Genetic switch that causes excessive sweating revealed, new hope for hyperhidrosis

Sweating so much that you have to change your clothes several times a day, avoiding all social contact out of shame and fear of being pointed at and ridiculed, isolating yourself to the point of depression. This is the life of many patients with hyperhidrosis, a condition that affects 2 to 5% of the population, with symptoms far more serious than simple embarrassment. Now science is raising new hopes, thanks to the discovery of a "genetic switch" that can trigger excessive sweating in some forms of hyperhidrosis. The disorder may be caused by an overactive "thermostat" in the nerves, which has reclassified it as "a treatable neurological condition." After extensive research, this is the conclusion of an international team led by Frank Bosmanbs of the Vrije Universiteit Brussel, a Dutch-speaking university in the Belgian capital. The work, published in Science Advances, provides "strong evidence that a genetically determined form of hyperhidrosis results from overstimulation of the nerves that control the sweat glands. The discovery, the authors hope, eliminates the stigma surrounding this problem and paves the way for targeted treatments with existing drugs." 

Excessive sweating is still too often dismissed as a "skin problem," a misconception that condemns patients to misunderstanding their condition and to being deprived of adequate treatment, scientists explain. Bosmans' team spent 10 years searching for answers to the disorder, in collaboration with Johns Hopkins University in the United States. By analyzing the DNA of over 180 people with hyperhidrosis, the scientists discovered defects in a specific protein channel present in our nerves: the ion channel Nav1.8. "It normally functions as a biological gate that regulates electrical signals in the nervous system," the researchers describe. But "in patients with hyperhidrosis, this gate remains too open due to a genetic predisposition. As a result, the nervous system that controls the sweat glands is constantly overstimulated. The nerves are in a state of constant activity," which results in excessive sweating. A "fact consistent with the clinical picture in which sweating is often triggered by emotional or stress-related stimuli, without the condition having a psychological origin." 

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To support their theory, the researchers developed an experimental model. Since mice sweat only from their paws, it took them two years to develop a microscopic measurement method to count sweat droplets using a mixture of iodine and starch. Ultimately, they observed that mice with the same genetic defect did indeed sweat excessively, but as soon as they were treated with a substance capable of blocking hyperactive nerve signals, their sweating decreased "significantly and reversibly." The genetic reality, however, is complex. For example, the team encountered a patient who had inherited an inhibitory nerve mutation, yet who nevertheless sweated excessively due to an additional, unique mutation in a local water channel within the sweat gland itself. This demonstrates that "hyperhidrosis is a condition in which multiple biological pathways can lead to the same overstimulation, which then becomes visible on the skin." Nevertheless, "the discovery offers the prospect of better and more targeted treatments," the authors propose.  

"Today," the scientists point out, "severe forms of hyperhidrosis are sometimes treated with procedures that interrupt the sympathetic nerve pathways in the chest. These treatments can be effective, but they are invasive, not suitable for everyone, and can cause unwanted side effects." The idea is that "a better understanding of the biological cause" of the disorder, "through in-depth genetic and functional research, could in the long term help to more accurately predict which patients would benefit most from localized sweat gland treatments, systemic medications, or therapies targeting the nervous system." 

A second important area of ​​research explored by the authors is so-called drug repurposing, meaning the targeted reevaluation—in light of new findings—of already available medications with a specific mechanism of action. The researchers report that "in the mouse model, several clinically relevant agents reduced excessive sweating, including treatments that affect cholinergic signaling, a mechanism by which nerve cells communicate with each other, or nerve cell excitability." This, they emphasize, also provides "biological context" for some patients' reports of the effects of cannabis products, since "some cannabinoids can affect sodium channels." This "does not mean that these agents can already be recommended as standard treatment," the scientists point out, "but that the research lays the rationale for controlled clinical trials. Thus, the management of hyperhidrosis is shifting from symptomatic treatment to a more mechanism-based approach." 

"The study," the authors conclude, "places hyperhidrosis within a broader context of autonomic nervous system disorders. Sweating is a visible function of the autonomic nervous system and can therefore serve as a measurable indicator of biological dysregulation. Further investigation is needed to determine whether similar ion channel mechanisms contribute to other forms of dysautonomia, such as those following infections." Meanwhile, however, "for patients, the message is clear: primary hyperhidrosis is not simply a cosmetic problem or a stress-related issue; for at least some patients, it is a real and potentially treatable biological disorder affecting the nerves and sweat glands." 

(Adnkronos)