Gaucher disease

Other Names: Acute cerebral Gaucher disease; Cerebroside lipidosis syndrome; Gaucher splenomegaly; Sphingolipidosis 1; Glucocerebrosidosis; Glucosylceramidase deficiency; Glucosyl cerebroside lipidosis; Kerasin lipoidosis; Kerasin thesaurismosis

Gaucher disease refers to a group of inherited metabolic diseases in which harmful amounts of fatty materials (lipids) accumulate in various cells and tissues in the body (lipid storage disorder).

Micrograph showing crinkled paper macrophages in the marrow space in a case of Gaucher disease, H&E stain.

Types

There are different types of Gaucher disease classified according to specific features and severity: Gaucher disease perinatal lethal, Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, and cardiovascular type or Type 3C (where the main problem is a hardening (calcification) of the heart valves). Gaucher disease type 1 is the most common form. The most severe type of Gaucher disease is called 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; distinctive facial features; and serious neurological problems.

Cause

Mutations in the GBA gene cause Gaucher disease. The GBA gene provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Mutations in the GBA gene greatly reduce or eliminate the activity of beta-glucocerebrosidase. Without enough of this enzyme, glucocerebroside and related substances can build up to toxic levels within cells. Tissues and organs are damaged by the abnormal accumulation and storage of these substances, causing the characteristic features of Gaucher disease.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

Signs and symptoms vary widely among affected individuals and may include skeletal disorders, enlarged spleen and liver (hepatosplenomegaly), liver malfunction, anemia, low platelet counts, bone problems, and neurological problems.

80%-99% of people have these symptoms

• Anemia
• Low number of red blood cells or hemoglobin
• Fatigue(Tired)
• Hepatomegaly(Enlarged liver)
• Splenomegaly(Increased spleen size)

30%-79% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Arthralgia(Joint pain)
• Ataxia
• Avascular necrosis(Death of bone due to decreased blood supply)
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Bone pain
• Delayed puberty(Delayed pubertal development)
• Delayed skeletal maturation(Delayed bone maturation)
• Depressivity(Depression)
• Developmental regression(Loss of developmental milestones)
• Dysphagia(Poor swallowing)
• Feeding difficulties in infancy
• Fever
• Generalized myoclonic seizure
• Joint dislocation(Joint dislocations)
• Osteopenia
• Recurrent fractures(Increased fracture rate)
• Strabismus
• Thrombocytopenia(Low platelet count)

Diagnosis

Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present. A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages. Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease

Treatment

The first drug for Gaucher's was alglucerase (Ceredase), which was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes. It was approved by the FDA in 1991 and has been withdrawn from the market. Available recombinant glucocerebrosidases are:

• Imiglucerase (approved in 1995)
• Velaglucerase (approved in 2010)
• Taliglucerase alfa (Elelyso)

Miglustat is a small molecule, orally available drug that was first approved for Gaucher's Disease in Europe in 2002. It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gaucher's. This approach is called substrate reduction therapy. Eliglustat (Cerdelga) (approved in 2014)s also a small molecule. The compound is believed to work by inhibition of glucosylceramide synthase.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Taliglucerase alfa (Brand name: Elelyso For Injection)Use as long-term enzyme replacement therapy in patients with Type 1 Gaucher disease
• Imiglucerase (Brand name: Cerezyme®)Enzyme replacement therapy in patients with type I Gaucher's disease.
• Miglustat (Brand name: Zavesca) Treatment of mild to moderate Type I Gaucher disease in adults for whom enzyme replacement therapy is not a therapeutic option (e.g., due to constraints such as allergy, hypersensitivity, or poor venous access).

Additional images

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  Sphingolipidoses

Gaucher disease Resources
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