Treatment in Fabry disease | Revista Clínica Española

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López Rodríguez" "autores" => array:1 [ 0 => array:3 [ "nombre" => "M." "apellidos" => "López Rodríguez" "email" => array:1 [ 0 => "monicaa.lopez@salud.madrid.org" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Grupo de Trabajo de Enfermedades Minoritarias, Sociedad Española de Medicina Interna (SEMI), Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento en la enfermedad de Fabry" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 659 "Ancho" => 833 "Tamanyo" => 21991 ] ] "descripcion" => array:1 [ "en" => "Chemical structure of migalastat Formula: C6H14ClNO4. Molecular weight: 199.63g/mol." ] ] ] "textoCompleto" => "BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the gene that encodes for the α-galactosidase A enzyme (gene GLA, located in the long arm of the X chromosome (Xq22.1)). The condition produces an accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3 or GL3) in the lysosomes of cells primarily of the renal epithelium, myocardium, neurons of the spinal ganglia, autonomic nervous system and endothelium. Under normal conditions, the α-galactosidase A enzyme degrades Gb3 to produce galactose and lactosylceramide.<a class="elsevierStyleCrossRef" href="#bib0200">1</a>The incidence rate of FD varies between 1 out of every 117,000 and 1 out of every 476,000 live newborns, This figure might be higher, due to late or incorrect diagnoses.<a class="elsevierStyleCrossRefs" href="#bib0205">2,3</a> More recent studies have estimated that approximately 1 of every 64,000 individuals could present FD.<a class="elsevierStyleCrossRef" href="#bib0215">4</a>In terms of clinical manifestations, the wide distribution of Gb3 involves multiple organs and systems. The involvement is therefore multisystemic. The typical clinical manifestations of FD change with age (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In a recent expert review on FD, the authors established a classical clinical pattern for the disease, consisting of the presence of angiokeratoma, neuropathic pain (acute or chronic) and ocular involvement (Cornea verticillata) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), with other accompanying manifestations.<a class="elsevierStyleCrossRef" href="#bib0220">5</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>We should consider Fabry disease as the suspected diagnosis in the following conditions<a class="elsevierStyleCrossRef" href="#bib0225">6</a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Family history of FD;</li><li class="elsevierStyleListItem" id="lsti0010">-Cornea verticillata;</li><li class="elsevierStyleListItem" id="lsti0015">-Anhidrosis or hypohidrosis;</li><li class="elsevierStyleListItem" id="lsti0020">-Angiokeratomas;</li><li class="elsevierStyleListItem" id="lsti0025">-Acroparesthesia. Peripheral polyneuropathy;</li><li class="elsevierStyleListItem" id="lsti0030">-Unexplained hypertrophic cardiomyopathy;</li><li class="elsevierStyleListItem" id="lsti0035">-Personal or family history of renal failure with no cardiovascular risk factors;</li><li class="elsevierStyleListItem" id="lsti0040">-Stroke in patients younger than 50 years with no cardiovascular risk factors;</li><li class="elsevierStyleListItem" id="lsti0045">-Personal or family history of intolerance to exercise, heat or cold.</li></ul>The confirmation diagnosis is performed through the biochemical demonstration of α-galactosidase A deficiency, whose activity can be measured in leukocytes, serum or fibroblasts using a radioimmunoassay.Enzyme activity below 0.06U/g in leukocytes (6.0–13.9), 0.06U/L in serum (1.7–7.9) and 0.6U/g in fibroblasts (20.9–39.7) is characteristic of the disease. In heterozygous women, a genetic-molecular study is necessary because enzyme levels could be normal. Plasma and urine Gb3 levels are often increased, but their usefulness in the diagnosis and follow-up is limited.<a class="elsevierStyleCrossRef" href="#bib0230">7</a> Lyso-Gb3 appears to be a more useful biomarker<a class="elsevierStyleCrossRefs" href="#bib0235">8,9</a> for diagnosing the disease but not so much for the follow-up and prognosis.For the screening, a clinical, biochemical and genetic study should be offered to relatives of all newly diagnosed patients, as well as the option of prenatal diagnosis, if applicable.<a class="elsevierStyleCrossRef" href="#bib0245">10</a> This prenatal diagnosis is performed by measuring α-galactosidase A activity in fetal cells.Nonspecific treatmentNeuropathic pain crises and acroparesthesia are treated with membrane-stabilizing drugs (carbamazepine, phenytoin). Angiokeratomas can benefit from laser therapy. In terms of cardiac manifestations, the recommendations for FD are the standard one for general clinical practice. Heart disease continues to account for most deaths in patients with FD of both sexes and phenotypes. It is therefore advisable to anticoagulate patients with FD and atrial fibrillation (AF) according to the current recommendations of the American Heart Association/American College of Cardiology guidelines on AF in patients with hypertrophic cardiomyopathy.<a class="elsevierStyleCrossRefs" href="#bib0250">11,12</a> In terms of arrhythmias, a number of studies have recommended the implantation of an implantable cardioverter defibrillator (ICD) as primary prevention for patients with ventricular arrhythmias and significant myocardial fibrosis.<a class="elsevierStyleCrossRef" href="#bib0260">13</a> With regard to the indications for pacemakers, these are governed by the current guidelines of clinical practice. In renal impairment, FD's similarity to diabetic nephropathy also translates to the therapeutic management. Strict blood pressure control with angiotensin-converting enzyme inhibitors (ACEIs) or ARB-II is therefore necessary. These drugs seem to be more effective in slowing the progression of renal failure the sooner they are employed. However, it is difficult to define their efficacy in isolation, given that most published studies assessed the drugs as adjuvant treatment to enzyme replacement therapy (ERT).<a class="elsevierStyleCrossRef" href="#bib0265">14</a> If the disease progresses to end-stage renal failure, clinicians resort to dialysis or kidney transplantation. There is no indication for anticoagulation (except in the presence of AF) for preventing strokes, although the use of antiplatelets does seem to be accepted.Enzyme replacement therapyAt the start of the 1970s, Brady<a class="elsevierStyleCrossRef" href="#bib0270">15</a> showed that active forms of α-galactosidase A could be obtained. However, the problem for almost 20 years was how to access sufficient quantities of enzyme to ensure continuity in the replacement therapy.We currently have 2 forms (α and β) of the replacement enzyme. They have a similar structure and efficacy but some differences in pharmacokinetics and posology. Their price is high.Published studies on long-term therapy with α and β have shown that both compounds are effective in stabilizing FD, especially if started in early phases.