GAUCHER DISEASE: UNDERSTANDING THE RARE GENETIC METABOLIC DISORDER

Medically Reviewed by Dr. Sony Sherpa, (MBBS) - August 19, 2024

Gaucher disease is a rare genetic metabolic disorder caused by glucocerebrosidase deficiency.

It is an autosomal recessive condition with a global prevalence of 1 in 40,000, yet it tends to be far more common in those of Ashkenazi Jewish descent (Eastern European). Among Ashkenazi Jews, disease incidence is approximately 1 in 450 individuals, with 1 in 10 known to be a carrier.^[1]

In this article, Gaucher disease and its types are explained alongside symptoms, diagnosis and treatment options.

What is Gaucher Disease?

Gaucher disease is a hereditary lysosomal storage disease that affects the metabolism of certain fatty substances called glucocerebrosides, causing them to accumulate in cells.

Glucocerebrosides (GCBs) are one of many kinds of cerebrosides, a type of fatty substance (sphingolipid) that makes up cell membranes. The lysosome of the cell is a fluid-filled organelle that houses enzymes which “digest” substances requiring disposal^[2]. GCBs are normally broken down in the lysosome of cells by an enzyme called glucocerebrosidase and are subsequently recycled as required.

In people with Gaucher disease, the GBA gene that produces the glucocerebrosidase enzyme is mutated, rendering the enzyme defective or deficient. Glucocerebrosidase deficiency causes GCB to build up in cells and tissues, especially in the liver, spleen, blood cells, bone marrow, lymph glands and neurons.

During the disease course, immune cells responsible for removing toxins (macrophages) attempt to clear away excess GCB. They eventually become overloaded, dysfunctional, and also accumulate in various tissues. These macrophages are referred to as Gaucher cells, characterized by their large size, swollen appearance, small nuclei and the presence of Gaucher deposits.^[3]

The accumulation of GCB and Gaucher cells leads to metabolic dysfunction and the classic symptoms seen in those with Gaucher disease.

Types of Gaucher Disease

There are three main variants of Gaucher disease, each classified by the presence or absence of neurological involvement.^[4]

Gaucher Disease Type 1

Type 1 is the most common and mild form of the disease. It does not affect the brain or nervous system. It mainly causes enlargement of the spleen and liver, anemia, low platelet count, bone pain, fractures, and osteoporosis. Life expectancy for people with type 1 Gaucher disease is typically normal.

Gaucher Disease Type 2

Type 2 Gaucher disease is a rare yet severe form that affects infants and children. It causes neurological problems such as seizures, muscle stiffness, eye movement disorders, swallowing difficulties, and developmental delay. This type usually has a rapid progression, resulting in death between 1-3 years of age.

Gaucher Disease Type 3

Type 3 is an intermediate form of the disease, also known as chronic neuronopathic Gaucher disease. It causes the same symptoms as type 1 and similar neurological problems as seen in type 2, yet with a much slower progression. It can also lead to early-onset dementia and Parkinson’s disease. Those with type 3 are affected before 10 years of age, with differing rates of progression. The average life expectancy of those with type 3 varies between 10 and 50 years of age.

Other Types

Two other types have been identified:

• Perinatal-lethal form, which results in stillbirth or death of the infant by 3 months due to severe swelling leading to hydrops fetalis or internal bleeding.
• Cardiovascular form that is associated with neurological problems, calcium deposits in the heart valves, hypertension and a greatly reduced lifespan.

Gaucher Disease Symptoms

The symptoms of Gaucher disease vary widely among individuals and types of the disease. Most people with Gaucher disease have mild or no symptoms until later on in life, while others may have severe and life-threatening complications that greatly reduce life expectancy.

Common Gaucher disease symptoms include:

• Abdominal pain and distension due to enlarged spleen and liver
• Chronic fatigue, weakness, and shortness of breath due to anemia
• Easy bruising and bleeding due to low white blood cell and platelet count
• Bone pain, fractures, and osteoporosis due to low oxygen and bone damage
• Yellowish-brown skin pigmentation due to excess iron
• Yellow fatty deposits on the white part of the eye (pinguecula) due to lipid accumulation

In types 2 and 3, neurological problems are evident and include:

• Seizures
• Muscle stiffness and twitches
• Eye movement disorders
• Swallowing difficulties
• Developmental delay
• Early-onset dementia and Parkinson’s disease

Those with Gaucher disease type 1 are at a higher risk for contracting certain types of cancer, Parkinson’s disease, autoimmune conditions, cerebrovascular and cardiovascular disease. Those being treated with enzyme replacement therapy may be at an increased risk for diabetes. ^[5]

Gaucher Disease Diagnosis and Genetic Testing

The diagnosis of Gaucher disease requires the confirmation of glucocerebrosidase deficiency and is based on physical examination, family history, blood tests, genetic tests, and imaging tests^[6].

