Marsili Syndrome as a Gateway to Novel Analgesic Targets

Congenital insensitivity to pain (CIP) comprises a group of rare genetic disorders caused by mutations in genes essential for pain sensing in humans. