rd3

Cancn - Mxico

AbstractResume

AFECCION RENAL TEMPRANA EN UNA FAMILIA CON FABRY

1, 2

Rivera Flores Javier Vernica X. Amaro Triana

1

Servicio de Nefrologa, Hospital de Especialidades Centro Mdico Nacional Siglo XXI. IMSS, Distrito Federal,

Mxico; Servicio de Nefrologa , Hospital General de zona No.8.IMSS, Distrito riverhemo@hotmail.com

Federal,Mxico ; .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 ve 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?

1 1 2 3 1

Authors: Politei J , Schenone AB , Cabrera G , Heguilen R , Szlago M .

1

Fundacin para el Estudio de las Enfermedades Neurometablicas (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 decient 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 signicant 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 ltration 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 decient 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.

a b c d d

Juan Politei , Monica Calvo , Segundo Fernandez , David Warnock , Eric Wallace , Graciela e

Serebrinsky

a

Fundacin para el Estudio de las Enfermedades Neurometablicas (FESEN), Buenos Aires, b c

Argentina; Hospital Zonal General de Agudos Evita, Buenos Aires, Argentina; Centro Mdico d

CIPERCA, Catamarca, Argentina; Department of Medicine, University of Alabama, Birmingham, AL, e

United States; Laboratorio de Biologa y Patologa 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

mol/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 -galactosidase A

leukocyte level was 2.9 (normal 30.5-57.7 nmol/h/mg) and a novel Gal A hemizygote mutation (C174G)

was identied. 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 -galactosidase A leukocyte level was 2.8 nmol/h/mg and a novel Gal A hemizygote

mutation (R363H) was identied. 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 ENZIMTICO EN PACIENTES

CON ENFERMEDAD DE FABRY. EXPERIENCIA ARGENTINA

Dr. Gustavo Cabrera, Dr. Juan Politei, Dr. Norberto Antongiovanni, Dr.Hernn Amartino, Dr

Adrin Fernndez

En nombre de GADYTEF (Grupo Argentino de Diagnstico 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 hipertroa

ventricular izquierda su signo cardinal. La aprobacin de la terapia de reemplazo enzimtico (TRE) ha generado

nuevas expectativas para estos pacientes. Diversos estudios en poblaciones seleccionadas han demostrado una

favorable respuesta cardiaca a corto plazo con reduccin de la masa ventricular izquierda. Este efecto se ha visto

opacado por la escasa respuesta de los pacientes con mayor compromiso orgnico y mayor edad. Resulta interesante

resaltar que en la mayora de estos estudios la edad media de los pacientes tratados supera los 40 aos en ambos

sexos y por esta razn los resultados en trminos de reduccin del compromiso cardiaco y eventos clnicos 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 clnicos mayores. Se evaluaron en forma prospectiva 39 pacientes (24 hombres) de

Argentina con diagnstico conrmado de EF. Todos los pacientes fueron tratados con agalsidasa beta

(Fabrazyme ) a 1mg/kg cada 14 das.

Los 39 pacientes con edades promedio de 27.511aos para los varones y 41.913para las mujeres recibieron

TRE durante una media de 67,237meses (85.730 y 4232 meses respectivamente).

Al inicio de la TRE 11(44%) hombres y 9 (60%) mujeres presentaban HVI, 5 varones y 3 mujeres enfermedad renal 2

crnica (ERC) (IFGe EPI < 60 ml/min/1,73 m ) y 18 varones y 13 mujeres proteinuria y/o albuminuria. Un varn de

27 aos 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

insuciencia renal crnica (IRC) en fase terminal.

Dos varones presentaron enfermedad coronaria. Uno antes de iniciar la TRE y el otro como complicacin tarda de

su mala evolucin general. Dos pacientes evolucionaron a IRC estadio 5, pero iniciaron la TRE con IRC estadio 3 y

tuvieron baja adhesin a la TRE y a la terapia antiproteinrica.

Solo una paciente de sexo femenino presento brilacin auricular (FA) bien tolerada y controlada con beta

bloqueantes. Ningn varn present arritmias.

