Case report
Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype–phenotype expression
Control de la proteinuria con aumento de dosis de agalsidasa alfa en un paciente con enfermedad de Fabry y expresión de genotipo-fenotipo atípica
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Ntetskas, Konstantinos Roufas, Polichronis Alivanis" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Christos" "apellidos" => "Paliouras" "email" => array:1 [ 0 => "chpaliouras@yahoo.gr" ] "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" => "Georgios" "apellidos" => "Aperis" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Foteini" "apellidos" => "Lamprianou" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Giorgos" "apellidos" => "Ntetskas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Konstantinos" "apellidos" => "Roufas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Polichronis" "apellidos" => "Alivanis" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Nephrology, General Hospital of Rhodes, Rhodes, Greece" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Acute Medical Unit, Antrim Area Hospital, Northern Ireland, United Kingdom" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author at</span>: Nephrology, General Hospital of Rhodes, Agioi Apostoloi, 85100 Rhodes, Greece." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Control de la proteinuria con aumento de dosis de agalsidasa alfa en un paciente con enfermedad de Fabry y expresión de genotipo-fenotipo atípica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 971 "Ancho" => 1486 "Tamanyo" => 138053 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Graphic albuminuria.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fabry disease is a rare genetic lysosomal storage disorder of glycosphingolipids with X-linked transmission and an estimated incidence of 1:40,000–1:117,000 live male births.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> Partial or complete deficiency of the enzyme alpha-galactosidase A (a-Gal A) results in altered metabolism and progressive lysosomal accumulation of the substrate (mostly globotriaosylceramide, Gb<span class="elsevierStyleInf">3</span>).<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> The responsible gene is located on the long arm of the chromosome X (Xq22). More than 600 mutations have been identified with variable phenotypical expression.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Clinically we distinguish the classical form and two variants, cardiac and renal. In the classical form clinical manifestations appear during childhood or early adolescence including acroparesthesias, angiokeratomas and corneal opacities.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> Progressive accumulation of Gb3 in the kidneys, heart and central nervous system lead to renal failure, hypertrophic cardiomyopathy and cerebral vascular accidents limiting life expectancy. The cardiac variant of the disease is associated with residual alpha-galactosidase A activity (>1%), appearing later in life. The patients suffer from left ventricular hypertrophy and hypertrophic cardiomyopathy with decreased systolic function. Other cardiac manifestations include valvular disease with thickened valves (especially left-sided) and regurgitation, myocardial ischemia, arrhythmias (frequently supraventricular) and ECG changes such as voltage criteria for LVH and repolarization abnormalities, shortened P-R, A-V block or bundle branch block.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> The clinical picture is dominated by the aforementioned cardiac manifestations, while the classical signs and symptoms are usually absent. Some patients may present a degree of proteinuria without severe renal failure.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Advances in the application of molecular genetic techniques have enabled the development of directed protein therapies for lysosomal storage diseases. In case of Fabry disease two formulations of recombinanat enzyme are currently available. Agalsidase-alfa (Replagal<span class="elsevierStyleSup">®</span>, Shire) is derived from human skin fibroblasts and is administered intravenously at dose of 0.2<span class="elsevierStyleHsp" style=""></span>mg/kg every 14 days. Accordingly, agalsidase-beta (Fabrazyme<span class="elsevierStyleSup">®</span>, Genzyme) is produced by Chinese Hamster ovary cell line and is given intravenously at dose of 1<span class="elsevierStyleHsp" style=""></span>mg/kg every 14 days.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We present the case of a male Fabry patient who was diagnosed with the missense mutation pN215S who in addition to cardiac involvement also presented serious extracardiac clinical manifestations. In our case, twenty months after the initiation of agalsidase-alfa in the conventional dose, an increment of proteinuria and left ventricular mass were noted. Switching the patient to double dose of the enzyme led to reduction of proteinuria and reestablishment of the cardiac indexes.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case report</span><p id="par0025" class="elsevierStylePara elsevierViewall">A 41-year old male was presented in the Renal Outpatient Clinic with proteinuria of 0.5<span class="elsevierStyleHsp" style=""></span>g/d and left ventricular hypertrophy. His renal function was normal (eGFR 122<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>). The patient underwent a renal biopsy which showed glomeruli with enlarged podocytes displaying abundant fine, granular and lucent protoplasm. Some tubular epithelial cells had a vacuolated and lucent cytoplasm or atrophy while mild interstitial fibrosis was also present (<10%). Immunofluorescence showed IgM deposition in mesangium of two glomeruli with granular distribution. Histological findings in association with the clinical manifestations led to further investigation toward diagnosis of Fabry disease. Indeed, low activity of α-Gal A in plasma and in leucocytes (0.3<span class="elsevierStyleHsp" style=""></span>nmoles/ml/h and 1.5<span class="elsevierStyleHsp" style=""></span>nmoles/mg protein/h, respectively) led to the aforementioned diagnosis. The subsequent familiar genetic investigation revealed that both he and his mother, a 70-year old female, had the pN215S missense mutation, corresponding to adenine replacement in the position 10135 with guanine (10135A<span class="elsevierStyleHsp" style=""></span>→<span class="elsevierStyleHsp" style=""></span>G).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Monitoring of the patients, performed twice a year, included biochemical exams of renal function and 24-h measurement of proteinuria, cardiac ultrasound and pro-BNP levels, plasma and urine levels of Gb3 as well as the titer of the anti-agalsidase antibodies and brain MRI scan every other year. The female suffered from left ventricular hypertrophy, without renal or CNS involvement. On the contrary, male patient had a complex phenotype with left ventricular hypertrophy, proteinuria and CNS lesions. Brain imaging with MRI scan showed vascular dolichoectasia in the vertebrobasilar junction and punctuated white matter lesions in the frontal lobe as well as in the basal ganglia.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The male patient was administered agalsidase-alfa (Replagal<span class="elsevierStyleSup">®</span>, Shire) in the recommended dose of 0.2<span class="elsevierStyleHsp" style=""></span>mg/kg/d every 2 weeks and an ACE inhibitor in the maximum tolerated dose (ramipril 5<span class="elsevierStyleHsp" style=""></span>mg daily). Enzyme replacement therapy began 3 months after the histologic diagnosis.</p><p id="par0040" class="elsevierStylePara elsevierViewall">During the first 20 months both renal and cardiac indexes remained stable and no other relevant event was noticed. At that point in the male patient a steep increase of proteinuria (from 560 to 2536<span class="elsevierStyleHsp" style=""></span>mg/d) as well as an increase in left ventricular mass (from 412 to 464.5<span class="elsevierStyleHsp" style=""></span>g) and pro-BNP levels (from 190 to 266.5<span class="elsevierStyleHsp" style=""></span>pg/ml) were observed. After measurement of Gb3 levels in plasma (5.86<span class="elsevierStyleHsp" style=""></span>nmol/ml) and exclusion of development of neutralizing anti-agalsidase-a IgG and IgA antibodies we considered to adapt the therapeutic regimen. Thus we administered, with the same frequency, double dose of enzyme (0.4<span class="elsevierStyleHsp" style=""></span>mg/kg/d). Seven months later, proteinuria decreased from 2536 to 986<span class="elsevierStyleHsp" style=""></span>mg/d and the indexes of cardiac size were reestablished. Accordingly