A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

Bone marrow burden score is not useful as a follow-up parameter in stable patients with type 1 Gaucher disease after 5 years of treatment.

INTRODUCTION: Gaucher disease (GD) is one of the most prevalent lysosomal disorders, with an estimated incidence of 1 in 40,000 live births worldwide. Skeletal involvement is one of the main features of GD, causing morbidity and impacting long-term quality of life in patients with type 1 GD. OBJECTIVES: To characterize bone marrow infiltration in patients with type 1 GD followed at the Gaucher Disease Referral Center of Porto Alegre, Brazil, and to assess whether the Bone Marrow Burden score (BMB) correlates with clinical or laboratory parameters. We also evaluated whether the BMB score is a suitable parameter for long-term follow-up of patients with type 1 GD. METHODS: All included patients underwent magnetic resonance imaging for BMB score calculation at baseline, 1 year, and every other year thereafter or as clinically indicated from 2012 to 2018. RESULTS: The BMB score tended to decrease during the first 5 years of treatment, at a rate of -1.08 points per year; after the 5-year mark, BMB tended to remain stable. CONCLUSIONS: The BMB score is useful for response monitoring in the first five years of treatment. We recommend that, after 5 years of treatment, MRI for BMB evaluation should only be performed in non-adherent patients or in those who develop symptoms of acute skeletal disease.

Eficacia y seguridad de imiglucerasa para el tratamiento de pacientes con enfermedad de Gaucher tipo 1 / Efficacy and safety of imiglucerase for the treatment of patients with Gaucher disease type 1