Los pacientes varones que no presentaron evento mostraron estabilizacin de la media del IMVI, mientras que los

que si presentaron eventos mostraron un incremento signicativo del mismo. En el caso de las mujeres la media

del IMVI se redujo en forma signicativa.

Se realiz un anlisis multivariado con el objeto de identicar 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

nica que alcanz potencia estadstica (p=0.001). Siendo la edad de los varones que presentaron evento de 37.2 8

aos vs. 25.6 10 aos.

CONCLUSIONES:

La respuesta favorable a largo plazo de la TRE en esta poblacin compuesta predominantemente por pacientes

jvenes, con una baja prevalencia de eventos clnicos mayores refuerza la necesidad de iniciar la TRE en estadios

tempranos de la enfermedad, previo al compromiso orgnico avanzado.

Resulta interesante resaltar que en la mayora de los estudios que evaluaron la respuesta a largo plazo de la TRE, la

edad media de los pacientes tratados supera los 40 aos y podra ser esta la razn por la que los resultados en estos

estudios no son los mejores a diferencia de nuestra cohorte cuya edad media es ms baja, 32.713 aos.

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 -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

(nonspecic change in periventricular white matter), hearing loss and proteinuria. The diagnosis of FD

was conrmed at age 26 through the low activity of -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 specic 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- Warnock DG, Mauer M. J Am Soc Nephrol. 2014 Apr;25(4):653-5. doi: Fabry disease: dose matters.

10.1681/ASN.2013121322. Epub 2014 Feb 20.

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

Weidemann F, Krmer J, Duning T, Lenders M, Canaan-Khl S, Krebs A, Guerrero Gonzlez H, Sommer

C, eyler N, Niemann M, Strk S, Schelleckes M, Reiermann S, Stypmann J, Brand SM, Wanner C,

Brand E.

3 - J Agalsidase benets renal histology in young patients with Fabry disease.

Tndel 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) 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 signicance 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 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.

DOENA DE FABRY COMO DIAGNSTICO DIFERENCIAL DE GLOMERULOPATIA

PROTEINRICA: RELATO DE CASO

1 2 2

Cassiano Augusto Braga Silva , Jos Andrade Moura Junior , Raphael Pereira Paschoalin , 2 2

Tlio Coelho Carvalho , Nathlia Pereira Paschoalin .

1,2

Department of Nephrology, Clnica Senhor do Bonm, Feira de Santana, Brasil;

cassianonefro@hotmail.com

INTRODUO: O envolvimento renal na doena de Fabry (DF) est relacionado ao progressivo

acmulo de GL3 nos podcitos, clulas epiteliais e tubulares, se manifestando inicialmente com

proteinria, podendo evoluir com doena renal crnica terminal (DRCt). A DF entra, portanto, como

diagnstico diferencial das glomerulopatias proteinricas, e seu reconhecimento reveste-se de extremo

valor frente disponibilidade da terapia de reposio enzimtica (TRE), que se iniciada precocemente,

pode mudar a histria natural da doena.

CASO CLNICO: D.O.B., 35 anos, procedente de Feira de Santana BA, Brasil. Em seguimento com

Nefrologia h 5 anos devido proteinria. Referia urina espumosa de longa data. Negava edemas e

outros sintomas. Mantinha funo renal normal (creatinina 1,0 mg/dL; uria 34 mg/dL). Urina tipo 1:

protena 2+. Proteinria de 24h: 1,04 g. Complemento, FAN e sorologias normais. US renal: nefropatia

parenquimatosa crnica. Bipsia renal em outubro/2010: GESF. Prescrito prednisona por 6 meses, e

posteriormente ciclofosfamida por mais 6 meses, sem evidncias de diminuio da proteinria. A partir

de ento, foi encaminhado para seguimento em nosso ambulatrio. Referia edema intermitente de

membros inferiores. Em uso de ramipril. Relatou ser portador de leses enegrecidas em regio

abdominal desde a infncia. Negava dores em articulaes. Hipoidrose discreta desde a adolescncia.

