Enfermedad de Gaucher en Argentina: un informe del Registro Internacional de Gaucher y del Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher

La Enfermedad de Gaucher por su baja frecuencia está incluida dentro de las enfermedades huérfanas. En 1991 comenzó el ingreso de pacientes en el Registro Internacional de Gaucher. En 1992 se incorporaron los primeros dos pacientes de Latinoamérica. En 2006 se creó el Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher siendo sus objetivos principales el entendimiento de la prevalencia, presentación, manejo y tratamiento de la Enfermedad de Gaucher en Argentina. Hasta el 1 de febrero del 2013 ingresaron al Registro Internacional 5.986 pacientes provenientes de 60 países, de los cuales 133 (2.22%) fueron argentinos. El análisis de esta publicación fue realizado sobre 133 pacientes con Enfermedad de Gaucher. Esta es la primera publicación del Grupo Argentino de Diagnóstico y Tratamiento en base a los datos del Registro Internacional. La casuística argentina mostró un predominio femenino y la forma clínica más frecuente fue el tipo 1 (97.7%, n=128). El genotipo fue identificado en 57 pacientes (42.9%), siendo el más frecuente el N370S/ otro alelo (82.5%). Entre los pacientes con datos reportados, los síntomas basales predominantes, previos al inicio del tratamiento con Imiglucerasa que predominaron fueron la esplenomegalia (100%, n=13) y la hepatomegalia (88.9%, n=8) y como citopenias más frecuentes, la trombocitopenia (64.2%, n=34) y la anemia (45.9%, n=28). La infiltración de la médula ósea como un marcador específico de enfermedad ósea se encontró en el 50% de los pacientes. En total, el 85.7% de los pacientes argentinos reciben terapia de reemplazo enzimático con Imiglucerasa, lográndose las metas terapéuticas, en la mayoría de los casos, en la última evaluación. Las metas terapéuticas más frecuentemente alcanzadas resultaron: el control de las manifestaciones óseas (dolor óseo y crisis ósea, 81.9% y 99% respectivamente) y la normalización de la hemoglobina (86.5%). La terapia de reemplazo enzimática con Imiglucerasa, a largo plazo en la población argentina demostró ser una herramienta eficaz para mejorar los parámetros clínicos y bioquímicos de la Enfermedad de Gaucher tipo1.Fil: Drelichman, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Fernández Escobar, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Basack, Nora. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Kohan, R.. Registro Argentino de Gaucher; ArgentinaFil: Watman, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Bolesina, M.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Elena, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Veber, S. E.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Dragosky, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Oncología Marie Curie; ArgentinaFil: Annetta, I.. Gobierno de la Ciudad de Buenos Aires. Hospital de Oncología Marie Curie; ArgentinaFil: Feliu, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sciuccati, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Cuello, María Fernanda. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fynn, Alcira. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Dodelson de Kremer, Raquel. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Angaroni, Celia Juana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Giner Ayala, Alicia. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Del Valle Oller, Ana María. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guelbert, Norberto Bernardo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Delgado, María Andrea. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Becerra, Adriana Berónica. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Oliveri, María Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Larroudé, M.. Centro Médico TIEMPO; ArgentinaFil: Masllorens, F.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Nacional “Prof. Dr. A. Posadas"; ArgentinaFil: Szlago, M.. Fundación para el eEstudio de las Enfermedades Neurometabólicas; Argentina. Laboratorio de Neuroquímica “Dr. N. A. Chamoles”; ArgentinaFil: Schenone, A.. Laboratorio de Neuroquímica “Dr. N. A. Chamoles”; Argentina. Fundación para el eEstudio de las Enfermedades Neurometabólicas; Argentin

Intravenous bisphosphonate treatment and pregnancy: Its effects on mother and infant bone health