INTRODUCCIÓN: En el Perú, la enfermedad de Gaucher es considerada una enfermedad rara de Alta Prioridad según el Listado de Enfermedades Raras y Huérfanas, aprobado mediante Resolución Ministerial N° 151-2014/MINSA, en el marco de la Ley N° 29698 que declaró de interés nacional la prevención, el diagnóstico, la atención integral de salud y la rehabilitación de las personas que padecen enfermedades raras o huérfanas. TECNOLOGÍA SANITARIA DE INTERÉS: Imiglucerasa es un análogo de la enzima humana ß-GA, producido por tecnología de ADN recombinante utilizando cultivo celular de mamífero procedente de ovario de hámster chino, con modificación para que la cadena de oligosacáridos en el sitio de glicosilación termine en manosa. Estas terminaciones de manosa son específicamente reconocidas por los receptores de carbohidrato endocíticos de los macrófagos, siendo estas células las que acumulan los lípidos en la EG. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de imiglucerasa comparado con la mejor terapia de soporte en pacientes con diagnóstico de enfermedad de Gaucher tipo 1. Se utilizó las bases de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database, priorizándose evidencia proveniente de (revisiones sistemáticas o meta-análisis de) ensayos clínicos controlados aleatorizados. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica, incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH) y la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Se hizo una búsqueda adicional en la página web de clinicaltrials.gov, para poder identificar ensayos clínicos en curso o que no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (tipo ensayos clínicos aleatorizados). RESULTADOS: La evidencia considerada en el presente dictamen incluye una guía de práctica clínica (GPC): la guía para el diagnóstico y tratamiento de la enfermedad de Gaucher tipo 1 desarrollado por el Centro Nacional de Excelencia Tecnológica en Salud de México (CENETEC 2013) ; tres evaluaciones de tecnología sanitaria (ETS), dos elaboradas por el National Institute for Health Research (NIHR) del Reino Unido (Connock et al. 2006; Wyatt et al. 2012) y una por la Canadian Agency for Drugs and Technologies in Health (CADTH 2011a) ; un ensayo clínico controlado aleatorizado (ECA) (Schiffmann et al. 2002) , que responde de manera indirecta a nuestra pregunta PICO de interés; y tres estudios observacionales grandes con información a largo plazo: dos basados en el Registro de Gaucher del ICGG con alglucerasa/imiglucerasa (Weinreb et al. 2013; Andersson et al. 2008) y uno en un programa de farmacovigilancia con imiglucerasa (Starzyk et al. 2007). Con respecto a la GPC, el CENETEC menciona que la TRE (imiglucerasa o velaglucerasa) es el tratamiento de elección en los pacientes adultos y pediátricos con diagnóstico confirmado de EG tipo 1. En cuanto a la evidencia para sustentar el uso de la TRE se cita una ETS del NIHR (Connock et al. 2006), que fue incluida y evaluada al detalle en la sección de ETS del presente dictamen. CONCLUSIONES: El presente dictamen tuvo como objetivo evaluar la mejor evidencia científica disponible hasta abril de 2019 en relación a la eficacia y seguridad de imiglucerasa, en comparación con la mejor terapia de soporte, en pacientes con EG tipo 1. La evidencia procedente de un ECA y de numerosos estudios no controlados sugiere que imiglucerasa tiene efectos en marcadores hematológicos y viscerales que, hasta la actualidad, no han demostrado predecir una mejora en la sobrevida global o la calidad de vida de los pacientes con EG tipo 1. Con respecto a las manifestaciones óseas, existe información controversial sobre los efectos que tendría la TRE en la DMO, el dolor óseo y la crisis ósea. Por una parte, la evidencia de alta calidad en pacientes adultos esplenectomizados sugiere que la TRE no tendría efectos sobre la mejora en la DMO, sino que, por el contrario, podría exacerbar la reducción de la misma. Mientras que, por otro lado, la evidencia de baja calidad en pacientes niños y adultos sugiere que el tratamiento a largo plazo con la TRE influenciaría positivamente sobre la DMO, el dolor óseo y/o la crisis ósea. La misma incertidumbre surgió en relación a los efectos que tendría la TRE sobre la normalización del crecimiento en los niños con EG tipo 1, pues la evidencia que soportó este enunciado se basó en pocos estudios con diseños antes-después, cuyos resultados podrían estar confundidos por los cambios en el desarrollo propios de esta etapa de vida. En reuniones con los especialistas clínicos de EsSalud, autores del presente dictamen, se manifestó que, si bien la evidencia científica sobre los efectos de imiglucerasa en desenlaces clínicos es limitada, los efectos demostrados en los principales parámetros hematológicos y viscerales de la enfermedad indican un potencial beneficio en determinados tipos de pacientes con EG tipo 1. Al respecto, manifestaron que su uso solo estaría justificado en casos sintomáticos con el fin de evitar las complicaciones de la enfermedad. También se consideró el contexto de vacío terapéutico y la amplia experiencia de uso de imiglucerasa en la institución, pues en la actualidad esta TRE es la única medicación especifica disponible para tratar la EG tipo 1. Así, teniendo en cuenta que la EG tipo 1 es causada por la deficiencia de la enzima ß-GA, y siendo que imiglucerasa compensa esta actividad enzimática deficiente, y ha demostrado tener efectos positivos en marcadores relacionados con los principales síntomas de la enfermedad (cambios hematológicos y en el volumen de los órganos), es razonable pensar que la TRE podría ofrecer un beneficio en los casos moderados o severos que presenten síntomas funcionales debido a las alteraciones hematológicas y la visceromegalia. Este juicio clínico es consistente con las recomendaciones hechas por consenso de expertos internacionales, como el protocolo nacional de Francia para el diagnóstico y tratamiento de la enfermedad de Gaucher (Haute Autorité de Santé 2007) , que limita el uso de imiglucerasa exclusivamente a la forma severa de la enfermedad. En ese sentido, en el Anexo 1 del presente dictamen, se establecen los nuevos criterios de inicio de la TRE en EsSalud, en base a la evidencia científica disponible y siguiendo las recomendaciones de expertos internacionales. Por otro lado, teniendo en cuenta que en la actualidad existen dos formas de imiglucerasa con registro sanitario vigente en el país: Cerezyme® (imiglucerasa 400UI), aprobado por la Food and Drug Administration [FDA] en 1994, y Abcertin® (imiglucerasa 200UI), aprobado por la Korea Food & Drug Administration [KFDA] en 2012, se realizó una búsqueda adicional de la evidencia para Abcertin®, que tiene una aprobación más reciente, con la finalidad de evaluar su eficacia y seguridad en los pacientes con EG tipo 1 y su potencial intercambiabilidad con la forma de imiglucerasa actualmente disponible en EsSalud (Cerezyme®). La información procedente de un ensayo clínico de fase II y un ensayo clínico de fase III indica que Abcertin® logra los mismos efectos que Cerezyme® en las principales manifestaciones de la EG tipo 1, en base a evidencia con limitaciones similares a las identificadas para Cerezyme®. Así, en base a estos hallazgos, y teniendo en cuenta que Abcertin® tiene características estructurales, fisicoquímicas y biológicas comparables a las de Cerezyme®, y que ha sido aprobado en un país de alta vigilancia sanitaria como lo es República de Corea, cumpliendo todas las exigencias establecidas por el ente regulador del país, se recomienda que Abcertin® sea considerado como una alternativa de tratamiento en pacientes con EG tipo 1. De este modo, a pesar de que la evidencia que respalda un beneficio clínico con imiglucerasa en pacientes con EG tipo1 es generalmente limitada, imiglucerasa puede ser considerado una alternativa terapéutica debido a su efecto sobre marcadores relacionados con los síntomas de la enfermedad que podrían reflejar razonablemente el bienestar del paciente. Por otro lado, dada la gran heterogeneidad de la enfermedad, desde formas asintomáticas hasta formas viscerales y esqueléticas sintomáticas, el uso de imiglucerasa no se justifica en todos los pacientes con EG tipo 1. El Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI aprueba el uso del producto farmacéutico imiglucerasa para el tratamiento de pacientes con enfermedad de Gaucher tipo 1, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en dicho periodo.

