3rd Latam Fabry Round Table ABSTRACT Resume

3

rd

Cancún - México

Abstract

Resume

AFECCION RENAL TEMPRANA EN UNA FAMILIA CON FABRY 1,

2

Rivera Flores Javier Verónica X. Amaro Triana 1

Servicio de Nefrología, Hospital de Especialidades Centro Médico Nacional Siglo XXI. IMSS, Distrito Federal, México; riverhemo@hotmail.com Servicio de Nefrología , Hospital General de zona No.8.IMSS, Distrito Federal,Mèxico ; xochi.ama@gmail.com .

As is well known the Fabry disease shows deposits of globotriaosylceramide intrauterine and in the childhood begins the clinical manifestations, especially to neurological and ophthalmological level. We present the case of a family with eight members with this disease (three men and five women, mutation c. 1156C>T p.Q386X) they are a clear example of the natural evolution,with kidney disorder mainly ;until the fateful death of one of them by a cerebral vascular accident, in 4 of the women shown by kidney biopsy the deposit of globotriaosylceramide ,including one of them at the time of diagnosis with 4 years of age . In addition in the rest with comorbidity of obesity and type 2 Diabetes Mellitus in two of them.And that so far after 3 years of diagnosis only 7 have received treatment and most of them with one to two years of delay once detected.

Fabry disease and ERT experience in 12 classic patients: different formulations - different outcome?

Authors: Politei J1, Schenone AB1, Cabrera G2, Heguilen R3, Szlago M1.

1

Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN), Buenos Aires, 2 3 Argentina; Department of Cardiology, Del Viso Medical Center, Buenos Aires, Argentina; Nephrology Service, Juan Fernandez Hospital, Buenos Aires, Argentina.

Introduction: Fabry disease (FD) is an X-linked inherited disorder of metabolism due to deficient or absent alpha-Galactosidase A (alpha-Gal A) activity. Subsequent to the approval of enzyme replacement therapy (ERT) in Europe in 2001 and in the United States in 2003, FD has taken a significant turn arousing the interest of a large number of specialists and its long term outcome is currently still being investigated. Aim: to describe the results of the multidisciplinary evaluation in 12 patients with FD with the same genetic mutation and their outcomes using different approved ERT Patients and methods: Twelve adult patients (8 males and 4 females) were included in this study. We measured baseline data and serial results of: renal (glomerular filtration rate, proteinuria and serum creatinine); cardiac (IV septum, left ventricular posterior wall and LV mass index) and cerebrovascular functioning (clinic exam and magnetic resonance). Neuropathic pain assessment was done with the Brief Pain Inventory (BPI) scale. Results: all cases were deficient alpha-Gal A activity and have the same genetic mutation (L415P). Duration of ERT ranges from 11 to 3 years. The BPI scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa treated patients after one year with posterior increase. During the agalsidase beta shortage two male patients were switched to agalsidasa alfa, after one year both cases presented an increase in BPI values after the improvement reached previously with agalsidasa beta. Females showed very mild compromise in BPI during the study period. Renal evolution showed a tendency towards a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. In two males where ERT was started in advanced CKD stage progressed to dialysis and left ventricular hypertrophy (LVH) increased. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain MRI showed increase of white matter lesions (WML) in 4 patients, 3 of them presented WML before ERT. Discussion: We found disparities in the follow up inasmuch as the use of different ERT formulations. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. The oldest patient in our serie who started ERT with advanced CKD stage and severe LVH progressed slowly during agalsidase beta treatment and decline faster receiving agalsidase alfa.

Following the previous reported recommendations on reintroduction of agalsidase beta for patients with FD in Europe after the enzyme shortage and after full discussion with the patients we decided to switch all patients to agalsidase beta.

FABRY DISEASE: LATE ONSET VARIANT IN PROTEINURIA AND DIALYSIS SCREENING. BE PREPARED FOR MORE CASES... AND MORE QUESTIONS. Juan Politeia, Monica Calvob, Segundo Fernandezc, David Warnockd, Eric Wallaced, Graciela e Serebrinsky a

Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN), Buenos Aires, b c Argentina; Hospital Zonal General de Agudos Evita, Buenos Aires, Argentina; Centro Médico d CIPERCA, Catamarca, Argentina; Department of Medicine, University of Alabama, Birmingham, AL, United States; eLaboratorio de Biología y Patología Molecular y Genetica, Buenos Aires, Argentina.

In 1995 the concept of "variants" or late onset Fabry disease (FD) phenotype was described. Aim: to describe 2 late onset male Fabry patients with severe kidney compromise where the diagnosis of Fabry disease was the result of screening in high risk populations. Patients and methods: Case 1: A 46 year-old male presented to his primary physician with lower extremity edema. His family history was negative for kidney disease. Blood pressure was 130/80 mmHg and laboratory tests showed 1.05 mg/ dL (92.82 μmol/L) creatinine and proteinuria of 1300 mg/day with unremarkable urine sediment. A renal biopsy was inconclusive but did not include electron microscopy. After 4 years of follow up and increased proteinuria, patient agreed to be part of a Fabry screening in patients with proteinuria. The α-galactosidase A leukocyte level was 2.9 (normal 30.5-57.7 nmol/h/mg) and a novel Gal A hemizygote mutation (C174G) was identified. A second renal biopsy showed prominent and numerous podocyte myelin-like inclusions, without tubular, mesangial or small artery and arteriole endothelial cell inclusions. Lyso-Gl3 in plasma: 2.9 ng/ml (≤ 0.9 ng/ml). Case 2: A 55 years old male, on dialysis treatment for 5 years was included in a Fabry screening project. His medical history included proteinuria since he was 32 years old and a kidney biopsy at the age of 40 described focal segmental glomerulopathy, but without electron microscopy studies. The α-galactosidase A leukocyte level was 2.8 nmol/h/mg and a novel Gal A hemizygote mutation (R363H) was identified. Lyso-Gl3 in plasma: 1.8 ng/ml. Discussion: Both cases showed normal brain MRI, mild left ventricular hypertrophy, normal dermatological exam (no angiokeratomas), and normal hearing function. One case had a few corneal deposits in the left lower quadrant in right eye.

Typical neuropathic pain and gastrointestinal complains were absent. Lyso-Gl3 plasma levels were slightly elevated. Our cases showed severe kidney damage, case 1 progressed to dialysis after 4 years of diagnosis. We found C174G mutation as a non-pathogenic polymorphism in one report and late onset variant in other, at the same time R363H was reported as a classical mutation in one report and late onset in other. More information is needed on the complete phenotypic spectrum of late onset variants, in this regard, detailed phenotypic descriptions of genetic variants, like the current cases report, are necessary additions to the Fabry literature.

EFECTO A LARGO PLAZO DE LA TERAPIA DE REEMPLAZO ENZIMÁTICO EN PACIENTES CON ENFERMEDAD DE FABRY. EXPERIENCIA ARGENTINA Dr. Gustavo Cabrera, Dr. Juan Politei, Dr. Norberto Antongiovanni, Dr.Hernán Amartino, Dr Adrián Fernández En nombre de GADYTEF (Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Fabry) E-mail: gustavo.h.cabrera@hotmail.com Muchos de los pacientes con enfermedad de Fabry (EF) presentan compromiso cardiaco, siendo la hipertrofia ventricular izquierda su signo cardinal. La aprobación de la terapia de reemplazo enzimático (TRE) ha generado nuevas expectativas para estos pacientes. Diversos estudios en poblaciones seleccionadas han demostrado una favorable respuesta cardiaca a corto plazo con reducción de la masa ventricular izquierda. Este efecto se ha visto opacado por la escasa respuesta de los pacientes con mayor compromiso orgánico y mayor edad. Resulta interesante resaltar que en la mayoría de estos estudios la edad media de los pacientes tratados supera los 40 años en ambos sexos y por esta razón los resultados en términos de reducción del compromiso cardiaco y eventos clínicos pueden no ser el mejor.

