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Last updated: 09/9/2024
Years published: 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2001, 2002, 2003, 2004, 2007, 2008, 2011, 2014, 2018, 2024
NORD gratefully acknowledges Ozlem Goker-Alpan, MD, Lysosomal Research and Treatment Center (LDRTC), Fairfax, VA, and the Gaucher Community Alliance for assistance in the preparation of this report.
Gaucher Disease (GD) is a lysosomal disorder characterized by an enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia) and skeletal abnormalities. In some forms of GD, the nervous system is primarily affected. The disease is caused by changes (variants) in the GBA1 gene, leading to a deficiency of the enzyme glucocerebrosidase, resulting in the accumulation of glucosylceramide (Gb1) and its derivative glucosylsphingosine (Lyso-Gb1) in lysosomes, affecting various organs and systems.
GD is categorized into three types: non-neuronopathic (GD1), acute neuronopathic (GD2) and chronic neuronopathic (GD3). Symptoms vary depending on the type, with GD1 often presenting from early childhood to adulthood, GD2 manifesting before birth (prenatally) or within the first weeks of life and GD3 symptoms typically appearing during early childhood.
GD3 (chronic neuronopathic) typically manifests in early childhood, with neurological symptoms developing gradually, such as cognitive decline, lack of coordination (ataxia) and myoclonic seizures. The progression and cognitive involvement in GD3 can vary significantly, with some individuals presenting with eye movement abnormality as the only neurological abnormality.
Subtypes of GD3:
Individuals with Gaucher disease may exhibit the following signs and symptoms:
Enlargement of the spleen (splenomegaly): Often one of the earliest signs occurring in childhood or adolescence. An enlarged spleen can lead to hypersplenism, where the spleen destroys blood cells, worsening anemia, thrombocytopenia and leukopenia. Splenic Infarcts though rare, may occur and cause abdominal pain and digestive issues.
Enlargement of the liver (hepatomegaly): May manifest in childhood or adolescence accompanying an enlarged spleen, and may result in liver dysfunction, though it is less common than splenomegaly.
Bone Abnormalities: Includes bone pain, fractures and skeletal abnormalities, which can occur at any age. Individuals with Gaucher disease who experience symptoms in childhood may develop widening of the long bones, known as โErlenmeyer flask deformities.โ Others may develop abnormal bone density or other skeletal changes later in life which can lead to bone fragility and fractures. Episodes of severe bone pain called โbone crisesโ due to infarctions or the death of bone tissue may occur.
Osteonecrosis is the most severe bone complication, which can lead to significant bone deformities, often requiring pain management and/or surgery.
Hematological abnormalities: Anemia and thrombocytopenia can occur at various stages and may worsen over time. Anemia or low red blood cell count can lead to fatigue and weakness. Low platelet counts can increase the risk of bruising and bleeding.
Neurological complications (in GD2 and GD3): Includes swallowing difficulties, seizures, muscle stiffness, coordination problems and developmental delay, typically appearing in infancy or childhood. The most common indicator of brain involvement in GD is abnormally slowed eye movements or inability to move the eyes horizontally.
Pulmonary complications: Lung problems primarily occur in severe forms of GD (GD2 and GD3) due to recurrent aspirations and/or primary involvement of the lungs, leading to respiratory distress in infancy and childhood.
Fatigue and chronic pain: Chronic fatigue can occur due to anemia, bone pain and other systemic issues. Generalized pain can be intermittent or persistent, especially related to bone and joint abnormalities.
Cardiovascular: Some individuals may develop cardiovascular issues, such as heart valve abnormalities and calcification of aorta. Increased pulmonary pressures can be observed on echocardiogram in rare instances.
Other co-morbidities: Patients with Gaucher disease may have a predisposition to develop a unique combination of other health problems, which vary in severity and may include:
Malignancies
Immunological abnormalities
Other metabolic issues
Protein-losing enteropathy: Loss of protein through the gastrointestinal tract, leading to low protein levels in the blood (hypoalbuminemia) and associated complications such as edema. This condition is more frequently observed in GD3.
Gaucheroma: A localized mass of Gaucher cells, typically found in the liver or spleen, more commonly associated with GD3. Gaucheromas can mimic tumors and may cause additional diagnostic challenges and complications.
Gaucher disease is caused by disease-causing variants in the GBA1 gene, leading to a deficiency of the enzyme glucocerebrosidase. This enzyme deficiency results in the accumulation of glucosylceramide and glucosylsphingosine in the lysosomes in various cells. Lysosomes are the major digestive units (organelles) in cells. In lysosomes, proteins also called enzymes help to break down or โdigestโ nutrients, including certain complex carbohydrates and fats. In Gaucher disease, sugar (glucose) containing complex fats known as sphingolipids, abnormally accumulate in the body because of the lack of the enzyme, glucocerebrosidase. This accumulation of lipids leads to the various symptoms or physical findings associated with this lysosomal storage disease.
In Gaucher disease, the primary cells and tissues affected are part of the reticuloendothelial system, particularly the immune cells known as macrophages. The accumulation of abnormal fat triggers inappropriate immune responses, leading to inflammation and cell death, including the neurons, responsible for the various symptoms seen in Gaucher disease.
Gaucher disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Gaucher disease occurs in 1 in 50,000 to 100,000 people in the general population. The incidence varies geographically, with GD1 being the most common genetic disorder in the Ashkenazi Jewish population, while GD2 and GD3 are more prevalent in Asian populations, including Japan, China, Taiwan and India.
A diagnosis of Gaucher disease may be suspected in individuals with unexplained anemia, easy bruising, unexplained bleeding, spleen enlargement, liver enlargement and chronic bone pain. The diagnosis is confirmed by an enzyme assay that measures acid beta-glucosidase activity in white blood cells or skin cells, and genetic testing for variants in the GBA1 gene.
Early diagnosis is critical, especially for severe forms of GD, which presents with rapidly progressing symptoms.
Bone marrow examination in Gaucher disease may reveal the presence of Gaucher cellsโenlarged macrophages with a characteristic โwrinkled tissue paperโ appearance. Although this examination can help confirm the diagnosis, it is not required when enzyme activity tests and molecular genetic testing are available and conclusive. Itโs important to note that other disorders, such as Niemann-Pick disease, chronic myeloid leukemia and multiple myeloma, can also produce cells that mimic the appearance of Gaucher cells in the bone marrow.
Ongoing Gaucher disease research includes:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
References
JOURNAL ARTICLES
Goker-Alpan O, Ivanova MM. Neuronopathic Gaucher disease: Rare in the west, common in the east. J Inherit Metab Dis. Published online May 20, 2024. doi:10.1002/jimd.12749 Link
Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here?. Mol Genet Metab. 2022;136(1):4-21. doi:10.1016/j.ymgme.2022.03.001
Aflaki E, Westbroek W, Sidransky E. The complicated relationship between Gaucher disease and Parkinsonism: Insights from a rare disease. Neuron. 2017;93(4):737-746. doi:10.1016/j.neuron.2017.01.018
INTERNET
Gaucher Disease. MedlinePlus. Nov 2022. https://medlineplus.gov/genetics/condition/gaucher-disease/#frequency Accessed Sept 9, 2024.
Hughes DA, Pastores GM. Gaucher Disease. 2000 Jul 27 [Updated 2023 Dec 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1269/ Accessed Sept 9, 2024.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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