<a class="elsevierStyleCrossRefs" href="#bib0275">16,17</a> However, some aspects of ERT still need to be resolved, mainly because well-designed studies with larger sample sizes are needed to compare the 2 molecules.Regarding the dosage of the 2 drugs, a dosage of 1mg/kg every 2 weeks is recommended for patients treated with agalsidase-β. It has been suggested that lower dosages of agalsidase-β might be insufficient for reducing left ventricular hypertrophy and preventing the disease progression.<a class="elsevierStyleCrossRef" href="#bib0285">18</a> A study assessed the pharmacokinetics of agalsidase-α, with different dosage patterns, and found that the standard dosage of 0.2mg/kg every 2 weeks was as effective as higher dosages or weekly doses in reducing Gb3, an elimination effect that was maintained for 4 weeks.<a class="elsevierStyleCrossRef" href="#bib0290">19</a>The efficacy of ERT is complicated by many factors, including the scarcity of controlled clinical trials whose duration is short and whose sample sizes are very small. The patients included in these clinical trials also have considerable clinical heterogeneity.So far, there has been no well-designed study that has compared the 2 ERTs (α and β). In fact, the comparison of the 2 presentations of agalsidase has been scarce or indirect. A Canadian clinical research group designed a randomized prospective study to directly compare the standard doses of agalsidase-α (0.2mg/kg) and agalsidase-β (1mg/kg) in adults. The study included 117 patients, with a 5 and 8-year follow-up, and concluded that there were no significant differences between the 2 drugs in the interval free of severe events.<a class="elsevierStyleCrossRef" href="#bib0295">20</a> A recent review published in Cochrane evaluated 9 clinical trials, with a total of 351 patients treated with agalsidase.<a class="elsevierStyleCrossRef" href="#bib0300">21</a> The authors concluded that the trials that compared the 2 ERTs versus placebo showed improvement with ERT in microvascular endothelial Gb3 deposits and in pain-related quality of life. However, there was no evidence on whether form α was superior to β or on the optimal dosage for either form. In terms of safety, the adverse events were more significant with agalsidase-β when compared with placebo. The authors stated that the influence of ERT on the risk of morbidity and mortality in FD is still unclear.Another relevant issue in ERT is the optimal moment to start this therapy. In this regard, ERT should be started when the first symptoms of FD occur or when there are incipient signs of visceral involvement (mainly pathological albuminuria), depending on each patient's individual circumstances.<a class="elsevierStyleCrossRefs" href="#bib0245">10,22</a>The evaluation of the enzyme treatment response is clinical. The response is assessed in the most debilitating symptoms for these patients’ quality of life (neuropathic pain), in the progression of renal failure (the slower the progression the earlier the start of treatment) and in stabilizing renal impairment, including with the regression of left ventricular hypertrophy. This response cannot be measured with objective parameters because neither Gb3 or lyso-Gb3 have been shown to be useful in the follow-up or in the treatment response.<a class="elsevierStyleCrossRefs" href="#bib0230">7,9,23</a>The criteria for interrupting the ERT are difficulties or noncompliance in the administration, persistent or severe reactions to the infusion (even despite specific prophylaxis) and in situations with a life expectancy shorter than a year (either due to the FD itself or other intercurrent diseases).<a class="elsevierStyleCrossRef" href="#bib0315">24</a>Migalastat: a New Therapeutic EraAfter more than a decade since the first authorization of ERT (2001), the European Medicines Agency authorized the marketing of a new treatment for FD: migalastat, a pharmacological chaperone that binds to certain mutations of α-Gal A, whose genotypes are known as amenable mutations.<a class="elsevierStyleCrossRef" href="#bib0320">25</a> Most of these mutations are missense type in the GLA gene and cause an abnormal folding of the α-Gal A protein, which prevents its displacement from the endoplasmic reticulum to the lysosome.<a class="elsevierStyleCrossRef" href="#bib0325">26</a>Migalastat is indicated for the long-term therapy of patients 16 years or older with clinical manifestations of FD, with amenable mutations. The recommended dose is 1 capsule (123mg of migalastat) on alternating days, at the same time of the day.<a class="elsevierStyleCrossRef" href="#bib0330">27</a> Migalastat represents a new paradigm in treating FD.Mechanism of action and preclinical dataThe chaperone migalastat is a low-molecular-weight iminosugar (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), a structural analog of the terminal galactose group of Gb-3, which typically is cleaved by α-galactosidase A.<a class="elsevierStyleCrossRefs" href="#bib0330">27,28</a> Migalastat is selectively and reversibly fixed (and with considerable affinity) to the active focus of certain mutant forms of α-Gal A (amenable mutations). The fixation of migalastat stabilizes the mutant α-Gal A, which facilitates its transport from the endoplasmic reticulum to the lysosome.<a class="elsevierStyleCrossRefs" href="#bib0340">29,30</a> The fixation depends on pH: migalastat presents greater fixation in less acidic conditions.<a class="elsevierStyleCrossRef" href="#bib0350">31</a> Given that the pH in the reticulum endoplasmic is less acidic than in the lysosome, migalastat is fixed to α-Gal A in the endoplasmic reticulum and releases α-Gal A in the lysosome, by which it performs its enzymatic function freely. Additionally, the fixation of migalastat to α-Gal A is competitive, i.e., once the migalastat/α-Gal A complex reaches the lysosome, the normal substrates (Gb3) of α-Gal A compete with migalastat. This encourages migalastat to release α-Gal.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The preclinical study was conducted in a transgenic murine model (Tg) with a knock-out mouse (Tg/KO) for FD.<a class="elsevierStyleCrossRef" href="#bib0355">32</a> After 24 weeks of treatment with migalastat, a significant dose-dependent increase was observed in α-Gal A activity, with reduced Gb3 levels in the skin, heart, kidneys, brain and plasma.Of particular interest is the analysis of the brain results by Khanna et al.,<a class="elsevierStyleCrossRef" href="#bib0355">32</a> who indicated that migalastat can cross the blood–brain barrier and reduce the substrate of the disease (Gb3) in the central nervous system of mice. This finding had not been observed in similar studies with ERT, due to its high molecular weight (approx. 110kDa). These data suggest that migalastat could offer an advantage over ERT for treating central nervous system manifestations in FD.Migalastat is better absorbed under fasting conditions (at least 2h between meals), and its elimination is slower in patients with severe chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0360">33</a>Efficacy in controlled clinical trialsSeveral phase-II clinical trials have evaluated migalastat.