Con el objeto de evaluar la respuesta cardiaca al tratamiento prolongado con agalsidasa recombinante humana y su efecto sobre eventos clínicos mayores. Se evaluaron en forma prospectiva 39 pacientes (24 hombres) de Argentina con diagnóstico confirmado de EF. Todos los pacientes fueron tratados con agalsidasa beta (Fabrazyme®) a 1mg/kg cada 14 días.

Los 39 pacientes con edades promedio de 27.5±11años para los varones y 41.9±13para las mujeres recibieron TRE durante una media de 67,2±37meses (85.7±30 y 42±32 meses respectivamente).

Al inicio de la TRE 11(44%) hombres y 9 (60%) mujeres presentaban HVI, 5 varones y 3 mujeres enfermedad renal crónica (ERC) (IFGe EPI < 60 ml/min/1,73 m2) y 18 varones y 13 mujeres proteinuria y/o albuminuria. Un varón de 27 años y otro de 33 se encontraba en estadio 4 y 5 de ERC, respectivamente.

Durante el seguimiento, Se observaron 8 eventos en 5 pacientes. Dos pacientes de sexo masculino fallecieron y fueron aquellos con enfermedad severa basal. Uno por sepsis a partir de abdomen agudo y el otro en el contexto de insuficiencia renal crónica (IRC) en fase terminal.

Dos varones presentaron enfermedad coronaria. Uno antes de iniciar la TRE y el otro como complicación tardía de su mala evolución general. Dos pacientes evolucionaron a IRC estadio 5, pero iniciaron la TRE con IRC estadio 3 y tuvieron baja adhesión a la TRE y a la terapia antiproteinúrica.

Solo una paciente de sexo femenino presento fibrilación auricular (FA) bien tolerada y controlada con beta bloqueantes. Ningún varón presentó arritmias.

Los pacientes varones que no presentaron evento mostraron estabilización de la media del IMVI, mientras que los que si presentaron eventos mostraron un incremento significativo del mismo. En el caso de las mujeres la media del IMVI se redujo en forma significativa.

Se realizó un análisis multivariado con el objeto de identificar la variable predictora de no evento en los pacientes de sexo masculino. La edad al incio de la TRE, entre el IMVI, el IFGe, la presencia de HTA y la proteinuria., fue la única que alcanzó potencia estadística (p=0.001). Siendo la edad de los varones que presentaron evento de 37.2± 8 años vs. 25.6± 10 años.

CONCLUSIONES: La respuesta favorable a largo plazo de la TRE en esta población compuesta predominantemente por pacientes jóvenes, con una baja prevalencia de eventos clínicos mayores refuerza la necesidad de iniciar la TRE en estadios tempranos de la enfermedad, previo al compromiso orgánico avanzado.

Resulta interesante resaltar que en la mayoría de los estudios que evaluaron la respuesta a largo plazo de la TRE, la edad media de los pacientes tratados supera los 40 años y podría ser esta la razón por la que los resultados en estos estudios no son los mejores a diferencia de nuestra cohorte cuya edad media es más baja, 32.7±13 años.

FABRY DISEASE: FOLLOW UP AND TREATMENT ENZYME REPLACEMENT IN MUNICIPAL HOSPITAL OF CHILD AND ADOLESCENT, GUARULHOS-SP Ana Carolina de Paula, Valter LS Dias Junior, Monique L. da Silva, Simone A. Sarres, Adriana Gomes SP, Christiane M S. Pinto, Alessandra P. Cantuaria, Lygia SL Lauand Municipal Hospital of Child and Adolescent, Guarulhos-SP Brazil

acpaula10@hotmail.com

INTRODUCTION: Fabry disease (FD) it is an inborn error of metabolism of glycosphingolipids, produced by mutations of the GLA gene encoding the α-galactosidase A lysosomal enzyme. The clinical presentation is variable and starts in childhood or adolescence. In Brazil, ANVISA approved two possibilities of treatment, enzyme replacement therapy (ERT) with agalsidase alfa and agalsidase beta.

OBJECTIVE: To report the follow up of a patient with FD in ERT 4 years in Municipal Hospital of Child and Adolescent, Guarulhos- SP. RESULTS: Male patient with acroparesthesia complaint, photophobia, intolerance to heat and cold, recurrent fever, fatigue and angiokeratomas since 12 years. In family history was referred to hemodialysis, renal transplantation, hypertrophic cardiomyopathy and stroke. In initial tests showed cardiac involvement (left ventricular dilation, ventricular ectopic activity and supraventricular), brain (nonspecific change in periventricular white matter), hearing loss and proteinuria. The diagnosis of FD was confirmed at age 26 through the low activity of α-galactosidase A in leukocytes (1.0 nmol / h / mg prot - reference value 26-53). The ERT agalsidase alfa started at age 27, biweekly infusion of 1-hour duration.

Adverse events showed lip edema and tremors, which were controlled with premedication. Periodic examinations are performed: measurement of lyso biomarker GB3, renal function, echocardiogram, ECG, holter monitoring, carotid Doppler ultrasound, audiometry and magnetic resonance imaging.

Initially, the patient showed improvement of acroparesthesia, photophobia, heat and cold intolerance and fatigue. However, after 3 years of ERT, the patient has a stroke, the pain symptoms returns, worsening audiometric, increase of proteinuria and specific biomarker (lyso GB3). In today's clinical context, together with the patient, was required to switch medication to agalsidase beta, in order to control the evolution of the disease and promote a better quality of life to the patient.

CONCLUSION: The possibility of using other medication that is ANVISA approved is an attempt to modify the natural history of the disease. Certainly, if the patient was without the possibility of treatment for damage to their health would be worse.

REFERENCES 1- Fabry disease: dose matters. Warnock DG, Mauer M. J Am Soc Nephrol. 2014 Apr;25(4):653-5. doi: 10.1681/ASN.2013121322. Epub 2014 Feb 20.

2 - Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch.

Weidemann F, Krämer J, Duning T, Lenders M, Canaan-Kühl S, Krebs A, Guerrero González H, Sommer C, Üçeyler N, Niemann M, Störk S, Schelleckes M, Reiermann S, Stypmann J, Brand SM, Wanner C, Brand E. 3 - J Agalsidase benefits renal histology in young patients with Fabry disease.

Tøndel C, Bostad L, Larsen KK, Hirth A, Vikse BE, Houge G, Svarstad E. J Am Soc Nephrol. 2013 Jan;24(1):137-48. doi: 10.1681/ASN.2012030316. Am Soc Nephrol. 2014 Apr;25(4):837-49. doi: 10.1681/ASN.2013060585. Epub 2014 Feb 20.

The alpha-galactosidase A mutation D313Y is or is not clinically relevant for Fabry disease?

Centro de Erros Inatos do Metabolismo (CETREIM) â&#x20AC;&#x201C; Instituto de Medicina Integral Professor Fernando Figueira (IMIP). Recife, Brazil.

Ana Paula Santana Gueiros Background: Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism resulting in the accumulation of globotriaosylceramide in cells of various tissues resulting in end-organ manifestations.

The pathological signiďŹ cance of the Fabry mutation D313Y is doubted, because, in general, D313Y patients do not present clinical manifestations consistent with FD. We report a clinical, biochemical and molecular genetic analysis of two patients with D313Y mutation.

Methods and Results: Index patient: LDS, male, 33Y. Patient with chronic kidney disease, unknown etiology, on dialysis since 2011. Presented neurological disorders that interfered on his way of processing information such as reading, depression and maniac ideas. A reduced alpha-galactosidase A activity of 0.68mol/L/h( dried blood spot - DBS - normal: >2.2mol/L/h) and the described D313Y mutation were detected. The analysis of his ďŹ rst-grade relatives was performed. The results showed D313Y mutation in the mother's gene and no mutation in his three sisters. The table below shows the clinical analysis of the patient and his mother.

Table- Clinical characteristics of the two Fabry patients with D313Y mutation

Magnetic resonance imaging (MRI); White matter lesion (WML) TBP: to be presented Conclusions: Our results suggest that D313Y mutation is associated with important clinical features. A detailed evaluation must be performed in those patients and their families since there are available therapeutic tools.

DOENÇA DE FABRY COMO DIAGNÓSTICO DIFERENCIAL DE GLOMERULOPATIA PROTEINÚRICA: RELATO DE CASO 1

2

2

Cassiano Augusto Braga Silva , José Andrade Moura Junior , Raphael Pereira Paschoalin , 2 2 Túlio Coelho Carvalho , Nathália Pereira Paschoalin .

1,2

Department of Nephrology, Clínica Senhor do Bonfim, Feira de Santana, Brasil; cassianonefro@hotmail.com

INTRODUÇÃO: O envolvimento renal na doença de Fabry (DF) está relacionado ao progressivo acúmulo de GL3 nos podócitos, células epiteliais e tubulares, se manifestando inicialmente com proteinúria, podendo evoluir com doença renal crônica terminal (DRCt). A DF entra, portanto, como diagnóstico diferencial das glomerulopatias proteinúricas, e seu reconhecimento reveste-se de extremo valor frente à disponibilidade da terapia de reposição enzimática (TRE), que se iniciada precocemente, pode mudar a história natural da doença.

CASO CLÍNICO: D.O.B., 35 anos, procedente de Feira de Santana – BA, Brasil. Em seguimento com Nefrologia há 5 anos devido proteinúria. Referia urina espumosa de longa data. Negava edemas e outros sintomas. Mantinha função renal normal (creatinina 1,0 mg/dL; uréia 34 mg/dL). Urina tipo 1: proteína 2+. Proteinúria de 24h: 1,04 g. Complemento, FAN e sorologias normais. US renal: nefropatia parenquimatosa crônica. Biópsia renal em outubro/2010: GESF. Prescrito prednisona por 6 meses, e posteriormente ciclofosfamida por mais 6 meses, sem evidências de diminuição da proteinúria. A partir de então, foi encaminhado para seguimento em nosso ambulatório. Referia edema intermitente de membros inferiores. Em uso de ramipril. Relatou ser portador de lesões enegrecidas em região abdominal desde a infância. Negava dores em articulações. Hipoidrose discreta desde a adolescência.

Negava outros achados ou sintomas característicos. Exame físico: 57 kg, 1,80 m. Angioqueratomas em região de “calção de banho”. Sem edemas. Sem outras alterações. Antecedentes familiares: irmão de 37 anos com hipoidrose intensa e angioqueratomas. Mãe apresenta dores generalizadas, principalmente em membros inferiores. Tia com DRC; tio faleceu em hemodiálise; outra tia já apresentou 3 episódios de AVC. Exames: uréia 42 mg/dL; creatinina 1,6 mg/dL; proteinúria de 24h: 2,05 g; urina tipo 1: proteína 1+.

Atividade enzimática Alfa-galactosidase: 0,2 μmol/L/h (VN ≥ 1,9 μmol/L/h). Lyso-Gb3: 92,5 ng/mL (VN ≤ 1,8 ng/mL). Análise genética: mutação no gene GLA (c.679C>T p.R227*). Foi submetido a outra biópsia renal. No momento, em uso de losartan 50 mg, e em TRE com Fabrazyme.

DISCUSSÃO: Relatamos aqui o caso de um paciente com quadro clínico clássico de DF, inicialmente tratado como portador de GESF, o que postergou o diagnóstico e consequentemente o início da TRE.

Clinical Profile of Females With Anderson-Fabry Disease in a Brazilian Community Curiati, MA; Mendes, CSC; Rand, MH; Kyosen, SO; Aranda, CS; Garrote, J; Martins, AM BACKGROUND AND OBJECTIVES: Anderson-Fabry Disease (AFD) females were thought to be asymptomatic or to develop only minor manifestations.

However several studies reported that heterozygous females do develop substantial symptoms. We aim to describe the clinical findings in female patients carrying a null mutation.

PATIENTS AND METHODS: We analyzed the clinical profile in 53 AFD female patients with a severe phenotype.

RESULTS: The patients, median age of 30 y (7y-68y), showed early symptoms: 74% presented acroparesthesia, median age 10y (4y - 51y). Hypoidrosis was present in 72%, angiokeratomes in 23%, depression in 45%. Heart MRI was performed in 43 patients: 51% normal, 49% abnormal. Brain MRI was performed in 41 patients: 51% normal, 49% abnormal. Proteinuria in 64%. Mutation analysis showed 35% of c.1095delT, 35% c.365del7, 21% p.W47X, 4% p.W004X and 4% unknown.

DISCUSSION/CONCLUSION: All mutations found are expected to cause a severe phenotype (null mutations). Our female patients showed early symptoms of the disease, most frequently acroparesthesia and proteinuria. They also showed high incidence of cardiac and neurologic abnormalities. Females with a null mutation have a significant risk for major organ involvement and decreased quality of life and must be monitored and treated accordingly.

A PEDIATRIC GROWTH SPURT FROM A FABRY DISEASE PATIENT AFTER ENZYMATIC REPLACEMENT THERAPY. Biagini, G¹; Biagini, GLK². ¹ Centro de infusão de Doença de Fabry, Instituto do Rim do Paraná, Curitiba, Paraná, Brasil; gilson.biagini@gmail.com. ² Disciplina de Endocrinologia-Doenças Ósteo-metabólicas.Faculdade Evangélica de Medicina doParaná, Curitiba, Paraná, Brasil; endocrino1999@hotmail.com.

INTRODUCTION: Fabry disease is a rare inherited disorder, defined as a Lysosomal Storage Disease.

Beginning in childhood, this abnormal buildup causes growth deficiency. A study based on Fabry Registry, collecting data from 352children, found that males exhibited height and weight values below the US 50th percentile while females had weight values above the US 50th percentile but their heights were below the US 25th.Enzyme Replacement Terapy (ERT) with Agalsidase beta efficacy and safety has been shown since 2008. A systematic PUBMED search for reported data on ERT pediatric. patients and their respective growth charts, to this day, yielded no results OBJECTIVE; The main objective of this poster is to show the growth chart of a patient on ERT for 3 years. CASE REPORT: A 13 yo (Tanner 0) male patient was diagnosed through a screening from his uncle case. Alfa galactosidase activity:0, mutation: c.32delg. Complaints: MMII pain and growth deficiency. TRE, betagalsidase (Fabrazyme), 1 mg/kg twice a month, was initiated onJuly 2012 when his heigh was within the US 10th SD (149 cm/ 4,88 in). After 2y6mo (Tanner 2) he gained 22cm, catching up to the US 25thSD (171 cm/5,6 in). RESULTS: Preliminary data suggest that on Fabry Disease mean final height may approach 50% of the target height. In this 16yo boy (Tanner 2), with FD after ERT treatment since he was 13yo (Tanner 0), we report a recovered growth velocity from 4 cm/y ( +10SDS) to 1 cm/month (+ 25SDS). This growth spurt resulted in 22 cm higher in 2y6mo. ERT showed efficacy in allowing GH and pubertal hormones action in this blunted neuroendocrine axis by Fabry Disease.

P.G35V: A NEW MUTATION, EARLY RENAL MANIFESTATIONS IN FABRY DISEASE Veloso, VSP1; Pereira, ERS1; Sousa, MF1; Ataides, TLA1; 1 1 1 Cunha TCM ; Rezende, JE ; Guimarães, MR .

1

Division of Nephrology, Department of Internal Medicine, Hospital das Clínicas, Universidade Federal de Goiás, Goiânia, Brazil.

Introduction: Fabry disease (FD) is an X-linked genetic disease that causes cellular accumulation of globotrialosilceramida (Gb3) due to lack of lisossomal activity of alpha galactosidase A (alpha-gal A) enzyme.

Kidney involvement is variable and common. It starts with deposition of Gb3 in every kidney cell causing proteinuria and progressive renal loss. Men classically develop chronic kidney disease that needs renal replacement therapy and women can present with different stages of severity. Case presentation: RMO, male, 43 years old(y.), with chronic kidney disease in replacement therapy of unknown cause since he was 35 y; presenting typical manifestations of FD. Enzymatic tests were done and detected low activitiy of alpha- GAL enzyme. Genotype confirmed the mutation p.G35V in homozygosity in exon 1, not already described in literature and with unknown clinical effect. The patient started enzymatic replacement therapy with human recombinant alpha-Gal A enzyme.

Family screening was done and 11 first and second-degree relatives had the mutation. One of the nephews of the index patient, 27 y; a mutation carrier presented severe neurologic symptoms, such as multiple strokes and movement loss. Five of the mutation carrier (2 sisters and 3 nephews) presented with proteinuria between 150 and 1000mg/24hours and underwent kidney biopsy. The electronic microscopy showed podocytes with lamellated membrane inclusion bodies and either “zebroid”and “myelin – like”appearance in endothelial cells. In addition, there is evidence of cardiologic involvement in 4 of these patients (short PR interval). Discussion: This case report illustrates the genetic inheritance of FD and its new mutation, not already described in medical literature. It has different characteristics and different stricken organs in the same family members. At the same time, is observed the predominance of kidney involvement in most of them. Conclusion: Doctors should be familiarized with signs and symptoms of FD and consider this pathology as a differential diagnosis once the delay in diagnose can lead to irreversible organ damage and reduce the efficacy of the specific treatment.

COGNITIVE IMPAIRMENT IN PATIENTS OF A FABRY DISEASE'S FAMILY Veloso,VSP¹; Pereira,ERS¹; Sousa,MF¹; Ataides,TLA¹; CunhaTCM¹; Rezende,JE¹; Guimaraes,MR¹; Mendonça,ACR¹; Diniz,DS¹ ¹Division of Nephrology, Department of Internal Medicine, Hospital Of Clinical, University Federal Of Goiás, Goiania, Brazil Introduc on: Inborn errors of metabolism lead to a heterogenic group of rare gene c disorders, Fabry disease being one of them. It is a lysosomal adult disease related to X-linked and enzyma c changes cause the accumula on of globotrialosilceramide (Gb-3) inheritance. Its main manifesta ons are cutaneous, neurologic, cardiac and renal. Objec ve: Because the neurological disorders, we evaluate possible cogni ve impairment in this group of pa ents. Case report: A six female pa ents' family, was referred to the Neurology Service of the Hospital das Clinicas de Goiás by the Nephrology Service of the same hospital. Neurological examina on and cogni ve assessment was done in all of them. Methodology: The pa ents underwent neurological examina on by a neurologist and for neuropsychologists who applied the BRB-N ba ery that assesses verbal memory (learning), visuospa al memory (learning), a en on, processing speed, working memory and seman c verbal fluency. MSFC was also applied to evaluate the agility of upper limb motor func on, walking speed and the a en on, processing speed and working memory. All procedures took place at the Centro de Referencia, Inves gação e Tratamento em Esclerose Múl pla (CRIEM) / FM / HC / UFG for a visit of approximately 2 hours.

Results: All pa ents showed cogni ve impairment in at least two tests (33.4% at 2, 50% at 3 and 16.6% at 5). The worst performance (100%) was the Paced Auditory Serial Addition Test (PASAT) test that assesses a en on, processing speed and working memory and be er performance on the Word List Genera on (WLG) (83.4%) which assesses verbal learning memory. Conclusion: According to our results we can state that the pa ents of Fabry disease, even if asymptoma c, early show cogni ve impairments, confirmed by performance in the PASAT (already validated for the Brazilian popula on). The performance at Nine-Hole Peg Test (9HPT) and Timed 25Foot Walk, were rela vely good. Half of the subjects assessed by 9HPT and 66.6% in the Timed 25-Foot Walk showed performance above normal that the engine point of view, most had no motor commitments.

NEUROLOGIC AND NEUROIMAGING FINDINGS IN PATIENTS WITH FABRY DISEASE Veloso, VSP1; Pereira, ERS1; Sousa, MF1; Ataides, TLA1; Cunha TCM1; Rezende, JE1; Guimarães, MR1.

1

Division of Nephrology, Department of Internal Medicine, Hospital das Clínicas, Universidade Federal de Goiás, Goiânia, Brazil.

Introduction: Fabry disease is a rare lysosomal disorder linked to the X chromosome that leads to the deficiency of galactosidase A (alpha-Gal A) and accumulation of globotrialosilceramida (Gb-3) in many body tissues, causing skin, neurologic, cardiac and renal manifestations. In severe cases, it courses with strokes, myocardial fibrosis, heart failure and chronic kidney disease. Objectives: We present the clinical and radiological neurologic findings of a series of patients from a single family with a confirmed diagnosis of Fabry disease. Case Report: From a patientindex with end-stage renal disease, it was possible to diagnose Fabry disease in eleven relatives. Patients were informed of the diagnosis and underwent thorough clinical evaluation and exams to identify manifestations of the disease in the heart, kidneys and nervous system. Neurological symptoms such as headache, hearing impairment, acroparesias, hypohidrosis, strokes and sleep disorders and mood were surveyed. Patients underwent clinical neurological examination and underwent neuroimaging (magnetic resonance angiography) and hearing evaluation (audiometry). Discussion: It was found a high prevalence of neurological signs and symptoms among patients examined. The course of the disease was more aggressive in some patients with recurrent strokes or severe sensorineural deafness. Radiological findings include white matter changes, but some patients have normal cranial magnetic resonance angiography. The patients are in follow-up, and seven of them started specific treatment of the disease with enzyme replacement therapy associated with the use of carbamazepine for neuropathic pain and angiotensin-converting enzyme inhibitors to control proteinuria.

FABRY DISEASE: EARLY AND SEVERE PRESENTATION IN WOMEN CARRIERS 1

1

1

1

Veloso, VSP ; Pereira, ERS ; Sousa, MF ; Ataides, TLA ; 1 1 1 Cunha TCM ; Rezende, JE ; Guimarães, MR .

1 Division of Nephrology, Department of Internal Medicine, Hospital das Clínicas, Universidade Federal de Goiás, Goiânia, Brazil.

Introduction: Fabry Disease (FD) is a rare lisossomal X-linked disease that leads to alphagalactosidase A (alpha-Gal A) deficiency and accumulation of globotrialosilceramida (Gb-3). It causes cellular disfunction and several clinical abnormalities. Retrospective case series: from a male index patient with FD in hemodialysis was possible to diagnose, after genotyping, 8 female carriers. The genetic investigation shows the mutation p.G35V in homozygosity in exon 1. The oldest one, with 71y, died of mesenteric ischemia two months after diagnosis. The average age at diagnostic was 31y. Only one of the patients, the daughter of the index case is oligosymptomatic. The other 6 patients had characteristic symptoms such as headache, hypoacusia and acroparesthesia. They were screened for kidney disfunction such as proteinuria and serum creatinine. They all had normal serum creatinine, but 4 of them already have proteinuria>150mg/24hours. They underwent percutaneous kidney biopsy with optic, electronic microscopic and immunofluorescence avaliation. They identified deposits of Gb-3 in the podocytes in all samples and signs of tubular atrophy and interstitial fibrosis in one patient with gross proteinuria. They were all screened for cardiac and neurologic involvement. Three sisters of the index case have cardiologic involvement. It was also noted that this new mutation has a more aggressive neurologic involvement, reaching central and periferic nervous system. Five of these patients already started enzymatic replacement therapy. Discussion: Recent evidences points that women in heterozygosis are potential patients and not only carrier of the new mutation. These patients can present the disease as severe as men, although the progression is slower. In this case series, the average age of diagnosis was 31y; about one decade earlier literature reports and already with important renal lesions, despite mild proteinuria. Conclusion: as FD presents an important decrease in quality of life and important organs dysfunctions, the early detection is crucial. It is a big challenge making early detection of FD and simple exams such as ophthalmologyc exam and ECG are large diagnostic weapons in this case. The main point is to find out the correct time to star treatment, before irreparable complications.