Negava outros achados ou sintomas caractersticos. Exame fsico: 57 kg, 1,80 m. Angioqueratomas em

regio de calo de banho. Sem edemas. Sem outras alteraes. Antecedentes familiares: irmo de 37

anos com hipoidrose intensa e angioqueratomas. Me apresenta dores generalizadas, principalmente

em membros inferiores. Tia com DRC; tio faleceu em hemodilise; outra tia j apresentou 3 episdios de

AVC. Exames: uria 42 mg/dL; creatinina 1,6 mg/dL; proteinria de 24h: 2,05 g; urina tipo 1: protena 1+.

Atividade enzimtica Alfa-galactosidase: 0,2 mol/L/h (VN 1,9 mol/L/h). Lyso-Gb3: 92,5 ng/mL (VN

1,8 ng/mL). Anlise gentica: mutao no gene GLA (c.679C>T p.R227*). Foi submetido a outra bipsia

renal. No momento, em uso de losartan 50 mg, e em TRE com Fabrazyme.

DISCUSSO: Relatamos aqui o caso de um paciente com quadro clnico clssico de DF, inicialmente

tratado como portador de GESF, o que postergou o diagnstico e consequentemente o incio da TRE.

Clinical Prole 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 ndings in female patients carrying a null mutation.

PATIENTS AND METHODS:

We analyzed the clinical prole 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 signicant 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, G; Biagini, GLK.

Centro de infuso de Doena de Fabry, Instituto do Rim do Paran, Curitiba, Paran, Brasil;

gilson.biagini@gmail.com.

Disciplina de Endocrinologia-Doenas steo-metablicas.Faculdade Evanglica de Medicina

doParan, Curitiba, Paran, Brasil; . endocrino1999@hotmail.com

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

Beginning in childhood, this abnormal buildup causes growth deciency. 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 efcacy 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 deciency. 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 nal 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 efcacy 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

1 1 1 1

Veloso, VSP ; Pereira, ERS ; Sousa, MF ; Ataides, TLA ; 1 1 1

Cunha TCM ; Rezende, JE ; Guimares, MR .

1

Division of Nephrology, Department of Internal Medicine, Hospital das Clnicas,

Universidade Federal de Gois, Goinia, 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

conrmed 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 rst 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 zebroidand myelin likeappearance 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 efcacy of the specic treatment.

COGNITIVE IMPAIRMENT IN PATIENTS OF A FABRY DISEASE'S FAMILY

Veloso,VSP; Pereira,ERS; Sousa,MF; Ataides,TLA; CunhaTCM; Rezende,JE; Guimaraes,MR;

Mendona,ACR; Diniz,DS

Division of Nephrology, Department of Internal Medicine, Hospital Of Clinical, University Federal Of

Gois, Goiania, Brazil

Introducon: Inborn errors of metabolism lead to a heterogenic group of rare genec disorders, Fabry disease

being one of them. It is a lysosomal adult disease related to X-linked and enzymac changes cause the

accumulaon of (Gb-3) inheritance. Its main manifestaons are cutaneous, neurologic, globotrialosilceramide

cardiac and renal. Objecve: Because the neurological disorders, we evaluate possible cognive impairment in

this group of paents. Case report: A six female paents' family, was referred to the Neurology Service of the

Hospital das Clinicas de Gois by the Nephrology Service of the same hospital. Neurological examinaon and

cognive assessment was done in all of them. Methodology: The paents underwent neurological examinaon

by a neurologist and for neuropsychologists who applied the BRB-N baery that assesses verbal memory

(learning), visuospaal memory (learning), aenon, processing speed, working memory and semanc verbal

uency. MSFC was also applied to evaluate the agility of upper limb motor funcon, walking speed and the

aenon, processing speed and working memory. All procedures took place at the Centro de Referencia,

Invesgao e Tratamento em Esclerose Mlpla (CRIEM) / FM / HC / UFG for a visit of approximately 2 hours.

Results: All paents showed cognive 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 aenon,

processing speed and working memory and beer performance on the Word List Generaon (WLG) (83.4%)

which assesses verbal learning memory. Conclusion: According to our results we can state that the paents of

Fabry disease, even if asymptomac, early show cognive impairments, conrmed by performance in the PASAT

(already validated for the Brazilian populaon). The performance at Nine-Hole Peg Test (9HPT) and Timed 25-

Foot Walk, were relavely 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

1 1 1 1

Veloso, VSP ; Pereira, ERS ; Sousa, MF ; Ataides, TLA ; 1 1 1

Cunha TCM ; Rezende, JE ; Guimares, MR .