<a class="elsevierStyleCrossRef" href="#bib0365">34</a> Two clinical trials were combined for 9 male patients with FD. Migalastat, at a dose of 150mg on alternating days, increased α-Ga A activity by at least 50% in the blood, skin and kidneys of 6 of the 9 patients. The 3 patients who showed no response had mutations in α-Gal A considered as “nonresponders”. In 9 women with FD, migalastat decreased the urine Gb3 levels. The baseline Gb3 levels were high in 7 of the 9 patients and decreased by 28% to 66% in the patients with amenable mutations (n=5) following treatment with migalastat for 48 weeks. The inclusion of Gb3 in the endothelial cells of the peritubular capillaries decreased in 4 patients with amenable mutations and in 2 with nonamenable mutations.<a class="elsevierStyleCrossRef" href="#bib0370">35</a>Germain et al.<a class="elsevierStyleCrossRef" href="#bib0375">36</a> published the results of the first phase-III clinical trial of migalastat, the FACETS study. A total of 67 patients with FD (36% men, 94% with multiple organ involvement), not previously treated with ERT or not treated with ERT for at least 6 months prior to the study, were randomized to 6 months of double-blind treatment with migalastat or placebo (stage 1), followed by an open extension of migalastat from month 6 to month 12 (stage 2) plus 1 additional year to month 24 (stage 3). At that point, the patients could choose to continue the treatment in a separate open extension study. The initial test used to determine the mutant forms of α-Gal A amenable to migalastat (human embryonic kidney assay) was improved before the unmasking of stage 1 by the test of amenability to migalastat validated according to good laboratory practices (GLPs) or GLP-validated human embryonic kidney assay, which showed that 50 of the 67 initially randomized participants presented mutations in α-Gal A amenable to migalastat. The analysis of the primary endpoint showed no significant therapeutic effect, probably because amenable and nonamenable α-Gal A mutations were included. When the authors only considered the patients with mutations amenable to migalastat at 6 months (n=45), a significant reduction was observed in the number of Gb3 inclusions per renal interstitial capillary in the migalastat group versus the placebo group (p=.008), which remained stable at 12 months of treatment with migalastat. The patients who changed from placebo to migalastat also presented a significant reduction in Gb-3 inclusions at 6 months of treatment (p=.01). There was also a significant reduction in plasma lyso-Gb3 levels after the first 6 months of treatment with migalastat versus placebo (p=.003). The patients who changed from placebo to migalastat at 6 months also experienced a significant reduction in plasma lyso-Gb3 levels between months 6 and 12 (p<.001). In the patients with amenable mutations who were treated with migalastat, the renal function remained stable during the 24 months of the study. The indexed left ventricular mass (ILVM) decreased significantly from the start to 18–24 months of treatment (−7.7g/m2; 95% CI −15.4 to −0.01; n=27).In terms of gastrointestinal symptoms, migalastat significantly improved the diarrhea and reflux at 6 months of the double-blind FACETS study. In terms of quality of life (measured with the 36-item Short-Form questionnaire) and the severity component (“pain at its worst”) of the Brief Pain Inventory, there was no worsening at 24 months of the study.<a class="elsevierStyleCrossRef" href="#bib0375">36</a>Mauer et al.<a class="elsevierStyleCrossRef" href="#bib0380">37</a> published results showing that migalastat reduced, in just 6 months, the Gb3 content of podocytes, a type of glomerular cell relatively resistant to ERT, in kidney biopsies of 8 men from the FACETS trial.Hughes et al.<a class="elsevierStyleCrossRef" href="#bib0385">38</a> published the results of the second phase-III clinical trial of migalastat (ATTRACT) to assess the effects of migalastat on the renal function of patients with FD previously treated with ERT for more than 12 months. Sixty patients with FD (44% men; 88% with multiple organ involvement) were randomized to migalastat for 18 months or to remain with ERT. Migalastat and ERT had similar effects on renal function. Plasma lyso-Gb3 levels remained low and stable in both cohorts. Twenty-nine percent of the patients who were treated with migalastat and 44% of those who were treated with ERT presented predefined renal, heart or cerebrovascular events. The ILVM was significantly reduced with migalastat at 18 months (−6.6g/m2; 95% CI −11.0 to −2.2), compared with baseline, while there was no significant change with ERT. The quality-of-life results remained stable and similar between the 2 groups.SafetyMigalastat was generally safe and well-tolerated. The adverse events that emerged after the start of treatment were comparable between the patients treated with migalastat and those treated with ERT. In the patients treated with ERT, infusion-related reactions were the most common (13.7% with agalsidase-α and 67% with agalsidase-β). Most of the adverse events that occurred after the start of treatment were mild to moderate, and there were no deaths. The most common adverse reaction reported with migalastat was headaches (10%).<a class="elsevierStyleCrossRef" href="#bib0330">27</a>Unmet needsERT has various limitations. The administration every 2 weeks exposes patients to progressively lower levels of the enzyme between one infusion and the next.<a class="elsevierStyleCrossRef" href="#bib0390">39</a> The intravenous administration has certain direct healthcare costs (disposal of partially used vials due to a low number of patients per hospital, medication prior to the infusion and management of infusion-related reactions and potential infections), indirect costs (transport to the hospital and lost productivity) and intangible costs (loss of the patients’ wellbeing and that of their relatives). The high molecular weight of the recombinant enzymes limits their ability to penetrate key tissues, such as myocytes and brain tissue, and generates neutralizing antibodies and immunogenicity reactions.Gene therapyVarious methods are being tested, such as the use of vectors (lentivirus, retroviruses and adenovirus) and even bone marrow transplantation. For FD, however, there is still a long road ahead, because most of these studies are in the animal experimentation phase.Genetic counselingAs with any genetic disease, a family study is required when a case of FD is detected, as well as informing the patient and family about the type of inheritance and offering the option of a prenatal diagnosis.ConclusionsFD is a complex paradigm of multisystem disease, whose target organs are mainly the peripheral nervous system, kidneys, heart, digestive system, eyes, ears, skin and central nervous system.In the past 20 years, we have witnessed a change in its management with ERT, which appears to change the course of the disease.Migalastat is the first and only tailored oral therapy (focused on the patient's genetic profile), with a new mechanism of action, which has been shown to be effective, safe and well-tolerated for treating patients with FD with amenable mutations, regardless of the disease phenotype and symptom severity. Migalastat therefore opens exciting lines of research, such as the clinical relevance it assumes by crossing the blood–brain barrier. There are a number of studies that have indicated the boosting effect of migalastat in its concomitant use with ERT.In general, for internists and other medical specialties, migalastat helps to understand the new and effective mechanism of action of molecular chaperones, which are being investigated in other diseases.FundingM. López received funding from Amicus Therapeutics for implementing this study.Conflict of interestsM. López has participated in advisory activities, such as speaking at meetings, and has attended congresses with funding from Shire, Sanofi-Genzyme and Amicus." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1118093" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1054272" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1118094" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1054271" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Nonspecific treatment" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Enzyme replacement therapy" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Migalastat: a New Therapeutic Era" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Mechanism of action and preclinical data" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Efficacy in controlled clinical trials" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Safety" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Unmet needs" ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Gene therapy" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Genetic counseling" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interests" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-02-19" "fechaAceptado" => "2018-03-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1054272" "palabras" => array:4 [ 0 => "Fabry disease" 1 => "Multisystemic" 2 => "Migalastat" 3 => "Chaperone" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1054271" "palabras" => array:4 [ 0 => "Enfermedad de Fabry" 1 => "Multisistémica" 2 => "Migalastat" 3 => "Chaperona" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Fabry disease is an X-linked inborn disease caused by deficit of alpha-galactosidase A. This results in accumulation of glycosphingolipids in all cells and tissues. All males should receive enzyme replacement treatment in case of very low or undetectable levels of alpha-galactosidase A. Female carriers and males with marginally levels of alpha-galactosidase A should be treated in case of renal, neurologic o cardiac manifestations. There are two intravenous formulations of human recombinant enzyme, agalsidase alpha and agalsidase beta, showing similar efficacy and safety. Patients with amenable mutations of alpha-galactosidase can be treated with oral migalastat hydrochloride. Migalastat hydrochloride is a pharmacological chaperone that facilitates trafficking of alpha-galactosidase A to lysosomes increasing enzyme activity. Patients treated with migalastat hydrochloride had significant improvements in left ventricular mass and gastrointestinal symptoms." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La enfermedad de Fabry es una enfermedad ligada al cromosoma X causada por un déficit de alfa-galactosidasa A. Esto da como resultado la acumulación de glicoesfingolípidos en todas las células y tejidos. Todos los varones deben tratarse con reemplazo enzimático en caso de presentar niveles muy bajos o indetectables de alfa-galactosidasa A. Las mujeres portadoras y los varones con niveles mínimos de alfa-galactosidasa A deben tratarse si existe afectación renal, neurológica o cardíaca. Para terapia de reemplazo enzimático existen dos formulaciones intravenosas, agalsidasa alfa y agalsidasa beta, que muestran una eficacia y seguridad similares. Los pacientes con mutaciones susceptibles del gen alfa-galactosidasa A pueden tratarse con migalastat oral. El migalastat es una molécula que facilita el paso de alfa-galactosidasa A a los lisosomas, produciendo aumento de actividad del enzima. Los pacientes tratados con migalastat muestran mejoras significativas en la masa del ventrículo izquierdo y en los síntomas gastrointestinales." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: López Rodríguez M. Tratamiento en la enfermedad de Fabry. Rev Clin Esp. 2018;218:489–495." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1290 "Ancho" => 2500 "Tamanyo" => 140412 ] ] "descripcion" => array:1 [ "en" => "Classical clinical pattern of Fabry disease." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 659 "Ancho" => 833 "Tamanyo" => 21991 ] ] "descripcion" => array:1 [ "en" => "Chemical structure of migalastat Formula: C6H14ClNO4. Molecular weight: 199.63g/mol." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviation: LVH, left ventricular hypertrophy." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Childhood \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adolescence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">30–40 years \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Angiokeratoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chronic kidney disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acroparesthesia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteinuria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Heart disease (LVH, arrhythmias) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Angiokeratoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipiduria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Stroke \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ocular disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hematuria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Abdominal pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypohidrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1907779.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical manifestations, according to age, in Fabry disease." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0200" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enzymatic abnormalities in diseases of sphingolipid metabolism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.O. 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Treatment in Fabry disease

Tratamiento en la enfermedad de Fabry

M. López Rodríguez

Grupo de Trabajo de Enfermedades Minoritarias, Sociedad Española de Medicina Interna (SEMI), Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fabry disease &#40;FD&#41; is a rare X-linked lysosomal storage disorder caused by mutations in the gene that encodes for the &#945;-galactosidase A enzyme &#40;gene GLA&#44; located in the long arm of the X chromosome &#40;Xq22&#46;1&#41;&#41;&#46; The condition produces an accumulation of the neutral glycosphingolipid globotriaosylceramide &#40;Gb3 or GL3&#41; in the lysosomes of cells primarily of the renal epithelium&#44; myocardium&#44; neurons of the spinal ganglia&#44; autonomic nervous system and endothelium&#46; Under normal conditions&#44; the &#945;-galactosidase A enzyme degrades Gb3 to produce galactose and lactosylceramide&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The incidence rate of FD varies between 1 out of every 117&#44;000 and 1 out of every 476&#44;000 live newborns&#44; This figure might be higher&#44; due to late or incorrect diagnoses&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">2&#44;3</span></a> More recent studies have estimated that approximately 1 of every 64&#44;000 individuals could present FD&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In terms of clinical manifestations&#44; the wide distribution of Gb3 involves multiple organs and