THE HARD WAY TO GET THE FIRST ENZYMATIC REPLACEMENT THERAPY FOR FABRY DISEASE IN ECUADOR

1

Espín-Villacrés VH Servicio de Genética, Hospital Carlos Andrade Marin Quito - Ecuador vhugoespin@gmail.com

This is a report of a young, 27 year old man affected by Fabry disease. His maternal grandfather died by a terminal renal condition of unknown etiology. In 2004, during a family trip to New York City, a complete family investigation was carried out at Human Genetics Lab of Mount Sinai School of Medicine. They discovered that her mother and sister were carriers and he was affected of Fabry disease. At this time he was an asymptomatic 17 years old man. Time after, a molecular sequencing find out 195R1G>C mutation at GLA gene Ten years after diagnosis, The Instituto de Seguridad Social Ecuatoriano (Social Security National Service) could have the legal chance to get agalsidase beta. After a year of complex and difficult paperwork, it was feasible to buy the enzyme and start the very first Fabry disease enzymatic replacement therapy in Ecuador.

The patient began his agalsidase infusions on 2014. He started therapy with normal renal function test and a normal brain NMR. At this time, after his fifth infusion, the patient had showed an important allergic reaction, and is now under anti-allergic treatment.

FABRY DISEASE IN COQUIMBO, CHILE : MORE THAN 12-YEARS FOLLOW UP. Carmen Varas (1) , María Griselda Gomez (2) , Fernando Molt (3) , Miguel Morales (4) , Giselle Myer (5) .

Hospital San Pablo, Coquimbo, Chile: 1 (Dermatology), 2 (Cardiology ) ,3 (Neurology ), 4 (Nefrology),5 (Internal Medicine) Email: fernando.molt@redsalud.gob.cl

Fabry´s disease (FD) is an X-linked recessive inborn error of metabolism of glycosphingolipids, caused by the deficiency of the lisosomal enzyme alpha-galactosidase. It is a rare disease with an estimated incidence rate of approximately 1:80.000 to 1:117,000 births in the general population. The growing knowledge about this disease has permitted the development of enzyme replacement therapy, which has modified the prognosis and quality of life of these patients. In Chile, the real incidence is unknown, but there has been an increase in the number of patients diagnosed during the past five years, mainly in the northern part of the country. In Chile, half of the patients are in the Coquimbo region, where the prevalence is 6,6:100.000/habitants. The affection of the disease is multisystemic, including: cardiac, renal, ophthalmic, dermic , digestive and neurological involvement, where the neurologic involvement is more early and widespread.

Method: Examination and interview to 66 patients with confirmed FD. Ad-hoc protocol was filled. All patients were admitted with a multidisciplinary team including neurologist, cardiologist, nephrologist, dermatologist and ophthalmologist. The enzyme dosage and punctual mutation in blood test was studied in each patient.

Results: 62.2% (41) female patients, 37.8% (25) male patients.. Onset symptoms age: 7 years old, with Hypertrophic Myocardiopathy in 56% of adults. After 40 years old, all men are afected , 82% of women.

65,7% with cornea verticillata. Renal involvement 40% of studied patients. 3 in hemodialysis, 1 transplant patient. 84% with chronic pain, 71% neuropathic pain, 84% with acroparesthesia. 3 patients were affected with clinical ischemic stroke: two lacunars and one embolic infarct. Mutation pP259R (65) pW81X (1).

Discussion: FD is a rare disease, but in Chile, there is a significant prevalence, with most of the cases in Coquimbo region. Neurologic involvement is the more early and widespread, including micro-fiber polyneuropathy with acroparesthesia and neuropathic pain. Nearly cardiologic and renal involvement. Skin lesions and cornea verticillata are an important clue in diagnosis. The development of enzyme replacement therapy, has modified the prognosis and quality of life of these patients. At this moment therapy is available only for 34 patients in our hospital.

PROSPECTIVE STUDY OF PATIENTS DIAGNOSED WITH FABRY DISEASE IN COLOMBIA 1 1 1 1 Beltran Johnny , Rubio Andrea , Jojoa Ruby , Granados María 1

Centro de Investigación y Atención Médica-Caimed, Bogotá DC, Colombia; johnny.beltran@caimed.com 2

Background: Fabry disease is an inherited, progressive multisystemic disorder caused by deficient activity of the enzyme α-galactosidase A. Due to its low frequency and heterogeneous presentation patients usually have delays in diagnosis. The present study describes the disease in a group of Colombian patients with confirmed diagnosis of EF without enzyme replacement therapy Methodology: Prospective study in which the following tests were performed to 36 confirmed non treated Fabry patients: complete medical evaluation, cerebral and cardiac magnetic resonance imaging with gadolinium, echocardiography, 24 hours holter, spirometry, audiometry, ophthalmologic evaluation, quantitative sensory determination and kidney function tests. The study was approved by an independent ethics committee and informed consent was obtained from each patient.

Results: Between August and December 2014, 36 subjects from 5 cities in the country were included. 32 (89%) were female and 8 (22%) children. The average age was 31.8 years (DE17-37). The most frequently reported symptoms were headache (64%), palpitations (42%) and intolerance to cold or heat (42%). The most important findings were: At cardiovascular level, 6 cases (21%) had left ventricular hypertrophy and 4 (11%) pulmonary hypertension. Among adults 39% had ventricular arrhythmias, 18% significant supra ventricular arrhythmias, 11% ST-segment abnormalities and in one case (4%) atrial flutter was found. Myocardial fibrosis was detected in 6 adults (27%) through cardiac resonance.

26 cases (72%) had cornea verticillata.

11 (31%) patients had microalbuminuria and 8 (22%) proteinuria, no cases of severe impairment of glomerular filtration rate (eGFR <60 ml / min). Other findings were: 33 (92%) cases had evidence of sensory disturbance, 7 (19%) impaired respiratory function and 4 (11%) hearing loss. 20 (55%) patients had an abnormal finding on brain scan.

Conclusions: This study describes the multisystemic spectrum of EF in a group of Colombian patients.

Pathological findings, especially cardiovascular level, ocular, neurological and renal, were significant in patients previously classified as asymptomatic. A complete and early assessment of a Fabry a patient is mandatory to define treatment indication.

FABRY NEPHROPATHY IN WOMEN 1

Quintero, Edwin 1

Department of Nephrology, Manuel Uribe Angel Hospital, Fresenius Medical Care, Medellín, Colombia; edwinquinteroh@gmail.com

Fabry disease, an X-linked genetic disorder with deficient α-galactosidase A activity, is characterized by kidney disease and kidney failure. The spectrum of kidney disease has not been well defined, especially in female patients.

Here we describe the cases of 2 females, 43 and 47 years old, cousins, diagnosed with Fabry disease [heterozygous mutation in exon 6 of the GLA gene (c.803_806delTAGT p.L268X)]. This mutation has been described as disease causing by Lee, 2000. Lyso- Gl3 and enzymatic activity were not performed at initial evaluation.

FAMILIAL HISTORY: index case is the brother of one of the subjects, currently on treatment and has kidney disease.

Both patients referred nonspecific pain in hands and feet since childhood, joint pain and chronic fatigue.

They had consulted several times without reaching a specific diagnosis.

When diagnosed with Fabry disease both were evaluated by a nephrologist, who conducted baseline studies to determine severity of systemic compromise. Both had: normal renal function measured by eGFR, microalbuminuria (-) and proteinuria (-), Echocardiogram without evidence of LVH, cornea verticillata present.

