What You Need to Know About Gaucher Disease

Gaucher disease is a genetic disorder in which a type of fatty substance, known as a lipid, begins to accumulate in the cells and organs of the body. The disease is characterized by anemia, easy bruising, bone lesions, neurological disorders, and the enlargement of the liver and spleen.

Gaucher disease is classified as a recessive autosomal disorder, meaning that it is a condition inherited from one’s parents. It is caused by a mutation of the so-called GBA gene of which there are more than 380 different variations. Depending on the types of mutations inherited, people can develop one of several different forms of the disease.

Of the three most common forms (type 1, type 2, and type 3), symptoms can range from mild and manageable to life-threatening. Life expectancy may also be impacted, particularly in persons with rarer forms of the disease.

Gaucher disease affects one of every 40,000 births in the United States, according to statistics from the Rockville, Maryland-based National Gaucher Foundation. Approximately one of every 100 people is believed to be a carrier of the GBA mutation. Among Ashkenazi Jews, the number is closer to one of every 15.

How the Disease Causes Illness

The GBA gene provides instructions for making a type of enzyme known as beta-glucocerebrosidase. This is the enzyme responsible for breaking down a type of lipid known as glucocerebroside.

In persons with Gaucher disease, beta-glucocerebrosidase no longer functions as it should. Without the means to break down lipids, levels begin to accumulate in cells, causing inflammation and interfering with normal cellular function.

The accumulation of lipids in macrophage cells (whose role is it is rid the body of waste) causes them to develop an engorged, "crumpled paper" appearance which pathologists refer to as "Gaucher cells."

The characteristics of the disease can vary by the types of cell involved:

• The accumulation of lipids in the bone marrow, liver, spleen, lungs, and other organs can lead to a marked reduction of red and white blood cells (pancytopenia), a swollen liver and spleen, and infiltrative lung disease.
• The accumulation of Gaucher cells in bone marrow can lead to the thinning of the outer structure of the bone, bone lesions, and low bone density (osteopenia).
• Disruption of the cellular balance in the epidermal layer of skin can result in visible changes to the skin’s color and texture.
• The accumulation of lipids in the central and peripheral nervous systems can cause damage to the insulated covering of nerve cells (myelin) as well as the nerve cells themselves.

Types of Gaucher Disease

Gaucher disease is broadly classified into one of three types. Due to the broad diversity of GBA mutations, the severity and course of the disease can vary enormously within each type. The types are defined as:

• Gaucher Disease Type 1: (Also known as non-neuropathic Gaucher disease) is the most common type, accounting for 95 percent of all cases. Symptoms typically appear in young adulthood and mainly affect the liver, spleen, and bone. The brain and nervous system are not manifestly affected.
• Gaucher Disease Type 2: (Also known as acute infantile neuropathic Gaucher disease) affects one of every 100,000 babies with symptoms usually starting within the first six months of birth. It affects multiple organ systems, including the nervous system, and usually leads to death before the age of two. Because the sufferers are so young, they do not survive long enough to develop bone abnormalities.
• Gaucher Disease Type 3: (Also known as chronic neuropathic Gaucher disease) occurs in one of every 100,000 births and can develop at any time from childhood to adulthood. It is considered a milder, slower-progressing form of type 2. People with type 3 usually live into their teens or early adulthood.

Symptoms

The symptoms of Gaucher disease can vary but will almost always have some level of blood, spleen, or liver involvement. Among the most common symptoms:

• Fatigue due to anemia
• Easy bruising due to a low platelet count
• Distended abdomen due to a swollen liver and spleen
• Yellowish-brown skin color
• Dry, flaky skin (ichthyosis)
• Bone pain, joint pain, bone fractures, and osteoporosis

Neurological symptoms are typically seen in type 2 and type 3 disease but may also occur in type 1. They may include:

• Type 1: Impaired cognition and sense of smell
• Type 2: Seizures, spasticity, apnea, and mental retardation
• Type 3: Muscle twitches, convulsions, dementia, and involuntary eye movements

People with Gaucher disease also appear to have a higher risk of myeloma (a cancer of plasma cells in bone marrow) and Parkinson’s disease (which is also related to GBA gene mutations).