systems&#46; The involvement is therefore multisystemic&#46; The typical clinical manifestations of FD change with age &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">In a recent expert review on FD&#44; the authors established a classical clinical pattern for the disease&#44; consisting of the presence of angiokeratoma&#44; neuropathic pain &#40;acute or chronic&#41; and ocular involvement &#40;<span class="elsevierStyleItalic">Cornea verticillata</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; with other accompanying manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">We should consider Fabry disease as the suspected diagnosis in the following conditions<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">Family history of FD&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cornea verticillata</span>&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">Anhidrosis or hypohidrosis&#59;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Angiokeratomas&#59;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Acroparesthesia&#46; Peripheral polyneuropathy&#59;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Unexplained hypertrophic cardiomyopathy&#59;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Personal or family history of renal failure with no cardiovascular risk factors&#59;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">Stroke in patients younger than 50 years with no cardiovascular risk factors&#59;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Personal or family history of intolerance to exercise&#44; heat or cold&#46;</p></li></ul></p><p id="par0075" class="elsevierStylePara elsevierViewall">The confirmation diagnosis is performed through the biochemical demonstration of &#945;-galactosidase A deficiency&#44; whose activity can be measured in leukocytes&#44; serum or fibroblasts using a radioimmunoassay&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Enzyme activity below 0&#46;06<span class="elsevierStyleHsp" style=""></span>U&#47;g in leukocytes &#40;6&#46;0&#8211;13&#46;9&#41;&#44; 0&#46;06<span class="elsevierStyleHsp" style=""></span>U&#47;L in serum &#40;1&#46;7&#8211;7&#46;9&#41; and 0&#46;6<span class="elsevierStyleHsp" style=""></span>U&#47;g in fibroblasts &#40;20&#46;9&#8211;39&#46;7&#41; is characteristic of the disease&#46; In heterozygous women&#44; a genetic-molecular study is necessary because enzyme levels could be normal&#46; Plasma and urine Gb3 levels are often increased&#44; but their usefulness in the diagnosis and follow-up is limited&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">7</span></a> Lyso-Gb3 appears to be a more useful biomarker<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;9</span></a> for diagnosing the disease but not so much for the follow-up and prognosis&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">For the screening&#44; a clinical&#44; biochemical and genetic study should be offered to relatives of all newly diagnosed patients&#44; as well as the option of prenatal diagnosis&#44; if applicable&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a> This prenatal diagnosis is performed by measuring &#945;-galactosidase A activity in fetal cells&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Nonspecific treatment</span><p id="par0090" class="elsevierStylePara elsevierViewall">Neuropathic pain crises and acroparesthesia are treated with membrane-stabilizing drugs &#40;carbamazepine&#44; phenytoin&#41;&#46; Angiokeratomas can benefit from laser therapy&#46; In terms of cardiac manifestations&#44; the recommendations for FD are the standard one for general clinical practice&#46; Heart disease continues to account for most deaths in patients with FD of both sexes and phenotypes&#46; It is therefore advisable to anticoagulate patients with FD and atrial fibrillation &#40;AF&#41; according to the current recommendations of the American Heart Association&#47;American College of Cardiology guidelines on AF in patients with hypertrophic cardiomyopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">11&#44;12</span></a> In terms of arrhythmias&#44; a number of studies have recommended the implantation of an implantable cardioverter defibrillator &#40;ICD&#41; as primary prevention for patients with ventricular arrhythmias and significant myocardial fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">13</span></a> With regard to the indications for pacemakers&#44; these are governed by the current guidelines of clinical practice&#46; In renal impairment&#44; FD&#39;s similarity to diabetic nephropathy also translates to the therapeutic management&#46; Strict blood pressure control with angiotensin-converting enzyme inhibitors &#40;ACEIs&#41; or ARB-II is therefore necessary&#46; These drugs seem to be more effective in slowing the progression of renal failure the sooner they are employed&#46; However&#44; it is difficult to define their efficacy in isolation&#44; given that most published studies assessed the drugs as adjuvant treatment to enzyme replacement therapy &#40;ERT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> If the disease progresses to end-stage renal failure&#44; clinicians resort to dialysis or kidney transplantation&#46; There is no indication for anticoagulation &#40;except in the presence of AF&#41; for preventing strokes&#44; although the use of antiplatelets does seem to be accepted&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Enzyme replacement therapy</span><p id="par0095" class="elsevierStylePara elsevierViewall">At the start of the 1970s&#44; Brady<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a> showed that active forms of &#945;-galactosidase A could be obtained&#46; However&#44; the problem for almost 20 years was how to access sufficient quantities of enzyme to ensure continuity in the replacement therapy&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">We currently have 2 forms &#40;&#945; and &#946;&#41; of the replacement enzyme&#46; They have a similar structure and efficacy but some differences in pharmacokinetics and posology&#46; Their price is high&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Published studies on long-term therapy with &#945; and &#946; have shown that both compounds are effective in stabilizing FD&#44; especially if started in early phases&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">16&#44;17</span></a> However&#44; some aspects of ERT still need to be resolved&#44; mainly because well-designed studies with larger sample sizes are needed to compare the 2 molecules&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding the dosage of the 2 drugs&#44; a dosage of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks is recommended for patients treated with agalsidase-&#946;&#46; It has been suggested that lower dosages of agalsidase-&#946; might be insufficient for reducing left ventricular hypertrophy and preventing the disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> A study assessed the pharmacokinetics of agalsidase-&#945;&#44; with different dosage patterns&#44; and found that the standard dosage of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks was as effective as higher dosages or weekly doses in reducing Gb3&#44; an elimination effect that was maintained for 4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The