Gaucher Disease Description

Disease process

Gaucher disease is one member of a family of rare inherited diseases called lysosomal storage disorders (LSDs). In each one of these diseases, specific substances are stored in specialized compartments in the cells, known as lysosomes. Lysosomes digest and eliminate foreign substances or break down substances into energy for the body. In Gaucher disease, lysosomes tend to build up and then cannot be broken down for use or elimination by the body. This is due to a missing or nonfunctional protein, known as an enzyme. Each LSD is characterized by a nonfunctioning or missing enzyme responsible for breaking down the specific substances. Symptoms unique to each LSD result when these specific substances begin to accumulate in cells and organs.

In Gaucher disease, the absent or nonfunctional enzyme (glucocerebrosidase) cannot break down the fatty substances (glucocerebrosides) for use or elimination by the body, so they continue to build up in cells (macrophages, a type of white blood cell that acts as a recycler for cellular debris and other harmful materials). This buildup results in a large accumulation in the organs, tissues, and bone marrow. (See diagram below).

When there is significant accumulation in the cells, some organs are unable to function properly, which leads to the symptoms that are common in Gaucher disease. These include anemia, fatigue, abdominal swelling, and bone pain. When the cells become enlarged due to the fatty substance accumulation inside, they are referred to as Gaucher cells. In some cases, Gaucher cells accumulate in the central nervous system, causing a range of symptoms, including eye movement disorders, difficulty in swallowing, seizures, loss of muscle coordination (called ataxia), and a hearing problem (called auditory processing disorder or APD). With APD, a person can hear but cannot recognize the differences between the sounds in words. For example, the word couch might be mistaken for the word cow.

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Types and symptoms

Gaucher disease has been divided into three types, which are classified according to the presence or absence of neurological symptoms. (See diagram below). The symptoms associated with Gaucher disease vary greatly from person to person and from type to type. Some people will develop few or no symptoms and others may have serious symptoms. The severity of the disease depends a great deal on how much glucocerebroside builds up in the cells, and in which organs of the body.

Type 1 Gaucher disease

The most common and most variable type of Gaucher disease is type 1, which affects more than 90% of Gaucher patients. Most patients with type 1 Gaucher disease do not have neurological symptoms (those involving the central nervous system), though new research indicates that neurological symptoms do exist in some type 1 patients. Affected individuals can show symptoms at any age, though some do not exhibit any symptoms until well into adulthood, if at all. These patients may display one or more of the following signs and symptoms:

• Enlarged spleen and liver may lead to a swollen abdomen, abdominal discomfort, and early fullness after eating
• Low levels of circulating red blood cells (anemia) may cause fatigue or shortness of breath during physical activity
• Low platelet count (thrombocytopenia) may result in bleeding problems and easy bruising, due to poor clotting
• Skeletal abnormalities may lead to bone pain, fractures, and thinning of the bone
• Lung impairment (rarely)

It is very difficult to predict how mild or severe an individual patient’s disease will be because the symptoms can vary a great deal, even within a family.

Type 1 Gaucher patients and their doctors should pay particular attention to bone disease, which usually has the greatest impact on a patient’s quality of life. Bone disease results when Gaucher cells form in the bone marrow, causing severe chronic pain, permanent bone damage, fractures, and physical disability. Delayed growth and/or short stature is common among children with Gaucher disease.

In addition, it has been documented that patients with type 1 Gaucher disease may face an increased risk later in life for developing additional diseases. These may include Parkinson’s disease, a progressive neurological disease, and multiple myeloma, a cancer of the plasma cells. Researchers do not know why these two diseases tend to occur in Gaucher patients, but the search continues for the mechanisms involved and the link to Gaucher disease.

It should be noted that there are some patients who show no symptoms of type 1 Gaucher disease and develop no complications at all—despite having a low level of enzyme activity.

This overview highlights the great range of symptoms in patients with Gaucher disease, and in particular, those with type 1 Gaucher disease.

Type 2 Gaucher disease

Type 2 Gaucher disease is the most severe form of the disease. A diagnosis is usually made in newborns when they show severe neurological symptoms that progressively worsen within the first months of life. Common signs and symptoms include:

• Eye movement disorders (strabismus)
• Arching of neck (hypertonia)
• Seizures
• Difficulty in swallowing and choking spells
• Enlarged spleen and liver, low red blood cell counts, easy bleeding or bruising, and lung involvement

Type 2 Gaucher disease develops rapidly in children and symptoms are severe. Because of the severity of the disease, life expectancy for these patients is greatly reduced.

Type 3 Gaucher disease

Type 3 Gaucher disease is less severe than type 2, but can be more severe than type 1. Symptoms usually develop in childhood. Most often, the initial problems are enlargement of the spleen and liver, poor feeding, and failure to gain weight. These signs and symptoms usually appear in the first year of life but may appear later. The range of symptoms leading to diagnosis is varied. For example, some patients will have an enlarged spleen and liver, while other patients will show neurological symptoms.

The key symptoms of type 3 Gaucher disease are:

• Enlarged liver and spleen
• Movement disorders (coordination and imbalance)
• Eye movement disorders
• Hearing issues (auditory processing disorder)
• Lung disease
• Seizures and cognitive impairment

It is important to recognize that not all patients will experience all aspects of the disease.

Initially, some type 3 patients are classified as type 1 patients, but when they develop neurological symptoms they are reevaluated to determine if they should be reclassified as type 3 patients. Because of the nontypical development of symptoms, diagnosis of type 3 Gaucher disease is difficult in the early stages or when it appears in a relatively mild form.

Usually, patients with type 3 Gaucher disease have symptoms that develop slowly and progressively worsen throughout their life. However, some patients do continue to develop physically and socially, despite being affected by neurological symptoms. They are able to attend school with additional resources to address their developmental educational needs.

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Prevalence

Although it can affect individuals of any ethnicity, type 1 Gaucher disease is most common in people of Ashkenazi (Eastern and Central European) Jewish heritage. The reason for the higher risk in this population is unclear, though the existence of a founder effect is one theory.

Estimated prevalence rates for Gaucher disease
General population	1 in 50,000 to 1 in 100,000 (all types)
Ashkenazi Jewish population	1 in 855 (type 1)

A founder effect occurs when there is a lack of genetic variation, often due to the geographic or reproductive isolation of a population. This effect is reflected in the prevalence rate, which measures disease among a specific population in a given period of time.

Type 2 Gaucher disease is extremely rare and does not occur with a higher frequency in any particular ethnic or demographic group.

Type 3 Gaucher disease is also very rare, except in the Norrbotten province of Sweden, where it is known as the Norrbottnian form of Gaucher disease. Through molecular studies, this form of the disease was traced back to a single person (founder) who arrived in Sweden about 400 years ago. However, type 3 Gaucher disease can affect individuals of any ethnic background.

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Inheritance

Our bodies are made up of cells that contain genetic information, called DNA. DNA is packaged into units called genes, and genes are located on chromosomes. Each gene provides specific information for our body, including instructions for growth and development, and for making proteins.

An individual typically has 23 pairs of chromosomes. Twenty-two of those pairs, called autosomes, are the same in men and women. The twenty-third pair, called the sex chromosomes, differs between men and women, with men having an X and a Y chromosome and women having two X chromosomes.

For each gene pair, we receive one copy of the gene from our father and one copy from our mother. In some genetic conditions, both copies of the gene pair must be altered in order for individuals to have symptoms of the condition. These conditions are called autosomal recessive conditions.

Gaucher disease is an inherited genetic disorder with an autosomal recessive inheritance pattern. A person will show features of the disease when he or she receives two nonworking copies of the gene related to Gaucher disease, one from each parent. In the majority of cases, both parents of a person with Gaucher disease have one working copy of the gene and one nonworking copy of the gene. They are not expected to show symptoms of Gaucher disease. They are referred to as carriers since they have one nonworking copy of the gene, but do not have Gaucher disease themselves. However, they can pass on the nonworking gene to their children.

If two carriers of Gaucher disease have children, there is a chance that their children may have Gaucher disease. However, there is also a chance that their children will not have Gaucher disease, or they will be carriers of Gaucher disease. If both parents are carriers, there is a one in four (25%) chance in each pregnancy that they would both pass on the nonworking Gaucher gene, and as a result, that child would be expected to have Gaucher disease. (See diagram below.)

All individuals with Gaucher disease have the condition because of an enzyme deficiency resulting from alterations (mutations) in the same gene. However, the exact mutation in that gene may differ among individuals. There are more than 200 different gene mutations responsible for the enzyme deficiency that causes Gaucher disease. Four particular mutations are relatively common. These four mutations account for 90% of type 1 Gaucher disease in the Ashkenazi Jewish population and about 50%-75% of the disease in the general population.

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Screening and genetic counseling

If you or someone in your extended family has been diagnosed with Gaucher disease, you may wonder how the disease could impact you or your children. Concerned couples and individuals have options to determine if they are carriers of Gaucher disease. DNA-based testing on a blood sample can identify mutations in the Gaucher gene (the gene responsible for making glucocerebrosidase). This method is considered more reliable for determining carrier status than enzyme-based testing. While measuring the enzyme level is a reliable test for the diagnosis of Gaucher disease, it does not always distinguish between carriers and noncarriers, and it does not predict the type and severity of the disease.

Genetic counseling is available to provide information on establishing a diagnosis, carrier testing, and reproductive options, including prenatal testing. If a family member has been diagnosed with Gaucher disease, prenatal testing can be performed to determine the status of a pregnancy with regard to Gaucher disease. Prior to the testing, your genetic counselor will discuss with you the benefits and risks of the test, as well as the information you can expect to learn from the test. You may wish to prepare for a genetic counseling appointment by learning as much as you can about the diagnosis of Gaucher disease in your family member, including the specific mutations that have led to their Gaucher disease.

Genetic counseling can be helpful in providing support and information on the medical, psychological, social, and economic issues confronted by individuals with Gaucher disease. In addition, there are other support resources available, including patient support organizations and informative Web sites. Please see Resources for more information and assistance.

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Diagnosis

In the past, the diagnosis for Gaucher disease was typically made by examining a patient’s bone marrow or performing tissue biopsies on his or her liver or spleen to look for cells filled with excess fatty substances (glucocerebrosides).

Today, the diagnosis can be made primarily from a single blood test, which is used either to measure the enzyme (glucocerebrosidase) activity or to perform DNA analysis to see if there is a gene variation. DNA-based testing of a blood sample can identify variations, or mutations, in the gene responsible for the production of glucocerebrosidase.

In addition to blood tests, your doctor may perform a physical exam along with other testing. Other testing may include:

• Routine blood tests to measure levels of platelets and red blood cells and to evaluate your overall health status
• Special blood tests for biochemical markers to evaluate disease burden and monitor treatment
• Magnetic resonance imaging (MRI) to investigate potential changes in the organs and bones
• Computed tomography (CT) scan to investigate potential changes in the organs and bones
• Dual energy x-ray absorptiometry (DXA) scan to check for effects on bone density

Because Gaucher disease is rare and the types of symptoms that a patient can have may be similar to those in other disorders, doctors may initially have difficulty diagnosing the disease accurately. A diagnosis may also be difficult because the disease can progress at varying rates, and certain symptoms might not appear right away.

Although Gaucher disease can be detected by simple tests, it is important that you provide the doctor with as much information as possible on symptoms and medical history. Doctors rely on many sources of information to consider or rule out conditions with similar symptoms before they reach a diagnosis, a process known as differential diagnosis. So, for example, giving information about a relative with similar symptoms might prompt the doctor to order a particular genetic test.

Again, because symptoms vary widely and can appear at any stage of life, diagnosing Gaucher disease can often be delayed.

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Management of Gaucher Disease

Today, there is a range of therapeutic options available to treat Gaucher disease and its symptoms. Several therapies are intended to target the biochemical process of Gaucher disease. Also, options are available or are being developed for treating symptoms of the disease. There is no cure for Gaucher disease, but ongoing research continues into new therapeutic approaches. As always, you will want to talk with your doctor or other healthcare professionals to learn more about your treatment options and to decide what is appropriate for you, your child, or family member.

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Long-term management of symptoms

Because there is no cure, the main goals in the treatment of Gaucher disease include managing symptoms and minimizing disease-related complications by taking medications and/or undergoing certain procedures, which may include:

• Joint replacement surgery
• Physical therapy
• Blood transfusion
• Antibiotics (to prevent infection)
• Pain medications (for pain management)
• Bisphosphonates (to strengthen bone)
• Removal of the spleen (not common clinical practice)

Type 1 Gaucher disease patients will be monitored for conditions that may arise later in life, such as Parkinson’s disease and multiple myeloma.

In addition to managing symptoms and disease-related complications, doctors have another goal: to deliver supportive care to patients and their families and caregivers in order to provide the best possible quality of life for everyone.

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Quality of life and support

In general, the quality of life for most Gaucher disease patients can be maintained, especially for those with mild symptoms. However, along with the physical symptoms and complications that occur with Gaucher disease, some patients may have a difficult time coping emotionally. Challenges may include reduced self-esteem, mood changes, extreme fatigue, and an inability to work or enjoy leisure activities. These effects can also have an impact on the patient’s family and caregivers. Therefore, based on the needs of the individual patient, a broader range of support services may be required.

Healthcare professionals work to address these feelings and provide support, reassurance, and encouragement. In addition, turning to family, friends, psychologists, psychiatrists, patient education, religion, Web sites, and patient support groups can benefit patients. Please see Resources for more information and assistance.

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