One of the patients showed nonspecific asymmetric, widespread deep white-matter lesions, hyperintense on T2-weighted and T2-FLAIR MRI, without neurologic symptoms or deficit at physical examination. Because of these findings it was decided to perform renal biopsy that reported:

Conclusions: Although both patients were oligosymptomatic and without apparent clinical renal damage, the renal biopsy confirmed organ damage. Although in both cases treatment with ERT was indicated, biopsy results were meaningful to further support treatment initiation at least in one of the presented cases. Renal biopsy might be a useful tool in some oligosymptomatic women to identify early organ damage due to Fabry disease.

QUANTITATIVE SENSORY TESTING IN FABRY DISEASE Fernando Ortiz-Corredor, MD 1,2, Jorge Diaz-Ruiz, MD 1,2, Edicson Ruiz-Ospina, MD 1, Sandra Castellar-Leones, MD 1, Johnny Beltrán, MD 3 1

Universidad Nacional de Colombia, 2 CIFEL, 3 CAIMED, Bogotá, Colombia; jorge.diazruiz@gmail.com

Background: Fabry disease is a rare condition X- linked inherited caused by a deficiency of ALPHAGALACTOSIDASE A enzyme, displaying multisystemic involvement accompanied by painful neuropathy. Although it has been classically considered as a disease which affects males recent studies have proven female carriers can exhibit peripheral nerve involvement. The aim of the study is to describe our findings in quantitative sensory testing and neuropathic symptom score applied in a group of heterozygote women.

Materials and methods: We studied 31 women with fabry disease confirmed by genetic tests. In order to exclude uremic neuropathy cases the individuals with creatinine clearance rate lower than 50ml/min were excluded.

Neuropathic Symptom Score (minimum score 0, maximum score 45) and Quantitative Sensory Testing (QST) were applied to all women included in the study. Warming and cooling thresholds were estimated on dorsal surfaces of hand and foot with CASE IV SYSTEM using 4,2,1 Stepping Algorithm. Thresholds to warming and cooling detection were considered markers for disturbance in small diameter fiber.

Thresholds for vibration detection were considered markers for disturbance in large nerve fibers. Highest temperature used was 45 degrees C. For data analysis we used JND (Just Noticeable Difference) which have possible values from 1 to 25. For pain answers results were dichotomized between normal and abnormal.

Results: We studied 31 women with mean age 31.3 years (Minimum 6, maximum 70; SD= 17, 1). Neuropathic Symptom score was 3,5 (minimum= 0, maximum= 27; SD= 5,7). The score didn't show any correlation with age. Mean JND values in foot for vibration, cooling and warming modalities was 13 (ED= 4,1; Abnormal 61%), 7,5 (SD= 2,3; abnormal 22,6%) and 10 (SD=4,8; Abnormal 41%) respectively. Values for heat pain algorithm were abnormal in 74,2%. Abnormalities seen in QST were correlated with age.

Conclusion: Our results suggest heterozygote women exhibit abnormalities in Quantitative Sensory Testing and in neuropathic symptoms which can be confirmed through Quantitative Sensory Testing studies. This abnormal findings are more common in lower limbs suggesting small fiber neuropathy which is length dependent and progresses through time.

DEPÓSITOS MASIVOS Y AFECCIÓN GLOMERULAR MARCADA EN UN PACIENTE CON ENFERMEDAD SILENTE: ¿ES NECESARIA LA BIOPSIA RENAL PROTOCOLARIA? 1

2

1

Ernesto L Chávez- López , Virgilia Soto- Abraham , Emmanuel Pedraza Servicio de Nefrología, Hospital General de México “Dr. Eduardo Liceaga”, México, D.F. 1 Servicio de Patología, Hospital General de México “Dr. Eduardo Liceaga”, México, D.F.

1

La Nefropatía por Fabry ocurre por la acumulación progresiva de GL-3 mediante 3 mecanismos básicos: endotelial (isquémica), daño podocítico y acúmulo tubulointersticial. De manera tradicional se ha considerado que las lesiones son universales en pacientes de 25 años de edad. La mayoría de los pacientes que progresan a Insuficiencia Renal crónica avanzada lo hacen alrededor de los 40 años.

Se ha identificado a la proteinuria como un factor de riesgo mayor para el desarrollo y progreso de enfermedad avanzada, sin embargo no existe consenso de realizar biopsia renal a pacientes asintomáticos.

Se presenta el caso de un paciente masculino de 17 años con anhidrosis y acroparestesias. Tiene dos tíos con Nefropatía por Fabry en hemodiálisis, uno finado. La función renal es normal y tiene microalbuminuria. No existe afección ocular, cardíaca o neurológica.

Ante el fenotipo de alto riesgo y la necesidad de tratamiento enzimático se realiza biopsia que muestra edema de podocitos y borramiento de procesos podales con “cuerpos cebroides” y lesiones similares en las células endoteliales.

Hemos planteado la necesidad de realizar biopsia renal de manera protocolaria, incluso en pacientes sin proteinuria y función renal normal pues la presencia de cambios histológicos tempranos pudiera tener implicaciones pronosticas en pacientes asintomáticos con Enfermedad de Fabry.

“RECHAZO HUMORAL EN INJERTO RENAL DE PACIENTE CON ENFERMEDAD DE FABRY” 1

2

2,

Pérez Tinoco Vladimir , Gómez Villanueva Damayanty , Vital Flores Socorro Ríos Zárate Claudia 2 3 Ivette , Soto Abraham Virginia 1 Departamento de Nefrología CM Licenciado Adolfo López Mateos , ISEM Toluca; vlad8308@hotmail.com 2Departamento de Nefrología, Hospital Juárez de México, Distrito Federal, México; balkis_25@hotmail.com; Departamento de Patología Hospital General de México.

BACKGROUND The renal trasplant restores satisfactory the kidney failure and the extra renal manifestations cause by Fabry Disease. The survival of the patient and graft is about 90% at 5 years and 66% at 10 years, with stable kidney function if the patient continue enzymatic treatment.

ABSTRACT A man 43 years old, with history con of chronic kidney disease secondary to Fabry disease with treatment with beta-galactosidase 10 gr each 14 days, smoking, hypertension, HAS; renal transplant from cadaveric donor on December 12, 2011. He received induction treatment with timoglobulin, 19 hours 10 minutes of cold ischemia, serum creatinine 1.5 mg/dl. Actually treatment with MMF 500mg /12hr, Tacrolimus 1mg /12 hr, prednisone 15 mg / 24 hr, Espironolactona 25 mg/24 hrs, telmisartan 40 mg/24hrs. One month post trasplantation with progressive creatinine increase and proteinuria, and he was treated with metilprednisolone 125mg /8h , no improvement.

Laboratories: Hb 13.6 g/dl, Htc 42.2%, leukocytes 6 10ᵌ/ul, plt 217 mil, Serum Creatinine 3.61 mg/dl, urea 152 mg/dl, sodium 144 mmol/L, K 4.8 mmol/L, proteinuria, 260 mg protein in 24 hours, TORCH no reactive, viral test negative, renal Gammagram 34.3 ml/min, kidney Doppler with normal graft , decreased echogenicity to the cortex, vascularity decreased to the cortex, RI < 0.75.

Renal biopsy 23 glomeruli glomerular hypertrofia and chronic hypoperfusion, rejection criteria of Banff 1A with humoral component, diffuse + C4d in peritubular capillaries. IF negative. EM without Fabry disease. The treatment was plasmapheresis and anti-CD20.

Several Fabry patients with successful kidney graft survived for 10-15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis.

An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. Postkidney transplantation outcomes among patients with Fabry disease remain controversial. This requires further investigation and may suggest a need for further attention to the minimization of cardiovascular death in this group of patients.