[Cavernoma complicated with biliopatia secondary to type 1 Gaucher disease: report of a Peruvian case]. / Cavernoma portal complicada con biliopatía secundario a enfermedad de Gaucher tipo 1: reporte de un caso peruano.

Gaucher disease is an autosomal recessive lysosomal storage disorder characterized by deficiency of beta-glucosidase that would lead to the accumulation of glucosylceramide mainly in cells of the mononuclear phagocytic system causing systemic effectations. We present a patient of twenty years who is suffering from chronic pain in the left hypochondrium with episodes of bleeding for 3 years and sensation of thermal rise, physical examination revealed jaundice and massive splenomegaly, without neurological involvement. Severe osteoporosis, pancytopenia, and the presence of portal vein thrombosis with cavernomatous transformation complicated by portal biliopathy simulating a klatskin tumor, marrow and enzymatic studies were compatible with Gaucher disease, were shown as unexpected findings. he received treatment with imiglucerase, following up. It is a rare case, of great interest, heterogeneity in its clinical manifestations and unpublished by its complication, constituting a challenge to reach its diagnosis of this orphan disease.

Cavernoma portal complicada con biliopatía secundario a enfermedad de Gaucher tipo 1: reporte de un caso peruano / Cavernoma complicated with biliopatia secondary to type 1 Gaucher disease: report of a Peruvian case

La enfermedad de Gaucher, es un trastorno autosómico recesivo de depósito lisosomal que se caracteriza por deficiencia de la beta-glucocerebrosidasa que lleva a la acumulación de glucosilceramida principalmente en células del sistema fagocítico mononuclear causando afectaciones sistémicas. Se presenta paciente varón de 20 años que cursa con dolor crónico en hipocondrio izquierdo con episodios de sangrados desde hace 3 años y sensación de alza térmica, al examen físico se identificó ictericia y esplenomegalia masiva, sin afectación neurológica. Como apoyo al diagnóstico se mostró osteoporosis severa, pancitopenia y como hallazgo inesperado la presencia de trombosis de vena porta con transformación cavernomatosa complicada con biliopatía portal simulando un tumor de klatskin, los estudios de médula y enzimáticos eran compatibles con enfermedad de Gaucher, por lo cual recibió tratamiento con imiglucerasa realizando seguimiento. Es un caso poco frecuente, de gran interés, heterogeneidad en sus manifestaciones clínicas e inéditas por su complicación, constituyendo un desafío llegar a su diagnóstico de esta enfermedad huérfana.

Gaucher disease is an autosomal recessive lysosomal storage disorder characterized by deficiency of beta-glucosidase that would lead to the accumulation of glucosylceramide mainly in cells of the mononuclear phagocytic system causing systemic effectations. We present a patient of twenty years who is suffering from chronic pain in the left hypochondrium with episodes of bleeding for 3 years and sensation of thermal rise, physical examination revealed jaundice and massive splenomegaly, without neurological involvement. Severe osteoporosis, pancytopenia, and the presence of portal vein thrombosis with cavernomatous transformation complicated by portal biliopathy simulating a klatskin tumor, marrow and enzymatic studies were compatible with Gaucher disease, were shown as unexpected findings. he received treatment with imiglucerase, following up. It is a rare case, of great interest, heterogeneity in its clinical manifestations and unpublished by its complication, constituting a challenge to reach its diagnosis of this orphan disease.

