Study Identifies Hundreds of Genes Connected to Pain in Fabry Disease

Potential pain-associated pathways and new therapeutic targets have been found in a mouse model of Fabry disease, which has altered expression of hundreds of genes in its nerve cells.

The study, “Signatures of Altered Gene Expression in Dorsal Root Ganglia of a Fabry Disease Mouse Model,” was published in the journal Frontiers in Molecular Neuroscience.

One of the earliest symptoms of Fabry disease is pain, which can start during childhood and occur as severe pain attacks that begin in the hands or feet and persist for several days or weeks, or chronic pain characterized by burning and tingling sensations.

Excessive accumulation of glycolipids — a type of fat molecule — within the neurons that are responsible for transmitting sensory information to the brain is thought to be behind these pain episodes.

The buildup of glycolipids occurs due to mutations in the α-galactosidase A gene and may lead to the degeneration of small sensory fibers. This results in a condition called small-fiber neuropathy.

To investigate the molecular and physiological mechanisms underlying the pathology of Fabry disease, researchers from the Medical University of Innsbruck, Austria, generated α-galactosidase A deficient mice that share many symptoms with Fabry patients, including altered temperature sensitivity and pain perception.

The team studied neurons from the dorsal root ganglion (DRG) in male mice, which are responsible for transmitting sensory perceptions to the spinal cord and the brain.

By comparing gene expression in DRG neurons from Fabry mice versus healthy mice, researchers generated a list of genes whose expression was altered in Faby disease. 

A total of 812 genes were found to have altered expression, representing 3.7 percent of the total genes detected.

A significant proportion of these genes was involved in cellular pathways related to “lysosome” and “ceramide metabolic process,” activities directly impaired by α-galactosidase A deficiency and known to be involved in Fabry disease.

Genes associated with important pathways of signal transmission within cells, matter recycling, and transfer of information along nerve cells were also found to be elevated in Fabry mice.

Higher expression of these genes could be related to hypersensitivity and changes in neuron excitability, possibly causing the pain attacks experienced by Fabry patients.

Levels of genes associated with immune-related pathways, autoimmunity, and infection were predominantly lowered in Fabry mice.

Many of the altered genes overlap with genes previously associated with other painful disorders, such as nerve injury and chronic pain, indicating shared mechanisms between these conditions and Fabry disease pain.

“These data give rise to subsequent functional studies on the importance of these deregulated genes for the pathogenesis of FD small fiber disease and neuropathic pain, and are expected to lead to the identification of novel treatment strategies, especially for neuropathic pain related symptoms in Fabry patients,” researchers wrote in their study.

The team adds that future work should include the investigation of female Fabry mice as well, which like humans have a milder disease than males, and that gene expression should be determined in other available Fabry mice models to confirm the validity of altered gene expression.