Changes in Gene Expression Linked to Pain, Cognitive Symptoms in Fabry Disease, Study Suggests

Changes in gene expression in the prefrontal cortex, the area of the brain responsible for attention and decision-making, may account for some of the cognitive symptoms and amplified pain perception observed in Fabry disease, a mouse study shows.

The study, “Altered Gene Expression in Prefrontal Cortex of a Fabry Disease Mouse Model,” was published in the Journal of Molecular Neuroscience.

Fabry disease is caused by a mutation in the α-galactosidase A (α-Gal A) gene, which prevents the body from making an enzyme called alpha-galactosidase A. This enzyme is responsible for breaking down a type of fat called globotriaosylceramide (Gb3 or GL-3) into building blocks the body’s cells can use.

When these fat molecules are not broken down properly due to a lack of alpha-galactosidase, they build up inside the cells and cause damage.

Cognitive deficits frequently occur in Fabry patients, who experience a decrease in health-related quality of life, and an increased risk for depression, anxiety, and acute psychotic symptoms, as well as personality and behavioral changes. In addition, deficits in general intellectual functioning, speed of information processing, reasoning, verbal fluency, and problem-solving are common.

One of the earliest symptoms of Fabry disease is numbness and pain, usually in the hands and feet as a result of damage to the peripheral nerves. This condition, called neuropathy, can occur as early as childhood, and is associated with an accumulation of Gb3 in neurons of the dorsal root ganglia (DRG) — a cluster of sensory neurons that bring information from the periphery to the spinal cord.

Recent studies have shown that the gene expression profile of the dorsal root ganglia in a mouse model of Fabry disease is different from that of healthy mice. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

In particular, genes that are more expressed in the dorsal root ganglia of Fabry mice are involved in nerve cell dysfunction, which is related to defects in certain areas of the brain including the prefrontal cortex.

This is particularly interesting since the prefrontal cortex is involved in tasks related to attention, planning, organizing, and task completion — some of the main difficulties experienced by Fabry patients.

In this study, researchers looked at alterations in gene expression in the prefrontal cortex of a Fabry mouse model. Compared with healthy mice, 135 genes were expressed at significantly higher levels, while 246 genes were significantly lower.

Genes expressed differently between Fabry and healthy mice were mainly involved in immune responses, cognitive deficits, and neurodegeneration.

“… gene expression changes in relevant brain areas may play a critically important part in the development of the FD pain phenotype,” the researchers wrote.

According to the authors, this study provides new knowledge on the possible contribution of gene expression, other than Gb3 accumulation in the central nervous system, to Fabry disease-related brain pathologies.