What Is Gaucher Disease?

Overview

The human body consists of different organs, which are made up of tissues that are themselves composed of cells. Inside each cell, there are various organelles that perform specific functions. The lysosome is an example of an organelle and it functions as the digestive system of the cell. Lysosomes contain a range of enzymes that help break down macromolecules (e.g., carbohydrates, proteins, lipids, nucleic acids). The inability of lysosomes to metabolise macromolecules results in their accumulation, which can be toxic for the cell.  This is known as lysosomal storage disease.

Gaucher disease is a rare disease that falls under the category of lysosomal storage disease. It is caused by a deficiency, or the absence, of the enzyme glucocerebrosidase, which is commonly found in lysosomes. It is an inherited metabolic disorder that causes cells rich in fat to accumulate in the bone marrow, the spleen, and the liver. It is an autosomal recessive disorder, meaning a child will be affected only if both parents are carriers of the disease-causing mutation. 

Types of gaucher disease

There are three different types of Gaucher disease:

• Type I (non-neuropathic): Type I Gaucher disease is commonly observed in adults. Neurological disorders are absent in Type I Gaucher disease and thus can be differentiated from other forms. Bone disease is present in 70-100% of the affected patients. Other signs include enlargement of the liver and/or spleen, anemia, thrombocytopenia, delayed growth, and delayed puberty. In some cases, the lungs can also become affected
• Type II (acute infantile neuronopathic gaucher disease): Type II Gaucher disease is a rare disease type that occurs in infancy, manifesting within the first six months of life. This type is the most severe form of Gaucher disease, with the life expectancy of an affected patient being less than two years. Type II Gaucher disease presents in patients as an enlargement of the spleen and the liver along with neurological symptoms. Because of the severe and irreversible damage to the brain, there is currently no cure for this type of Gaucher disease
• Type III (Chronic neuronopathic gaucher disease): Type III is the juvenile form of Gaucher disease, typically developing in children and adolescents. Although the life expectancy is shortened by the disease, affected patients can survive into adulthood. Yet, type III Gaucher disease progresses rapidly, with both visceral and neurological signs appearing from the onset of the condition¹

Patients affected by type II and type III Gaucher disease experience neurological symptoms due to the acute and chronic effects the condition has on the central nervous system. Hence, these two types are referred to as neuronopathic Gaucher disease.

Causes of gaucher disease

Gaucher disease is caused by a genetic mutation in the GBA 1 gene, which is found on chromosome one. The GBA 1 gene encodes the enzyme glucocerebrosidase, which helps in the conversion and breakdown of a sugar that contains fat (glucosylceramide) into ceramide and glucose. When this enzyme is absent, glucosylceramide accumulates in the lysosomes of specific cells called Gaucher cells, which are rich in fat. Examples of Gaucher cells include macrophages (immune cells) and neurones (brain cells). Abnormal accumulation of glucosylceramide in various organs can lead to an enlarged spleen and/or liver, bone disease, and neurological disorders. Mutations in the GBA 1 gene have also been linked to Parkinson’s disease. However, the exact relation is yet to be discovered.²

Signs and symptoms of gaucher disease

The symptoms of Gaucher disease can vary from patient to patient, ranging from mild to severe. Some of these include:

• Spleen enlargement (splenomegaly)
• Liver enlargement (hepatomegaly)
• Abdominal pain
• Lack of coordination and movement
• Seizures
• Thrombocytopenia (low platelet level)
• Anemia (low red blood cells and haemoglobin count)
• Bone disease 
• Abnormal bleeding and bruising 
• Delayed growth and delayed puberty

Management and treatment for gaucher disease

The available treatments for Gaucher disease are:

• Enzyme replacement therapy: involves the administration of proteins that can produce glucocerebrosidase to compensate for the deficiency or absence of this enzyme in patients with Gaucher disease. It is given as an intravenous injection every two weeks
• Substrate reduction therapy: small molecule drugs are given that bind to excess glucosylceramide, inactivating it and reducing the buildup of the substance inside cells. This kind of treatment is given as an oral medication³
• Partial or total removal of the spleen (splenectomy) is a rare, but sometimes necessary, form of treatment
• Blood transfusion is required to treat severe anemia
• Joint replacement surgery is required to increase the mobility of joints and provide relief from bone pain⁴
• Bone marrow transplantation can reverse the disease state of non-neuropathic Gaucher disease. However, due to complications and risks associated, it is rarely done.

It is important to further understand Gaucher disease to improve diagnosis, treatment strategies, and management of symptoms. Thus, clinical trials can improve researchers’ and clinicians’ understanding of the disease to achieve this. Clinical trials require human volunteers affected by Gaucher disease to participate. 

Diagnosis of gaucher disease

A common diagnostic test done to detect Gaucher disease is the beta-glucosidase leukocyte (BGL) test. It detects the enzyme activity of glucocerebrosidase. Diagnosis can be further clarified with genetic testing for mutations in the GBA 1 gene. Genetic testing can also detect carriers of the disease-causing mutation, helping them receive genetic counselling about the risk of transmitting Gaucher disease to their children.

Risk factors

The main risk factor is the presence of a mutated GBA 1 gene. Carriers of the mutation are asymptomatic. One in four children born to these parents is affected.

Complications

Type 1 Gaucher disease patients show increased risks of developing Parkinson's disease and Lewy body dementia (a condition characterised by abnormal deposition of proteins in brain cells).

FAQs

How can I prevent Gaucher disease?

There is no known way to prevent Gaucher disease; However, receiving treatment early on can reduce the severity of the disease. If you are a carrier of Gaucher disease and plan to start a family, genetic counselling and prenatal screening can reduce the chance of transmitting the mutated gene to the child.

How common is gaucher disease?

Gaucher disease is a rare disease affecting 1 in 40,000 live births. The highest incidence is seen in the Jewish community of Eastern Europe, where it occurs in every 1 in 450 people.

What can I expect if I have gaucher disease?

Splenomegaly, hepatomegaly, brain disorders, and bone disorders are commonly observed in individuals with Gaucher disease.

When should I see a doctor?

If Gaucher disease runs in the family or the listed symptoms are observed, seeking medical attention and receiving a screening immediately is imperative.

Summary

Gaucher disease is a rare disease caused by a genetic mutation in the GBA 1 gene, which produces the enzyme glucocerebrosidase. Without the effective functioning of this enzyme, a build-up of glucosylceramide occurs in the spleen, liver, and bone marrow. The associated symptoms are enlargement of the liver and/ or spleen, bone disease, and neurological disorders. Screening for Gaucher disease is based on genetic testing and the BGL blood test. Treatment options include enzyme replacement therapy, substrate reduction therapy, and symptom management. Active participation of patients in clinical trials will provide further insight into the disease and lead to the development of new treatments and screening methods.