Introduction: Type 1 Gaucher's disease (GD1) is a lysosomal storage disorder associated with disabling bone involvement. The choice treatment for Gaucher's disease is enzyme replacement therapy (ERT). The use of bisphosphonate treatment for osteopenia and osteoporosis has been suggested. Case: A 22-year-old woman diagnosed with GD1 had received ERT intermittently, depending on availability of the enzyme since the enzyme was not always available. Due to severe bone involvement and multiple vertebral fractures, intravenous administration of 60 mg of pamidronate every 3 months and safe contraception were indicated. Fifteen days after receiving the fourth infusion, the patient informed us she was pregnant. A baby girl was born by cesarean delivery at week 37, showing no evidence of skeletal abnormality or clinical signs of hypocalcemia. The baby developed normally, presenting no significant pathology. At present (age 15 months), height, body weight, and bone mineral density by DXA are within normal range. The mother showed stable total skeleton and right femoral neck bone mineral density (BMD) values, no new fractures, and only ~3% decrease in lumbar spine BMD 15 months post-delivery and after a 1 year breastfeeding period (expected average ~7-8%). Conclusion: It could be posited that pamidronate exerted a positive protective effect on the mother's skeleton with no evidence of adverse effects on pregnancy or on the baby's health to date.Fil: Mastaglia, Silvina Rosana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Watman, N. P.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Oliveri, María Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

