GBA1

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.

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 (described above) 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.

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 (described above) 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.