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cardiac and renal&#46; In the classical form clinical manifestations appear during childhood or early adolescence including acroparesthesias&#44; angiokeratomas and corneal opacities&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> Progressive accumulation of Gb3 in the kidneys&#44; heart and central nervous system lead to renal failure&#44; hypertrophic cardiomyopathy and cerebral vascular accidents limiting life expectancy&#46; The cardiac variant of the disease is associated with residual alpha-galactosidase A activity &#40;&#62;1&#37;&#41;&#44; appearing later in life&#46; The patients suffer from left ventricular hypertrophy and hypertrophic cardiomyopathy with decreased systolic function&#46; Other cardiac manifestations include valvular disease with thickened valves &#40;especially left-sided&#41; and regurgitation&#44; myocardial ischemia&#44; arrhythmias &#40;frequently supraventricular&#41; and ECG changes such as voltage criteria for LVH and repolarization abnormalities&#44; shortened P-R&#44; A-V block or bundle branch block&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> The clinical picture is dominated by the aforementioned cardiac manifestations&#44; while the classical signs and symptoms are usually absent&#46; Some patients may present a degree of proteinuria without severe renal failure&#46;<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&#46; In case of Fabry disease two formulations of recombinanat enzyme are currently available&#46; Agalsidase-alfa &#40;Replagal<span class="elsevierStyleSup">&#174;</span>&#44; Shire&#41; is derived from human skin fibroblasts and is administered intravenously at dose of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 14 days&#46; Accordingly&#44; agalsidase-beta &#40;Fabrazyme<span class="elsevierStyleSup">&#174;</span>&#44; Genzyme&#41; is produced by Chinese Hamster ovary cell line and is given intravenously at dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 14 days&#46;</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&#46; In our case&#44; twenty months after the initiation of agalsidase-alfa in the conventional dose&#44; an increment of proteinuria and left ventricular mass were noted&#46; Switching the patient to double dose of the enzyme led to reduction of proteinuria and reestablishment of the cardiac indexes&#46;</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&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;d and left ventricular hypertrophy&#46; His renal function was normal &#40;eGFR 122<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46; The patient underwent a renal biopsy which showed glomeruli with enlarged podocytes displaying abundant fine&#44; granular and lucent protoplasm&#46; Some tubular epithelial cells had a vacuolated and lucent cytoplasm or atrophy while mild interstitial fibrosis was also present &#40;&#60;10&#37;&#41;&#46; Immunofluorescence showed IgM deposition in mesangium of two glomeruli with granular distribution&#46; Histological findings in association with the clinical manifestations led to further investigation toward diagnosis of Fabry disease&#46; Indeed&#44; low activity of &#945;-Gal A in plasma and in leucocytes &#40;0&#46;3<span class="elsevierStyleHsp" style=""></span>nmoles&#47;ml&#47;h and 1&#46;5<span class="elsevierStyleHsp" style=""></span>nmoles&#47;mg protein&#47;h&#44; respectively&#41; led to the aforementioned diagnosis&#46; The subsequent familiar genetic investigation revealed that both he and his mother&#44; a 70-year old female&#44; had the pN215S missense mutation&#44; corresponding to adenine replacement in the position 10135 with guanine &#40;10135A<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>G&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Monitoring of the patients&#44; performed twice a year&#44; included biochemical exams of renal function and 24-h measurement of proteinuria&#44; cardiac ultrasound and pro-BNP levels&#44; plasma and urine levels of Gb3 as well as the titer of the anti-agalsidase antibodies and brain MRI scan every other year&#46; The female suffered from left ventricular hypertrophy&#44; without renal or CNS involvement&#46; On the contrary&#44; male patient had a complex phenotype with left ventricular hypertrophy&#44; proteinuria and CNS lesions&#46; 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&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The male patient was administered agalsidase-alfa &#40;Replagal<span class="elsevierStyleSup">&#174;</span>&#44; Shire&#41; in the recommended dose of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d every 2 weeks and an ACE inhibitor in the maximum tolerated dose &#40;ramipril 5<span class="elsevierStyleHsp" style=""></span>mg daily&#41;&#46; Enzyme replacement therapy began 3 months after the histologic diagnosis&#46;</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&#46; At that point in the male patient a steep increase of proteinuria &#40;from 560 to 2536<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; as well as an increase in left ventricular mass &#40;from 412 to 464&#46;5<span class="elsevierStyleHsp" style=""></span>g&#41; and pro-BNP levels &#40;from 190 to 266&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; were observed&#46; After measurement of Gb3 levels in plasma &#40;5&#46;86<span class="elsevierStyleHsp" style=""></span>nmol&#47;ml&#41; and exclusion of development of neutralizing anti-agalsidase-a IgG and IgA antibodies we considered to adapt the therapeutic regimen&#46; Thus we administered&#44; with the same frequency&#44; double dose of enzyme &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#41;&#46; Seven