1

Division of Nephrology, Department of Internal Medicine, Hospital das Clnicas,

Universidade Federal de Gois, Goinia, Brazil.

Introduction: Fabry disease is a rare lysosomal disorder linked to the X chromosome that leads to the deciency 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 brosis,

heart failure and chronic kidney disease. Objectives: We present the clinical and radiological neurologic ndings of

a series of patients from a single family with a conrmed diagnosis of Fabry disease. Case Report: From a patient-

index 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 ndings include white matter changes, but some patients have normal cranial

magnetic resonance angiography. The patients are in follow-up, and seven of them started specic treatment of the

disease with enzyme replacement therapy associated with the use of carbamazepine for neuropathic pain and

a n g i o t e n s i n - c o n v e r t i n g e n z y m e i n h i b i t o r s t o c o n t r o l p r o t e i n u r i a .

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 ; Guimares, MR .1

Division of Nephrology, Department of Internal Medicine, Hospital das Clnicas,

Universidade Federal de Gois, Goinia, Brazil.

Introduction: Fabry Disease (FD) is a rare lisossomal X-linked disease that leads to alphagalactosidase A (alpha-Gal

A) deciency 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 immunouorescence avaliation. They identied deposits of Gb-3 in the podocytes in all

samples and signs of tubular atrophy and interstitial brosis 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 nd 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

Espn-Villacrs VH1

Servicio de Gentica, 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 nd 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 difcult

paperwork, it was feasible to buy the enzyme and start the very rst 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 fth 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.

(1) (2) (3) (4)

Carmen Varas , Mara Griselda Gomez , Fernando Molt , Miguel Morales , 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

Fabrys disease (FD) is an X-linked recessive inborn error of metabolism of glycosphingolipids, caused

by the deciency 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

modied 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 ve 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 conrmed FD. Ad-hoc protocol was lled. 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 signicant prevalence, with most of the cases in Coquimbo

region. Neurologic involvement is the more early and widespread, including micro-ber 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 modied 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 COLOMBIA1 1 1 1

Beltran Johnny , Rubio Andrea , Jojoa Ruby , Granados Mara

1

Centro de Investigacin y Atencin Mdica-Caimed, Bogot DC, Colombia; 2

johnny.beltran@caimed.com

Background: Fabry disease is an inherited, progressive multisystemic disorder caused by decient

activity of the enzyme -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 conrmed diagnosis of EF without enzyme replacement therapy

Methodology: Prospective study in which the following tests were performed to 36 conrmed 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 ndings were: At cardiovascular level, 6 cases (21%) had left ventricular

hypertrophy and 4 (11%) pulmonary hypertension. Among adults 39% had ventricular arrhythmias, 18%

signicant supra ventricular arrhythmias, 11% ST-segment abnormalities and in one case (4%) atrial

utter was found. Myocardial brosis 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 ltration rate (eGFR

FABRY NEPHROPATHY IN WOMEN

1

Quintero, Edwin

1

Department of Nephrology, Manuel Uribe Angel Hospital, Fresenius Medical Care, Medelln,

Colombia; edwinquinteroh@gmail.com

Fabry disease, an X-linked genetic disorder with decient -galactosidase A activity, is characterized by

kidney disease and kidney failure. The spectrum of kidney disease has not been well dened, 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 nonspecic pain in hands and feet since childhood, joint pain and chronic fatigue.

They had consulted several times without reaching a specic 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 nonspecic asymmetric, widespread deep white-matter lesions,

hyperintense on T2-weighted and T2-FLAIR MRI, without neurologic symptoms or decit at physical

examination. Because of these ndings it was decided to perform renal biopsy that reported:

Conclusions: Although both patients were oligosymptomatic and without apparent clinical renal

damage, the renal biopsy conrmed 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 Beltrn, MD 3

1

Universidad Nacional de Colombia, 2 CIFEL, 3 CAIMED, Bogot, Colombia;

jorge.diazruiz@gmail.com

Background:

Fabry disease is a rare condition X- linked inherited caused by a deciency of ALPHA-

GALACTOSIDASE 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 ndings 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 conrmed 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 ber.