ENFERMEDAD DE ANDERSON-FABRY.REPORTE DE UNA FAMILIA CON UNA MUTACION NUEVA EN EL GEN GLA 1

1

2

3

4

Fátima Sierra , Azucena Sánchez Verónica Salazar , Pablo Radillo Departamento de Genética, Hospital de la Mujer, SSA, Puebla, México; fatsie2002@yahoo.com.mx, 2 Departamento de Genética, Hospital General Regional 36,IMSS, Puebla, México;azugenetics@gmail.com.3,4Genzyme México.

Introducción:La Enfermedad de Anderson-Fabry, (AFD) OMIM 301500 es una enfermedad ligada al cromosoma X. Este defecto enzimático ocasiona el depósito lisosomal progresivo de globotrialosilceramida (GL-3) dentro de las células especialmente cardiomiocítos, células renales, endoteliales neuronales y vasculares ocasionando daño sistémico progresivo.El gen GLA (Xq22.1) es el único asociado a AFD, contiene 7 exones y codifica para la enzima a-GalactosidasaA.Sintratamiento los pacientes con EAD tienen una progresión letal.

Descripción del caso: Se trata de una familia mexicana de 5 generaciones con 95 miembros (Fig. 1), se incluyeron mujeres y varones. Cinco pacientes masculinos fallecieron entre la segunda y tercera década de la vida por insuficiencia renal crónica, su diagnóstico se realizó en base a su historia clínica y al árbol genealógico. Hasta el momento en 15 pacientes se ha confirmado por estudio molecular una mutación patógena del gen GLA. Actualmente tres mujeres y un hombre se encuentran con Terapia de Reemplazo Enzimático (ERT) con Agalsidasa Beta a dosis de 1mg/kg/bisemanal.

Discusión: Esta mutación patogénica de tipo microdeleción c.260delA (p.Glu87Glyfs*34), en el exón 2 del gen GLA, predice la generación de una proteína trunca sin actividad enzimática (mutación amorfa y con pérdida completa de la función). Esta mutación no ha sido previamente reportada en la literatura. La diversidad de presentación clínica es muy amplia (Tabla 1), ya que existen integrantes de esta familia completamente asintomáticos, otros integrantes jóvenes para la edad promedio de inicio de la sintomatología, con daño renal y neurológico importante. Continuar con el seguimiento e iniciar con la ERT en algunos integrantes de esta familia es primordial. Conclusiones: Reconocer la AFD, representa un desafío clínico; en nuestro país es una entidad subdiagnosticada por su amplio espectro de presentación clínica (que genera confusión con otros padecimientos) y por desconocimiento de la misma enfermedad. Es imperante formar grupos interdisciplinarios con entrenamiento para la sospecha, diagnóstico y tratamiento de estos pacientes.Aún tenemos mucho que aprender sobre este padecimiento y son estos foros de presentación los que permitirán con la experiencia de todos hacer diagnósticos tempranos para iniciar TRE a tiempo.

Bibliografía.

Riccio E, Capuano et al. Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature. G Ital Nefrol. 2013, sep-oct; 30(5).

Aortic Stenosis in Fabry disease Patients Juan Manuel Romero Trejo, Guillermo Valadez Juvera, Sergio Figueroa Sauceda Cardiology Deparment UMAE Ciudad Obregón, Mexican Institute of Social Security (IMSS), Mexico. cardiorom61@hotmail.com Introduction: one of the lesser reported cardiac manifestations of Fabry disease (FD) is aortic stenosis (AS).

Literature reports have described isolated cases; no specific mutations have been associated to these cases. The purpose of this presentation is to describe this valvulopathy in two members of a same family with FD. Case reports: Case 1 is a 54 year old male with end stage renal disease with a kidney transplant was diagnosed with Fabry disease (R342X mutation), and was started on ERT with agalsidase beta. Initial cardiologic evaluation through EKG and echocardiogram revealed moderate ventricular hypertrophy with mild mitral, tricuspid and aortic valve insufficiency. Four years later he presented with vertigo, dyspnea and chest pain. A new echocardiogram revealed a deterioration of the patient's valvulopathy: severe aortic valve calcification associated with double aortic lesion: severe stenosis with a maximal gradient of 34 mmHg, medium gradient of 18 mmHg and max velocity of 2.9 m/seg with mild insufficiency; ejection fraction 66%. Treatment was adjusted with ACEi, diuretics and beta blocker, with which the patient returned to NYHA functional class 1. One year later, echocardiographic evaluation reveals a maximal gradient of 46 mmHg, medium gradient of 22 mmHg and max velocity of 3.4 m/seg, ejection fraction 66%; patient's cardiac status remains unchanged.

Case2 is the cousin of case 1. He is a 44 year old male diagnosed with Fabry disease (R342X mutation), with ESRD treated initially with hemodialysis via AV fistula and afterwards with kidney transplant. He received ERT with agalsidase beta for 6 years in the USA; however he was later sent to Mexico and could not continue on ERT. Five years later he was diagnosed with chronic allograft nephropathy established by kidney biopsy (T cell mediated damage with interstitial fibrosis and mild tubular atrophy). In that same date he presented with moderate dyspnea, chest pain and syncope. His AV fistula had a flow of 3 lts/min and a venous aneurysm. Echocardiography was performed revealing severe aortic stenosis, with calcification, valve area 0.62 cm2, maximal transvalvular velocity 4.9, maximal gradient 118 mmHg, median gradient 68 mmHg, LVEF 68%, mild insufficiency, severe left ventricle hypertrophy. He died shortly after due to cardiac complications.

Discussion: Both patients presented with the same valvular clinical feature at a late age and stage of disease evolution. Although the patients had multiorgan symptomatology, the relevance of the case is the mainly valvular manifestations of AFD. It is important to establish the factors that might have influenced the difference in outcome: allograft rejection, return to hemodialysis and the additional workload associated with an AV fistula are some of the elements that favoured a poorer outcome in patient 2. On the other hand, discontinuation of ERT seems to have also played a role: the patient who had continuous ERT has evolved satisfactorily in spite of older age; the patient whose ERT was suspended presented with rapid deterioration and death. This issue has particular relevance, considering that literature has demonstrated that earlier treatment initiation with ERT in these patients might avoid or slow this clinical feature and reduce early age mortality.

Ventricular tachyarrhythmias in Fabry disease: Relevance of ERT dose apropos of a case Juan Manuel Romero Trejo1,Sergio Figueroa Sauceda1,Guillermo Valadez Juvera1 Cardiology Department, UMAE Ciudad Obregón, Mexican Institute of Social Security (IMSS), Mexico. cardiorom61@hotmail.com Introduction: Cardiopathyin Fabry disease (FD) has diverse manifestations, of which arrhythmias are of special importance due to the mortality risk they pose. Many literature reports demonstrate that enzyme replacement therapy (ERT) can reduce cardiac events. Two ERT's are available commercially; theoretically both enzymes are biochemically identical and at their recommended dose have similar efficiency and security profiles. We present the case of a patient with severe classic FD whose cardiac manifestations demonstrated a dose response.

Case report: the patient is a 59 year old female diagnosed with classic FD. On evaluation, she presented achroparesthesias, occasional fainting spells, hypoacusia, abdominal discomfort and angiokeratomas. She was hypertensive and received therapy with an angiotensin receptor blocker. Her clinical studies demonstrated cornea verticillata, non-nephrotic proteinuria, stage 3 chronic kidney disease (eGFR 54 ml/min), sensorineural left hypoacusia and ischemic white matter lesions in both hemispheres, predominantly frontoparietal. She was started on ERT with agalsidase beta 1.0 mg/kg/EOW on 2004. Clinical evolution was satisfactory, with cardiovascular stability, reduction of analgesics for achroparesthesias and no new syncope events. On October 2011 she was switched to agalsidase alpha 0.2 mg/kg/EOW due to shortage of the other commercial product. On May 2012 she was sent to our clinic due to persistent vertigo and various syncope events. She referred that acroparesthesias and abdominal discomfort had reappeared, and her hearing had deteriorated. She had been monitoring her heart rate, which was 40 beats per minute (BPM). She was studied with 24-hour Holter which demonstrated sinus bradicardia (38 BPM) as well as recurrent monomorphic ventricular tachycardia events, for which an automatic implantable cardioverter defibrillator (AICD) was recommended.It was installed on September 2012, and the decision was taken to reswitch the patient to agalsidase beta 1.0 mg/kg/EOW. From November 2012 to May 2014, the patient denies new syncope events; no ventricular tachycardia events have been detected on subsequent 24-hour Holter studies, and the historical AICD register demonstratesminimal activity.