Taliglucerase alfa in Gaucher disease: Description of a Brazilian experience.

We evaluated retrospectively, efficacy and safety of taliglucerase alfa for Gaucher disease in a Brazilian population. Thirteen patients were included for efficacy analysis only one of them naïve to enzyme replacement therapy. All the parameters evaluated remained stable throughout treatment (mean duration 3,5years). Only three patients (out of 35) had to discontinue treatment due to a serious adverse event. In conclusion, treatment with taliglucerase alfa was found to be safe and efficient.

Could enzyme replacement therapy promote immune tolerance in Gaucher disease type 1?

Among the lysosomal storage disorders, Gaucher disease (GD) features some of the most striking alterations in the immune system, including increased levels of cytokines and chemokines. Although studies have demonstrated the efficacy of enzyme replacement therapy (ERT) for GD, the ideal dosage remains controversial. In this study, we report differences in levels of cytokines (IL-6, TNF-a, and IFN-y) and chemokines (IL-8, IP-10, and MCP-1) in patients with GD type 1 treated with different ERT dosages and treatment durations. Patients were recruited from two ERT centers in Brazil and divided into two groups according to treatment facility. Comparison between groups showed that patients in group 1 had received ERT for longer (p=0.0078) and at higher doses (p=0.0002) than those in group 2. Patients in group 1 exhibited decreased levels of IL-6 (p=0.0006), TNF-α (p<0.0001), IFN-γ (p<0.0001), IL-8 (p=0.0083), IP-10 (p<0.0001), and MCP-1 (p<0.0001) when compared to patients in group 2. Otherwise, patients in both groups were clinically similar, with no differences in hemoglobin, platelet, or leukocyte counts. Our data suggest that in GD type 1 the dosage and duration of therapy may be associated with establishment of peripheral tolerance and, consequently, decreased serum levels of inflammatory cytokines and chemokines.

Alfataliglicerase para o tratamento da doença de Gaucher (2017) / Alphataliglycerase for the treatment of Gaucher disease (2017)

INTRODUÇÃO: Em dezembro de 2016, a ANVISA publicou a ampliação da faixa etária de uso da alfataliglicerase para crianças a partir de 4 anos de idade com diagnóstico de Doença de Gaucher. Anteriormente, a alfataliglicerase tinha registro apenas para adultos. A DOENÇA: A doença de Gaucher (DG) é a mais comum das glicoesfingolipidoses e a primeira a ter tratamento específico com terapia de reposição enzimática (TRE). É uma doença autossômica recessiva, causada pela atividade deficiente da enzima betaglicocerebrosidase, que compromete o metabolismo lipídico, resultando em acúmulo de glicocerebrosídio nos macrófagos (1-9); a beta-glicocerebrosidase é codificada pelo gene GBA1, localizado no cromossomo 1p21. As principais manifestações clínicas da DG decorrem do acometimento hematológico (anemia, plaquetopenia), visceral (hepatomegalia, esplenomegalia) e esquelético (dor óssea, osteopenia), além do acometimento neurológico presente em algumas formas da doença. Segundo dados do Ministério da Saúde, há 670 pacientes com DG em tratamento no Brasil, sendo que aproximadamente 96% fazem uso de TRE e 4% de inibição de síntese de substrato (ISS). A identificação da doença em seu estágio inicial e o encaminhamento ágil e adequado para o atendimento especializado dá à Atenção Básica um caráter essencial para um melhor resultado terapêutico e prognóstico dos casos. O diagnóstico precoce da DG depende de um alto grau de suspeição, por parte de médicos generalistas, diante de casos de atraso de crescimento e desenvolvimento de hepatoesplenomegalia, por exemplo. ALFATALIGLICERASE: A alfataliglicerase foi aprovada para tratamento dos pacientes adultos com DG em 2012 pela Food and Drug Administration (FDA), e, em 2013, pela Agência Nacional de Vigilância Sanitária (ANVISA). Em 2014 a FDA aprovou o uso para pacientes pediátricos, e em 2016 a ANVISA autorizou o uso da alfataliglicerase para pacientes a partir dos 4 anos de idade. A eficácia e a segurança da alfataliglicerase foram estudadas em um ensaio clínico multicêntrico, duplo-cego e randomizado, com duração de 9 meses, que incluiu 32 pacientes com idade igual ou superior a 18 anos (29 pacientes completaram todas as etapas do estudo) (24). Um grupo de pacientes recebeu 30 U/kg/infusão de alfataliglicerase a cada duas semanas (grupo A, com 16 pacientes) e o outro, 60 U/kg/infusão a cada duas semanas (grupo B, também com 16 pacientes). Os critérios de inclusão englobavam a presença de esplenomegalia e trombocitopenia e ausência de tratamento prévio com TRE ou ISS. O desfecho primário foi o volume do baço e os desfechos secundários, o nível de hemoglobina, a contagem de plaquetas e o volume do fígado. Observou-se em ambos os grupos, melhora do volume esplênico (média de redução de 26,9% no grupo A e de 38% no grupo B), do volume hepático e dos níveis de hemoglobina. Em relação à contagem plaquetas, houve um aumento estatisticamente significativo no grupo B. Os eventos adversos mais comuns foram hipersensibilidade, cefaleia e prurido, com frequência similar nos grupos de 30 e 60 U/kg/infusão. Oito por cento dos pacientes apresentaram reações de hipersensibilidade. Aproximadamente 6% desenvolveram anticorpos IgG à alfataliglicerase, mas não foi observada associação entre o desenvolvimento de anticorpos e as reações de hipersensibilidade. Dois estudos de extensão avaliaram a eficácia e a segurança de alfataliglicerase em longo prazo (36 meses e 5 anos de acompanhamento), nos pacientes do estudo pivotal. Os resultados demonstraram melhoria contínua dos parâmetros da doença durante o período avaliado, sem novas implicações quanto a segurança, contribuindo para geração de dados clínicos adicionais de eficácia e segurança deste medicamento. RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC presentes na 53ª reunião ordinária do plenário do dia 09/03/2017, deliberaram por unanimidade recomendar a incorporação da alfataliglicerase para o uso pediátrico na Doença de Gaucher. Foi assinado o Registro de Deliberação nº 246/2017. DECISÃO: A PORTARIA Nº 25, DE 20 DE JULHO DE 2017 Torna pública a decisão de ampliar o uso da alfataliglicerase para uso pediátrico na Doença de Gaucher no âmbito do Sistema Único de Saúde - SUS.

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study.

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment-naïve, anemic patients with GD1 (4-62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 10(9) /L (P=0.002); 45 U/kg: +66.4%; +40.9 × 10(9) /L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: -50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: -39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug-related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease-specific parameters measured demonstrated clinically meaningful improvements after 12 months.

[Gaucher disease in Latin America. A report from the Gaucher Disease International Registry and the Latin American Group for Gaucher Disease]. / Enfermedad de Gaucher en Latinoamérica. Un informe del Registro Internacional y del Grupo Latinoamericano para la enfermedad de Gaucher.

Gaucher disease -due to its low frequency- is considered an orphan disease. In 1991 the International Gaucher Registry was created and in 1992 the first patients from Latin America were enrolled. In 2008 the Latin American Group for Gaucher Disease was initiated. Its main objectives are to promote regional consensus, to stimulate the enrollment of patients into the International Gaucher Registry and the enhancement of knowledge on this disease, and to achieve better care and quality of life of patients in our Region. Until April 2010, 5828 patients have been enrolled all around the world, 911 (15.6%) from Latin America. This is the first comprehensive report of the disease in the Region. In our population there is a predominance of females, the most common clinical form is the type I (95%) and the age at diagnosis is before 20 years in 68% of patients. The most frequent clinical manifestations at diagnosis are splenomegaly (96%) and anemia (49%). Eighty percent of patients had radiographic findings of bone involvement. In our Region, the vast majority of patients (89%) had received enzyme replacement therapy with imiglucerase; with a long follow-up (up to 10 years) they have achieved the therapeutic goals, showing the great effectiveness of therapy. While the percentage of patients with therapy is high, discontinuations are common. The main deficiencies in our Region are: the lack of visceral volumetric evaluations and densitometries as well as molecular analysis for some patients. The main problem is the under-diagnosis of patients.

