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Turkish Journal of Haematology :... Jun 2022Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting... (Review)
Review
Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting proper treatment and preventing complications. Splenomegaly, anemia, and thrombocytopenia are the most common findings in GD and so most patients are initially referred to hematologists. The Turkish Society of Hematology established its Rare Hematological Diseases Subcommittee in 2015. One of the main topics of this subcommittee was to increase and improve awareness and education of rare diseases among hematologists in Turkey. This review presents GD with an overview of its clinical features, pathophysiology, and treatment options for hematologists.
Topics: Anemia; Gaucher Disease; Glucosylceramidase; Humans; Splenomegaly; Thrombocytopenia; Turkey
PubMed: 35439918
DOI: 10.4274/tjh.galenos.2021.2021.0683 -
International Journal of Molecular... Feb 2017Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to... (Review)
Review
Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD-but also carriers of mutation-have been found to be predisposed to developing Parkinson's disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).
Topics: Gaucher Disease; Humans; Metabolic Networks and Pathways; Models, Biological; Monitoring, Physiologic; Prognosis
PubMed: 28218669
DOI: 10.3390/ijms18020441 -
Skin Therapy Letter Mar 2018Fabry disease (FD) is an X-linked lysosomal storage disease. A lack of alpha-galactosidase activity results in the accumulation of globotriaosylceramide in cells of... (Review)
Review
Fabry disease (FD) is an X-linked lysosomal storage disease. A lack of alpha-galactosidase activity results in the accumulation of globotriaosylceramide in cells of various systems, leading to multi-systemic effects. The cutaneous hallmark of FD is a specific distribution of angiokeratoma. Other common symptoms include cornea verticillata, acroparesthesia, and sweating abnormalities. FD-specific symptoms, history, as well as examination of angiokeratoma can assist in the differential diagnosis. Enzyme replacement therapy is the current mainstay of treatment.
Topics: Fabry Disease; Humans; Randomized Controlled Trials as Topic
PubMed: 29562089
DOI: No ID Found -
Revista Da Associacao Medica Brasileira... Jan 2020Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between... (Review)
Review
Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain. Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency. The latter being the main cause of death in FD. The gold standard for diagnosis is the genetic analysis in search of mutation, in addition to family history. In homozygous patients, the enzyme activity can also be used. Once the diagnosis is confirmed, the patient and their family should receive genetic counseling. The treatment, in turn, currently focuses mainly on replacing the enzyme that is absent or deficient by means of enzyme replacement therapy, with the purpose of avoiding or removing deposits of Gb3. Chaperones can also be used for the treatment of some cases. It is considered that the specific treatment should be initiated as soon as a diagnosis is obtained, which can change the prognosis of the disease.
Topics: Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Kidney; Male; Renal Insufficiency, Chronic; Trihexosylceramides
PubMed: 31939530
DOI: 10.1590/1806-9282.66.S1.10 -
Pathobiology : Journal of... 2016We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective... (Review)
Review
We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective function of the catabolic enzyme β-glucocerebrosidase (GBA), leading to an accumulation of its substrate, glucocerebroside. Clinical signs and symptoms include neurological dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia and thrombocytopenia. Enzyme replacement therapy with recombinant GBA is the mainstay of treatment for GD, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions.
Topics: Enzyme Replacement Therapy; Gaucher Disease; Genetic Therapy; Glucosylceramidase; Humans; Hypersplenism; Splenomegaly
PubMed: 26588331
DOI: 10.1159/000440865 -
Journal of Bone and Mineral Research :... Jun 2019Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the... (Review)
Review
Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Topics: Bone Diseases; Bone Marrow; Bone Remodeling; Bone and Bones; Gaucher Disease; Humans; Practice Patterns, Physicians'
PubMed: 31233632
DOI: 10.1002/jbmr.3734 -
Molecular Genetics and Metabolism May 2022Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ... (Review)
Review
Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.
Topics: Biomarkers; Child; Child, Preschool; Disease Progression; Gaucher Disease; Humans; Lysosomes; Phenotype
PubMed: 35367141
DOI: 10.1016/j.ymgme.2022.03.001 -
Molecular Genetics and Metabolism Feb 2021Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic... (Review)
Review
Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges.
Topics: Blood-Brain Barrier; Gaucher Disease; Genetic Association Studies; Glucosylceramidase; Humans; Phenotype; Severity of Illness Index
PubMed: 33483255
DOI: 10.1016/j.ymgme.2021.01.002 -
International Journal of Molecular... Feb 2023Sphingolipidoses are defined as a group of rare hereditary diseases resulting from mutations in the genes encoding lysosomal enzymes. This group of lysosomal storage... (Review)
Review
Sphingolipidoses are defined as a group of rare hereditary diseases resulting from mutations in the genes encoding lysosomal enzymes. This group of lysosomal storage diseases includes more than 10 genetic disorders, including GM1-gangliosidosis, Tay-Sachs disease, Sandhoff disease, the AB variant of GM2-gangliosidosis, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease, Farber disease, etc. Enzyme deficiency results in accumulation of sphingolipids in various cell types, and the nervous system is also usually affected. There are currently no known effective methods for the treatment of sphingolipidoses; however, gene therapy seems to be a promising therapeutic variant for this group of diseases. In this review, we discuss gene therapy approaches for sphingolipidoses that are currently being investigated in clinical trials, among which adeno-associated viral vector-based approaches and transplantation of hematopoietic stem cells genetically modified with lentiviral vectors seem to be the most effective.
Topics: Humans; Sphingolipids; Sphingolipidoses; Gaucher Disease; Tay-Sachs Disease; Genetic Therapy
PubMed: 36835039
DOI: 10.3390/ijms24043627 -
European Journal of Heart Failure Jul 2020Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable...
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management.
Topics: Consensus; Enzyme Replacement Therapy; Fabry Disease; Heart Failure; Humans; alpha-Galactosidase
PubMed: 32640076
DOI: 10.1002/ejhf.1960