efficacy of ERT is complicated by many factors&#44; including the scarcity of controlled clinical trials whose duration is short and whose sample sizes are very small&#46; The patients included in these clinical trials also have considerable clinical heterogeneity&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">So far&#44; there has been no well-designed study that has compared the 2 ERTs &#40;&#945; and &#946;&#41;&#46; In fact&#44; the comparison of the 2 presentations of agalsidase has been scarce or indirect&#46; A Canadian clinical research group designed a randomized prospective study to directly compare the standard doses of agalsidase-&#945; &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; and agalsidase-&#946; &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; in adults&#46; The study included 117 patients&#44; with a 5 and 8-year follow-up&#44; and concluded that there were no significant differences between the 2 drugs in the interval free of severe events&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> A recent review published in Cochrane evaluated 9 clinical trials&#44; with a total of 351 patients treated with agalsidase&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a> The authors concluded that the trials that compared the 2 ERTs versus placebo showed improvement with ERT in microvascular endothelial Gb3 deposits and in pain-related quality of life&#46; However&#44; there was no evidence on whether form &#945; was superior to &#946; or on the optimal dosage for either form&#46; In terms of safety&#44; the adverse events were more significant with agalsidase-&#946; when compared with placebo&#46; The authors stated that the influence of ERT on the risk of morbidity and mortality in FD is still unclear&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Another relevant issue in ERT is the optimal moment to start this therapy&#46; In this regard&#44; ERT should be started when the first symptoms of FD occur or when there are incipient signs of visceral involvement &#40;mainly pathological albuminuria&#41;&#44; depending on each patient&#39;s individual circumstances&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">10&#44;22</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The evaluation of the enzyme treatment response is clinical&#46; The response is assessed in the most debilitating symptoms for these patients&#8217; quality of life &#40;neuropathic pain&#41;&#44; in the progression of renal failure &#40;the slower the progression the earlier the start of treatment&#41; and in stabilizing renal impairment&#44; including with the regression of left ventricular hypertrophy&#46; This response cannot be measured with objective parameters because neither Gb3 or lyso-Gb3 have been shown to be useful in the follow-up or in the treatment response&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">7&#44;9&#44;23</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The criteria for interrupting the ERT are difficulties or noncompliance in the administration&#44; persistent or severe reactions to the infusion &#40;even despite specific prophylaxis&#41; and in situations with a life expectancy shorter than a year &#40;either due to the FD itself or other intercurrent diseases&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Migalastat&#58; a New Therapeutic Era</span><p id="par0140" class="elsevierStylePara elsevierViewall">After more than a decade since the first authorization of ERT &#40;2001&#41;&#44; the European Medicines Agency authorized the marketing of a new treatment for FD&#58; migalastat&#44; a pharmacological chaperone that binds to certain mutations of &#945;-Gal A&#44; whose genotypes are known as amenable mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a> Most of these mutations are missense type in the GLA gene and cause an abnormal folding of the &#945;-Gal A protein&#44; which prevents its displacement from the endoplasmic reticulum to the lysosome&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Migalastat is indicated for the long-term therapy of patients 16 years or older with clinical manifestations of FD&#44; with amenable mutations&#46; The recommended dose is 1 capsule &#40;123<span class="elsevierStyleHsp" style=""></span>mg of migalastat&#41; on alternating days&#44; at the same time of the day&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a> Migalastat represents a new paradigm in treating FD&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Mechanism of action and preclinical data</span><p id="par0150" class="elsevierStylePara elsevierViewall">The chaperone migalastat is a low-molecular-weight iminosugar &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; a structural analog of the terminal galactose group of Gb-3&#44; which typically is cleaved by &#945;-galactosidase A&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">27&#44;28</span></a> Migalastat is selectively and reversibly fixed &#40;and with considerable affinity&#41; to the active focus of certain mutant forms of &#945;-Gal A &#40;amenable mutations&#41;&#46; The fixation of migalastat stabilizes the mutant &#945;-Gal A&#44; which facilitates its transport from the endoplasmic reticulum to the lysosome&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">29&#44;30</span></a> The fixation depends on pH&#58; migalastat presents greater fixation in less acidic conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> Given that the pH in the reticulum endoplasmic is less acidic than in the lysosome&#44; migalastat is fixed to &#945;-Gal A in the endoplasmic reticulum and releases &#945;-Gal A in the lysosome&#44; by which it performs its enzymatic function freely&#46; Additionally&#44; the fixation of migalastat to &#945;-Gal A is competitive&#44; i&#46;e&#46;&#44; once the migalastat&#47;&#945;-Gal A complex reaches the lysosome&#44; the normal substrates &#40;Gb3&#41; of &#945;-Gal A compete with migalastat&#46; This encourages migalastat to release &#945;-Gal&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The preclinical study was conducted in a transgenic murine model &#40;Tg&#41; with a knock-out mouse &#40;Tg&#47;KO&#41; for FD&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> After 24 weeks of treatment with migalastat&#44; a significant dose-dependent increase was observed in &#945;-Gal A activity&#44; with reduced Gb3 levels in the skin&#44; heart&#44; kidneys&#44; brain and plasma&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Of particular interest is the analysis of the brain results by Khanna et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> who indicated that migalastat can cross the blood&#8211;brain barrier and reduce the substrate of the disease &#40;Gb3&#41; in the central nervous system of mice&#46; This finding had not been observed in similar studies with ERT&#44; due to its high molecular weight &#40;approx&#46; 110<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#46; These data suggest that migalastat could offer an advantage over ERT for treating central nervous system manifestations in FD&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Migalastat is better absorbed under fasting conditions &#40;at least 2<span class="elsevierStyleHsp" style=""></span>h between meals&#41;&#44; and