Gaucher disease is a rare, inherited disorder. It is a type of lipid metabolism disorder. If you have it, you do not have enough of an enzyme called glucocerebrosidase. This causes too much of a fatty substance to build up in your spleen, liver, lungs, bones and, sometimes, your brain. This prevents these organs from working properly.

There are three types:

• Type 1, the most common form, causes liver and spleen enlargement, bone pain and broken bones, and, sometimes, lung and kidney problems. It does not affect the brain. It can occur at any age.
• Type 2, which causes severe brain damage, appears in infants. Most children who have it die by age 2.
• In type 3, there may be liver and spleen enlargement. The brain is gradually affected. It usually starts in childhood or adolescence.

Gaucher disease has no cure. Treatment options for types 1 and 3 include medicine and enzyme replacement therapy, which is usually very effective. There is no good treatment for the brain damage of types 2 and 3.

Gaucher disease is one of the inherited metabolic disorders known as lipid storage diseases. Lipids are fatty materials that include oils, fatty acids, waxes, and steroids (such as cholesterol and estrogen). People living with Gaucher disease either do not make enough of the enzyme glucocerebrosidase (needed to break down lipids) or they have enzymes that do not work properly. Fatty materials can build up in the brain and other organs as a result.

General symptoms may begin in early life or adulthood and include skeletal disorders and bone lesions that may cause pain and fractures, enlarged spleen and liver, liver malfunction, anemia, and yellow spots in the eyes.

Gaucher disease is broken up into three common types.

• Type 1 (or nonneuropathic) most often does not affect the brain. Symptoms may begin early in life or in adulthood. Many people with a mild form of the disease may not show any signs. People with type 1:
  • Usually bruise easily due to low blood platelets
  • Feel fatigued due to anemia
  • May have an enlarged liver and spleen

• Type 2 (acute infantile neuropathic Gaucher disease) symptoms usually begin by 3 months of age. Children with type 2 usually die before 2 years of age. Symptoms include:
  • Extensive brain damage
  • Seizures
  • Spasticity
  • Poor ability to suck and swallow
  • Enlarged liver and spleen

• Type 3 (or chronic neuropathic Gaucher disease) includes:
  • Signs of brain involvement
  • Seizures
  • Skeletal irregularities
  • Eye movement disorders
  • Cognitive deficit
  • Poor coordination
  • Enlarged liver and spleen
  • Breathing problems
  • Blood disorders

Treatment can prevent or lessen some symptoms of the disease. Enzyme replacement therapy is available for most people with types 1 and 3 Gaucher disease. The U.S. Food and Drug Administration (FDA) has also approved eligustat tartrate for Gaucher treatment. Rarely, surgery to remove the whole or part of the spleen may be required. Blood transfusions may benefit some people who are anemic. Other people may need joint replacement surgery to improve mobility and quality of life. There is no effective treatment for severe brain damage that may affect people with types 2 and 3 Gaucher disease.

Successful bone marrow transplants can reverse the non-neurological effects of the disease, but the procedure carries a high risk and is rarely performed in people with Gaucher disease. People with Gaucher disease type 1 are at increased risk for Parkinson's disease and Lewy Body Dementia. Gaucher disease type 2 is usually fatal by age 2. People with Gaucher type 3 may have a shortened life expectancy.

Gaucher disease occurs in 1 in 50,000 to 100,000 people in the general population. Type 1 is the most common form of the disorder in Europe, Israel, Canada, and the United States. This form occurs more frequently in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds; it affects 1 in 500 to 1,000 people of Ashkenazi Jewish heritage. Types 2 and 3 are uncommon and do not occur more frequently in people of Ashkenazi Jewish descent. These types can be more prevalent than type 1 in certain regions, such as Egypt, India, Japan, Poland, and Sweden.

What is Gaucher disease?

Gaucher disease is an autosomal recessive inherited disorder of metabolism where a type of fat (lipid) called glucocerebroside cannot be adequately degraded. Normally, the body makes an enzyme called glucocerebrosidase that breaks down and recycles glucocerebroside - a normal part of the cell membrane. People who have Gaucher disease do not make enough glucocerbrosidase. This causes the specific lipid to build up in the liver, spleen, bone marrow and nervous system interfering with normal functioning.

There are three recognized Types of Gaucher disease and each has a wide range of symptoms. Type 1 is the most common, does not affect the nervous system and may appear early in life or adulthood. Many people with Type 1 Gaucher disease have findings that are so mild that they never have any problems from the disorder. Type 2 and 3 do affect the nervous system. Type 2 causes serious medical problems beginning in infancy, while Type 3 progresses more slowly than Type 2. There are also other more unusual forms that are hard to categorize within the three Types.