Thresholds for vibration detection were considered markers for disturbance in large nerve bers. 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 conrmed through Quantitative Sensory Testing

studies. This abnormal ndings are more common in lower limbs suggesting small ber neuropathy

which is length dependent and progresses through time.

DEPSITOS MASIVOS Y AFECCIN GLOMERULAR MARCADA EN UN PACIENTE CON

ENFERMEDAD SILENTE: ES NECESARIA LA BIOPSIA RENAL PROTOCOLARIA?

1 2 1

Ernesto L Chvez- Lpez , Virgilia Soto- Abraham , Emmanuel Pedraza1

Servicio de Nefrologa, Hospital General de Mxico Dr. Eduardo Liceaga, Mxico, D.F.1

Servicio de Patologa, Hospital General de Mxico Dr. Eduardo Liceaga, Mxico, D.F.

La Nefropata por Fabry ocurre por la acumulacin progresiva de GL-3 mediante 3 mecanismos bsicos: endotelial

(isqumica), dao podoctico y acmulo tubulointersticial. De manera tradicional se ha considerado que las

lesiones son universales en pacientes de 25 aos de edad. La mayora de los pacientes que progresan a Insuciencia

Renal crnica avanzada lo hacen alrededor de los 40 aos.

Se ha identicado 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 asintomticos.

Se presenta el caso de un paciente masculino de 17 aos con anhidrosis y acroparestesias. Tiene dos tos con

Nefropata por Fabry en hemodilisis, uno nado. La funcin renal es normal y tiene microalbuminuria. No existe

afeccin ocular, cardaca o neurolgica.

Ante el fenotipo de alto riesgo y la necesidad de tratamiento enzimtico se realiza biopsia que muestra edema de

podocitos y borramiento de procesos podales con cuerpos cebroides y lesiones similares en las clulas

endoteliales.

Hemos planteado la necesidad de realizar biopsia renal de manera protocolaria, incluso en pacientes sin proteinuria

y funcin renal normal pues la presencia de cambios histolgicos tempranos pudiera tener implicaciones

pronosticas en pacientes asintomticos con Enfermedad de Fabry.

RECHAZO HUMORAL EN INJERTO RENAL DE PACIENTE CON ENFERMEDAD DE FABRY

1 2 2,

Prez Tinoco Vladimir , Gmez Villanueva Damayanty , Vital Flores Socorro Ros Zrate Claudia 2 3

Ivette , Soto Abraham Virginia 1

Departamento de Nefrologa CM Licenciado Adolfo Lpez Mateos , ISEM Toluca; 2

vlad8308@hotmail.com Departamento de Nefrologa, Hospital Jurez de Mxico, Distrito Federal,

Mxico; balkis_25@hotmail.com; Departamento de Patologa Hospital General de Mxico.

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 10/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 hypertroa 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 2 3 4

Ftima Sierra , Azucena Snchez Vernica Salazar , Pablo Radillo1

Departamento de Gentica, Hospital de la Mujer, SSA, Puebla, Mxico; , fatsie2002@yahoo.com.mx2

Departamento de Gentica, Hospital General Regional 36,IMSS, Puebla, 3,4

Mxico;azugenetics@gmail.com. Genzyme Mxico.

Introduccin:La Enfermedad de Anderson-Fabry, (AFD) OMIM 301500 es una enfermedad ligada al cromosoma

X. Este defecto enzimtico ocasiona el depsito lisosomal progresivo de globotrialosilceramida (GL-3) dentro de

las clulas especialmente cardiomioctos, clulas renales, endoteliales neuronales y vasculares ocasionando dao

sistmico progresivo.El gen GLA (Xq22.1) es el nico asociado a AFD, contiene 7 exones y codica para la enzima

a-GalactosidasaA.Sintratamiento los pacientes con EAD tienen una progresin letal.

Descripcin 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 dcada de la vida por

insuciencia renal crnica, su diagnstico se realiz en base a su historia clnica y al rbol genealgico. Hasta el

momento en 15 pacientes se ha conrmado por estudio molecular una mutacin patgena del gen GLA.