months later&#44; proteinuria decreased from 2536 to 986<span class="elsevierStyleHsp" style=""></span>mg&#47;d and the indexes of cardiac size were reestablished&#46; Accordingly plasmatic levels of Gb3 were 5&#46;11<span class="elsevierStyleHsp" style=""></span>nmol&#47;ml&#46; Targeting to verify this apparent dose-dependent effect&#44; the conventional dose was re-administered and one month later proteinuria relapsed &#40;2886<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Therefore the patient switched to the double dose&#46; After 24 months&#44; he still presents albuminuria of 1053<span class="elsevierStyleHsp" style=""></span>mg&#47;d and stable cardiac size and function &#40;LV mass<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>414&#46;8<span class="elsevierStyleHsp" style=""></span>g&#44; pro-BNP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>166&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41;&#46; Repeated brain MRI scan showed no evolution of the lesions&#46;</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&#44; all types of renal cells as well as the endothelium of the blood vessels may be affected&#44; podocyte injury is central in the pathophysiology of Fabry nephropathy&#46;<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&#46;<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&#8211;5th decade&#44; progressing to end stage renal disease after 1&#8211;13 years&#46;<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&#46; Retrospective studies of ERT-untreated cohorts showed that the level of proteinuria was independently associated with the rate of decline of eGFR&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10&#44;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&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12&#44;13</span></a> Clinically&#44; the maximal renal protection is achieved when ERT is given before the development or in an early stage of CKD &#40;eGFR &#62;60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> or proteinuria &#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13&#8211;15</span></a> On the contrary&#44; the effectiveness of ERT is much less consistent in face of an advanced renal failure and irreversible organ damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a> Thus proteinuria must be a major therapeutic target in Fabry nephropathy&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient was diagnosed with the missense mutation pN215S &#40;transition of A<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>G in codon 215 of exon 5 with substitution of an asparagine by a serine&#41;&#46; This genetic defect usually leads to a late-onset phenotype&#44; dominated by cardiac manifestations&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">18&#44;19</span></a> However&#44; in this case the phenotypic expression was different with renal and CNS involvement besides cardiac hypertrophy&#46; To our knowledge this is the first case of a Fabry patient with the pN215S mutation and extracardiac clinical manifestations&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although the patient had normal renal function&#44; control of proteinuria to levels &#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;d was necessary&#46; Low blood pressure &#40;100&#47;65<span class="elsevierStyleHsp" style=""></span>mmHg&#41; prevented us from further titration of the ACE inhibitor&#46; Thus&#44; we decided to increase the administered enzyme by doubling the recommended dose&#46; 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&#46;<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&#46; This dose-dependent effect was verified by switching the patient to the conventional dose of agalsidase-alfa for one month period&#44; after which a re-deterioration of proteinuria was noticed&#46; Therefore the patient switched to the double dose regaining the prior albuminuria levels and stable cardiac size and function&#46; The findings sustained 24 months later&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although long-term administration of enzyme replacement therapy &#40;ERT&#41; appears safe and effective leading to clinical stabilization&#44;<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&#46; A dose-dependent effect has been observed in such a case with advanced nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> In an open-label&#44; prospective clinical trial of 11 male patients with advanced Fabry nephropathy &#40;mean baseline eGFR 53&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; and rapid annual decline of eGFR &#40;&#8722;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;8<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#44; switching agalsidase-alfa regimen from the conventional biweekly dosing to weekly infusions of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg for a 24-month period slowed eGFR&#39;s decline &#40;&#8722;3&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46;<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&#46; who administered 3 different ERT regimens in 52 Fabry patients &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg agalsidase-alfa&#44; 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg or 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg agalsidase beta&#41;&#46; After 12 months of follow-up the patients who received 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of agalsidase-beta presented decreased levels of urinary Gb3 levels&#44; independent of their anti-agalsidase antibody status&#46; Moreover&#44; a reduction of left ventricular mass was observed&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> However&#44; the