Discussion: Many studies have demonstrated that both enzymes at their commercialized dose have the same clinical effect. However, our case was associated with clinical deterioration when the patient was switched to a lower dose; leading to a severe clinical cardiac event and AICD implantation requirement. When the shortage issue concluded and patient could be switched back to a higher dose, electrophysiological signs and symptoms disappeared; AICD monitoring demonstratesminimal to null activity. Since every case can present differently, it is essential to determine the optimal dose for each individual patient in order to avoid possible subdosing, particularly in patients who have FD preestablished organ damage.

FABRY DISEASE IN A MALE PATIENT: DE NOVO MUTATION OR GERMLINE MOSAICISM? Karen Dublán García1, Pablo Radillo Díaz2 1

Department of Nephrology , Hospital General de Zona 1, IMSS, Durango, México; 2 kdublangarcia@yahoo.com.mx Department of Nephrology, Centro Médico Coyoacán, Mexico City, Mexico, pablo.radillo@genzyme.com Background: Fabry disease (FD) is an innate error of glycosphingolipid catabolism due to a genetic defect in the gene which codifies for alphagalactosidase A (α-Gal A) production (GLA gene). Mutations affecting the GLA gene result in deficiency of this lysosomal enzyme, which in turn leads to progressive accumulation of neutral glycosphingolipids, primarily globotriaosylceramide (GL-3), in different cell types throughout the body, including renal glomerular and tubular epithelial cells, myocardial cells and valvular fibrocytes, and nervous system.

FD has an X linked inheritance. Currently, more than 600 disease-causing mutations in the GLA gene have been described. Most of these mutations are private, restricted to an individual family. De novo mutations are rare; population reports establish their frequency between 4 and 7%.

We present the case of a pediatric male patient with a previously unreported de novo mutation, which during family tree analysis, revealed a positive sibling, but no mutation found in the mother.

Case presentation: A 17 year old male patient from Durango, México with a negative family history presented at our ward. His initial symptoms began at 10 years of age and were primarily neurological: recurrent and progressive acroparesthesias several times a week, upper and lower extremity weakness with movement limitations and fainting spells; he also complained of intermittent fever, hypohidrosis, abdominal pain and diarrhea. Clinical evaluation of the patient revealed tortuosity of retinal vessels, sinus bradycardia and hypotension and distal hyperesthesia in arms and legs. Fabry disease was suspected; α-Gal A enzyme activity, GLA gene analysis and lysoGL-3 measurement confirmed the diagnosis.

Family tree evaluation was carried out; one six-year-old brother also had the mutation; however no mutation was found in the mother's molecular analysis.

FD specific evaluation of the index case revealed positive 24-hour proteinuria (6,5mg/kg/hr reference <4ml/kg/hr); CNS MRI was normal. Kidney biopsy was conducted; electron microscopy analysis of specimens revealed dense lamellar bodies corresponding to lipid material deposits in all cell groups, confirming the presence of a pathological mutation.

Conclusions: De novo onset mutations are rare; however, even more infrequent is the presence of germline mutations, which have been reported only periodically in case reports. Unfortunately, female germline cells are difficult to obtain to confirm this diagnosis.

MIOCARDIOPATIA HIPERTROFICA POR ENFEMEDAD DE FABRY. FALLA DE EFICACIA DE AGALSIDASA-ALFA. Marín Gutiérrez F. J., Martínez Hernández C. G., Silva Ortíz J. A., Ramos D. Department of Internal Medicine – Cardiology, 50th General Hospital, Mexican Social Security Institute, San Luis Potosí, S. L. P., México; franciscojavier_marin@hotmail.com, cegemahe@yahoo,com.mx Introduction: Fabry disease is a rare condition characterized by multiorganic involvement of the skin, heart, peripheral nerves, brain, ear, kidney, gastrointestinal, and small vessels, and consists of lysosomal deposits by X linked a galactosidase enzyme deficiency Treatment is based on enzyme replacement therapy (ERT), which must be administrated continuously to avoid disease progression. We present a case with important cardiac and renal involvement, whose evolution was modified by ERT dose reduction, as confirmed by imaging and biomarker evaluations.

Case presentation: A 35 year old male diagnosed with rapidly progressive kidney failure in 2009; family history revealed another brother who had died of ESRD of unknown etiology. Kidney biopsy was performed, with findings suggestive of FD. Confirmation was made through enzymatic and molecular analyses. He started hemodialysis on November 2009, and began agalsidase beta on the same date. Initial cardiac evaluation demonstrated an EKG with mild abnormalities compatible with myocardial hypertophy and systolic overload, and echocardiogram which reported left ventricle mild dilation (51mm), concentric hypertophy (13 and 14 mm septum and inferior Wall respectively), EF: 71% with normal global and segmental wall movement. No valve abnormalities were reported.

In 2011, he was switched to agalsidasa alpha due to agalsidasa beta shortage. By the end of 2013 he presented a deterioration in NYHA functional class; a new echocardiogram at that date revealed worsening hypertrophy (21 and 23 mm of septum and inferior Wall respectively), EF: 62%, 536g of caclulated ventricular mass, normal global and segmentary Wall movement. Systolic pulmonary pressure 42 mmHg. A new EKG also showed deterioration.

Cardiac MRI was performed to see if myocardial hypertrophy was caused by hypertension or Fabry disease.

Images clearly demonstrated speckling compatible with lipid accumulation. GL-3 and lyso GL-3 were considerably above normal levels. ERT switch was considered, but patient died at the beginning of 2015 from cardiac arrest, before this was possible.

Discussion: More than 50% of all Fabry patients have a cardiac involvement (ie, Fabry cardiomyopathy), the most frequent pattern is concentric left ventricular hypertrophy (LVH) without LV outflow tract obstruction. Enddiastolic wall thickness of up to 16 mm can be found and is aasociated with higher mortality risk. In these patients LV systolic function, measured by ejection fraction, is normal. This distinguishes Fabry cardiomyopathy from idiopathic hypertrophic cardiomyopathy (HCM) and can be used to screen Fabry patients among individuals with unexplained LVH. The end-stage Fabry cardiomyopathy is characterized by intramural replacement fibrosis also limited to the basal postero-lateral wall of the LV. The non-invasive gold-standard to detect myocardial fibrosis is late gadolinium-enhanced magnetic resonance imaging (MRI). An indirect way to screen for regional myocardial fibrosis is functional strain rate imaging by echocardiography. Our patient had considerable damage which rapidly progressed, in part possibly due to hypertension and volume overload related toESRD; however, MRI images and biomarker measurement demonstrated that progression also was related to classic substrate deposition. In these cases, higher ERT dose must be considered, since this could result in better outcomes.

References: 1. Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international. Fabry outcome survey. Eur Heart J 2007;28:1228e35.

2. Barbey F, Brakch N, Linhart A, et al. Cardiac and vascular hypertrophy in Fabry disease: evidence for a new mechanism independent of blood pressure and glycosphingolipid deposition. Arterioscler Thromb Vasc Biol 2006;26:839e44.

3. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J 2005;26:1221e7.

4. Monserrat L, Gimeno-Blanes JR, Marin F, et al. Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2007;50:2399e403.

5. Weidemann F, Strotmann JM, Niemann M, et al. Heart valve involvement in Fabry cardiomyopathy. Ultrasound Med Biol 2009;35:730e5.

6. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003;24:2151e5.

Lapa Produções Criativas / Abril 2015