Neuronopathic Gaucher Disease

Background Enzymatic deficiency in patients with Gaucher disease (GD) may induce a cascade of events that results in production of reactive oxygen species that can then generate oxidative stress. Objectives This study assessed the oxidant-antioxidant status in Egyptian patients with GD under enzyme replacement therapy (ERT) and its relation to disease severity. Methods This study included 40 patients with GD with median age 10 years (11 had type 1 GD and 29 had type 3 GD). All patients were on stable dose of enzyme replacement therapy (ERT). All included patients were subjected to detailed medical history with special emphasis on hepatic, skeletal, hematological and skeletal manifestations as well as history of splenectomy and ERT (dose, type and duration. Abdominal ultrasonography was performed. Severity score index was assessed. Complete blood count, liver enzymes, lyso GL1, malondialdehyde (MDA) as an index for lipid peroxidation was measured and antioxidant enzymes (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx] and peroxiredoxin 2 [PRDX2] levels) were assessed. Oxidant-antioxidant status was compared with levels of 40 age and sex-matched healthy controls. Results Patients with GD had significantly higher levels of MDA compared with healthy controls (median, 19.6 versus 7.19 mg/dL; p < 0.001). GSH was significantly lower in GD patients with a median 0.95 versus healthy controls 8.92 mg/dL (p < 0.001). Mean levels of SOD, GPX and PRDX2 were significantly decreased in GD patients (p < 0.001 for all). Severity score index was positively correlated to MDA (r = - 0.511, p = 0.023) while negatively correlated to PRDX2 (r = - 0.562, p = 0.01). PRDX2 was negatively correlated to lyso GL1 (r = -0.569, p = 0.009). Conclusions Oxidative stress is prevalent in pediatric patients with GD and related to disease severity. This helps to understand GD pathophysiology ad allow the use of antioxidants as an adjuvant therapy to decrease disease burden.

Gaucher disease (GD) is an autosomal recessive inborn error of metabolism caused by acid β-glucocerebrosidase deficiency, which presents with a wide spectrum of clinical manifestations, ranging from perinatal-lethal to asymptomatic forms. GD type 1 (GD1) is the most frequent visceral form, whereas types 2 (GD2) and 3 (GD3) are associated with neurodegeneration (neuronopathic GD, nGD) and share overlapping manifestations, presenting as a continuum of neurological disease severity. Traditionally, GD2 is the most severe form and has a rapidly progressive course with death by age two to four years. Currently available treatments for GD include enzyme replacement therapy and substrate reduction therapy to ameliorate visceral, hematologic, and skeletal abnormalities; however, they are not efficacious for neurological manifestations. More recently, ambroxol has been suggested as an augmentative pharmacological chaperone for nGD. This comparative case series of three patients aims to demonstrate the impact of early neonatal initiation of ambroxol on neurological outcomes in our index case (Patient A), compared to two other patients (Patients B and C) who began ambroxol treatment at 10 months and 4 years and 1 month of age, respectively, after a later diagnosis of nGD with already established neurological symptoms. Patient A has normal age-related developmental milestones at four years, while Patients B and C have persistence of developmental delay albeit some forward progression in the former. Our report highlights that early neonatal diagnosis and ambroxol therapy could potentially be a game changer in mitigating disease progression in nGD by modifying the natural history of GD2. Expanding newborn screening will facilitate early diagnosis and significantly impact clinical outcomes and quality of life in GD patients with early initiation of treatment.

Immune Thrombocytopenia in Type I Gaucher Disease.

Introduction: Types 2 and 3 Gaucher disease (GD) are neuronopathic forms that are mainly distinguished by the rate of neurological degeneration. All symptomatic children with type 1 or 3 GD should receive enzyme replacement therapy (ERT), whereas the treatment of children with type 2 GD is usually supportive. Case Presentation: We present the case of a 3-month-old Japanese girl diagnosed with neuronopathic GD. She initially presented with failure to thrive and inspiratory stridor. Treatment using ERT was initiated at 5 months of age. Genetic analysis of glucosylceramidase beta (GBA) revealed a compound heterozygous mutation including RecNciI and the novel missense mutation c.1052G > T (p.W351L). Although several clinical improvements were observed, she showed rapid neurological deterioration at 8 months of age. Conclusions: The patient with the compound heterozygous mutation including RecNciI and c.1052G > T (p.W351L) in GBA presented with clinical symptoms consistent with those of type 2 GD. ERT was initiated at 5 months of age; however, it failed to prevent refractory seizures and neurological deterioration.

Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy

Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to β-glucocerebrosidase deficiency and glucosylceramide accumulation. Methods: We analyzed short- and long-term dynamics of lyso-glucosylceramide (lyso-Gb1) in a large cohort of GD patients undergoing enzyme replacement therapy (ERT). Results: Eight-years analysis of lyso-Gb1 revealed statistically insignificant variability in the biomarker across the years and relatively high individual variability in patients' results. GD type 1 (GD1) patients exhibited higher variability compared to GD type 3 (GD3) patients (coefficients of variation: 34% and 23%, respectively; p-value = 0.0003). We also investigated the short-term response of the biomarker to enzyme replacement therapy (ERT), measuring lyso-Gb1 right before and 30 min after treatment administration. We tested 20 GD patients (16 GD1, 4 GD3) and observed a rapid and significant reduction in lyso-Gb1 levels (average decrease of 17%; p-value < 0.0001). This immediate response reaffirms the efficacy of ERT in reducing substrate accumulation in GD patients but, on the other hand, suggests the biomarker's instability between the infusions. Conclusions: These findings underscore lyso-Gb1's potential as a reliable biomarker for monitoring efficacy of treatment. However, individual variability and dry blood spot (DBS) testing limitations urge a further refinement in clinical application. Our study contributes valuable insights into GD patient management, emphasizing the evolving role of biomarkers in personalized medicine.

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.

Rationale:Gaucher disease (GD) is an autosomal recessive disorder that leads to multiorgan complications caused by β-glucocerebrosidase deficiency due to mutations in the β-glucocerebrosidase-encoding gene (GBA). GD morbidity in Japan is quite rare and clinical phenotype and gene mutation patterns of patients with GD in Japan and Western countries differ considerably. Of Japanese patients with GD, 57% develop types 2 or 3 GD with neurologic manifestations and younger onset, whereas only 6% of patients with GD develop those manifestations in Western countries. Thus, it is relatively difficult to find and diagnose GD in Japan.Patient concerns:A 69-year-old Japanese female with mild anemia and thrombocytopenia but without neurologic symptoms was initially referred for gastric cancer. Preoperative 18F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed accumulation in the bone marrow and paraabdominal lymph nodes. Following bone marrow aspiration found, abnormal foamy macrophages in the bone marrow and electron microscopy revealed that the macrophages were filled with tubular-form structures. Adding to these signs suggestive of a lysosomal disease, serum β-glucocerebrosidase activity test found decreased. Sequencing of the patient's GBA gene revealed a RecNciI recombinant mutation and the novel mutation K157R (c.587A>G).Diagnoses:On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made.Interventions:Enzyme replacement therapy (ERT) with velaglucerase α was started after the diagnosis of type 1 GD.Outcomes:The patient's β-glucocerebrosidase activity as well as hemoglobin and platelet levels were restored by ERT without any side effects. Bone marrow aspirations 10 months after the start of the treatment with velaglucerase α showed reduction of Gaucher cells in bone marrow to 2% from 4% of total cellularity.Lessons:This is the first report of 18F-FDG PET/CT application providing a clue for GD diagnosis. A novel mutation in GBA is described, which implies a potential pool of patients with GD with this mutation in Japan.

Persistent immune alterations and comorbidities in splenectomized patients with Gaucher disease

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapies (ERTs). More recently, oral substrate reduction therapies (SRTs) were approved for treatment of GD. Although both therapies alleviate disease symptoms, attitudes toward SRTs and patient perceptions of health while using SRT have not been well established. Electronic surveys were administered to adults with GD and asked about treatment history, attitudes toward SRTs, and perception of health while using SRTs as compared to ERTs, if applicable to the participant. ERT users that were offered treatment with SRTs cited potential side effects, wanting more research on SRTs, and satisfaction with their current treatment regimen as reasons for declining SRTs. SRT users expressed convenience and less invasiveness as reasons for choosing SRTs. Additionally, those using SRTs most often perceived their health to be similar to when they previously used ERT. Participant responses illustrate that attitudes toward SRTs can be variable and that one particular treatment may not be ideal for all patients with GD depending on individual perceptions of factors such as convenience, invasiveness, or side effects. Thus, individuals with GD should be counseled adequately by healthcare providers about both ERTs and SRTs for treatment of GD now that SRTs are clinically available.

In Gaucher disease, the infiltration of the bone marrow by glucocerebroside-laden macrophages (Gaucher cells) triggers a diverse pattern of skeletal disease that results in crippling complications. Reliable ascertainment of the severity and pattern of skeletal disease is essential to determine disease status and the response to enzyme replacement therapy (ERT). Although there is ample documentation of reversal of haematological and visceral disease by ERT, there is a paucity of data on skeletal response to ERT in children. To delineate the pattern of bone disease in children with Gaucher disease in Egypt and to evaluate its response to ERT. Twenty-two children with Gaucher disease were treated with ERT. Phenotyping by clinical, laboratory and radiological criteria was performed at baseline and following 11.2 +/- 4 months of ERT. Genotyping for glucocerebrosidase (GBA) mutations was performed by gene sequencing, and genotype-phenotype correlations were performed.Results. Two-thirds of the patients were from consanguineous pedigrees and 14/22 patients were homozygous or compound heterozygous for L444P and D409H mutations. Bone involvement was detected by plain radiology in 11 children (50%) and in 16 (73%) by magnetic resonance imaging (MRI). There was no correlation of severity of bone involvement and GBA genotype. ERT ameliorated bone disease: 10 of the 11 children with abnormal radiographic findings at baseline showed improvement in skeletal lesions; while 9/16 showed improvement of marrow disease by MRI. Radiographic sensitivity and specificity were 62% and 82% compared to MRI for detection of bone involvement in this patient population. At baseline, bone pain was present in 5 patients and ERT resulted in complete symptomatic remission in all of them. ERT was associated with significant improvement in growth parameters and amelioration of haematological and visceral involvement. Symptomatic and radiological skeletal disease is common in children with Gaucher disease in Egypt. MRI is the most accurate technique for detecting early skeletal involvement. There was no correlation between severity of skeletal involvement and GBA genotype. ERT was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain.