Gaucher disease is caused by changes (mutations) in a single gene called GBA. Mutations in the GBA gene cause very low levels of glucocerebrosidase. A person who has Gaucher disease inherits a mutated copy of the GBAgene from each of his/her parents.

Gaucher disease occurs in about 1 in 50,000 to 1 in 100,000 individuals in the general population. Type 1 is found more frequently among individuals who are of Ashkenazi Jewish ancestry. Type 1 Gaucher disease is present 1 in 500 to 1 in 1000 people of Ashkenazi Jewish ancestry, and approximately 1 in 14 Ashkenazi Jews is a carrier. Type 2 and Type 3 Gaucher disease are not as common.

What are the symptoms of Gaucher disease?

Symptoms of Gaucher disease vary greatly among those who have the disorder. The major clinical symptoms include:

• Enlargement of the liver and spleen (hepatosplenomegaly).

• A low number of red blood cells (anemia).

• Easy bruising caused, in part, by a low level of platelets (thrombocytopenia).

• Bone disease (bone pain and fractures).

Other symptoms depending on the type of Gaucher disease include heart, lung and nervous system problems.

The symptoms of Type 1 Gaucher disease include bone disease, hepatosplenomegaly, anemia and thrombocytopenia, and lung disease.

The symptoms in Type 2 and Type 3 Gaucher disease include those of Type 1 and other problems involving the nervous system such as eye problems, seizures and brain damage. In Type 2 Gaucher disease, severe medical problems begin in infancy. These individuals usually do not live beyond age two. There are also some patients with Type 2 Gaucher disease that die in the newborn period, often with severe skin problems or excessive fluid accumulation (hydrops). Individuals with Type 3 Gaucher disease may have symptoms before they are two years old, but often have a more slowly progressive disease process and the extent of brain involvement is quite variable. They usually have slowing of their horizontal eye movements.

Recently it has been observed that both patients with Gaucher disease and Gaucher carriers have an increased risk of developing Parkinson disease and related disorders.

How is Gaucher disease diagnosed?

The diagnosis of Gaucher disease is based on clinical symptoms and laboratory testing. A diagnosis of Gaucher disease is suspected in individuals who have bone problems, enlarged liver and spleen (hepatosplenomegaly), changes in red blood cell levels, easy bleeding and bruising from low platlets or signs of nervous system problems.

Laboratory testing involves a blood test to measure the activity level of the enzyme glucocerebrosidase. Individuals who have Gaucher disease have very low levels of this enzyme activity. A second type of laboratory test involves DNA analysis of the GBA gene for the four most common GBA mutations. Both enzyme and DNA testing can be done prenatally. A bone marrow or liver biopsy is not necessary to establish the diagnosis.

When the specific gene mutation causing Gaucher disease is known in a family, DNA testing can be used to accurately identify carriers. However it is often not possible to predict the patient's clinical course based upon DNA testing.

What is the treatment for Gaucher disease?

Enzyme replacement therapy is now available as an effective treatment for individuals who have symptoms from Gaucher disease. The treatment involves giving a modified form of the enzyme, glucocerbrosidase, by intravenous infusion every two weeks. Enzyme replacement therapy helps to stop progression and often reverse many of the symptoms of Gaucher disease, but does not affect the nervous system involvement.

Several other therapies including oral treatments are in various stages of development.

Other treatments that have been required include: removal of the spleen (splenectomy); blood transfusions; pain medications; and joint replacement surgery.

Is Gaucher disease inherited?

Gaucher disease is inherited in families in an autosomal recessive manner. Normally, a person has two copies of the genes that provide instructions for making the enzyme, glucocerbrosidase. For most individuals, both genes work properly. When one of the two genes is not functioning properly, the person is a carrier. Carriers do not have Gaucher disease because they have one normally functioning gene that makes enough of the enzyme to carry out normal body functions. When an individual inherits an altered gene from each carrier parent, he or she has Gaucher disease.

Carrier parents have, with each pregnancy, a 1 in 4 (25 percent) chance to have a baby born with Gaucher disease; a 1 in 2 (50 percent) chance to have a child who is a carrier like themselves; and a 1 in 4 (25 percent) chance to have a child who is neither affected nor a carrier.

Variants (also known as mutations) in the GBA1 gene cause Gaucher disease. The GBA1 gene provides instructions for making an enzyme called lysosomal acid glucosylceramidase. This enzyme breaks down a fatty substance called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Variants in the GBA1 gene greatly reduce or eliminate the activity of lysosomal acid glucosylceramidase. 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.

Normal Function

The GBA1 gene provides instructions for making an enzyme called lysosomal acid glucosylceramidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Lysosomal acid glucosylceramidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Glucocerebroside is a component of the membrane that surrounds cells. It gets broken down by lysosomal acid glucosylceramidase when cells die, and the components are reused as new cells are formed.

