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An autosomal recessive inherited genetic disorder of metabolism in
which a dangerous level of a fatty substance called glucocerebroside collects in the liver, spleen, bone marrow, lungs, and at times in the brain. Gaucher disease is caused by mutations in a gene called GBA. Changes in the GBA gene cause low levels of glucocerebrosidase.[1] An individual with thisdisorder inherits a mutated copy of the GBA gene from each of his or her parents. Signs and symptoms of this disease can vary broadly among individuals and types.[2]
Gaucher disease occurs in about 1 in 50,000 to 100,000 individuals in the overall general population. Type 1 is the most common form and is frequent among individuals who are of Ashkenazi Jewish ancestry. Type 1 is seen in 1 in 500 to 1000 people of this type of Jewish descent and roughly 1 in 14 Ashkenazi Jews is a carrier. Type 2 and 3 of this disease are not as common.[4]
These are the following types and their presentations.
Type
Presentation
Type 1
Most common form of this condition and is named Non-neuronopathic Gaucher Disease due to the lack of involvement of the brain and spinal cord.[4] Symptoms at this stage can range from very mild to severe at times and can develop at any age. Chief signs and symptoms may include enlargement of the spleen and liver (hepatosplenomegaly), a decrease in blood platelets causing, bruising (thrombocytopenia), lung disease, decrease in number of red blood cells (anemia), and bone defects such as deep pain felt in the bone, arthritis and fractures.[4]
Type 2
Classified as a neuropathic form of the disease due to its involvement of the brain and spinal cord (central nervous system).[4] At this stage, liver and spleen enlargement can be evident as early as 3 months of age. Individuals may have substantial brain damage, seizures, abnormal eye movements and usually die prior to the age of 2.[2]
Type 3
Type 3 is also categorized as a neuronopathic disorder because it also affects the central nervous system, but progresses at a slower rate than type 2. At this stage, spleen and liver magnification is unpredictable, and brain association including seizures steadily become evident.[2] Key signs and symptoms can include eye movement disorders, blood disorders, and skeletal abnormalities.[2]
Perinatal Lethal Form
This category causes life-threatening problems beginning prior to birth or in infancy.[4]Elements of this category may include significant swelling caused by fluid accumulation before birth (hydrops fetalis), dry skin (ichthyosis) enlarged spleen and liver, distinct facial features; and severe neurological problems. Most infants with this form only survive for a few days after birth.[4]
Cardiovascular Type
This form mainly affects the heart. It causes the heart valves to harden or calcify. Individuals with this form may also have eye abnormalities, swelling of the spleen and bone disease.[4]
Individuals diagnosed with Gaucher disease have extremely low levels of the glucocerebrosidase activity.
Analysis of DNA. This analysis looks for the GBA gene and the four most frequent GBA mutations.[1]
When the GBA gene mutation is known in a family, DNA testing should be completed and used to correctly recognize any carriers.[1]
Etiology/Causes
Gaucher disease is caused by a mutated gene called GBA. It is inherited in an autosomal recessive way when a person has two copies of the genes that supply directions for constructing the enzyme, glucocerbrosidase.[1] For healthy people, both genes work correctly.[1] When one of the genes is not functioning appropriately the person becomes a carrier for the disorder.
Carriers do not have the disease because they have one functioning gene that creates adequate amounts of the enzyme for normal body function. When an individual inherits a mutated gene from each carrier parent, he or she then develops Gaucher disease.[1]
Carrier parents have a 1 in 4 or 25% chance to conceive a child born with the disease. They have a 1 in 2, or 50 % chance to have a child who is a carrier, and a 1 in 4, or 25% chance to produce a child who is neither has the disease or is a carrier.[1]
Enzyme replacement therapyis utilized for individuals with types 1 and 3 of the disease. Enzyme therapy works by decreasing skeletal abnormalities, decreasing liver and spleen size/inflammation, and reversesother symptoms of the disorder, including abnormal blood counts. The treatment includes a modified form of the glucocerbrosidase by IV infusion every two weeks.[14]Enzyme therapy has no effects on the neurological aspects of the disorder.[14]
The most effective dosing regimen of ERT is still debatable. Believers in of low dose regimens focus on the high costs of the enzyme. Others argue that high doses are necessary for the ideal effect to alleviate the severity of the disease, especially in children.[15]
One strategy used is called top-down, with the dose being fairly high in the beginning and then slowly decreased to reach a maintenance level. [10]
Another strategy used is called the step-up approach, in which the dose is low in the beginning and then built up if necessary, during the disease.[15]
Both approaches have been compared in a recent study showing similar results for hematologic and visceral components, and a higher dose was better for improvement in surrogate factors including chitotriosidase and bone marrow involvement.[15]
Some evidence shows that sudden cessation of therapy is not suggested due to a rebound phenomena occurance. A paper published by de Fost et al. shows that, in stable patients, the sudden reduction of the of the enzyme from weekly/biweekly infusions to a single monthly infusion, with a stable monthly dose may result in therapeutic failure in some patients.[15]
A different study from Spain shows that after 2–3 years of initial biweekly enzyme replacement therapy treatment, infusion intervals were extended to 3 weeks with a 33% decline of the monthly dose. Within a few years, all of participants with the disease had to restart the original enzyme replacement therapy schedule because of a symptomatic setback of the disease.[15]
Increase in signal intensity in MRI of bone marrow
U.S. Food and Drug Administration approved velaglucerase alfa for injection (VPRIV) for long-term enzyme replacement therapy for Type 1 Gaucher disease. VPRIV is an alternative to Cerezyme (imiglucerase), another enzyme replacement therapy which is currently in short supply.[16]
“The approval of VPRIV will provide a safe and effective alternative treatment for patients with Gaucher disease,” said Julie Beitz, M.D., director of the FDA’s Office of Drug Evaluation III. “Patients who previously received Cerezyme as an enzyme replacement therapy for their Type 1 Gaucher disease can be safely switched to VPRIV.”[16]
Substrate Reduction Therapy (SRT) slows the build-up of unwanted fatty substance in Gaucher cells. Lysosomes then are able to try to catch up and eliminate the extra fatty substance.[17] SRT is taken orally by mouth every day in pill form.[17] It provides another option to enzyme replacement therapy.
Miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) was introduced 6 years ago. This inhibits glucosylceramide synthase, which stops new synthesis of glucosylceramide in addition to the accumulated lipid.[15]
There are currently less than ten clinical studies on miglustat published in the literature today. These current studies show that miglustat is useful in most patients with only mild disease at controlling the hematologic and visceral problems.[15]
Miglustat is not tolerated as well as enzyme replacment therapy due to problems such as weight loss and diarrhea.
Concerns about miglustat-induced cognitive problems have been resolved currently. The impact of miglustat, on neurological types of Gaucher disease is still under the investigation phase of development. In Europe, patients who cannot receive enzyme replacment therapy are able to receive miglustat as an alternative.[15]
There is no effective treatment for brain damage with types 2 and 3.[2]
Physical Therapy Management (current best evidence)
There currently is no protocol or best treatment plans for gaucher disease, but exercise has been shown to be essential for children and adults that are diagnosed with Gaucher disease.
Moderate exercise >3 days/week is recommended with a healthy diet for proper health and weight management
Those with enlarged spleens there is a possibility to bleed because of low platelet count, and all are advised to stay away from contact sports due to increased risk of pathological fracture
Swimming is a good exercise for many patients due to gravity lessened movement. It strengthens muscles with minmized pressure on joint
Those with hip/knee replacements should avoid exercises such as jogging and downhill skiing due to high impact.
Differential Diagnosis
The following may be associated with and/or differentially diagnosed for Gaucher disease:
The National Institute of Neurological Disorders and Stroke (NINDS) support research innovative ways to treat and prevent lipid storage disorders. This includes clinical studies by the NINDS Developmental and Metabolic Neurology Branch.[2]
Research on Gaucher disease and a link between Gaucher disease and Parkinson disease is currently being done at the Medical Genetics Branch of the National Human Genome Research Institute by Dr. Ellen Sidransky. Information about the research on Gaucher disease can be found at [Www.genome.gov/Staff/Sidransky www.genome.gov/Staff/Sidransky].[14]
References
↑ 1.01.11.21.31.41.51.61.7National Human Genome Research Institute. Learning about gaucher disease. National Human Genome Research Institute: genome.gov. http://www.genome.gov/25521505. Updated September 2, 2010. Accessed March 5, 2011.
↑ 4.04.14.24.34.44.54.6National Library of Medicine. Genetics home reference: Gaucher disease. National Library of Medicine: National Institutes of Health. http://ghr.nlm.nih.gov/condition/gaucher-disease. Updated January 2008. Published March 13, 2011. Accessed March 14, 2011.
↑Genzyme Therapeutics Corporation. Gaucher disease information. fckLRhttp://www.cerezyme.com/healthcare/disease/cz_hc_disease.aspfckLRAccessed April 2, 2011.
↑ 10.010.110.2Cambridge University Hospitals: NHS Foundation Trust. Gaucher.fckLRhttp://www.cuh.org.uk/addenbrookes/services/clinical/lysosomal/disorders/gaucher.html. Accessed April 1, 2011.
↑ 11.011.111.211.311.411.5Genzyme. Lysosomal Learning. fckLRhttp://www.lysosomallearning.com/healthcare/about/lsd_hc_abt_gaucher1.aspfckLRAccessed April 1, 2011.
↑ 12.012.114.Genzyme Corporation. Gaucher Care. fckLRhttp://www.gauchercare.com/en/healthcare/information/SignsAndSymptoms.aspx. Accessed April 1, 2011
↑ 14.014.114.2National Human Genome Research Institute. Learning about gaucher disease. National Human Genome Research Institute: genome.gov. http://www.genome.gov/25521505. Updated September 2, 2010. Accessed March 5, 2011.
↑ 15.0015.0115.0215.0315.0415.0515.0615.0715.0815.09Schmitz, J., Poll, W.L., Dahl, S. Therapy of adult Gaucher disease. Haematologica, Vol 92, Issue 2, 148-152 doi:10.3324/haematol.11193.fckLRhttp://www.haematologica.org/cgi/content/full/92/2/148/T10920148
↑Patterson, M.C. The Role of Small Molecule Inhibition in the Balance for Inborn Errors of Metabolism. Medscape Education. 2011. http://www.medscape.org/viewarticle/523700_2. Accessed April 2, 2011.
↑ 19.019.1Accordant Health Services: CVS Caremark. Exercise and Gaucher Disease.fckLRhttp://www.cvscaremarkspecialtyrx.com/patients/condition-resources-tools/lysosomal-storage-disorders/gaucher-disease/staying-healthy/exerc. Updated April 30, 2010. Accessed April 1, 2011.
