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Gaucher disease (GD, OMIM 230800) is one of the most common lysosomal disorders, being caused by the deficient activity of the enzyme acid ß-glucocerebrosidase (Gcase). Three clinical forms of Gaucher's disease (GD) are classified based on neurological involvement. Type 1 (GD1) is non-neuronopathic, while types 2 (GD2) and 3 (GD3) are neuronopathic forms. Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages, it undergoes deacylation to become glycosylsphingosine (lyso-Gb1), which has shown to be a useful and reliable biomarker for the diagnosis and monitoring of treated and untreated patients with GD. Multiple myeloma (MM) is one of the leading causes of cancer-related death among patients with GD and monoclonal gammopathy of undetermined significance (MGUS) is a non-neoplastic condition that can be a telltale sign of a B clonal proliferation caused by the chronic activation of B cells. This study aimed to quantify Lyso-Gb1 levels in dried blood spots (DBS) and cerebrospinal fluid (CSF) as biomarkers for Gaucher disease (GD) and discuss the association of this biomarker with other clinical parameters. This is a mixed-methods study incorporating both cross-sectional and longitudinal elements within a cohort design with a convenience-sampling strategy. Data collection took place from January 2012 to March 2023. Lyso-Gb1 extraction from DBS involved the use of a methanol-acetonitrile-water mixture, followed by incubation and centrifugation. Analysis was performed using UPLC-MS/MS with MassLynx software version 4.2 and the control group for the DBS measurements included general newborns. CSF Lyso-Gb1 was extracted using ethyl acetate, analyzed by UPLC-MS/MS with a calibration curve, and expressed in pmol/L. Lysosomal activity in CSF was assessed by measuring chitotriosidase (Cht), and other lysosomal enzyme activities were assessed as previously described in the literature. Patients with metachromatic leukodystrophy (MLD) were used as controls. Thirty-two treated patients (twenty-nine GD1 and three GD3, all on ERT except for one GD type on SRT with eliglustat) and three untreated patients (one GD1, one GD2, and one GD3) were included. When analyzing only the treated GD1 group, a significant correlation was found between lyso-Gb1 and age (rho = -0.447, p = 0.001), ChT, and IgG levels (rho = 0.73, p < 0.001; and rho = 0.36, p = 0.03, respectively). Five GD1 patients (three females, mean age 40 years) also had their CSF collected and analyzed. The average measurement of lyso-Gb1 in CSF was 94 pmol/L (range: 57.1-157.9 pmol/L) versus <6.2 pmol/L in the control group (MLD). This is the first time, to the best of our knowledge, that lyso-Gb1 has been associated with IgG levels. While this finding reflects a risk for MGUS or MM and not only chronic plasma B-cell activation, it still requires further studies. Moreover, the analysis of CSF lyso-Gb1 levels in GD1 patients was demonstrated to be significantly higher than the control group. This raises the hypothesis that CSF lyso-Gb1 may serve as a valuable indicator for neurological involvement in GD, providing insights into the potential implications for neurological manifestations in GD, including GD1. The correlation between lyso-Gb1 and ChT levels in treated GD1 patients further underscores the interconnectedness of lysosomal markers and their relevance in monitoring.

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Gaucher and Fabry diseases are lysosomal storage disorders in which deficient enzyme activity leads to pathological accumulation of sphingolipids. These diseases have a broad phenotypic presentation. Musculoskeletal symptoms and pain complaints are frequently reported by patients. Thus, rheumatologists can be contacted by these patients, contributing to the correct diagnosis, earlier indication of appropriate treatment and improvement of their prognosis. This review describes important concepts about Gaucher and Fabry diseases that rheumatologists should understand to improve patients' quality of life and change the natural history of these diseases.

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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.

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Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of ß-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12 ) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.

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Gaucher disease (GD) is caused by a genetic deficiency of the lysosomal enzyme glucocerebrosidase (GCase) leading to the accumulation of glucocerebroside in the liver, spleen, and bone marrow. The early diagnosis allows a prompt enzyme replacement therapy reversing cytopenias and visceromegaly and preventing irreversible bone lesions. Current diagnostic algorithms are based on well-recognized hematological manifestations. Although bone symptoms are present in 25-32% of the patients, they are not usually suspected as associated with Gaucher disease at clinical presentation. We designed an educational program aimed to give advice on the skeletal involvement in GD and a new diagnostic algorithm that considers bone symptoms to facilitate its early diagnosis (BIG project: Bone Involvement in Gaucher Disease). The study aims at describing the BIG project and the results of its application in our clinic in various cities in Argentina. Within the frame of this project, between March 2017 and December 2018, 38 dry blood spot samples from patients with bon e manifestations suspected of having GD were submitted to quantification of GCase activity. One sample did not meet the inclusion criteria. Deficient GCase activity was detected in three of the remaining 37 samples. The diagnosis of GD was confirmed in two girls who presented bone manifestations of 4 and 2 years of evolution, respectively, without hematological alterations. The third patient with low enzyme activity had normal leukocyte GCase. The two newly diagnosed cases of GD show the efficacy of our dual strategy aimed to facilitate the early diagnosis of this rare disease.