Gaucher's disease (GD) is one of the most prevalent lysosomal storage disorders (LSDs) and a rare genetic disease for which specific therapy is now available. GD is an autosomal, recessive, inborn error of glycosphingolipid metabolism, due to a deficiency in the enzyme acid beta-glucosidase. Partial deficiency of acid beta-glucosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant anemia and thrombocytopenia in non-neuronopathic, type 1 GD. Severe deficiency of glucocerebrosidase caused by severe mutations is additionally associated with neurological manifestations in the less common type 2 and type 3 GD subtypes. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype/phenotype relationship and the identification of modifier loci that impact on GD phenotypes remains a critical area for research. Enzyme replacement therapy (ERT) is proven to be safe and effective in the treatment of type 1 GD, establishing imiglucerase as the current standard of care. Amelioration of hepatosplenomegaly and of hematological manifestations is usually apparent within 6-12 months, whereas the bone disease responds more slowly. ERT cannot reverse the neurological deficits in type 2 or type 3 GD. Small molecule inhibitors of glucosylceramide synthase are being developed for substrate reduction therapy. Other potential therapeutic options such as chaperon-mediated enzyme enhancement therapy and gene therapy are being explored.

Increased Incidence of Autoimmune and Lymphoproliferative Disorders in Gaucher Patients Accompanied with Significantly Impaired Dendritic Cell Function,

Enzyme replacement therapy (ERT) has been shown to be effective at reducing the accumulation of undegraded substrates in lysosomal storage diseases. Most ERT studies have been performed with recombinant proteins that are mixtures of phosphorylated and non-phosphorylated enzyme. Because different cell types use different receptors to take up phosphorylated or non-phosphorylated enzyme, it is difficult to determine which form of enzyme contributed to the clinical response. Here we compare the uptake, distribution, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase (GUSB) in the MPS VII mouse. Highly phosphorylated murine GUSB was efficiently taken up by a wide range of tissues. In contrast, non-phosphorylated murine GUSB was taken up primarily by tissues of the reticuloendothelial (RE) system. Although the tissue distribution was different, the half-lives of both enzymes in any particular tissue were similar. Both preparations of enzyme were capable of preventing the accumulation of lysosomal storage in cell types they targeted. An important difference in clinical efficacy emerged in that phosphorylated GUSB was more efficient than non-phosphorylated enzyme at preventing the hearing loss associated with this disease. These data suggest that both forms of enzyme contribute to the clinical responses of ERT in MPS VII mice but that enzyme preparations containing phosphorylated GUSB are more broadly effective than non-phosphorylated enzyme.

Gaucher's disease (GD), a lysosomal storage disorder, poses significant treatment challenges. This 23-year study assesses survival rates and treatment efficacy in Brazilian GD patients, integrating data from a 16-year cohort (2000-2015) and the TABNET/DATASUS medicines distribution data (1999-2022). To investigate the survival of GD patients in Brazil, identifying key risk factors and evaluating the impact of treatments funded by the Brazilian National Health System (SUS). A 16-year retrospective cohort study was conducted using the National Database of SUS. Patients diagnosed with GD and treated with Enzyme Replacement Therapy (ERT) or Substrate Synthesis Inhibition (SSI) from 2000 to 2015 were included. Survival analysis was performed using Kaplan-Meier method and Cox proportional hazards model. The data from TABNET/DATASUS system from 1999 to 2022 was used to assess the trend in drug distribution beyond the main cohort. The study included 1,234 patients. Survival rates at 5 and 10years were 93.2% and 88.5%, respectively, with age and comorbidities like diabetes, cardiovascular diseases, and Parkinson's disease significantly affecting survival. Patients who received doses lower than DDD (n = 880) demonstrated a survival probability of 91.8%. In contrast, those with doses equal to the DDD (n = 15) showed a 100% survival probability, as no events were observed in this group. The greater than DDD group (n = 339) exhibited a survival probability of 81%. A log-rank test indicated a borderline statistical significance (p = 0.058) in the survival distributions among the different DDD adherence, with the lower dose group showing a favorable trend. This study provides insights into the survival rates and associated risk factors for GD patients in Brazil, contributing to the global understanding of GD and its management. While we acknowledge the inherent limitations of relying largely on electronic medical records and categorical codes, our findings underscore the need for early diagnosis, timely initiation of treatment, effective management of comorbidities, and personalized dosing strategies to improve patient outcomes. Future studies should aim to incorporate clinical verification of electronic data to further enhance the reliability and applicability of these findings.