Johns Hopkins Medicine researchers have identified a genetic driver of primary idiopathic hyperhidrosis, a chronic condition that causes excessive sweating, providing some of the strongest evidence to date that the disorder can originate in the nervous system and may be treatable with targeted therapies.
The federally funded study, published in Science Advances on July 17, shows that rare variants in the SCN10A gene, which encodes a sodium channel known as NaV1.8, can cause overactivity in nerve pathways that control sweating. The discovery challenges the long-standing belief that primary hyperhidrosis is solely a disorder of the sweat glands and opens the door to investigating more personalized treatment approaches.
"Despite affecting an estimated 2% to 5% of the population, hyperhidrosis has remained a poorly understood condition," says senior author Malcolm Brock, M.D., professor of surgery at the Johns Hopkins University School of Medicine. "For decades, hyperhidrosis has largely been viewed as a disorder of the sweat glands. Our findings show that, for some patients, the problem actually begins in the nerves that control sweating, providing a biological explanation for the condition and a potential pathway to more effective treatments."
People with primary hyperhidrosis experience sweating far beyond what is needed to regulate body temperature. The condition commonly affects the hands, feet, underarms and face, and can interfere with work, social interactions and quality of life. Although several treatments are available, many patients receive only partial relief.
To better understand the disorder, the Johns Hopkins Medicine-led team analyzed genetic data from families with inherited hyperhidrosis. Researchers discovered that nearly 1 in 5 affected families carried rare variants in SCN10A, making it the strongest genetic signal identified in the study.
The investigators then engineered mice to carry the SCN10A genetic variant. The animals developed excessive sweating similar to that seen in humans, providing direct evidence that the mutation can drive the disorder. Additional studies revealed that the NaV1.8 channel is present in sympathetic nerve cells that help regulate sweat production, and that the disease-causing variant increases the activity of those cells.
"We found that this mutation essentially turns up the volume on the nerve signals that stimulate sweating," Brock says. "That insight gives us a specific target to pursue for future therapies."
Perhaps most encouraging, the researchers found that excessive sweating in the mouse model could be significantly reduced using drugs that inhibit sodium channel activity. Several medications already used clinically for hyperhidrosis also showed effectiveness in the model, suggesting that patients could eventually benefit from treatments tailored to the biological cause of their disease.
The findings may also help explain why some patients do not respond to therapies aimed primarily at the sweat glands.
"Our results suggest that hyperhidrosis is not one disease with one cause," says Brock. "Some cases may be driven by the sweat glands themselves, while others appear to originate in the nervous system. Understanding those differences is critical if we're going to develop more effective treatments."
The researchers say the work represents an important step toward precision medicine for hyperhidrosis, and it could have broader implications for understanding disorders involving autonomic nervous system dysfunction. Future studies will focus on validating the findings in human tissues and evaluating potential targeted therapies.
The study was supported by the National Institutes of Health, the American Heart Association, Dysautonomia International, the Research Foundation Flanders and other funding organizations, and was led by researchers from the Johns Hopkins University School of Medicine in collaboration with investigators from Ghent University, Vrije Universiteit Brussel, Juntendo University and several other institutions.
