What are the common signs or symptoms of Gaucher disease, and when should someone suspect it?

Gaucher disease, caused by GBA1 gene mutations, often presents with an enlarged liver and spleen (hepatosplenomegaly), low blood counts (anemia or thrombocytopenia), and bone pain or fractures. In rarer, more severe forms, neurological problems can occur. Symptoms can vary widely, from mild to severe, and may appear at any age.

What are the main treatment approaches for Gaucher disease?

The primary treatment for Gaucher disease is enzyme replacement therapy (ERT), which involves intravenous infusions of a synthetic enzyme to replace the deficient lysosomal acid glucosylceramidase. Substrate reduction therapy (SRT) is another option, which reduces the amount of fatty substance the body produces. Symptomatic treatments for bone pain or other issues may also be used.

How is Gaucher disease inherited, and what does it mean for family members?

Gaucher disease is an autosomal recessive condition. This means a person must inherit two altered copies of the GBA1 gene, one from each parent, to develop the disease. Individuals who inherit only one altered copy are carriers and typically do not show symptoms but can pass the gene to their children. Genetic counseling can help families understand their risk.

GBA1 gene

The GBA1 gene provides instructions for making an enzyme called lysosomal acid glucosylceramidase, which is critical for breaking down fatty substances within cells.

Normal Function

The GBA1 gene provides instructions for making an enzyme called lysosomal acid glucosylceramidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Lysosomal acid glucosylceramidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Glucocerebroside is a component of the membrane that surrounds cells. It gets broken down by lysosomal acid glucosylceramidase when cells die, and the components are reused as new cells are formed.

Health Conditions Related to Genetic Changes

Gaucher disease

Many variants (also called mutations) in the GBA1 gene have been identified in people with Gaucher disease, a disorder with varied features that affect many parts of the body. Affected individuals can have enlargement of the liver and spleen (hepatosplenomegaly), blood cell abnormalities, and rarely, severe neurological problems. The variants occur in both copies of the gene in each cell. Most of the GBA1 gene variants responsible for Gaucher disease change single protein building blocks (amino acids) in lysosomal acid glucosylceramidase, altering the structure of the enzyme and preventing it from working normally. Other variants delete or insert genetic material in the GBA1 gene or lead to the production of an abnormally short, nonfunctional version of the enzyme.

Variants in the GBA1 gene greatly reduce or eliminate the activity of lysosomal acid glucosylceramidase in cells. As a result, glucocerebroside is not broken down properly. This molecule and related substances can build up in white blood cells called macrophages in the spleen, liver, bone marrow, and other organs. The abnormal accumulation and storage of these substances damages tissues and organs, causing the characteristic features of Gaucher disease.

Parkinson's disease

Changes in the GBA1 gene are also associated with Parkinson's disease and parkinsonism, which are similar disorders that affect movement. Characteristic features include tremors and impaired balance and coordination (postural instability). People with Gaucher disease have variants in both copies of the GBA1 gene in each cell, while those with a variant in just one copy of the gene are called carriers. People with Gaucher disease and people who are carriers of a GBA1 gene variant have an increased risk of developing Parkinson's disease or parkinsonism.

Symptoms of Parkinson's disease and parkinsonism result from the loss of nerve cells (neurons) that produce dopamine. Dopamine is a chemical messenger that transmits signals within the brain to produce smooth physical movements. It remains unclear how GBA1 gene variants are related to these disorders. Studies suggest that changes in this gene may contribute to the faulty breakdown of toxic substances in neurons by impairing the function of lysosomes. Alternatively, the changes may increase the formation of abnormal protein deposits. As a result, toxic substances or protein deposits could accumulate and kill dopamine-producing neurons, leading to abnormal movements and balance problems.

Dementia with Lewy bodies

GBA1 gene variants can increase the risk of developing dementia with Lewy bodies; however, some people with a variant in the GBA1 gene never develop this condition. Dementia with Lewy bodies is characterized by intellectual decline (dementia); visual hallucinations; sudden changes in attention and mood; and movement problems characteristic of Parkinson's disease such as rigidity of limbs, tremors, and impaired balance and coordination.

Variants in one copy of the GBA1 gene increase the risk of developing dementia with Lewy bodies. These variants result in the production of an altered lysosomal acid glucosylceramidase enzyme. This abnormal enzyme may interfere with the function of lysosomes and the normal breakdown of a protein called alpha-synuclein, which increases the risk that these proteins accumulate and form Lewy bodies. Accumulation of these protein clusters throughout the brain impairs neuron function and ultimately causes cell death. Over time, the loss of neurons increasingly impairs intellectual and motor function and the regulation of emotions, resulting in the signs and symptoms of dementia with Lewy bodies.

Other Names for This Gene

GBA
GLCM_HUMAN
GLUC