plasmatic levels of Gb3 were 5.11<span class="elsevierStyleHsp" style=""></span>nmol/ml. Targeting to verify this apparent dose-dependent effect, the conventional dose was re-administered and one month later proteinuria relapsed (2886<span class="elsevierStyleHsp" style=""></span>mg/d) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Therefore the patient switched to the double dose. After 24 months, he still presents albuminuria of 1053<span class="elsevierStyleHsp" style=""></span>mg/d and stable cardiac size and function (LV mass<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>414.8<span class="elsevierStyleHsp" style=""></span>g, pro-BNP<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>166.5<span class="elsevierStyleHsp" style=""></span>pg/ml). Repeated brain MRI scan showed no evolution of the lesions.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">Although, all types of renal cells as well as the endothelium of the blood vessels may be affected, podocyte injury is central in the pathophysiology of Fabry nephropathy.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> Progressive damage of the glomerular filtration barrier leads to the early appearance of the albumin in the urine sub form of microalbuminuria.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> Non-nephrotic range proteinuria developes frequently during the 3rd decade of life and renal failure in the 4th–5th decade, progressing to end stage renal disease after 1–13 years.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> In Fabry patients proteinuria is an independent factor of worsening of renal function and progression to ESRD. Retrospective studies of ERT-untreated cohorts showed that the level of proteinuria was independently associated with the rate of decline of eGFR.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10,11</span></a> Administration of ERT improves renal histopathology leading to significant clearance of the Gb3 deposits from the renal interstitial vascular endothelium and other glomerular cells.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12,13</span></a> Clinically, the maximal renal protection is achieved when ERT is given before the development or in an early stage of CKD (eGFR >60<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> or proteinuria <1<span class="elsevierStyleHsp" style=""></span>g/d).<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13–15</span></a> On the contrary, the effectiveness of ERT is much less consistent in face of an advanced renal failure and irreversible organ damage.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16,17</span></a> Thus proteinuria must be a major therapeutic target in Fabry nephropathy.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient was diagnosed with the missense mutation pN215S (transition of A<span class="elsevierStyleHsp" style=""></span>→<span class="elsevierStyleHsp" style=""></span>G in codon 215 of exon 5 with substitution of an asparagine by a serine). This genetic defect usually leads to a late-onset phenotype, dominated by cardiac manifestations.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">18,19</span></a> However, in this case the phenotypic expression was different with renal and CNS involvement besides cardiac hypertrophy. To our knowledge this is the first case of a Fabry patient with the pN215S mutation and extracardiac clinical manifestations.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although the patient had normal renal function, control of proteinuria to levels <1<span class="elsevierStyleHsp" style=""></span>g/d was necessary. Low blood pressure (100/65<span class="elsevierStyleHsp" style=""></span>mmHg) prevented us from further titration of the ACE inhibitor. Thus, we decided to increase the administered enzyme by doubling the recommended dose. This choice was based upon previous in vitro observation that administration of recombinant human galactosidase is associated with increased tissue enzymatic activity in a dose-dependent manner.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> During the next seven months we observed a gradual decrease in proteinuria levels as well as in left ventricular mass. This dose-dependent effect was verified by switching the patient to the conventional dose of agalsidase-alfa for one month period, after which a re-deterioration of proteinuria was noticed. Therefore the patient switched to the double dose regaining the prior albuminuria levels and stable cardiac size and function. The findings sustained 24 months later.