Gaucher's Disease

Girl with Gaucher disease. Source: NIH

Other Names

• Glucocerebroside lipidosis
• Cerebroside Lipidosis Syndrome
• Gauchers Disease
• Gaucher's disease
• Gaucher splenomegaly
• Gaucher syndrome
• GD
• Glucocerebrosidase deficiency
• Glucocerebrosidosis
• Glucosylceramidase deficiency
• Glucosylceramide beta-glucosidase deficiency
• Glucosylceramide lipidosis
• Glucosyl cerebroside lipidosis
• Kerasin histiocytosis
• Kerasin lipoidosis
• Kerasin thesaurismosis
• Lipoid histiocytosis (kerasin type)

Types

Type 1

Type 1 GD is the most common and generally the most mild form; it is more descriptively known as the adult chronic non-neuropathic form of the disease. Symptoms range from mild to severe and may appear any time from childhood to adulthood. The average age at diagnosis is 21 years.

Type 2

Type 2 GD is known as a neuronopathic forms of the disorder because it is characterized by problems that affect the central nervous system. Type 2 is known as the infantile neuronopathic form and accounts for less than 1% of cases; patients often die within the first year of life.

Type 3

Like Type 2, Type 3 GD is also known as a neuronopathic form of the disorder and is characterized by problems that affect the central nervous system. Type 3 is also known as the juvenile form and has features of both Types 1 and 2; it accounts for less than 5% of cases.

Perinatal lethal form

The most severe type of Gaucher disease is the perinatal lethal form. This condition causes severe or life-threatening complications starting before birth or in infancy. Features of the perinatal lethal form can include extensive swelling caused by fluid accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or other skin abnormalities; hepatosplenomegaly (enlargement of the liver and spleen); distinctive facial features; and serious neurological problems. As its name indicates, most infants with the perinatal lethal form of Gaucher disease survive for only a few days after birth.

Cardiovascular type

Another form of Gaucher disease is known as the cardiovascular type because it primarily affects the heart, causing the heart valves to harden (calcify). People with the cardiovascular form of Gaucher disease may also have eye abnormalities, bone disease, and mild enlargement of the spleen (splenomegaly).

Signs and Symptoms

• Type 1 disease: Major signs and symptoms include enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells (anemia), easy bruising caused by a decrease in blood platelets (thrombocytopenia), lung disease, and bone abnormalities such as bone pain, fractures, and arthritis.

• Types 2 and 3 disease: In addition to the signs and symptoms described above, these conditions can cause abnormal eye movements, seizures, and brain damage. Type 2 Gaucher disease usually causes life-threatening medical problems beginning in infancy. Type 3 Gaucher disease also affects the nervous system, but tends to progress more slowly than type 2.

Causes

Gaucher disease is caused by the absence, or near-absence, of glucocerebrosidase activity due to mutations in the GBA gene that codes for the glucocerebrosidase enzyme (also known as beta-glucocerebrosidase). Since the normal enzyme breaks down glucocerebrosides into a sugar (glucose) and a simpler fat molecule (ceramide), absence of the enzyme results in accumulation of the glucocerebroside which damages the spleen, liver, and bone.

Diagnosis

The definitive diagnosis of Gaucher disease is based on the microscopic appearance of abnormal accumulations of glucocerebrosides in the bone marrow, spleen, or liver, but a high level of confidence can be obtained with a positive family history and suggestive physical exam findings. Enzymatic tests will show <30% of normal levels. The disease may be diagnosed prenatally with samples taken from the chorionic villus. The responsible gene (beta glucosidase, GBA) may also be sequenced to make an even more specific diagnosis of the mutation(s) involved.

Diagnosis of which of the three types of Gaucher disease (described above) is present is based on history, symptoms and physical examination, rather than enzymatic, microscopic, or molecular test results.

Treatment

Highly effective enzyme replacement therapy is available for most patients with types 1 and 3 Gaucher disease. This therapy decreases liver and spleen size, reduces skeletal anomalies, and successfully reverses other symptoms of the disorder, including abnormal blood counts. Bone marrow transplantation (a procedure to replace damaged or destroyed blood-forming cells) can reverse the non-neurological effects of type 1 Gaucher disease, but it carries a high mortality rate due to imperfect donor matches. This procedure has been replaced by enzyme replacement therapy. There is no effective treatment for severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.

Chances of Developing Gaucher's Disease

Type 1 is the most common form of the disorder, and occurs more frequently in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds. This condition affects 1 in 500 to 1,000 people of Ashkenazi Jewish heritage. The other forms of Gaucher disease are uncommon, and do not occur more frequently in people of Ashkenazi Jewish descent.

Heredity

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

History

Philippe Gaucher, a French physician, first described the disease in 1882. For many decades there was no hope of cure, until the the possibility that the therapeutic replacement of the missing enzyme was suggested by de Duve, who wrote: “Any substance that is taken up intracellularly by an endocytic process is likely to end up within lysosomes. This obviously opens up many possibilities for interaction, including replacement therapy”^[1]. The first human trials of enzyme replacement therapy were done in the early 1990s. ^[2] with encouraging clinical results. However, the therapy is expensive, costing over $400,000 per year.^[3]

Epidemiology

Incidence and prevalence

The National Gaucher Foundation states that around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher disease, giving a prevalence of 1 in 40,000: among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15. Type 2 disease shows no particular preference for any ethnic group. Type 3 disease is especially common in the population of the Northern Swedish region of Norrbotten, with an incidence of 1 in 50,000. ^[4]

Clinical Trials

Select this link to view a list of studies currently seeking patients.

References

1. ↑ de Duve C. From Cytases to Lysosomes. Fed Proc. 1964 Sep-Oct;23:1045-9. http://pubmed.gov/14209796 Citation
2. ↑ Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, et al. Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 1991 May 23;324(21):1464-70. [1]
3. ↑ Beutler E. Enzyme replacement in Gaucher disease. PLoS Med. 2004 Nov;1(2):e21. Epub 2004 Nov 30. Abstract Full Text PDF
4. ↑ National Gaucher Disease FoundationGaucherdisease.org

External Links

Online Books - Medical and science texts Scriver's Online Metabolic and Molecular Bases of Inherited Disease (OMMBID):Gaucher Disease

OMIM - Genetic disorder catalog (4 links)