its elimination is slower in patients with severe chronic kidney disease&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Efficacy in controlled clinical trials</span><p id="par0170" class="elsevierStylePara elsevierViewall">Several phase-II clinical trials have evaluated migalastat&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> Two clinical trials were combined for 9 male patients with FD&#46; Migalastat&#44; at a dose of 150<span class="elsevierStyleHsp" style=""></span>mg on alternating days&#44; increased &#945;-Ga A activity by at least 50&#37; in the blood&#44; skin and kidneys of 6 of the 9 patients&#46; The 3 patients who showed no response had mutations in &#945;-Gal A considered as &#8220;nonresponders&#8221;&#46; In 9 women with FD&#44; migalastat decreased the urine Gb3 levels&#46; The baseline Gb3 levels were high in 7 of the 9 patients and decreased by 28&#37; to 66&#37; in the patients with amenable mutations &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; following treatment with migalastat for 48 weeks&#46; The inclusion of Gb3 in the endothelial cells of the peritubular capillaries decreased in 4 patients with amenable mutations and in 2 with nonamenable mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">35</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Germain et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a> published the results of the first phase-III clinical trial of migalastat&#44; the FACETS study&#46; A total of 67 patients with FD &#40;36&#37; men&#44; 94&#37; with multiple organ involvement&#41;&#44; not previously treated with ERT or not treated with ERT for at least 6 months prior to the study&#44; were randomized to 6 months of double-blind treatment with migalastat or placebo &#40;stage 1&#41;&#44; followed by an open extension of migalastat from month 6 to month 12 &#40;stage 2&#41; plus 1 additional year to month 24 &#40;stage 3&#41;&#46; At that point&#44; the patients could choose to continue the treatment in a separate open extension study&#46; The initial test used to determine the mutant forms of &#945;-Gal A amenable to migalastat &#40;human embryonic kidney assay&#41; was improved before the unmasking of stage 1 by the test of amenability to migalastat validated according to good laboratory practices &#40;GLPs&#41; or GLP-validated human embryonic kidney assay&#44; which showed that 50 of the 67 initially randomized participants presented mutations in &#945;-Gal A amenable to migalastat&#46; The analysis of the primary endpoint showed no significant therapeutic effect&#44; probably because amenable and nonamenable &#945;-Gal A mutations were included&#46; When the authors only considered the patients with mutations amenable to migalastat at 6 months &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45&#41;&#44; a significant reduction was observed in the number of Gb3 inclusions per renal interstitial capillary in the migalastat group versus the placebo group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;008&#41;&#44; which remained stable at 12 months of treatment with migalastat&#46; The patients who changed from placebo to migalastat also presented a significant reduction in Gb-3 inclusions at 6 months of treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46; There was also a significant reduction in plasma lyso-Gb3 levels after the first 6 months of treatment with migalastat versus placebo &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;003&#41;&#46; The patients who changed from placebo to migalastat at 6 months also experienced a significant reduction in plasma lyso-Gb3 levels between months 6 and 12 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; In the patients with amenable mutations who were treated with migalastat&#44; the renal function remained stable during the 24 months of the study&#46; The indexed left ventricular mass &#40;ILVM&#41; decreased significantly from the start to 18&#8211;24 months of treatment &#40;&#8722;7&#46;7<span class="elsevierStyleHsp" style=""></span>g&#47;m<span class="elsevierStyleSup">2</span>&#59; 95&#37; CI &#8722;15&#46;4 to &#8722;0&#46;01&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In terms of gastrointestinal symptoms&#44; migalastat significantly improved the diarrhea and reflux at 6 months of the double-blind FACETS study&#46; In terms of quality of life &#40;measured with the 36-item Short-Form questionnaire&#41; and the severity component &#40;&#8220;pain at its worst&#8221;&#41; of the Brief Pain Inventory&#44; there was no worsening at 24 months of the study&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Mauer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> published results showing that migalastat reduced&#44; in just 6 months&#44; the Gb3 content of podocytes&#44; a type of glomerular cell relatively resistant to ERT&#44; in kidney biopsies of 8 men from the FACETS trial&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Hughes et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> published the results of the second phase-III clinical trial of migalastat &#40;ATTRACT&#41; to assess the effects of migalastat on the renal function of patients with FD previously treated with ERT for more than 12 months&#46; Sixty patients with FD &#40;44&#37; men&#59; 88&#37; with multiple organ involvement&#41; were randomized to migalastat for 18 months or to remain with ERT&#46; Migalastat and ERT had similar effects on renal function&#46; Plasma lyso-Gb3 levels remained low and stable in both cohorts&#46; Twenty-nine percent of the patients who were treated with migalastat and 44&#37; of those who were treated with ERT presented predefined renal&#44; heart or cerebrovascular events&#46; The ILVM was significantly reduced with migalastat at 18 months &#40;&#8722;6&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;m<span class="elsevierStyleSup">2</span>&#59; 95&#37; CI &#8722;11&#46;0 to &#8722;2&#46;2&#41;&#44; compared with baseline&#44; while there was no significant change with ERT&#46; The quality-of-life results remained stable and similar between the 2 groups&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Safety</span><p id="par0195" class="elsevierStylePara elsevierViewall">Migalastat was generally safe and well-tolerated&#46; The adverse events that emerged after the start of treatment were comparable between the patients treated with migalastat and those treated with ERT&#46; In the patients treated with ERT&#44; infusion-related reactions were the most common &#40;13&#46;7&#37; with agalsidase-&#945; and 67&#37; with agalsidase-&#946;&#41;&#46; Most of the adverse events that occurred after the start of treatment were mild to moderate&#44; and there were no deaths&#46; The most common adverse reaction reported with migalastat was headaches &#40;10&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Unmet needs</span><p id="par0200" class="elsevierStylePara elsevierViewall">ERT has various limitations&#46; The administration every 2 weeks exposes patients to progressively lower levels of the enzyme between one infusion and the next&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> The intravenous administration has certain direct healthcare costs &#40;disposal of partially used vials due to a low number of patients per hospital&#44; medication