La enfermedad de Gaucher (EG) es causada p or una deficiencia genética de la glucocerebrosidasa (GCasa) que provoca acumulación de glucocerebrósido en hígado, bazo y médula ósea. La terapia temprana de reemplazo enzimático revierte citopenias, visceromegalias y previene lesiones óseas irreversibles, por lo cual el diagnóstico precoz es fundamental. Los algoritmos diagnósticos en uso apuntan a manifestaciones hematológicas clásicas. Los síntomas óseos están presentes en 25-32% de los pacientes pero no suelen despertar sospecha de EG. Diseñamos un programa educativo sobre la afecta ción ósea de la EG y un algoritmo focalizado en la presentación con manifestaciones óseas para facilitar su diagnóstico precoz (proyecto BIG: Bone Involvement in Gaucher Disease). El objetivo del trabajo es describir el proyecto BIG y los resultados de su aplicación en nuestra consulta. Entre marzo de 2017 y diciembre de 2018 se recibieron 38 muestras de sangre seca de pacientes con alguna manifestación ósea sospechosa de EG para cuantificar la actividad de GCasa. Una muestra no cumplía los criterios de inclusión y en 3 de las 37 restantes se observó actividad deficiente de GCasa. El diagnóstico de EG se confirmó por medición de GCasa en leucocitos en dos niñas con manifestaciones óseas de 4 y 2 años de evolución, respectivamente, sin citopenia ni visceromegalia clínicamente evidentes. En el otro paciente con baja actividad la medición en leucocitos fue normal. Los casos detectados muestran la efectividad de un programa educacional de difusión y la utilidad de un algoritmo de detección precoz basado en síntomas óseos que facilitaría el diagnóstico de EG.

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Desmoid-type fibromatosis (DF) is a tumor with high local recurrence rate. Sixteen patients (18 desmoid tumors) were retrospectively evaluated. Initial surgery was performed in 13/18 tumors, with complete resection in 6 (one with free margin and five with microscopic residual disease); 10/13 had local relapse. Eleven patients with 13 tumors underwent treatment with methotrexate-vinblastine. The response rate to chemotherapy was 54%, and up to 81% if stable disease cases were included. The best response was partial remission. Only 2 had grade 4 toxicity. Twelve of 15 patients had sequelae. In 8 cases sequelae were directly related to the surgical intervention and 3 of them were severe. The 5-year progression-free survival and overall survival were 30% and 93.3%, respectively. DF has a high local relapse rate, regardless of surgical margin involvement. Low dose chemotherapy achieved stable disease and even remission of the lesions with low toxicity. The high rate of sequelae is probably related to the initial surgery performed in the majority of patients and may be avoided by the use of neoadjuvant low dose chemotherapy.

La fibromatosis tipo desmoide (FD) es un tumor con alta tasa de recurrencia local. Dieciséis pacientes (18 tumores desmoides) fueron evaluados retrospectivamente. La cirugía inicial se realizó en 13/18 tumores, con resección completa en 6 (uno con margen libr e y cinco con margen microscópicamente comprometido); 10/13 tuvieron recaída local. Once pacientes con 13 tumores recibieron tratamiento con metotrexato/ vinblastina. La tasa de respuesta a la quimioterapia fue del 54% y de hasta el 81% si se incluyen los casos que lograron enfermedad estable. La mejor respuesta fue remisión parcial. Solo 2 tuvieron toxicidad grado 4. Doce de 15 pacientes tuvieron secuelas. En 8 casos, las secuelas estuvieron directamente relacionadas con la intervención quirúrgica y 3 de ellas fueron graves. La sobrevida libre de progresión a 5 años y la supervivencia global fueron del 30% y del 93.3%, respectivamente. La FD tiene una alta tasa de recaída local, independientemente del margen quirúrgico. Dosis bajas de quimioterapia lograron una enfermedad estable e incluso la remisión de las lesiones, con baja toxicidad. La alta tasa de secuelas probablemente esté relacionada con la cirugía inicial realizada en la mayoría de los pacientes y podría evitarse mediante el uso de quimioterapia neoadyuvante en dosis bajas, como sugieren las estrategias actuales de tratamiento.

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Resumen La enfermedad de Gaucher (EG) es causada por una deficiencia genética de la glucocerebrosidasa (GCasa) que provoca acumulación de glucocerebrósido en hígado, bazo y médula ósea. La terapia temprana de reemplazo enzimático revierte citopenias, visceromegalias y previene lesiones óseas irreversibles, por lo cual el diagnóstico precoz es fundamental. Los algoritmos diagnósticos en uso apuntan a manifestaciones hematológicas clásicas. Los síntomas óseos están presentes en 25-32% de los pacientes pero no suelen despertar sospecha de EG. Diseñamos un programa educativo sobre la afectación ósea de la EG y un algoritmo focalizado en la presentación con manifestaciones óseas para facilitar su diagnóstico precoz (proyecto BIG: Bone Involvement in Gaucher Disease). El objetivo del trabajo es describir el proyecto BIG y los resultados de su aplicación en nuestra consulta. Entre marzo de 2017 y diciembre de 2018 se recibieron 38 muestras de sangre seca de pacientes con alguna manifestación ósea sospechosa de EG para cuantificar la actividad de GCasa. Una muestra no cumplía los criterios de inclusión y en 3 de las 37 restantes se observó actividad deficiente de GCasa. El diagnóstico de EG se confirmó por medición de GCasa en leucocitos en dos niñas con manifestaciones óseas de 4 y 2 años de evolución, respectivamente, sin citopenia ni visceromegalia clínicamente evidentes. En el otro paciente con baja actividad la medición en leucocitos fue normal. Los casos detectados muestran la efectividad de un programa educacional de difusión y la utilidad de un algoritmo de detección precoz basado en síntomas óseos que facilitaría el diagnóstico de EG.

Abstract Gaucher disease (GD) is caused by a genetic deficiency of the lysosomal enzyme glucocerebrosidase (GCase) leading to the accumulation of glucocerebroside in the liver, spleen, and bone marrow. The early diagnosis allows a prompt enzyme replacement therapy reversing cytopenias and visceromegaly and preventing irreversible bone lesions. Current diagnostic algorithms are based on well-recognized hematological manifestations. Although bone symptoms are present in 25-32% of the patients, they are not usually suspected as associated with Gaucher disease at clinical presentation. We designed an educational program aimed to give advice on the skeletal involvement in GD and a new diagnostic algorithm that considers bone symptoms to facilitate its early diagnosis (BIG project: Bone Involvement in Gaucher Disease). The study aims at describing the BIG project and the results of its application in our clinic in various cities in Argentina. Within the frame of this project, between March 2017 and December 2018, 38 dry blood spot samples from patients with bone manifestations suspected of having GD were submitted to quantification of GCase activity. One sample did not meet the inclusion criteria. Deficient GCase activity was detected in three of the remaining 37 samples. The diagnosis of GD was confirmed in two girls who presented bone manifestations of 4 and 2 years of evolution, respectively, without hematological alterations. The third patient with low enzyme activity had normal leukocyte GCase. The two newly diagnosed cases of GD show the efficacy of our dual strategy aimed to facilitate the early diagnosis of this rare disease.

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Abstract Desmoid-type fibromatosis (DF) is a tumor with high local recurrence rate. Sixteen patients (18 desmoid tumors) were retrospectively evaluated. Initial surgery was performed in 13/18 tumors, with complete resection in 6 (one with free margin and five with microscopic residual disease); 10/13 had local relapse. Eleven patients with 13 tumors underwent treatment with methotrexate-vinblastine. The response rate to chemotherapy was 54%, and up to 81% if stable disease cases were included. The best response was partial remission. Only 2 had grade 4 toxicity. Twelve of 15 patients had sequelae. In 8 cases sequelae were directly related to the surgical intervention and 3 of them were severe. The 5-year progression-free survival and overall survival were 30% and 93.3%, respectively. DF has a high local relapse rate, regardless of surgical margin involvement. Low dose chemotherapy achieved stable disease and even remission of the lesions with low toxicity. The high rate of sequelae is probably related to the initial surgery performed in the majority of patients and may be avoided by the use of neoadjuvant low dose chemotherapy.