Enfermedad de Gaucher en Latinoamérica: Un informe del Registro Internacional y del Grupo Latinoamericano para la Enfermedad de Gaucher / Gaucher disease in Latin America: A report from the Gaucher Disease International Registry and the Latin Americam Group for Gaucher Disease

La enfermedad de Gaucher, por su escasa frecuencia, está incluida dentro de las llamadas enfermedades huérfanas. En 1991 se creó el Registro Internacional de Gaucher y en 1992 se incorporaron los primeros pacientes de Latinoamérica. En el año 2008 se creó el Grupo Latinoamericano para la Enfermedad de Gaucher (GLAEG) cuyos principales objetivos son fomentar la realización de consensos regionales, difundir el ingreso de pacientes al registro internacional y aumentar el conocimiento sobre la enfermedad para lograr mejorar la atención y la calidad de vida de los pacientes. Hasta abril del 2010 ingresaron 5828 pacientes de todo el mundo, 911 (15.6%) son de Latinoamérica. Este es el primer informe global de la enfermedad en la Región: hay un predominio del sexo femenino, la forma clínica más frecuente es el tipo I (95%); al diagnóstico la mayoría son <20 años (68%). Las manifestaciones clínicas más frecuentes al diagnóstico son esplenomegalia (96%) y anemia (49%), el 80% presentó hallazgos radiológicos de compromiso óseo. En nuestra Región, la gran mayoría de los pacientes (89%) ha recibido alguna vez terapia de reemplazo enzimática con imiglucerasa logrando, con un seguimiento prolongado (hasta10 años), las metas terapéuticas que muestran la gran eficacia de la terapia. Si bien el porcentaje de pacientes con terapia es alto, las suspensiones de tratamiento son frecuentes. Las principales deficiencias en nuestra Región son: la carencia de evaluaciones viscerales volumétricas, de densitometría y de estudios moleculares en algunos pacientes. El principal problema es el subdiagnóstico.

Gaucher disease -due to its low frequency- is considered an orphan disease. In 1991 the International Gaucher Registry was created and in 1992 the first patients from Latin America were enrolled. In 2008 the Latin American Group for Gaucher Disease was initiated. Its main objectives are to promote regional consensus, to stimulate the enrolment of patients into the International Gaucher Registry and the enhancement of knowledge on this disease, and to achieve better care and quality of life of patients in our Region. Until April 2010, 5828 patients have been enrolled all around the world, 911 (15.6%) from Latin America. This is the first comprehensive report of the disease in the Region. In our population there is a predominance of females, the most common clinical form is the type I (95%) and the age at diagnosis is before 20 years in 68% of patients. The most frequent clinical manifestations at diagnosis are splenomegaly (96%) and anemia (49%). Eighty percent of patients had radiographic findings of bone involvement. In our Region, the vast majority of patients (89%) had received enzyme replacement therapy with imiglucerase; with a long follow-up (up to 10 years) they have achieved the therapeutic goals, showing the great effectiveness of therapy. While the percentage of patients with therapy is high, discontinuations are common. The main deficiencies in our Region are: the lack of visceral volumetric evaluations and densitometries as well as molecular analysis for some patients. The main problem is the under-diagnosis of patients.

Enfermedad de Gaucher en Latinoamérica: Un informe del Registro Internacional y del Grupo Latinoamericano para la Enfermedad de Gaucher / Gaucher disease in Latin America: A report from the Gaucher Disease International Registry and the Latin Americam Group for Gaucher Disease

La enfermedad de Gaucher, por su escasa frecuencia, está incluida dentro de las llamadas enfermedades huérfanas. En 1991 se creó el Registro Internacional de Gaucher y en 1992 se incorporaron los primeros pacientes de Latinoamérica. En el año 2008 se creó el Grupo Latinoamericano para la Enfermedad de Gaucher (GLAEG) cuyos principales objetivos son fomentar la realización de consensos regionales, difundir el ingreso de pacientes al registro internacional y aumentar el conocimiento sobre la enfermedad para lograr mejorar la atención y la calidad de vida de los pacientes. Hasta abril del 2010 ingresaron 5828 pacientes de todo el mundo, 911 (15.6%) son de Latinoamérica. Este es el primer informe global de la enfermedad en la Región: hay un predominio del sexo femenino, la forma clínica más frecuente es el tipo I (95%); al diagnóstico la mayoría son <20 años (68%). Las manifestaciones clínicas más frecuentes al diagnóstico son esplenomegalia (96%) y anemia (49%), el 80% presentó hallazgos radiológicos de compromiso óseo. En nuestra Región, la gran mayoría de los pacientes (89%) ha recibido alguna vez terapia de reemplazo enzimática con imiglucerasa logrando, con un seguimiento prolongado (hasta10 años), las metas terapéuticas que muestran la gran eficacia de la terapia. Si bien el porcentaje de pacientes con terapia es alto, las suspensiones de tratamiento son frecuentes. Las principales deficiencias en nuestra Región son: la carencia de evaluaciones viscerales volumétricas, de densitometría y de estudios moleculares en algunos pacientes. El principal problema es el subdiagnóstico.(AU)

