Gaucher disease (NORD): Year of the Zebra

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Gaucher disease is an inherited condition characterized by insufficient levels of the enzyme glucocerebrosidase, also called beta-glucosidase.
It’s named for the French physician, Philippe Gaucher, who first described the condition. Glucocerebroside is a glycolipid, which is a molecule containing both sugar and fat, that's included in the membrane of many different cells.
Glucocerebroside is formed through a set of reactions in the cell that require enzymes. Once the glucocerebroside is made it becomes a part of various cells and when these cells become old or damaged, they are often engulfed, or eaten, by immune cells called macrophages.
Macrophages contain lysosomes, which are organelles that act as the cells’ digestive center. Inside lysosomes, large, potentially harmful substances are broken down, to be either discharged or reused by the body.
One example is glucocerebroside which is broken down by the enzyme glucocerebrosidase, or GBA, which is a product of the GBA gene.
In Gaucher disease, the GBA gene is faulty, meaning it has a mutation that leads to a reduction in the level or activity of glucocerebrosidase.
Hence, glucocerebroside can’t be broken down and it accumulates inside the lysosomes of macrophages. So under a microscope, macrophages have a characteristic lipid-laden, or “fatty” appearance, similar to “crumpled tissue-paper.” These transformed macrophages are called Gaucher cells, and they accumulate in multiple organs and tissues, including the bone marrow, liver, and spleen.
While the reason is unclear, Gaucher cells and other nearby macrophages secrete damaging lysosomal enzymes and inflammatory signals into the surrounding area.
This causes an immune response and production of scar tissue, resulting in many characteristic signs and symptoms. GBA gene mutations are inherited in an autosomal recessive manner.There are a few subtypes of Gaucher disease.
In type 1, some individuals are asymptomatic, but when there are signs and symptoms they can be due to bone marrow fibrosis, which causes reduced production of red blood cells, resulting in anemia and associated fatigue.
Rarely, white blood cells are also affected, causing leukopenia. There can also be bone infarctions, caused by reduced blood flow to part of a bone, can lead to a painful “bone crisis”, and result in physical deformity and avascular necrosis, or death of bone tissue.
Osteoporosis, or low bone density, is another manifestation. Both the liver and spleen can become enlarged, and when platelets are sequestered, or trapped, within the enlarged spleen, this can cause thrombocytopenia, or low platelets in the blood.
This can lead to bleeding and easy bruising. Type 2, also called acute neuronopathic Gaucher disease, is characterized by severe neurological involvement early in life due to glucocerebroside buildup in the brain.
In addition to the symptoms associated with type 1, there’s also loss of motor skills, decreased muscle tone, muscle spasms, and trouble swallowing.
This can progress to severe breathing and feeding difficulties, and death within the first few years of life. Lastly, type 3, also called chronic neuronopathic Gaucher disease, is like type 2, but the symptoms develop at a slower rate, and in some individuals can develop over decades.
Seizures can be a major problem for some individuals with type 3 Gaucher disease. Diagnosis of Gaucher disease relies on clinical presentation, and measuring glucocerebrosidase enzyme activity with the beta-glucocerebrosidase leukocyte blood test.
Genetic testing can be done to look for mutations in the GBA gene.Treatment depends on the severity of the condition, and can include enzyme replacement therapy with a synthetic form of glucocerebrosidase, as well as substrate reduction therapy designed to block the enzyme that helps synthesizes glucocerebroside.
Symptoms can be managed with supportive therapy.All right, as a quick recap...Gaucher disease is an inherited condition characterized by insufficient levels of glucocerebrosidase.
Glucocerebroside accumulates in the lysosomes of macrophages that accrue in multiple tissues and cause damage. The types 2 and 3 forms of Gaucher disease involve the brain, while type 1 does not.
Diagnosis includes measuring the glucocerebrosidase enzyme activity and genetic testing, and treatment includes a manufactured form of glucocerebrosidase.