Some of the tests used for diagnosis include:

• Glucocerebrosidase enzyme test: A blood test that measures the level of glucocerebrosidase enzyme activity in white blood cells is the first step in confirming the diagnosis. A low level indicates Gaucher disease.
• DNA analysis: A genetic test can identify the specific mutation in the GBA gene that causes Gaucher disease. This can help confirm the diagnosis and determine the Gaucher disease type.
• Dual energy X-ray absorptiometry (DEXA): An imaging test that uses low-level X-rays to measure bone density. DEXA is used to monitor bone damage and osteoporosis caused by Gaucher disease.
• Magnetic resonance imaging (MRI): Another type of imaging test that uses radio waves and a magnetic field to create detailed images of internal organs and tissues. Classic spleen and liver enlargement, as well as brain abnormalities, can be evaluated using MRI.

Treatment for Gaucher Disease^[7]

Until a cure is found, Gaucher disease treatment is supportive and aims to manage symptoms, prevent irreversible damage, and improve quality of life. It is vital to consult with a specialist experienced in treating Gaucher disease before opting for therapy or any other intervention.

Available treatment options are as follows:

• Enzyme replacement therapy (ERT): This involves intravenous infusion of synthetic glucocerebrosidase enzyme every two weeks. This improves symptoms by providing more of the enzyme required to break down GCB, helping to improve overall health in those with the disease.
• Substrate reduction therapy (SRT): This consists of taking oral medication that inhibits the production of glucocerebroside in the body. SRT reduces glucocerebroside levels and accumulation, helping to slow disease progression.
• Bone marrow transplantation (BMT): Some with Gaucher disease need a bone marrow transplant to replace damaged bone marrow and improve red blood cell count. ^[8]
• Splenectomy: The spleen is commonly removed in those with Gaucher disease later on in life to help improve abdominal pain and blood cell count. Studies suggest that those who underwent splenectomy with the condition lived an average of 4 years less than those who opted out.
• Bisphosphonates: These are a class of drugs that help strengthen bones and prevent fractures. This, combined with regular weight-bearing exercise, can help treat osteoporosis caused by Gaucher disease.

Aside from the above treatments, those with Gaucher disease need to be careful with regard to infection and injury. Pain, bleeding, bruising and other medications may need to be managed with expert guidance and advice.

Living with Gaucher Disease

Gaucher disease is a chronic and progressive condition that requires lifelong monitoring and treatment. Most people with Gaucher disease can live normal and productive lives with proper medical care and support.

Here are some tips for those living with Gaucher disease:

• Follow the treatment plan prescribed by your doctor and report any changes in symptoms or side effects
• Have regular check-ups and tests to monitor your organ function, bone health, and blood counts
• Eat a balanced diet rich in calcium and take vitamin D3 and K2 supplements to support bone health
• Avoid foods high in trans-fats, sugar and refined fructose that may worsen liver function
• Exercise regularly to maintain muscle strength and joint mobility
• Avoid activities that may increase the risk of injury or bleeding
• Seek emotional and social support from family, friends, and support groups
• Educate yourself and others about Gaucher disease and its impact

Conclusion

Gaucher disease is a rare genetic lysosomal storage disorder that affects the breakdown of glucocerebrosides in the body. It causes various symptoms and complications, depending on the type and severity of the disease. It is inherited in an autosomal recessive pattern and is more common among people of Ashkenazi Jewish ancestry. Gaucher disease treatment aims to manage symptoms, prevent irreversible damage, and improve quality of life. Available treatment options include enzyme replacement therapy, substrate reduction therapy, bone marrow transplantation, splenectomy, bisphosphonates, and supportive care. People with Gaucher disease can live normal and productive lives with proper medical care and support.

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