2002; 01

F e r r a t a S t o r t i F o u n d a t i o n account diverse parameters such as peripheral cell counts, enzyme levels, histopathologic features, in addition to the percentage of BM blasts. Design and Methods Patients This is a multicenter retrospective analysis of 234 MDS patients evaluated from 1984 to 2000 proceeding from Argentinian hematologic centers: Instituto de Investigaciones Hematológicas (IIHE-MA); Hospital Privado de Córdoba, Hospital General de Agudos Dr. Carlos G. Durand, Hospital General de Agudos José María Ramos Mejía and others. A diagnosis of MDS was made after inspection of peripheral blood (PB) and BM to document the requisite dysplastic cytologic features. Trephine biopsy, cytogenetic studies, cytochemical and iron stains, immunophenotyping and, in some cases, ferrokinetics studies were performed to provide confirmatory diagnosis. All patients were categorized according to FAB criteria; 4,13 all had primary MDS without documented preceding radio-or chemotherapy. Most patients received supportive care, such as transfusion or polyvitamin therapy; only a minority received varying amounts of chemotherapy. Infections, bleeding, BM failure and LE were considered as MDS-related causes of death. The IPSS was applied according to Greenberg et al. 9 Table 1 provides a summary of the patients' clinical data. BM blasts, cytopenias, cytogenetic groups, FAB and IPSS classifications are presented in percentages and in absolute numbers, at the time of diagnosis. For each of these variables, the estimated median SV and the time to 25% of patients evolving to LE are also given. Cytogenetic pattern Chromosome analyses of 198 patients with MDS were performed in BM samples, according to standard procedures of our laboratory. Inclusion in the study required the analysis of ≥ 11 metaphase cells per patient. Chromosome identification and karyotype designation were made taking into account the International System for Human Cytogenetic Nomenclature. Statistics The Kaplan-Meier method was used for the univariate estimation of SV time and LE calculated from the day of diagnosis. Each variable was analyzed using the log-rank test. The level of statistical significance was fixed at 0.05. Results Patients The clinical, demographic and cytogenetic findings are summarized in Percentage of BM myeloblasts SV and LE curves for groups divided according to IPSS cut-off of blast percentage were significantly different (p<0.001). The median SV was 80 months and the LE (25%) was not achieved in the group with <5% blasts; while, for the groups with 5-10%, 11-20% and >20% blasts the median SV and LE (25%) were 31 and 17; 36 and 9; 9 and 3 months, respectively. However, no differences were observed between the group with 5-10% blasts and that with 11-20% regarding SV (p=0.225) and LE (p=0.085). Number of cytopenias SV and LE curves drawn according to the number of cytopenias defined by the IPSS were significantly different (p<0.001). The median SV was 77 months and the LE (25%) was not achieved in patients with 1 or no cytopenia; while, for those patients having 2 or 3 cytopenias the median SV was 31 months and LE had occurred in 25% by 9 months ( Detection of risk groups in MDS Cytogenetic findings A total of 198 cases could be successfully analyzed since no metaphases were available from 36 (15%). An abnormal karyotype was observed in 82 (41%) patients at diagnosis. The most common cytogenetic abnormalities were: -7 or del(7q) [ Twenty-two patients showed complex karyotypes Cytogenetic findings were subdivided according to IPSS into 126 (64%) good, 41 (21%) intermediate and 31 (15%) poor and the SV and LE curves according to these subdivisions showed significant differences (p=0.013 and p<0.001). The median SV and the times to 25% of patients undergoing LE were 60 and 46, 34 and 19, 28 and 5 months in the groups with good, intermediate and poor cytogenetic findings, respectively ( We observed that the proportion of normal karyotypes decreased according to worsening prognostic IPSS subgroup, since 48% of cases with normal karyotypes were present in the IPSS low risk group while only 4% of them were in the IPSS high risk group. The correlation between cytogenetic subgroups and IPSS showed that 84% of patients belonging to the good risk cytogenetic group were in low (48%) and Int-1 (36%) IPSS risk groups; 61% of patients with an intermediate cytogenetic risk group were in the Int-1 IPSS group; whereas, 84% of patients with poor cytogenetic findings were in Int-2 (42%) and high (42%) IPSS risk groups. These data show the importance of cytogenetic parameters IPSS SV and LE curves plotted according to IPSS stratification were significantly different (p<0.001). The median SV and the LE (25%) were not achieved in the low risk group but were 42 and 45; 33 and 25; 14 and 5 months for the Int-1, Int-2 and high risk groups, respectively ( IPSS vs. FAB subtyped patients The correlation between IPSS and FAB classifications identified patients with RA (5%) and RARS (15%) within the Int-2 group and those with RAEB (19%) within the high risk group as having worse prognosis The IPSS was not informative about RAEBt because the patients had an uniformly poor outcome in relation to their high blast count. With respect to CMML, it was too favorable because all patients (92%) were included in the low and Int-1 risk groups. Discussion In this study we evaluated the IPSS and its prognostic variables in a large group of patients with FAB-classified primary MDS over the past sixteen years. The median SV for our patients according to their FAB subtype was similar to those previously reported, From our studies and others, The karyotype of BM at diagnosis coincided strongly with chromosome alterations reported in other large series. The percentage of blasts in BM aspirates is one of the parameters with strong prognostic value. Several scoring systems have proposed different cut-offs 1,6,7 for this percentage besides the generally accepted one in the FAB criteria. Considering that there were great variations in SV and LE among patients belonging to the same FAB subtype, this integration of IPSS and FAB criteria allowed identification of worse prognostic subgroups within patients with RA, RARS and RAEB. The score value for blast percentage was null in RA and RARS, but adding the increased number of cytopenias and a poor cytogenetic pattern demonstrated the worse prognosis for these cases. These variables also improved the subdivision of RAEB patients in addition to their division according to blast percentage. FAB classification IPSS RA (%) RARS (%) RAEB (%) RAEBt (%) CMML (%) Total(%) Low 50 Our univariate analyses showed that FAB classification, IPSS and its variables, percentage of blasts, cytogenetic pattern and number of cytopenias, were predictive for SV and LE. These results showed that Argentine MDS patients have a similar behavior to other MDS populations and that the stratification of patients according to IPSS taking into account FAB subtypes will be helpful in developing risk-adapted therapeutic strategies for MDS. Contributions and Acknowledgments CB and IL were responsible for the conception and design of the study, interpretation of its results PEER REVIEW OUTCOMES What is already known on this topic Prognostication is particularly relevant in myelodysplastic syndromes (MDS). The major challenge for a prognostic score is to demonstrate its prognostic accuracy in an independent population. What this study adds This study shows the International Prognostic Scoring System (IPSS) for MDS is also valuable in an Argentinian cohort of MDS patients. This is of interest as the IPSS did not include South American patients. These data reinforce the argument that the IPSS should be used for planning therapy in MDS. Manuscript processing Potential implications for clinical practice Identification of differents groups of risk is very important for clinical practice in myelodysplastic patients. Guillermo F. Sanz, Associate Editor © F e r r a t a S t o r t i F o u n d a t i o

La presencia del alelo -308 A del TNFa se asocia con anemia y plaquetopenia en pacientes con Síndromes Mielodisplásicos