prior to the infusion and management of infusion-related reactions and potential infections&#41;&#44; indirect costs &#40;transport to the hospital and lost productivity&#41; and intangible costs &#40;loss of the patients&#8217; wellbeing and that of their relatives&#41;&#46; The high molecular weight of the recombinant enzymes limits their ability to penetrate key tissues&#44; such as myocytes and brain tissue&#44; and generates neutralizing antibodies and immunogenicity reactions&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Gene therapy</span><p id="par0205" class="elsevierStylePara elsevierViewall">Various methods are being tested&#44; such as the use of vectors &#40;lentivirus&#44; retroviruses and adenovirus&#41; and even bone marrow transplantation&#46; For FD&#44; however&#44; there is still a long road ahead&#44; because most of these studies are in the animal experimentation phase&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Genetic counseling</span><p id="par0210" class="elsevierStylePara elsevierViewall">As with any genetic disease&#44; a family study is required when a case of FD is detected&#44; as well as informing the patient and family about the type of inheritance and offering the option of a prenatal diagnosis&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0215" class="elsevierStylePara elsevierViewall">FD is a complex paradigm of multisystem disease&#44; whose target organs are mainly the peripheral nervous system&#44; kidneys&#44; heart&#44; digestive system&#44; eyes&#44; ears&#44; skin and central nervous system&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">In the past 20 years&#44; we have witnessed a change in its management with ERT&#44; which appears to change the course of the disease&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Migalastat is the first and only tailored oral therapy &#40;focused on the patient&#39;s genetic profile&#41;&#44; with a new mechanism of action&#44; which has been shown to be effective&#44; safe and well-tolerated for treating patients with FD with amenable mutations&#44; regardless of the disease phenotype and symptom severity&#46; Migalastat therefore opens exciting lines of research&#44; such as the clinical relevance it assumes by crossing the blood&#8211;brain barrier&#46; There are a number of studies that have indicated the boosting effect of migalastat in its concomitant use with ERT&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">In general&#44; for internists and other medical specialties&#44; migalastat helps to understand the new and effective mechanism of action of molecular chaperones&#44; which are being investigated in other diseases&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Funding</span><p id="par0235" class="elsevierStylePara elsevierViewall">M&#46; L&#243;pez received funding from Amicus Therapeutics for implementing this study&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0240" class="elsevierStylePara elsevierViewall">M&#46; L&#243;pez has participated in advisory activities&#44; such as speaking at meetings&#44; and has attended congresses with funding from Shire&#44; Sanofi-Genzyme and Amicus&#46;</p></span></span>"
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          "titulo" => "Enzyme replacement therapy"
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          "titulo" => "Migalastat&#58; a New Therapeutic Era"
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            0 => "Fabry disease"
            1 => "Multisystemic"
            2 => "Migalastat"
            3 => "Chaperone"
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            0 => "Enfermedad de Fabry"
            1 => "Multisist&#233;mica"
            2 => "Migalastat"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Fabry disease is an X-linked inborn disease caused by deficit of alpha-galactosidase A&#46; This results in accumulation of glycosphingolipids in all cells and tissues&#46; All males should receive enzyme replacement treatment in case of very low or undetectable levels of alpha-galactosidase A&#46; Female carriers and males with marginally levels of alpha-galactosidase A should be treated in case of renal&#44; neurologic o cardiac manifestations&#46; There are two intravenous formulations of human recombinant enzyme&#44; agalsidase alpha and agalsidase beta&#44; showing similar efficacy and safety&#46; Patients with amenable mutations of alpha-galactosidase can be treated with oral migalastat hydrochloride&#46; Migalastat hydrochloride is a pharmacological chaperone that facilitates trafficking of alpha-galactosidase A to lysosomes increasing enzyme activity&#46; Patients treated with migalastat hydrochloride had significant improvements in left ventricular mass and gastrointestinal symptoms&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Fabry es una enfermedad ligada al cromosoma X causada por un d&#233;ficit de alfa-galactosidasa A&#46; Esto da como resultado la acumulaci&#243;n de glicoesfingol&#237;pidos en todas las c&#233;lulas y tejidos&#46; Todos los varones deben tratarse con reemplazo enzim&#225;tico en caso de presentar niveles muy bajos o indetectables de alfa-galactosidasa A&#46; Las mujeres portadoras y los varones con niveles m&#237;nimos de alfa-galactosidasa A deben tratarse si existe afectaci&#243;n renal&#44; neurol&#243;gica o card&#237;aca&#46; Para terapia de reemplazo enzim&#225;tico existen dos formulaciones intravenosas&#44; agalsidasa alfa y agalsidasa beta&#44; que muestran una eficacia y seguridad similares&#46; Los pacientes con mutaciones susceptibles del gen alfa-galactosidasa A pueden tratarse con migalastat oral&#46; El migalastat es una mol&#233;cula que facilita el paso de alfa-galactosidasa A a los lisosomas&#44; produciendo aumento de actividad del enzima&#46; Los pacientes tratados con migalastat muestran mejoras significativas en la masa del ventr&#237;culo izquierdo y en los s&#237;ntomas gastrointestinales&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; L&#243;pez Rodr&#237;guez M&#46; Tratamiento en la enfermedad de Fabry&#46; Rev Clin Esp&#46; 2018&#59;218&#58;489&#8211;495&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Childhood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adolescence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">30&#8211;40 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Angiokeratoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chronic kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acroparesthesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteinuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heart disease &#40;LVH&#44; arrhythmias&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Angiokeratoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lipiduria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ocular disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hematuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Abdominal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypohidrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
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              "identificador" => "bib0210"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2018.03.008

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