Health Conditions Related to Genetic Changes

Gaucher disease

Many variants (also called mutations) in the GBA1 gene have been identified in people with Gaucher disease, a disorder with varied features that affect many parts of the body. Affected individuals can have enlargement of the liver and spleen (hepatosplenomegaly), blood cell abnormalities, and rarely, severe neurological problems. The variants occur in both copies of the gene in each cell. Most of the GBA1 gene variants responsible for Gaucher disease change single protein building blocks (amino acids) in lysosomal acid glucosylceramidase, altering the structure of the enzyme and preventing it from working normally. Other variants delete or insert genetic material in the GBA1 gene or lead to the production of an abnormally short, nonfunctional version of the enzyme.

Variants in the GBA1 gene greatly reduce or eliminate the activity of lysosomal acid glucosylceramidase in cells. As a result, glucocerebroside is not broken down properly. This molecule and related substances can build up in white blood cells called macrophages in the spleen, liver, bone marrow, and other organs. The abnormal accumulation and storage of these substances damages tissues and organs, causing the characteristic features of Gaucher disease.

Parkinson's disease

Changes in the GBA1 gene are also associated with Parkinson's disease and parkinsonism, which are similar disorders that affect movement. Characteristic features include tremors and impaired balance and coordination (postural instability). People with Gaucher disease (described above) have variants in both copies of the GBA1 gene in each cell, while those with a variant in just one copy of the gene are called carriers. People with Gaucher disease and people who are carriers of a GBA1 gene variant have an increased risk of developing Parkinson's disease or parkinsonism.

Symptoms of Parkinson's disease and parkinsonism result from the loss of nerve cells (neurons) that produce dopamine. Dopamine is a chemical messenger that transmits signals within the brain to produce smooth physical movements. It remains unclear how GBA1 gene variants are related to these disorders. Studies suggest that changes in this gene may contribute to the faulty breakdown of toxic substances in neurons by impairing the function of lysosomes. Alternatively, the changes may increase the formation of abnormal protein deposits. As a result, toxic substances or protein deposits could accumulate and kill dopamine-producing neurons, leading to abnormal movements and balance problems.

Dementia with Lewy bodies

GBA1 gene variants can increase the risk of developing dementia with Lewy bodies; however, some people with a variant in the GBA1 gene never develop this condition. Dementia with Lewy bodies is characterized by intellectual decline (dementia); visual hallucinations; sudden changes in attention and mood; and movement problems characteristic of Parkinson's disease (described above) such as rigidity of limbs, tremors, and impaired balance and coordination.

Variants in one copy of the GBA1 gene increase the risk of developing dementia with Lewy bodies. These variants result in the production of an altered lysosomal acid glucosylceramidase enzyme. This abnormal enzyme may interfere with the function of lysosomes and the normal breakdown of a protein called alpha-synuclein, which increases the risk that these proteins accumulate and form Lewy bodies. Accumulation of these protein clusters throughout the brain impairs neuron function and ultimately causes cell death. Over time, the loss of neurons increasingly impairs intellectual and motor function and the regulation of emotions, resulting in the signs and symptoms of dementia with Lewy bodies.

Other Names for This Gene

• GBA
• GLCM_HUMAN
• GLUC

Genomic Location

Gaucher disease is a genetic condition. Babies inherit it from their biological (birth) parents.

• Gaucher disease is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking GBA gene to their baby. Only babies with two nonworking GBA genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the GBA gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the GBA gene, they have a 1 in 4 chance of having a child with Gaucher disease.
  • Carriers for Gaucher disease often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with Gaucher disease.
  • Parents who already have a child with Gaucher disease still have a 1 in 4 chance of having another child with Gaucher disease. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of Gaucher disease may appear anywhere from birth to adulthood, depending on the type and severity of Gaucher disease a baby has.

Early signs of the condition may include the following:

• Large liver and spleen (hepatosplenomegaly)
• Low number of red blood cells (anemia)
• Easy bruising
• Bone pain
• Bone fractures
• Lung disease
• Unusual eye movements
• Seizures

Newborn screening for Gaucher disease requires collecting a small amount of blood from your baby’s heel. Screening measures how much of the GBA enzyme is in your baby’s blood. Babies with a low level of this enzyme might have Gaucher disease.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Gaucher disease is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood or urine tests
• DNA testing using a blood or cheek swab sample

You should complete any recommended follow-up testing as soon as possible. Infants with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Enzyme replacement therapy (ERT)
• Medications to help prevent blood clots (anticoagulants)
• Pain medicines
• Medicines to reduce glucocerebroside (substrate reduction therapy)

Children who receive early and ongoing treatment for Gaucher disease can live longer and have better growth.