Los Síndromes Mielodisplásicos (SMD) son un grupo heterogéneo de alteraciones hematológicas caracterizados, en parte, por la presencia de citopenias periféricas. El factor de necrosis tumoral alfa (TNFa) es una citoquina proinflamatoria con un rol predominante en la patofisiología de los SMD: niveles circulantes en plasma incrementados y una mayor expresión en células de médula ósea asociada con aumento en la tasa de apoptosis. El bloqueo del TNFa estimula la formación de colonias hematopoyéticas in vitro y mejora las citopenias periféricas in vivo. Objetivo: Analizar la presencia del polimorfismo de nucleótido simple (SNP) -308G/A del TNFa en pacientes con SMD de novo debido a que la presencia del alelo A se asocia con su mayor producción. Se estudiaron 107 pacientes (53 AR, 11 AS, 27 AREB, 2 AREBt y 14 LMMC), con una mediana de edad: 66 (14- 86) años, relación de sexos M/F=1,2 (59/48), mediana de sobrevida: 39,5 (1-170) meses. El SNP se analizó mediante amplificación por PCR y digestión con la enzima NcoI. Las frecuencias genotípicas halladas fueron: 0,74 G/G y 0,26 A/A+A/G en los pacientes vs 0,86 y 0,14 en los controles (n=94), respectivamente (p=0,0356; odds ratio-OR: 2,208). Los pacientes que portaban el alelo A presentaron un menor nivel de hemoglobina (8,7 vs 9,9 g/dL, p=0,0240), menor recuento de plaquetas (95000 vs 135000 /μL, p=0,0359) y menor edad (61 vs 68 años, p=0,0131) al diagnóstico. Además, se observó que estos pacientes presentaron un riesgo 4 veces aumentado de requerir transfusiones (78% vs 47%, p=0,0070, OR: 3,912). No se observaron diferencias estadísticas con otros parámetros clínicos analizados. Estos resultados fueron similares a los observados al excluir los pacientes con LMMC. El genotipo constitutivo asociado con alta expresión se encuentra 2 veces aumentado en los pacientes con SMD. La presencia del alelo -308 A se asoció con menor edad, mayor grado de anemia y trombocitopenia al diagnóstico. Estos resultados avalarían la hipótesis de que el TNFa podría actuar como un modificador de la severidad de la enfermedad. Estos pacientes se verían favorecidos, potencialmente, con terapias que bloqueen o modulen el TNFa.yelodysplastic Syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s) as a result of an ineffective hematopoiesis. MDS patients show increased levels of Tumor Necrosis Factor alpha (TNFa) which is a multifunctional proinflammatory cytokine. The aim of this work is to examine the presence of -308G/A TNFα variants and to analyze whether it is associated with clinical parameters in a cohort of 107 Argentinean de novo MDS patients. The A/A+A/G genotype at TNFα -308 was overrepresented 2-fold in our population (p=0.0356, odds ratio-OR: 2.208). The presence of the high expressing -308A allele was associated with lower hemoglobin level (8.7 vs 9.9 g/dL; p=0.0240), reduced platelet counts (95000 vs 135000 /µL; p=0.0359) and younger age (61 vs 68 years; p=0.0131) at diagnosis. Also, these patients showed 4-fold higher risk of transfusion requirement (78% vs 47%, p=0.0070) during the follow up. In conclusion, the presence of an inherited -308A TNFα, which increases its transcription level, was associated with MDS phenotype in our cohort of Argentine MDS patients. And, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.Fil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bestach, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Flores, M. G.. Gobierno de la Ciudad de Buenos Aires. Hospital Interzonal de Agudos Dr. C. Durand; ArgentinaFil: Sieza, Y. Hospital Interzonal de Agudos Gral. San Martín, La Plata; ArgentinaFil: Gelemur, M.. Hospital Interzonal de Agudos Gral. San Martín, La Plata; ArgentinaFil: Venturini, C.. Instituto Privado de Hematología y Hemoterapia, Paraná; ArgentinaFil: Negri Aranguren, Pablo. Instituto Privado de Hematología y Hemoterapia, Paraná; ArgentinaFil: Watman, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; ArgentinaFil: Bengió, R.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

A reappraisal of Gaucher disease-diagnosis and disease management algorithms

Type 1 (non neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and non-specific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease