What Is Gaucher's Disease? What Causes Gaucher's Disease?

Date: Jul-15-2013Gaucher's (Gaucher) disease, also known as glucocerebrosidase deficiency, occurs when a certain lipid, glucosylceramide, accumulates in the bone marrow, lungs, spleen, liver and sometimes the brain. Patients with Gaucher's disease have a hereditary deficiency of glucocerebrosidase, an enzyme that helps the body process glucosylceramide. Glucosylceramide is also known as glucocerebroside.

When glucocerebrosidase is faulty, the lipid (fat) glucosylceramide builds up, especially in the macrophages. Macrophage is a type of white blood cell.

Gaucher's is a Lysosomal Storage Disease - a patient with a lysosomal storage disease lacks an enzyme that eliminates unwanted substances within the cells. The enzymes exist in lysosomes, sac-like structures inside the cells. Lysosomes are the recycling centers of cells - they break down unwanted substances into simpler ones so that the cell can use them to make new material or expel them. If the enzyme that breaks down the waste product is lacking, waste builds up in the cells, eventually undermining its proper function, this can lead to serious health problems. We know of at lest 40 lysosomal storage diseases.

According to the National Gaucher Foundation, Gaucher's disease is present in approximately 1 in every 20,000 live births. The US Food and Drug Administration (FDA), however, says between 1 in 50,000 and 1 in 100,000 people have Gaucher's disease. Approximately 1% of the US population are carriers for Type 1 Gaucher's disease.

One in every 450 babies born to Ashkenazi Jewish parents has Gaucher's disease, an article in the American Journal of Human Genetics reported. The authors added that the carrier rate among Ashkenazi Jews is 8.9%.
What are the signs and symptoms of Gaucher's disease?

A symptom is something the patient feels and describes, such as a headache, while a sign is something others can detect, e.g. a rash.

Most patients describe their first symptom as a swollen stomach. This is usually one of the first warning signs that sends patients to the doctor - an enlarged abdomen. This is because the spleen has swollen.

One of the spleen's functions is to weed out old blood cells. When the spleen enlarges too much, sometimes to 25 times its normal size, it weeds out too many blood cells, including good ones. This can lead to anemia. Patients with insufficient blood cells suffer from fatigue, because they are not getting enough oxygen and energy. If the spleen has taken out too many platelets, which are essential for coagulation (clotting), the patient will bleed and bruise more.

People with Gaucher's disease do not all have the same symptoms.

There are three main types of Gaucher's disease:
Gaucher's disease Type 1

This is the most common type accounting for approximately 9 in every 10 cases, also the one with the least severe symptoms. Patients are usually diagnosed in their late twenties to early thirties, although the disease can become apparent at any age. Signs and symptoms may include:

Anemia
Delayed puberty
Fatigue
Frequent nosebleeds
Hepatomegaly - enlarged liver
Osteopenia (bone thinning), bone fractures, and bone pain. Damage to the shoulder or hip joints are common.
Osteoporosis - demineralization of the bones
Pingueculae - yellow spots in the eyes
Splenomegaly - enlarged spleen
Thrombocytopenia - low blood platelet numbers, resulting in easy bruising and slow clotting times (easy bleeding)

Type 1 Gaucher's disease is most prevalent in the Ashkenazi Jewish population.
Gaucher's disease Type 2

Also known as the acute neuropathic form, Gaucher's disease Type 2 is the most severe and rarest form of Gaucher's disease, with an incidence of 1 in 100,000 live births. Typically, signs and symptoms appear when the infant is three to four months old. There are brainstem abnormalities and serious and rapidly progressing brain damage. Most patients with this form do not survive beyond three years of age. Signs and symptoms may include:

All those possible in Type 1, plus..
Mental retardation
Apnea - breathing stops temporarily during sleep
Dementia
Seizures
Rigidity

Gaucher's disease Type 3

This form is rarer than Type 1, but more common than Type 2. Signs and symptoms usually appear during childhood or teenage years. This chronic disease progresses more slowly that Type 2. Brain damage is possible, but not as severe as in Type 2. Signs and symptoms may include:

All those possible in Type 1, plus..
Mental retardation
Dementia
Convulsions
Ocular muscle apraxia - abnormal eye movements
Myoclonus - muscle twitches

In Norbottnian Gaucher's Disease, a subclassification of Type 3, symptoms may not become evident until the patient is a young adult.
What are the causes of Gaucher's disease?

Gaucher's disease is caused by a recessive mutation of the gene called GBA, located on chromosome 1. The GBA gene tells the body to produce glucocerebrosidase. Glucocerebrosidase, an enzyme (protein), breaks down a type of fat (lipid) known as glucosylceramide into sugar and simple fats, which the body uses for energy.

If the GBA gene is faulty there is a deficiency of the enzyme glucocerebrosidase, which leads to an excessive accumulation of glucosylceramide, which starts to collect inside the cells of the brain, bone marrow, lungs, spleen and liver, and interferes with their normal functioning.
How is Gaucher's disease inherited?

A baby inherits Gaucher's disease in an "autosomal recessive manner".

Autosomal recessive is a mode of inheritance

of genetic traits

A "healthy" person carries two copies of the genes that tell the body to produce the enzyme glucocerebrosidase. In most cases, the two genes function properly.

If one of the genes is faulty, the person will not develop Gaucher's disease because one normally-functioning gene is enough to make the body produce enough of the enzyme, but he/she is a "carrier".

If a baby inherits a faulty gene from each parent, i.e. has two faulty genes, he/she has Gaucher's disease. Both parents need to be carriers for their offspring to develop Gaucher's disease.

If both parents are carriers, each pregnancy has a:

25% chance of producing an offspring with Gaucher's disease
50% risk of having a child who is a carrier
25% chance the child is neither affected nor a carrier (if he/she inherits a properly-functioning gene from each parent).

How is Gaucher's disease diagnosed?

If the doctor identifies some signs and symptoms and suspects Gaucher's disease, or if there is a family history, tests to check levels of the enzyme glucocerebrosidase will be recommended. Genetic tests are also possible.

Blood test - in order to determine whether levels of glucocerebrosidase are too low. People with Gaucher's disease have very low levels of glucocerebrosidase, while carriers have lower-than-normal levels, but higher than those with Gaucher's.

Genetic testing - the test looks for the four most common genetic mutations - N370S, L444P, 84gg and IVS2[+1] - as well as some less common ones. This test is not 100% reliable because we probably have not yet identified all the genetic mutations associated with Gaucher's disease. Genetic testing of these four mutations is 90% to 95% accurate in diagnosing Gaucher's disease in the Ashkenazi Jewish population, and 50% to 70% accurate in the general population.

Genetic testing combined with the enzyme assay test helps diagnose Gaucher's disease accurately.

Prenatal screening - women who are carriers of the of one faulty GBA gene and want to know whether their fetus has Gaucher's disease can have:

Amniocentesis - cells in the amniotic fluid are tested
Chorionic villus sampling - tissue from the placenta is tested

Preconception screening - couples thinking about having a baby and either have a family history of Gaucher's disease or are of Ashkenazi Jewish ancestry may consider genetic screening. Doctors advise talking to a genetic counselor.
What are the treatment options for Gaucher's disease?

For patients with Type 2 Gaucher's Disease enzyme replacement therapy is available, but there is no effective treatment for the severe brain damage that comes with this condition.

Some patients with mild Type 1 may not need any treatment at all, but should be periodically monitored.

For patients with Type 1 or 3 Gaucher's disease, the following therapies may help:

Enzyme replacement therapy (ERT) - the deficient glucocerebrosidase is replaced with intravenous recombinant glucocerebrosidase (imiglucerase). ERT is more effective for most patients with Type 1, and some with Type 3. ERT can help prevent hepatomegaly (enlarged liver) and splenomegaly (enlarged spleen), improve bone density as well as blood platelet count. ERT does not treat problems with the nervous system (brain damage) in patients with Types 2 and 3.

Cerezyme (imiglucerase for injection) is approved for the long-term treatment of adult and pediatric patients who have a confirmed diagnosis of Type 1 Gaucher's disease that results from either anemia, low blood platelet count (thrombocytopenia), bone disease or enlarged liver/spleen (hepatomegaly or splenomegaly). According to the Genzyme Corporation, more than 5,600 patients in 90 countries with Type 1 Gaucher's have been treated with Cerezyme since 1994.

Elelyso (taliglucerase alfa), according to its manufacturer, Pfizer Inc., is the first plant cell-based ERT for Type 1 Gaucher's disease treatment.

Substrate reduction therapy (SRT) - the aim here is to reduce the production and buildup of substrate (waste material) within cells. SRT reduces the amount of waste a cell makes so that for patients who are deficient in glucocerebrosidase, the glucocerebrosidase they do have is better able to prevent the waste from building up within cells.

Miglustat (Zavesca) is approved by the FDA as an oral prescription medication for adults with mild to moderate Type 1 Gaucher's disease. According to Actelion Pharmaceuticals US, Inc., the makers of the drug, Zavesca should only be used in patients who cannot be treated with ERT. Patients should either have never received ERT or have been off it for at least six months.

Do not take Zavesca if you plan to become pregnant, are pregnant, or breastfeeding.

Bone marrow transplant - also known as stem cell transplant, replaces bone marrow that has been damaged by Gaucher's with healthy bone marrow stem cells. Bone marrow is a spongy tissue that exists in the hollow centers of some bones. Bone marrow cells produce blood cells, including red and white blood cells, and platelets (which help stop bleeding).

Bone marrow transplantation is only used in severe cases of Gaucher's disease. There is a risk of serious complications, including infection and rejection.

Complications of Gaucher's disease

Gaucher's is a progressive disease. What complications there are depend on the type and severity of initial symptoms.

The following complications are possible for patients with any type of Gaucher's:
Bone pain - in some cases pain may be severe. Generally, severity of pain is linked to risk/frequency of fractures.

Bleeding - the patient may experience frequent and severe nosebleeds as well as skin bruising.

Cancer risk - researchers reported in JAMA Internal Medicine (June 2007 issue) that patients with Gaucher's disease have a higher risk of developing pancreatic cancer, malignant melanoma and non-Hodgkin lymphoma. They added that there appears to be no significant increase in the risk of other malignancies, including multiple myeloma.

Canadian researchers wrote in The International Journal of Cell Biology "The extent of the association between Gaucher disease and cancer remains unclear."

In the American Journal of Hematology, Yale scientists wrote that Gaucher's disease patients should be monitored for cancers including multiple myeloma.

Parkinson's disease - scientists from University College London reported in the journal Cell Metabolism that mutations responsible for Gaucher's disease are linked to a higher risk of developing Parkinson's disease later in life.

Type 2 Gaucher's disease is associated with serious complications, including dysphagia (difficulty swallowing), problems walking and seizures. These problems get worse and eventually lead to the death of the patient.

The most common complication for patients with Type 3 Gaucher's disease is calcification of the heart valves, which can lead to aortic stenosis.
What is the life expectancy of somebody with Gaucher's disease?

Patients who are diagnosed promptly and receive treatment early on have better life expectancies than those who are not.

The Center for Jewish Genetics says that with proper treatment Type 1 Gaucher's patients can expect normal lifespans.

Researchers reported in the American Journal of Hematology (December 2008 issue) that the average life expectancy of somebody with Type 1 Gaucher's disease was 68 years, compared to 77 years in the rest of the population.

Most patients with Type 2 Gaucher's disease die within their first three years of life.

Regarding Type 3 Gaucher's disease, the National Gaucher Foundation says that "life expectancy without therapeutic intervention is likely to be substantially diminished, and is dictated by the degree of involvement of the liver and spleen, and lungs."

In the video below, patients discuss their symptoms of Gaucher's disease.

Written by Christian Nordqvist

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