Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to ß-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.

A 20-Year Longitudinal Study of Plasma Chitotriosidase Activity in Treated Gaucher Disease Type 1 and 3 Patients-A Qualitative and Quantitative Approach.

Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload. Gaucher disease (GD) is a recessively inherited disorder resulting in storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. It is directly caused by the deficiency of beta-glucocerebrosidase (GBA) activity. Chitotriosidase has been measured systematically each year in the same group of 49 patients with type 1 and 3 GD for over 20 years. Our analysis showed that chitotriosidase is very sensitive biomarker to enzyme replacement therapy (ERT). The response to treatment introduction is of an almost immediate nature, lowering pathologically high chitotriosidase levels by a factor of 2 in a time scale of 8 months, on average. Long term enzyme replacement therapy (ERT) brings chitotriosidase activity close to reference values. Finally, reducing the dose of ERT quickly boosts chitotriosidase activity, but restoring the initial dose of treatment brings chitotriosidase level of activity back onto the decreasing time trajectory.

Gaucher's disease in Lithuania: its diagnosis and treatment.

Gaucher's disease is a lysosomal storage disease caused by the lack of beta-glucocerebrosidase enzyme, leading to the accumulation of glucocerebroside. Gaucher's disease is the most frequent type of sphingolipidosis as well as the most frequent lysosomal disease. Clinically, two forms of Gaucher's disease are defined: nonneuronopathic form, so-called type 1, characterized by hepatosplenomegaly, thrombocytopenia, anemia, and osteopenia, and neuronopathic form, known as types 2 and 3, which are also characterized by hepatosplenomegaly, hematological and bone changes; however, involvement of the central nervous system dominates in the clinical picture. Severe deficiency of beta-glucocerebrosidase activity allows confirming the diagnosis based on the clinical picture or the findings of bone marrow examination. Treatment with human glucocerebrosidase was introduced in 1991. Clinically good results are achieved: not only accumulation of glucocerebroside is stopped, but also positive changes in the reticuloendothelial system and an improvement in development and hematological parameters of children are observed as well as the development of bone lesions is reduced. To date, Gaucher's disease has been diagnosed in 8 patients in Lithuania: 3 persons have type 3 and 5 have type 1 disease. Enzyme replacement therapy was started in 2001, and currently 6 persons are being treated. In majority of patients, Gaucher's disease was suspected after exclusion of other possible proliferative diseases. All patients within the first or second year of treatment achieved the therapeutic goals, namely: normalization of hematological parameters, reduction in liver and spleen volumes, and bone pain relief.

Two cases of neuronopathic form of Gaucher disease - diagnostic difficulties.

BACKGROUND: Gaucher disease is one of the most common inherited lysosomal storage diseases caused by the deficiency of the enzyme ß-glucocerebrosidase, leading to the accumulation of glucocerebroside. Depending on the clinical manifestations, two different forms of the disease are distinguished - the non-neuronopathic form (type 1) with a variety of presentations - from asymptomatic to symptomatic patients (characterized by hepatosplenomegaly, thrombocytopenia, anemia and osteopenia), and the neuronopathic form (known as types 2 and 3). Besides visceral, osseous, and hematopoietic organ lesions, neuronopathic forms are associated with central nervous system involvement (bulbar and pyramidal signs, horizontal saccadic eye movements, myoclonic epilepsy, progressive development delay). In type 2, the neurological symptoms appear earlier and are more severe, the survival time is shorter. In type 3, the neurological symptoms are milder and allow patients to live a fully productive life. CASE PRESENTATION: This article includes a review of two cases of neuronopathic Gaucher disease: type 2 and severe type 3. Both patients presented symptoms during infancy and the manifestations were similar but varied in intensity and the dynamics of progress. Enzyme replacement therapy was started in both cases, which decreased visceral symptoms. CONCLUSIONS: Both described cases indicate the lack of knowledge and the tendency of doctors to disregard the possibility of Gaucher disease in their paediatrics patients.

Do Not Miss the (Genetic) Diagnosis of Gaucher Syndrome: A Narrative Review on Diagnostic Clues and Management in Severe Prenatal and Perinatal-Lethal Sporadic Cases.

With a growing number of proved therapies and clinical trials for many lysosomal storage disorders (LSDs), a lot of hope for many patients and families exists. However, there are sometimes cases with poor prognosis, fatal outcomes when our efforts must be directed towards a prompt and correct genetic diagnosis, which offers the only possibility of providing the family with appropriate prevention and treatment. To address this issue, in this article, we present the clinical and genetic hallmarks of the lethal form of Gaucher disease (PLGD) and discuss the potential management. We hope that this will draw attention to its specific manifestations (such as collodion-baby phenotype, ichthyosis, arthrogryposis), which differ from best-known GD complications and ensure appropriate diagnostic assessment to provide families at risk with reliable counselling and treatment to avoid the medical complication of GD.

Primary gastric Burkitt lymphoma-induced anaemia: a case report and a literature review.

BACKGROUND: Primary tumours of the gastrointestinal tract are very uncommon in children. They can present with anaemia caused by gastrointestinal acute or chronic bleeding. One of the most common gastrointestinal tumours is Burkitt lymphoma. This lymphoma is a highly aggressive, rapidly growing B-cell neoplasm, making survival without treatment possible only for a few weeks. For this reason it requires immediate hospitalization and treatment. CASE REPORT: We report a case of a gastric Burkitt lymphoma in an adolescent girl who presented with anaemia due to gastrointestinal bleeding. She received out-patient care with iron medications orally due to suspected iron-deficiency anaemia but there was no sufficient effect. The patient was referred to Children's Oncohematology Department with a progression of symptoms (weakness, fatigue, sound in the ears, and nausea) five months after anaemia was diagnosed in the complete blood count. The imaging tests showed a massive solid tumour with bleeding in the stomach. The final diagnosis was a histologically atypical Burkitt lymphoma. Chemotherapy treatment was started according to NHL-BFM 2004 paediatric protocol. CONCLUSIONS: Non-Hodgin's lymphoma is the most common malignancy of the gastrointestinal tract in children and about 75% of these tumours are Burkitt lymphomas. They can present with anaemia in the complete blood count due to bleeding. Reticulocyte test and serum ferritin level test help to differentiate pathophysiological origin of anaemia. Combination chemotherapy according to standardized protocols is the best current standard of care and has a very good clinical response without unfavourable risk factors.

Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease.

BACKGROUND: The clinical presentation of Gaucher disease (GD), an inherited lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, is highly variable, and three clinical types are distinguished based upon the presence of neurologic symptoms. Thrombocytopenia, anemia, hepatosplenomegaly, and bone manifestations are the most typical signs of GD type 1 (GD1). CASE PRESENTATION: We present the case of an unsplenectomized man suffering from heterozygous GD1 with mutations of c.1226A>G (N370S) and RecNci I (L444P, A456P, and V460V) in the GBA1 gene, who developed recurrent pulmonary aspergillosis caused by Aspergillus fumigatus and a mycobacterial infection caused by Mycobacterium avium. Despite long-lasting therapy of both aspergillosis (including antifungal drugs and surgery), and the mycobacterial infection (triple therapy with rifampicin, ethambutol, and clarithromycin), recurrent positivity for M. avium and A. fumigatus was detected. CONCLUSIONS: Symptomatic lung involvement and an increased susceptibility to pulmonary infections are uncommon in GD and, if present, are often associated with more severe disease manifestations. To our knowledge, this is the first published report on the association of GD and pulmonary aspergillosis and mycobacterial infection. It illustrates the increased susceptibility of untreated GD patients to opportunistic pulmonary infections and ineffective eradication of these infections despite adequate therapy.

Liposomal amphotericin B and surgery as successful therapy for pulmonary Lichtheimia corymbifera zygomycosis in a pediatric patient with acute promyelocytic leukemia on antifungal prophylaxis with posaconazole.

Pulmonary zygomycosis, also referred to as mucormycosis, is a fungal infection of lungs caused by fungi of the order Mucorales in the class of Zygomycetes. It is usually associated with high morbidity and mortality. Here, we report the case of a 14-year-old girl with pediatric acute promyelocytic leukemia (APL) on antifungal prophylaxis with posaconazole, who developed pulmonary Lichtheimia corymbifera (formerly Absidia corymbifera) zygomycosis. She was successfully treated by means of liposomal amphotericin B (L-AmB) and surgery. To our knowledge, this is the first published report on pediatric APL and pulmonary zygomycosis in the English language literature. At present, the patient is in complete remission of her APL and without any signs of recurrence of zygomycosis. This report suggests that efficient diagnostics, increased physician awareness, and reliance on adjunctive surgical therapy can result in a favorable outcome of pulmonary zygomycosis in immunocompromised children with hematological malignancies.