Dementia with Lewy bodies – SNCA, SNCB, GBA and APOE genes

Dementia with Lewy bodies, or diffuse Lewy body disease, is a disorder of the nervous system characterized by: decreased intellectual abilities; parkinsonism; visual hallucinations; behavioural fluctuations; and sleep disorders. Other signs associated with this process include orthostatic hypotension, syncope, decreased sense of smell, increased saliva production, incontinence or constipation. It generally affects older adults, and in most cases it develops between 50 and 85 years old. The life expectancy of affected people can vary, although they generally survive between 5 and 7 years after their diagnosis.

Mutations in the SNCA gene (synuclein alpha) or in the SNCB gene (synuclein beta), lead to the development of this disease, while mutations in the GBA (glucosylceramidase beta) and APOE (apolipoprotein E) genes increase the risk of develop the condition, but they are not a direct cause.

The SNCA gene, located on the long arm of chromosome 4 (4q22.1) encodes the alpha-synuclein protein. Although the role of alpha-synuclein is not fully known, studies suggest that it plays an important role in maintaining an adequate supply of synaptic vesicles at presynaptic terminals. Alpha-synuclein can also play a role in the movement of microtubules and help regulate the release of dopamine, a fundamental neurotransmitter to control the onset and arrest of voluntary and involuntary movements. SNCA gene mutations result in the synthesis of an alpha-synuclein protein with an abnormal form. The deformed proteins are grouped, forming the main component of Lewy bodies. These groups of proteins are present in neurons throughout the brain, and over time, the loss of neurons affected by these Lewy bodies increasingly deteriorates both intellectual and motor functions and the regulation of emotion, leading to signs. and symptoms of dementia with Lewy bodies. At least six mutations in the SNCA gene that cause dementia with Lewy bodies have been identified.

The SNCB gene, located on the long arm of chromosome 5 (5q35.2), encodes the beta-synuclein protein. Beta-synuclein is probably involved in synaptic plasticity, a process that allows neurons to change and adapt over time, which is necessary for learning and memory. In addition, beta-synuclein can also prevent harmful accumulation of alpha-synuclein in neurons. At least two mutations in the SNCB gene have been described in individuals with dementia with Lewy bodies. The mutations described result in the synthesis of a protein with altered function. A decrease in functional beta-synuclein probably results in the accumulation of alpha-synuclein and in the formation of Lewy bodies.

The GBA gene, located on the long arm of chromosome 1 (1q22), encodes beta-glucocerebrosidase, an enzyme found in lysosomes throughout the body. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell and recycle worn cell components. Beta glucocerebrosidase is an enzyme that helps break down glucocerebraside molecules into a simpler fat molecule. Mutations in a copy of the GBA gene result in the synthesis of an altered beta-glucocerebrosidase enzyme, which can interfere with the function of lysosomes and the normal breakdown of the alpha-synuclein protein, which increases the risk that these proteins accumulate and form Lewy bodies.

The APOE gene, located on the long arm of chromosome 19 (19q13.32), encodes the apolipoprotein E protein, which binds to lipids to form lipoproteins. Lipoproteins are responsible for assembling cholesterol and other fats and transporting them through the bloodstream. Maintaining normal cholesterol levels is essential for the prevention of cardiovascular diseases, including heart attacks and strokes. There are at least three slightly different versions of the APOE gene (e2, e3 and e4). The e4 version of the APOE gene may increase the risk of developing dementia with Lewy bodies. People who inherit a copy of the APOE e4 allele are more likely to develop dementia with Lewy bodies. Although it is not clear how the APOE e4 allele contributes to the development of this disease, it is believed that apolipoprotein E encoded from the e4 allele can disrupt the transport of the alpha-synuclein protein inside and outside the cells. When alpha-synuclein gets trapped inside or outside the cells, it accumulates in groups, forming Lewy bodies. Some people with the APOE e4 allele develop Alzheimer's disease, while others develop dementia with Lewy bodies.

When dementia with Lewy bodies is due to mutations of the SNCA or SNCB gene, it is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. In these cases, an affected person usually has an affected parent. People with a mutation in a copy of the GBA gene or a copy of the APOE allele inherit an increased risk of developing the disease, not the disease itself. This higher risk is inherited with an autosomal dominant pattern. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with dementia with Lewy bodies, by means of the complete PCR amplification of the exons of the SNCA, SNCB, GBA and APOE genes, respectively, and their subsequent sequencing.

Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).