Resumen La fibromatosis tipo desmoide (FD) es un tumor con alta tasa de recurrencia local. Dieciséis pacientes (18 tumores desmoides) fueron evaluados retrospectivamente. La cirugía inicial se realizó en 13/18 tumores, con resección completa en 6 (uno con margen libre y cinco con margen microscópicamente comprometido); 10/13 tuvieron recaída local. Once pacientes con 13 tumores recibieron tratamiento con metotrexato/vinblastina. La tasa de respuesta a la quimioterapia fue del 54% y de hasta el 81% si se incluyen los casos que lograron enfermedad estable. La mejor respuesta fue remisión parcial. Solo 2 tuvieron toxicidad grado 4. Doce de 15 pacientes tuvieron secuelas. En 8 casos, las secuelas estuvieron directamente relacionadas con la intervención quirúrgica y 3 de ellas fueron graves. La sobrevida libre de progresión a 5 años y la supervivencia global fueron del 30% y del 93.3%, respectivamente. La FD tiene una alta tasa de recaída local, independientemente del margen quirúrgico. Dosis bajas de quimioterapia lograron una enfermedad estable e incluso la remisión de las lesiones, con baja toxicidad. La alta tasa de secuelas probablemente esté relacionada con la cirugía inicial realizada en la mayoría de los pacientes y podría evitarse mediante el uso de quimioterapia neoadyuvante en dosis bajas, como sugieren las estrategias actuales de tratamiento.

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Antecedentes: La enfermedad de Gaucher es causada por la acumulación del glicolípido glucosilceramidasa en el sistema macrofagocítico debido a la deficiencia de la enzima glucocerebrosidasa. Se han descrito tres formas clínicas de la enfermedad. La prevalencia mundial es de 1 caso en 40,000-100,000 nacimientos, aunque en poblaciones de ascendencia judío askenazi puede ser tan alta como 1 en 850 individuos. El diagnóstico definitivo se obtiene a través de observación directa de células Gaucher en médula ósea y la confirmación diagnóstica de las mutaciones en el cromosoma 1q21.31. Descripción del Caso: Femenina de 30 años con historia de 4 meses de hepatoesplenomegalia, leucopenia, neutropenia y trombocitopenia. Células de Gaucher se observaron en biopsia de médula ósea. Se confirmaron las variantes heterocigotas en los Exones 4 y 10 del Cromosoma 1q2. La paciente fue tratada con 5 mg de ácido fólico y multivitaminas. Es candidata para Terapia de Reemplazo de la Enzima con imiglucerasa, sin embargo, éste no está disponible en Honduras por su alto costo. Paciente continúa en seguimiento 5 años después del diagnóstico. Conclusión: La incidencia en Honduras es desconocida. Otros casos podrían permanecer sin ser diagnosticados debido a la complejidad del diagnóstico en el primer nivel de atención. Las enfermedades metabólicas son un reto para el sistema de salud debido al acceso limitado a la atención médica de calidad y a la escasez de médicos especialistas capacitados. Una de las fortalezas de este caso es el estudio laboratorial completo que incluye confirmación genética de la enfermedad...(AU)

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BACKGROUND: Gaucher disease (GD) is caused by deficiency of beta-glucocerebrosidase (GCase) due to biallelic variations in the GBA1 gene. Parkinson's disease (PD) is the second most common neurodegenerative condition. The classic motor symptoms of PD may be preceded by many non-motor symptoms (NMS), which include hyposmia, rapid eye movement (REM) sleep behavior disorder, constipation, cognitive impairment, and depression. Population studies have identified mutations in GBA1 as the main risk factor for idiopathic PD. The present study sought to evaluate the prevalence of NMS in a cohort of patients with GD type 1 from Southern Brazil. METHODOLOGY: This is an observational, cross-sectional study, with a convenience sampling strategy. Cognition was evaluated by the Montreal Cognitive assessment (MoCa), daytime sleepiness by the Epworth Scale, depression by the Beck Inventory, constipation by the Unified Multiple System Atrophy Rating Scale, and REM sleep behavior disorder by the Single-Question Screen; hyposmia by the Sniffin' Sticks. Motor symptoms were assessed with part III of the Unified Parkinson's Disease Rating Scale. All patients were also genotyped for the GBA1 3'-UTR SNP (rs708606). RESULTS: Twenty-three patients (female = 13; on enzyme replacement therapy = 21, substrate reduction therapy = 2) with a mean age of 41.45 ± 15.3 years (range, 22-67) were included. Eight patients were found to be heterozygous for the 3'-UTR SNP (rs708606). Fourteen patients (8 over age 40 years) presented at least one NMS; daytime sleepiness was the most frequent (n = 10). Two patients (aged 63 and 64, respectively) also presented motor symptoms, probably drug-related. CONCLUSIONS: NMS were prevalent in this cohort. We highlight the importance of a multidisciplinary follow-up focusing on earlier diagnosis of PD, especially for patients with GD type 1 over the age of 40.

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