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although long-term administration of enzyme replacement therapy (ERT) appears safe and effective leading to clinical stabilization,<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> there are still controversies regarding the appropriate ERT regimen in case of progressive clinical deterioration. A dose-dependent effect has been observed in such a case with advanced nephropathy.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> In an open-label, prospective clinical trial of 11 male patients with advanced Fabry nephropathy (mean baseline eGFR 53.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.3<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>) and rapid annual decline of eGFR (−8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.8<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>), switching agalsidase-alfa regimen from the conventional biweekly dosing to weekly infusions of 0.2<span class="elsevierStyleHsp" style=""></span>mg/kg for a 24-month period slowed eGFR's decline (−3.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.4<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>).<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The question of the optimal ERT dose has also been tested by Vedder et al. who administered 3 different ERT regimens in 52 Fabry patients (0.2<span class="elsevierStyleHsp" style=""></span>mg/kg agalsidase-alfa, 0.2<span class="elsevierStyleHsp" style=""></span>mg/kg or 1<span class="elsevierStyleHsp" style=""></span>mg/kg agalsidase beta). After 12 months of follow-up the patients who received 1<span class="elsevierStyleHsp" style=""></span>mg/kg of agalsidase-beta presented decreased levels of urinary Gb3 levels, independent of their anti-agalsidase antibody status. Moreover, a reduction of left ventricular mass was observed.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> However, the results of a comparative trial between the two products administered in 34 patients at the same dose (0.2<span class="elsevierStyleHsp" style=""></span>mg/kg biweekly), showed no difference regarding reduction of left ventricular mass after 12 and 24 months of treatment. There was also no difference concerning other clinical or laboratory parameters (eGFR, pain, plasma and urinary Gb3 levels, anti-agalsidase antibodies) or treatment failure between the two treatment groups.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> In our case administration of double of the recommended dose of agalsidase-alfa, besides better compliance, was followed by a significant decrement of proteinuria as well as decrease of the left ventricular mass.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion, individualization of ERT should be considered in selected cases of Fabry disease when conventional dosing and symptomatic treatment are not effective to control clinical manifestations. However, additional investigation is required in order to evaluate cost–effectiveness of such an intervention.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflict of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres818379" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec815408" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres818378" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec815407" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-12-31" "fechaAceptado" => "2015-02-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec815408" "palabras" => array:4 [ 0 => "Fabry disease" 1 => "Enzyme replacement therapy" 2 => "Mutation pN215S" 3 => "Proteinuria" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec815407" "palabras" => array:4 [ 0 => "Enfermedad de Fabry" 1 => "Terapia sustitutiva enzimática" 2 => "Mutación pN215S" 3 => "Proteinuria" ] ] ] ] "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 rare X-linked lysosomal storage disorder of glycosphingolipids, caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement. We report a case of a male Fabry patient with the pN215S mutation and a generalized disease. He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme. Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration.</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 un trastorno hereditario raro ligado al cromosoma X, que se caracteriza por un almacenamiento lisosómico de glucoesfingolípidos causado por una deficiencia parcial o completa de la enzima lisosómica α-galactosidasa A (a-Gal<span class="elsevierStyleHsp" style=""></span>A). La mutación sin sentido pN215S suele provocar una forma más leve de la enfermedad, con afectación cardíaca aislada. Se describe un caso de enfermedad de Fabry en un paciente varón con la mutación pN215S y enfermedad generalizada. El paciente presentó una recidiva de la proteinuria que respondió al aumento de dosis de la enzima recombinante administrada. Debe considerarse la posible conveniencia de una individualización de la terapia sustitutiva enzimática en casos seleccionados que presenten deterioro clínico.</p></span>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 971 "Ancho" => 1486 "Tamanyo" => 138053 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Graphic albuminuria.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 12 | 16 |
| 2024 October | 42 | 44 | 86 |
| 2024 September | 46 | 25 | 71 |
| 2024 August | 59 | 60 | 119 |
| 2024 July | 39 | 26 | 65 |
| 2024 June | 58 | 33 | 91 |
| 2024 May | 40 | 31 | 71 |
| 2024 April | 48 | 29 | 77 |
| 2024 March | 48 | 28 | 76 |
| 2024 February | 38 | 35 | 73 |
| 2024 January | 34 | 21 | 55 |
| 2023 December | 23 | 23 | 46 |
| 2023 November | 53 | 26 | 79 |
| 2023 October | 54 | 23 | 77 |
| 2023 September | 25 | 21 | 46 |
| 2023 August | 39 | 28 | 67 |
| 2023 July | 39 | 26 | 65 |
| 2023 June | 28 | 19 | 47 |
| 2023 May | 52 | 29 | 81 |
| 2023 April | 32 | 13 | 45 |
| 2023 March | 55 | 20 | 75 |
| 2023 February | 28 | 16 | 44 |
| 2023 January | 32 | 21 | 53 |
| 2022 December | 71 | 25 | 96 |
| 2022 November | 74 | 29 | 103 |
| 2022 October | 70 | 38 | 108 |
| 2022 September | 35 | 25 | 60 |
| 2022 August | 57 | 42 | 99 |
| 2022 July | 27 | 42 | 69 |
| 2022 June | 33 | 30 | 63 |
| 2022 May | 30 | 25 | 55 |
| 2022 April | 25 | 57 | 82 |
| 2022 March | 58 | 54 | 112 |
| 2022 February | 34 | 35 | 69 |
| 2022 January | 29 | 35 | 64 |
| 2021 December | 44 | 36 | 80 |
| 2021 November | 29 | 37 | 66 |
| 2021 October | 65 | 47 | 112 |
| 2021 September | 41 | 36 | 77 |
| 2021 August | 33 | 41 | 74 |
| 2021 July | 89 | 46 | 135 |
| 2021 June | 44 | 26 | 70 |
| 2021 May | 57 | 40 | 97 |
| 2021 April | 97 | 40 | 137 |
| 2021 March | 38 | 31 | 69 |
| 2021 February | 48 | 16 | 64 |
| 2021 January | 42 | 21 | 63 |
| 2020 December | 30 | 23 | 53 |
| 2020 November | 35 | 18 | 53 |
| 2020 October | 25 | 25 | 50 |
| 2020 September | 25 | 22 | 47 |
| 2020 August | 43 | 13 | 56 |
| 2020 July | 53 | 13 | 66 |
| 2020 June | 33 | 20 | 53 |
| 2020 May | 48 | 8 | 56 |
| 2020 April | 35 | 16 | 51 |
| 2020 March | 32 | 14 | 46 |
| 2020 February | 33 | 21 | 54 |
| 2020 January | 30 | 20 | 50 |
| 2019 December | 47 | 33 | 80 |
| 2019 November | 37 | 22 | 59 |
| 2019 October | 32 | 23 | 55 |
| 2019 September | 33 | 13 | 46 |
| 2019 August | 29 | 13 | 42 |
| 2019 July | 24 | 28 | 52 |
| 2019 June | 23 | 28 | 51 |
| 2019 May | 21 | 16 | 37 |
| 2019 April | 67 | 28 | 95 |
| 2019 March | 29 | 23 | 52 |
| 2019 February | 27 | 16 | 43 |
| 2019 January | 27 | 17 | 44 |
| 2018 December | 138 | 29 | 167 |
| 2018 November | 263 | 17 | 280 |
| 2018 October | 200 | 16 | 216 |
| 2018 September | 97 | 8 | 105 |
| 2018 August | 47 | 10 | 57 |
| 2018 July | 45 | 11 | 56 |
| 2018 June | 42 | 12 | 54 |
| 2018 May | 55 | 11 | 66 |
| 2018 April | 88 | 9 | 97 |
| 2018 March | 44 | 8 | 52 |
| 2018 February | 45 | 8 | 53 |
| 2018 January | 32 | 5 | 37 |
| 2017 December | 40 | 8 | 48 |
| 2017 November | 31 | 4 | 35 |
| 2017 October | 29 | 9 | 38 |
| 2017 September | 30 | 7 | 37 |
| 2017 August | 22 | 8 | 30 |
| 2017 July | 26 | 10 | 36 |
| 2017 June | 30 | 12 | 42 |
| 2017 May | 34 | 10 | 44 |
| 2017 April | 21 | 6 | 27 |
| 2017 March | 16 | 8 | 24 |
| 2017 February | 37 | 12 | 49 |
| 2017 January | 21 | 11 | 32 |
| 2016 December | 23 | 6 | 29 |
| 2016 November | 40 | 15 | 55 |
| 2016 October | 57 | 14 | 71 |
| 2016 September | 69 | 2 | 71 |
| 2016 August | 70 | 3 | 73 |
| 2016 July | 103 | 7 | 110 |
| 2016 June | 91 | 0 | 91 |
| 2016 May | 115 | 0 | 115 |
| 2016 April | 102 | 0 | 102 |
| 2016 March | 72 | 0 | 72 |
| 2016 February | 49 | 0 | 49 |
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