Genetic Risk

As with any autosomal recessive disorder, Gaucher occurs when two parents who don’t have the disease each contribute a recessive gene to their offspring. The parents are considered "carriers" because they each have one dominant (normal) copy of the gene and one recessive (mutated) copy of the gene. It is only when a person has two recessive genes that Gaucher can occur.

If both parents are carriers, their child’s risk of getting Gaucher is as follows:

• 25 percent chance of inheriting two recessive genes (affected)
• 50 percent chance of one dominant and one recessive gene (carrier)
• 25 percent chance of getting two dominant genes (unaffected)

Genetics can further define a person's risk of having a child with Gaucher disease. This is especially true of Ashkenazi Jews whose risk of Gaucher is 100 times greater than that of the general population.

Autosomal disorders are largely defined by so-called "founder populations" in which an inherited disease can be traced back to a common ancestor. Due to the lack of genetic diversity within these groups, certain mutations are passed more readily to offspring, resulting in higher rates of autosomal diseases.

The mutation affecting Ashkenazi Jews is associated with type 2 and can be traced as far back as the Middle Ages.

Similarly, type 3 is seen primarily in people from the Norrbotten region of Sweden and was traced back to a single founder who arrived in northern Sweden in or before the 16th century.

Diagnosis

Persons suspected of having Gaucher disease will undergo tests to check the level of beta-glucocerebrosidase in their blood. Levels under 15 percent of normal, along with clinical symptoms, is usually enough to confirm the diagnosis. If there is any doubt, a genetic test can be used to identify the GBA mutation.

The doctor would also perform tests to assess the damage to the bones, spleen, or liver. This may involve liver function tests, a dual-energy X-ray absorptiometry (DEXA) scan to measure bone density, or a magnetic resonance imaging (MRI) scan to evaluate the condition of the liver, spleen, or bone marrow.

Treatment Options

If a person has Gaucher disease type 1 or type 3, treatment would include enzyme replacement therapy (ERT). This would involve the delivery of synthetic beta-glucocerebrosidase through an intravenous drip.

The U.S. Food and Drug Administration (FDA) has approved three such drugs for this use:

• Cerezyme (Imiglucerase)
• Elelyso (Taliglucerase)
• Vpriv (Velaglucerase)

While ERT is effective in decreasing the size of the liver and spleen, reducing skeletal abnormalities, and reversing other symptoms of the disease, it is extremely costly (over $200,000 per year). It is also less able to cross the blood-brain barrier, meaning that it may not be effective in treating severe brain-related disorders.

Moreover, because Gaucher is a relatively rare disease, no one is quite sure what dosage is needed to achieve the optimal result without overtreating the disease.

Beyond ERT, two oral medications have also been approved by the FDA to inhibit the production of lipids in people with type 1 Gaucher disease:

• Zavesca (Miglustat)
• Cerdelga (Eliglustat)

Sadly, there is no effective treatment for Gaucher disease type 2. Efforts would be centered on managing the symptoms of the disease and would typically involve the use of antibiotics, anti-convulsive medications, assisted respiration, and feeding tubes.

Genetic Screening

Because Gaucher disease is a recessive disorder passed from parents to offspring, most adults aren’t aware that they are carriers because they don’t have the disease themselves.

If you belong to a high-risk group or have a family history of Gaucher disease, you may want to undergo genetic screening to identify your carrier status. However, the test can only identify the eight most common GBA mutations and may have limitations in what it can tell you about your actual risk.

Couples with known or suspected risk can also opt to have genetic tests performed during pregnancy by extracting fetal cells with amniocentesis or chorionic villus screening (CVS). If a Gaucher concern is noted, a more comprehensive screening can be performed to better identify the type.

If a positive result is returned, is important to speak with a specialist physician to fully understand what the diagnosis means and what your options are. There are no right or wrong choices, just personal ones to which you and your partner have every right to confidentiality and respect.