results of a comparative trial between the two products administered in 34 patients at the same dose &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg biweekly&#41;&#44; showed no difference regarding reduction of left ventricular mass after 12 and 24 months of treatment&#46; There was also no difference concerning other clinical or laboratory parameters &#40;eGFR&#44; pain&#44; plasma and urinary Gb3 levels&#44; anti-agalsidase antibodies&#41; or treatment failure between the two treatment groups&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> In our case administration of double of the recommended dose of agalsidase-alfa&#44; besides better compliance&#44; was followed by a significant decrement of proteinuria as well as decrease of the left ventricular mass&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; 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&#46; However&#44; additional investigation is required in order to evaluate cost&#8211;effectiveness of such an intervention&#46;</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&#46;</p></span></span>"
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            2 => "Mutation pN215S"
            3 => "Proteinuria"
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            0 => "Enfermedad de Fabry"
            1 => "Terapia sustitutiva enzim&#225;tica"
            2 => "Mutaci&#243;n pN215S"
            3 => "Proteinuria"
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        "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&#44; caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A &#40;a-Gal A&#41;&#46; The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement&#46; We report a case of a male Fabry patient with the pN215S mutation and a generalized disease&#46; He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme&#46; Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration&#46;</p></span>"
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        "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&#44; que se caracteriza por un almacenamiento lisos&#243;mico de glucoesfingol&#237;pidos causado por una deficiencia parcial o completa de la enzima lisos&#243;mica &#945;-galactosidasa A &#40;a-Gal<span class="elsevierStyleHsp" style=""></span>A&#41;&#46; La mutaci&#243;n sin sentido pN215S suele provocar una forma m&#225;s leve de la enfermedad&#44; con afectaci&#243;n card&#237;aca aislada&#46; Se describe un caso de enfermedad de Fabry en un paciente var&#243;n con la mutaci&#243;n pN215S y enfermedad generalizada&#46; El paciente present&#243; una recidiva de la proteinuria que respondi&#243; al aumento de dosis de la enzima recombinante administrada&#46; Debe considerarse la posible conveniencia de una individualizaci&#243;n de la terapia sustitutiva enzim&#225;tica en casos seleccionados que presenten deterioro cl&#237;nico&#46;</p></span>"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Mehta"
                            1 => "R&#46; Ricci"
                            2 => "U&#46; Widmer"
                            3 => "F&#46; Dehout"
                            4 => "A&#46; Garcia de Lorenzo"
                            5 => "C&#46; Kampmann"
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                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2362.2004.01309.x"
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                        "tituloSerie" => "Eur J Clin Invest"
                        "fecha" => "2004"
                        "volumen" => "34"
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                      "autores" => array:1 [
                        0 => array:2 [
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                            0 => "R&#46; Quinta"
                            1 => "D&#46; Rodrigues"
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                            3 => "M&#46;F&#46; Macedo"
                            4 => "O&#46; Azevedo"
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                    0 => array:2 [
                      "doi" => "10.1016/j.gene.2013.11.073"
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                    0 => array:2 [
                      "titulo" => "A systematic review on screening for Fabry disease&#58; prevalence of individuals with genetic variants of unknown significance"
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                          "autores" => array:6 [
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                            1 => "B&#46;E&#46; Smid"
                            2 => "B&#46;J&#46;H&#46;M&#46; Poorthuis"
                            3 => "M&#46; Biegstraaten"
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                      "doi" => "10.1136/jmedgenet-2013-101857"
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                          "autores" => array:6 [
                            0 => "M&#46; Ries"
                            1 => "U&#46; Ramaswami"
                            2 => "R&#46; Parini"
                            3 => "B&#46; Lindblad"
                            4 => "C&#46; Whybra"
                            5 => "I&#46; Willers"
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                      "doi" => "10.1007/s00431-003-1299-3"
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                        "volumen" => "162"
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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
Christos Paliourasa,
Autor para correspondencia
chpaliouras@yahoo.gr

Corresponding author at: Nephrology, General Hospital of Rhodes, Agioi Apostoloi, 85100 Rhodes, Greece.