Gaucher disease -due to its low frequency- is considered an orphan disease. In 1991 the International Gaucher Registry was created and in 1992 the first patients from Latin America were enrolled. In 2008 the Latin American Group for Gaucher Disease was initiated. Its main objectives are to promote regional consensus, to stimulate the enrolment of patients into the International Gaucher Registry and the enhancement of knowledge on this disease, and to achieve better care and quality of life of patients in our Region. Until April 2010, 5828 patients have been enrolled all around the world, 911 (15.6%) from Latin America. This is the first comprehensive report of the disease in the Region. In our population there is a predominance of females, the most common clinical form is the type I (95%) and the age at diagnosis is before 20 years in 68% of patients. The most frequent clinical manifestations at diagnosis are splenomegaly (96%) and anemia (49%). Eighty percent of patients had radiographic findings of bone involvement. In our Region, the vast majority of patients (89%) had received enzyme replacement therapy with imiglucerase; with a long follow-up (up to 10 years) they have achieved the therapeutic goals, showing the great effectiveness of therapy. While the percentage of patients with therapy is high, discontinuations are common. The main deficiencies in our Region are: the lack of visceral volumetric evaluations and densitometries as well as molecular analysis for some patients. The main problem is the under-diagnosis of patients.(AU)

The management of Gaucher disease in developing countries: a successful experience in Southern Brazil.

OBJECTIVE: Gaucher disease (GD) is a genetic disease caused by glucocerebrosidase deficiency. GD is treated by enzyme replacement therapy (ERT) with imiglucerase, a high-cost drug provided by the Brazilian Ministry of Health (BMH). This study reports the implementation of the BMH guidelines for GD in the southernmost state of the country. METHODS: We review the clinical and laboratorial data for patients seen at the reference center for GD from Rio Grande do Sul, Brazil (July 2003 to June 2006). RESULTS: Twenty-five patients were included in this study. At baseline, 19/20 were on ERT (mean dosage of imiglucerase = 51.8 U/kg/infusion), 3/17 presented anemia, and 5/16 thrombocytopenia. The amount of imiglucerase prescribed to these patients was adjusted according to the guidelines in July 2003; out of them, 18 were receiving ERT in the reference center at month 36 (mean dosage of imiglucerase = 27.5 U/kg/infusion), 2/18 presented anemia, and 4/18 presented thrombocytopenia. The analysis of the liver, spleen, and bone data presented some limitations, but the available information suggests that patients did not deteriorate. GD patients who initiated ERT after July 2003 (n = 5) received lower dosage of imiglucerase since the beginning of the treatment; most of them demonstrated clinical and laboratorial response. From baseline to month 36, the consumption of imiglucerase by the reference center showed a significant reduction, which represented savings of USD 3 million to the public health system. CONCLUSIONS: The model of care of GD patients suggested by the BMH guidelines appears to be cost-effective and could be an example for management of rare diseases in underdeveloped countries.

Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease.

OBJECTIVE: To investigate the spectrum and prevalence of cognitive deficits among children with type 3 (chronic neuronopathic) Gaucher disease (GD). STUDY DESIGN: A case review study identified 32 children (male/female; 17:15) with type 3 GD who had received enzyme replacement therapy (ERT) or a bone marrow transplant. The diagnosis of GD was established by enzymatic assay and DNA testing. Subjects were assessed with standard neuropsychological testing, and data from the most recent evaluation were included. RESULTS: Neuropsychometric assessments demonstrated a wide spectrum of full-scale IQ scores ranging from 39 to 124 (mean 75). About 60% of subjects had intellectual skills below average. There were significant discrepancies between verbal and performance IQ, with a range between -6 and 38 points (P = .02). This gap was more prominent in older subjects, with better performance in the verbal areas. No correlation was observed between intelligence measures and genotype or the extent of systemic involvement. The dosage, age at initiation, and the length of ERT had no significant effect on IQ scores. CONCLUSIONS: In type 3 GD, cognitive deficits, characterized by visual-spatial dysfunction, are common but underappreciated and appear resistant to ERT.