocardial cells promotes inflammation, increased extracellular matrix deposition and fibrosis.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> It has been postulated that myocardial cell and excito-conduction tissue dysfunction in AFD is produced by impaired NO production. The constitutive isoforms eNOS and neural NOS (nNOS) produce small quantities of NO, which acts as a regulator of vasodilation. Due to the reduced NO, endothelial dysfunction is produced, which ends up damaging the myofilaments and DNA, which promotes cell apoptosis and leads to electrical instability and conduction disorders.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">40</span></a> In contrast, inducible NOS (iNOS) allows cells to release large quantities of NO in response to inflammatory cytokines. The cytotoxic activity of NO by itself is weak but can react with ROS, generating nitrotyrosine,<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> which causes structural impairment of the myofilaments and protein kinases, altering contractility and distensibility through phosphorylation of these enzymes. The oxidative damage in the DNA of cardiomyocytes has been described in several conditions, such as myocardial ischemia, cardiomyopathies and heart failure, causing mutagenic effects and cell death.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> Thus, apoptosis was shown to be 187-fold greater in patients with AFD than in control patients.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> It has been observed in women with AFD that immunohistochemical detection of iNOS and nitrotyrosine is limited to affected areas of the heart, which indicates the direct effect of Gb3 and its metabolites, inducing intracellular oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Pathophysiology of renal impairment</span><p id="par0080" class="elsevierStylePara elsevierViewall">Renal impairment in AFD is mainly characterized by early damage to podocytes and fibrosis produced in epithelial cells.<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">26,42</span></a> Podocytes cover and participate in the patency of the glomerular basement membrane.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">43</span></a> Damage to podocytes can be observed in the absence of proteinuria in patients with AFD during childhood and adolescence.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42,44–46</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Our knowledge of the pathogenesis of glomerulosclerosis in AFD is limited. In podocytes, Gb3 deposition increases the expression of the fibrogenic cytokine TGF-β1, which increases extracellular matrix synthesis (fibronectin and type IV collagen).<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Gb3 promotes an inflammatory condition similar to that of hyperglycemia. Gb3 promotes the release of inflammatory cytokines through the CD74 receptor pathway, thereby modulating the function of podocytes.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42,47</span></a> The damage to podocytes is the event that triggers chronic kidney disease with proteinuria, and the loss of podocytes leads to glomerulosclerosis.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Most recently, podocytes have been recognized as the cells that are loaded with glycolipids the soonest.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> The loss of podocytes is observed at this point in children with minimal albuminuria and therefore plays a fundamental role in the progression of nephropathy in AFD.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42,45</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition to the direct effects of glycolipids in tubular cells, proteinuria by itself could activate tubular cells and induce an inflammatory response and interstitial fibrosis. It has been shown that the family of Akt proteins (serine/threonine kinases) inhibits the podocyte apoptosis.<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a> The loss of Akt2 or the reduction of one of its phosphorylations can worsen the podocyte lesion, promoting the onset of proteinuria.<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">AGA-deficient podocytes show pronounced alteration of protein LC3-II, which is a marker of autophagy that is produced in basal form and after Akt induction. The amount of LC3-II is correlated with the number of autophagosomes, which suggests that podocyte autophagy is activated in patients with AFD.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Mammalian target of rapamycin (mTOR) signaling has been identified as a critical regulator of autophagy, suppressing the formation of autophagic vesicles.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Recent data have also implicated the mTOR signaling of podocytes in the regulation of autophagosomes and the regeneration of autolysosome vesicles.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> In patients with AFD, an impairment in podocyte regulation can directly affect the stability of Akt and mTOR and autophagy signaling.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a> Similarly, after Atk induction through IL-1β signaling, the podocytes show reduced activity of the Akt-mTOR pathway, which reinforces the theory that autophagy is increased in the podocytes of patients with Fabry disease.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Gb3 can activate the innate immunity-related, Toll-like receptor type 4 (TLR4)-dependent and cluster of differentiation 1d (CD1d) pathways, promoting inflammatory cascades through invariant natural killer T cells (iNKTs). TLR4 can also increase TGF-β expression in podocytes, leading to extracellular matrix remodeling and glomerular fibrosis, which also contributes to the nephropathy of AFD.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">From a structural viewpoint, the first renal event that occurs in AFD is pedicel effacement, even in the absence of proteinuria.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42,51</span></a> A renal biopsy would therefore serve as a marker of early impairment, with important implications in terms of the indication for ERT.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pathophysiology of nervous system involvement</span><p id="par0110" class="elsevierStylePara elsevierViewall">The pathophysiological basis of neuronal damage is not well known. It has been proposed that the peripheral nervous system accumulates Gb3 in both the Schwann cells and in the dorsal spinal lymph nodes, affecting the small fibers A-delta and C, resulting not only in neuropathic pain but also autonomic abnormalities.<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">52,53</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">With regard to central nervous system involvement, the presence of “cerebral angiopathy” has been postulated, in which the intimately involved elements are endothelial dysfunction, brain hyperperfusion and a ROS-dependent prothrombotic state.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Biomarkers in Fabry disease</span><p id="par0120" class="elsevierStylePara elsevierViewall">There is no ideal biomarker in AFD.<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Proteinuria and albuminuria can be useful in assessing nephropathy.<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Cystatin C and the amino-terminal fragment of the brain natriuretic propeptide (NT-proBNP) are useful as biomarkers of early renal damage in patients with AFD.<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">56,57</span></a> The usefulness of NT-proBNP as a diagnostic and prognostic predictor of heart disease has subsequently been confirmed.<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">58–60</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Measuring Gb3 concentrations in plasma and especially in urine is diagnostic for most patients. However, the values can be normal in a number of variants of the disease or in certain GLA gene mutations. Globotriaosylsphingosine (Lyso-Gb3), a Gb3 derivative, can also have prognostic utility for hemizygous women and for monitoring the response to ERT.<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">61,62</span></a> Lyso-Gb3 levels are higher in the plasma of male patients and in patients with a classical phenotype compared with hemizygous patients.<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> In women, both symptomatic and asymptomatic, plasma Lyso-Gb3 levels are high proportionally to the reduced activity of AGA.<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> However, there is no correlation between urinary lyso-Gb3 levels and glomerular filtration rate and cannot therefore be considered a single marker of renal impairment.<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a> Lyso-Gb3 levels in urine and plasma have been shown to decrease in patients after a year of ERT, which is associated in women with reduced left ventricular hypertrophy and<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a> in both sexes with a reduced risk of developing new lesions in the white matter of the central nervous system.<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Other potential biomarkers in AFD are plasma 3-nitrotyrosine,<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> podocyturia and urinary excretion of CD80.<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary, the pathophysiology of AFD encompasses numerous molecular abnormalities that involve damage to the endothelial and muscle cells of the vessels, cardiomyocytes and cardiac excito-conduction system, as well as renal podocyte dysfunction (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Our understanding of the pathophysiology of the nervous system impairment is highly limited. There is a need for studies to help identify new therapeutic targets and reliable biomarkers for diagnosis and prognosis.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">Dr. Torralba is a consultant of <span class="elsevierStyleGrantSponsor" id="gs1">Genzyme Corporation</span> and <span class="elsevierStyleGrantSponsor" id="gs2">Shire Company</span> and has participated as speaker in conferences on lysosomal storage diseases. Dr. Torralba has received financial support for research studies of both companies. This article, however, was prepared independently in its entirety.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres964028" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec934096" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres964029" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec934097" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Vascular dysfunction" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Globotriaosylceramide deposition" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Vascular structural disorders" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Activated endothelium" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Prothrombotic state" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Pathophysiology of cardiac involvement" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Pathophysiology of renal impairment" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Pathophysiology of nervous system involvement" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Biomarkers in Fabry disease" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-07" "fechaAceptado" => "2017-06-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec934096" "palabras" => array:2 [ 0 => "Fabry disease" 1 => "Pathophysiology" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec934097" "palabras" => array:2 [ 0 => "Enfermedad de Fabry" 1 => "Fisiopatología" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Fabry disease is a lysosomal condition with systemic clinical expression, caused by the tissue deposit of globotriaosylceramide, due to a deficit in its degradation. As with most lysosomal diseases, the presence of a mutation in a gene does not explain the pathophysiological disorders shown by patients. We conducted a comprehensive review of the pathogenic mechanisms that occur in Fabry disease.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Fabry es una entidad lisosomal de expresión clínica sistémica, causada por el depósito tisular de globotriaosilceramida, debido a un déficit en su degradación. Como en la mayoría de las enfermedades lisosomales, la existencia de una mutación en un gen no explica las alteraciones fisiopatológicas que presentan los pacientes. Se realiza una revisión exhaustiva de los mecanismos patogénicos que acontecen en la enfermedad de Fabry.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Olivera-González S, Josa-Laorden C, Torralba-Cabeza MA. Fisiopatología de la enfermedad de Fabry. Rev Clin Esp. 2018;218:22–28.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1407 "Ancho" => 3192 "Tamanyo" => 200672 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Degradation pathway for complex lipids.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1962 "Ancho" => 2526 "Tamanyo" => 411888 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Scheme-summary of the pathophysiology of Fabry disease.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:65 [ 0 => array:3 [ "identificador" => "bib0330" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "2002 [updated 2017]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fabry disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. 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