Overabundance of Nerve Fibers in the Skin May Affect Pain Sensitivity, Study Suggests

Some people with Rett syndrome have an overabundance of nerve fibers associated with the senses in their skin, which may be linked to why some patients have cold hands and feet or are insensitive to pain, a small study found.

The findings, “A clinical case–control comparison of epidermal innervation density in Rett syndrome,” were published in the journal Brain and Behavior.

Some clinical observations and preclinical findings suggest that people with Rett syndrome may have problems in the regions of their peripheral nervous system that affect the senses, including the ability to feel pain.

Common examples of such symptoms include hands and feet that are frequently cold — a diagnostic feature of the disease — or insensitivity to pain.

As a neurodevelopmental disease, the involvement of the central nervous system (CNS) — brain and spinal cord  — in Rett syndrome is well established. However, much less is known about how the disease affects the peripheral nervous system: all the nerves that run through the body and connect all organs, including the skin, to the spinal cord and brain.

Very little research has looked at the peripheral nerves of Rett patients, and the few studies that did so found no major remarks, except for a possible increase in small nerve fibers. This possibility was backed by recent findings in rat models of the disease, whose skin was seen to be hyperinnervated, meaning it had an overabundance of nerve fibers.

Researchers now designed a small clinical study to test if the peripheral nerves in Rett patients would show a similar pattern of hyperinnervation.

They examined punch skin biopsies — small sections of the skin removed for testing — of four young girls with Rett, ages 12 to 19, and compared them with eight samples from healthy girls.

Human skin contains many specialized sensory nerve fibers and nerve endings responsible for conveying different kinds of sensory information, including body temperature, pressure, vibration, texture, or pain. This collectively account for what we know as the sense of “touch.”

The researchers theorized that the density of nerve fibers at the epidermis, or the outermost layer of the skin, would be altered in Rett patients.

By looking under a microscope, the team confirmed that, on average, there was a greater density of nerve fibers in the epidermis of girls with Rett syndrome.

Using specific dyes, they observed that these fibers were producing chemical messengers — neurotransmitters and neuromodulators — used to communicate sensory signals, including pain.

Other qualitative observations also suggested an altered composition of the skin’s nervous tissue in these individuals.

“Because of the limited sample size, we were not able to meaningfully relate the peripheral neurobiology findings with the clinical presentation of these patients,” the researchers said. “Future work should align a biobehavioral investigation to characterize cutaneous innervation and neurobiology in relation to thermal, sensory, and pain responsivity at the patient level.” 

Such studies would be important to characterize the sensory features of Rett syndrome “and more importantly suggest possible new treatment targets to improve patient outcomes,” they added.