, Georgios Aperisb, Foteini Lamprianoua, Giorgos Ntetskasa, Konstantinos Roufasa, Polichronis Alivanisa
a Nephrology, General Hospital of Rhodes, Rhodes, Greece
b Acute Medical Unit, Antrim Area Hospital, Northern Ireland, United Kingdom
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    "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&#58;40&#44;000&#8211;1&#58;117&#44;000 live male births&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> Partial or complete deficiency of the enzyme alpha-galactosidase A &#40;a-Gal A&#41; results in altered metabolism and progressive lysosomal accumulation of the substrate &#40;mostly globotriaosylceramide&#44; Gb<span class="elsevierStyleInf">3</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> The responsible gene is located on the long arm of the chromosome X &#40;Xq22&#41;&#46; More than 600 mutations have been identified with variable phenotypical expression&#46;<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&#44; cardiac and renal&#46; In the classical form clinical manifestations appear during childhood or early adolescence including acroparesthesias&#44; angiokeratomas and corneal opacities&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> Progressive accumulation of Gb3 in the kidneys&#44; heart and central nervous system lead to renal failure&#44; hypertrophic cardiomyopathy and cerebral vascular accidents limiting life expectancy&#46; The cardiac variant of the disease is associated with residual alpha-galactosidase A activity &#40;&#62;1&#37;&#41;&#44; appearing later in life&#46; The patients suffer from left ventricular hypertrophy and hypertrophic cardiomyopathy with decreased systolic function&#46; Other cardiac manifestations include valvular disease with thickened valves &#40;especially left-sided&#41; and regurgitation&#44; myocardial ischemia&#44; arrhythmias &#40;frequently supraventricular&#41; and ECG changes such as voltage criteria for LVH and repolarization abnormalities&#44; shortened P-R&#44; A-V block or bundle branch block&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> The clinical picture is dominated by the aforementioned cardiac manifestations&#44; while the classical signs and symptoms are usually absent&#46; Some patients may present a degree of proteinuria without severe renal failure&#46;<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&#46; In case of Fabry disease two formulations of recombinanat enzyme are currently available&#46; Agalsidase-alfa &#40;Replagal<span class="elsevierStyleSup">&#174;</span>&#44; Shire&#41; is derived from human skin fibroblasts and is administered intravenously at dose of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 14 days&#46; Accordingly&#44; agalsidase-beta &#40;Fabrazyme<span class="elsevierStyleSup">&#174;</span>&#44; Genzyme&#41; is produced by Chinese Hamster ovary cell line and is given intravenously at dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 14 days&#46;</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&#46; In our case&#44; twenty months after the initiation of agalsidase-alfa in the conventional dose&#44; an increment of proteinuria and left ventricular mass were noted&#46; Switching the patient to double dose of the enzyme led to reduction of proteinuria and reestablishment of the cardiac indexes&#46;</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&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;d and left ventricular hypertrophy&#46; His renal function was normal &#40;eGFR 122<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46; The patient underwent a renal biopsy which showed glomeruli with enlarged podocytes displaying abundant fine&#44; granular and lucent protoplasm&#46; Some tubular epithelial cells had a vacuolated and lucent cytoplasm or atrophy while mild interstitial fibrosis was also present &#40;&#60;10&#37;&#41;&#46; Immunofluorescence showed IgM deposition in mesangium of two glomeruli with granular distribution&#46; Histological findings in association with the clinical manifestations led to further investigation toward diagnosis of Fabry disease&#46; Indeed&#44; low activity of &#945;-Gal A in plasma and in leucocytes &#40;0&#46;3<span class="elsevierStyleHsp" style=""></span>nmoles&#47;ml&#47;h and 1&#46;5<span class="elsevierStyleHsp" style=""></span>nmoles&#47;mg protein&#47;h&#44; respectively&#41; led to the aforementioned diagnosis&#46; The subsequent familiar genetic investigation revealed that both he and his mother&#44; a 70-year old female&#44; had the pN215S missense mutation&#44; corresponding to adenine replacement in the position 10135 with guanine &#40;10135A<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>G&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Monitoring of the patients&#44; performed twice a year&#44; included biochemical exams of renal function and 24-h measurement of proteinuria&#44; cardiac ultrasound and pro-BNP levels&#44; plasma and urine levels of Gb3 as well as the titer