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Rare disorder reveals insights into touch and body awareness

With eyes open, left, the patients had no trouble touching targets. With their eyes closed, right, they had difficulty.Bönnemann Lab, NIH/NINDS, Bethesda, MD

Dr. Carsten G. Bönnemann’s research team at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) uses cutting-edge genetic techniques to help diagnose children with disorders that are difficult to characterize. The investigators examined 2 unrelated patients—one 8 and the other 18 years old—who seemed to have a unique disorder. Both had abnormally curved spines diagnosed as progressive scoliosis. They had hip, finger, and foot deformities. They also had movement and balance problems, including trouble walking and loss of some forms of touch. Despite their difficulties, both appeared to cope with these challenges by relying heavily on vision and other senses.

To look for genetic similarities, the researchers performed whole-exome sequencing on the patients. The exome is the DNA in the genome that codes for proteins. Most disease-causing genes are found within these areas. The study appeared online on September 21, 2016, in the New England Journal of Medicine.

In collaboration Dr. Alexander T. Chesler’s team at NIH’s National Center for Complementary and Integrative Health (NCCIH), the researchers discovered that both patients had mutations that blocked the normal production or activity of PIEZO2 proteins. PIEZO2 is a mechanically activated ion channel found in sensory neurons. It generates electrical nerve signals in response to changes in cell shape, such as when skin is pressed.

A series of tests showed that the 2 patients were less sensitive to certain forms of touch compared to healthy people who served as controls. Both patients couldn’t feel vibrations from a buzzing tuning fork or tell whether 1 or 2 ends of a small caliper were pressed against their palms. They could, however, feel pinpricks, pressure pain, and heat as well as the control participants.

Both patients felt the brushing of hairy skin, which has mechanoreceptors that don’t require PIEZO2. However, one said it felt prickly instead of pleasant. The differences reported by the patients were reflected in fMRI brain scans.

Further tests at the NIH Clinical Center in Bethesda, Maryland, showed that the patients had proprioception problems. Blindfolding them made walking extremely difficult, causing them to stagger and stumble from side to side while assistants prevented them from falling. Blindfolds made it harder for them to reliably reach for an object in front of their faces than it was for unaffected volunteers. Without watching, the patients also were poor at judging the direction their joints were being moved.

“Our study highlights the critical importance of PIEZO2 and the senses it controls in our daily lives,” Bönnemann says. “Understanding its role in these senses may provide clues to a variety of neurological disorders.”

“Results from basic laboratory research guided our examination of the children,” Chesler explains. “Now we can take that knowledge back to the lab and use it to design future experiments investigating the role of PIEZO2 in nervous system and musculoskeletal development.”