Actualmente tres mujeres y un hombre se encuentran con Terapia de Reemplazo Enzimtico (ERT) con

Agalsidasa Beta a dosis de 1mg/kg/bisemanal.

Discusin: Esta mutacin patognica de tipo microdelecin c.260delA (p.Glu87Glyfs*34), en el exn 2 del gen

GLA, predice la generacin de una protena trunca sin actividad enzimtica (mutacin amorfa y con prdida

completa de la funcin). Esta mutacin no ha sido previamente reportada en la literatura. La diversidad de

presentacin clnica es muy amplia (Tabla 1), ya que existen integrantes de esta familia completamente

asintomticos, otros integrantes jvenes para la edad promedio de inicio de la sintomatologa, con dao renal y

neurolgico importante. Continuar con el seguimiento e iniciar con la ERT en algunos integrantes de esta familia

es primordial. Conclusiones: Reconocer la AFD, representa un desafo clnico; en nuestro pas es una entidad

subdiagnosticada por su amplio espectro de presentacin clnica (que genera confusin con otros padecimientos) y

por desconocimiento de la misma enfermedad. Es imperante formar grupos interdisciplinarios con entrenamiento

para la sospecha, diagnstico y tratamiento de estos pacientes.An tenemos mucho que aprender sobre este

padecimiento y son estos foros de presentacin los que permitirn con la experiencia de todos hacer diagnsticos

tempranos para iniciar TRE a tiempo.

Bibliografa.

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 Obregn, 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 specic 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

insufciency. 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 calcication 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 insufciency; 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 stula 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 brosis and mild tubular atrophy). In that same date he presented with moderate dyspnea,

chest pain and syncope. His AV stula had a ow of 3 lts/min and a venous aneurysm. Echocardiography was

performed revealing severe aortic stenosis, with calcication, valve area 0.62 cm2, maximal transvalvular velocity

4.9, maximal gradient 118 mmHg, median gradient 68 mmHg, LVEF 68%, mild insufciency, 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 inuenced the difference in outcome:

allograft rejection, return to hemodialysis and the additional workload associated with an AV stula 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

1 1 1

Juan Manuel Romero Trejo ,Sergio Figueroa Sauceda ,Guillermo Valadez Juvera

Cardiology Department, UMAE Ciudad Obregn, 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 efciency and security proles. 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 debrillator (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?

1 2

Karen Dubln Garca , Pablo Radillo Daz

1

Department of Nephrology , Hospital General de Zona 1, IMSS, Durango, Mxico; 2

kdublangarcia@yahoo.com.mx Department of Nephrology, Centro Mdico Coyoacn, 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 codies for alphagalactosidase A (-Gal A) production (GLA gene). Mutations affecting the GLA gene

result in deciency 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 brocytes, 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, Mxico 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; -Gal A enzyme activity, GLA gene analysis and

lysoGL-3 measurement conrmed 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 specic evaluation of the index case revealed positive 24-hour proteinuria (6,5mg/kg/hr reference

MIOCARDIOPATIA HIPERTROFICA POR ENFEMEDAD DE FABRY.

FALLA DE EFICACIA DE AGALSIDASA-ALFA.

Marn Gutirrez F. J., Martnez Hernndez C. G., Silva Ortz J. A., Ramos D.

Department of Internal Medicine Cardiology, 50th General Hospital, Mexican Social Security Institute,

San Luis Potos, S. L. P., Mxico; 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 deciency 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 modied by ERT dose reduction, as conrmed 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 ndings

suggestive of FD. Conrmation 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 outow tract obstruction. End-

diastolic 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 brosis also

limited to the basal postero-lateral wall of the LV. The non-invasive gold-standard to detect myocardial brosis is

late gadolinium-enhanced magnetic resonance imaging (MRI). An indirect way to screen for regional myocardial

brosis 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 specic abnormality of the myocardial interstitium. Eur Heart J

2003;24:2151e5.

Lapa P

rodues C

riativas / A

bril 2015

Page 1Page 2Page 3Page 4Page 5Page 6Page 7Page 8Page 9Page 10Page 11Page 12Page 13Page 14Page 15Page 16Page 17Page 18Page 19Page 20Page 21Page 22