of the anti-agalsidase antibodies and brain MRI scan every other year&#46; The female suffered from left ventricular hypertrophy&#44; without renal or CNS involvement&#46; On the contrary&#44; male patient had a complex phenotype with left ventricular hypertrophy&#44; proteinuria and CNS lesions&#46; 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&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The male patient was administered agalsidase-alfa &#40;Replagal<span class="elsevierStyleSup">&#174;</span>&#44; Shire&#41; in the recommended dose of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d every 2 weeks and an ACE inhibitor in the maximum tolerated dose &#40;ramipril 5<span class="elsevierStyleHsp" style=""></span>mg daily&#41;&#46; Enzyme replacement therapy began 3 months after the histologic diagnosis&#46;</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&#46; At that point in the male patient a steep increase of proteinuria &#40;from 560 to 2536<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; as well as an increase in left ventricular mass &#40;from 412 to 464&#46;5<span class="elsevierStyleHsp" style=""></span>g&#41; and pro-BNP levels &#40;from 190 to 266&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; were observed&#46; After measurement of Gb3 levels in plasma &#40;5&#46;86<span class="elsevierStyleHsp" style=""></span>nmol&#47;ml&#41; and exclusion of development of neutralizing anti-agalsidase-a IgG and IgA antibodies we considered to adapt the therapeutic regimen&#46; Thus we administered&#44; with the same frequency&#44; double dose of enzyme &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#41;&#46; Seven months later&#44; proteinuria decreased from 2536 to 986<span class="elsevierStyleHsp" style=""></span>mg&#47;d and the indexes of cardiac size were reestablished&#46; Accordingly plasmatic levels of Gb3 were 5&#46;11<span class="elsevierStyleHsp" style=""></span>nmol&#47;ml&#46; Targeting to verify this apparent dose-dependent effect&#44; the conventional dose was re-administered and one month later proteinuria relapsed &#40;2886<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Therefore the patient switched to the double dose&#46; After 24 months&#44; he still presents albuminuria of 1053<span class="elsevierStyleHsp" style=""></span>mg&#47;d and stable cardiac size and function &#40;LV mass<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>414&#46;8<span class="elsevierStyleHsp" style=""></span>g&#44; pro-BNP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>166&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41;&#46; Repeated brain MRI scan showed no evolution of the lesions&#46;</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&#44; all types of renal cells as well as the endothelium of the blood vessels may be affected&#44; podocyte injury is central in the pathophysiology of Fabry nephropathy&#46;<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&#46;<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&#8211;5th decade&#44; progressing to end stage renal disease after 1&#8211;13 years&#46;<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&#46; Retrospective studies of ERT-untreated cohorts showed that the level of proteinuria was independently associated with the rate of decline of eGFR&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10&#44;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&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">12&#44;13</span></a> Clinically&#44; the maximal renal protection is achieved when ERT is given before the development or in an early stage of CKD &#40;eGFR &#62;60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> or proteinuria &#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13&#8211;15</span></a> On the contrary&#44; the effectiveness of ERT is much less consistent in face of an advanced renal failure and irreversible organ damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">16&#44;17</span></a> Thus proteinuria must be a major therapeutic target in Fabry nephropathy&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient was diagnosed with the missense mutation pN215S &#40;transition of A<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>G in codon 215 of exon 5 with substitution of an asparagine by a serine&#41;&#46; This genetic defect usually leads to a late-onset phenotype&#44; dominated by cardiac manifestations&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">18&#44;19</span></a> However&#44; in this case the phenotypic expression was different with renal and CNS involvement besides cardiac hypertrophy&#46; To our knowledge this is the first case of a Fabry patient with the pN215S mutation and extracardiac clinical manifestations&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although the patient had normal renal function&#44; control of proteinuria to levels &#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;d was necessary&#46; Low blood pressure &#40;100&#47;65<span class="elsevierStyleHsp" style=""></span>mmHg&#41; prevented us from further titration of the ACE inhibitor&#46; Thus&#44; we decided to increase the administered enzyme by doubling the recommended dose&#46; 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&#46;<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&#46; This dose-dependent effect was verified by switching the patient to the conventional dose of agalsidase-alfa for one month period&#44; after which a re-deterioration of proteinuria was noticed&#46; Therefore the patient switched to the double dose regaining the prior albuminuria levels and stable cardiac size and function&#46; The findings sustained 24 months later&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although long-term administration of enzyme replacement therapy &#40;ERT&#41; appears safe and effective leading to clinical stabilization&#44;<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&#46; A dose-dependent effect has been observed in such a case with advanced nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> In an open-label&#44; prospective clinical trial of 11 male patients with advanced Fabry nephropathy &#40;mean baseline eGFR 53&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; and rapid annual decline of eGFR &#40;&#8722;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;8<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#44; switching agalsidase-alfa regimen from the conventional biweekly dosing to weekly infusions of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg for a 24-month period slowed eGFR&#39;s decline &#40;&#8722;3&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46;<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&#46; who administered 3 different ERT regimens in 52 Fabry patients &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg agalsidase-alfa&#44; 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg or 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg agalsidase beta&#41;&#46; After 12 months of follow-up the patients who received 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of agalsidase-beta presented decreased levels of urinary Gb3 levels&#44; independent of their anti-agalsidase antibody status&#46; Moreover&#44; a reduction of left ventricular mass was observed&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> However&#44; the results of a comparative trial between the two products administered in 34 patients at the same dose &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg biweekly&#41;&#44; showed no difference regarding reduction of left ventricular mass after 12 and 24 months of treatment&#46; There was also no difference concerning other clinical or laboratory parameters &#40;eGFR&#44; pain&#44; plasma and urinary Gb3 levels&#44; anti-agalsidase antibodies&#41; or treatment failure between the two treatment groups&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> In our case administration of double of the recommended dose of agalsidase-alfa&#44; besides better compliance&#44; was followed by a significant decrement of proteinuria as well as decrease of the left ventricular mass&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; 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&#46; However&#44; additional investigation is required in order to evaluate cost&#8211;effectiveness of such an intervention&#46;</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&#46;</p></span></span>"
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        "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&#44; caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A &#40;a-Gal A&#41;&#46; The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement&#46; We report a case of a male Fabry patient with the pN215S mutation and a generalized disease&#46; He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme&#46; Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration&#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 un trastorno hereditario raro ligado al cromosoma X&#44; que se caracteriza por un almacenamiento lisos&#243;mico de glucoesfingol&#237;pidos causado por una deficiencia parcial o completa de la enzima lisos&#243;mica &#945;-galactosidasa A &#40;a-Gal<span class="elsevierStyleHsp" style=""></span>A&#41;&#46; La mutaci&#243;n sin sentido pN215S suele provocar una forma m&#225;s leve de la enfermedad&#44; con afectaci&#243;n card&#237;aca aislada&#46; Se describe un caso de enfermedad de Fabry en un paciente var&#243;n con la mutaci&#243;n pN215S y enfermedad generalizada&#46; El paciente present&#243; una recidiva de la proteinuria que respondi&#243; al aumento de dosis de la enzima recombinante administrada&#46; Debe considerarse la posible conveniencia de una individualizaci&#243;n de la terapia sustitutiva enzim&#225;tica en casos seleccionados que presenten deterioro cl&#237;nico&#46;</p></span>"
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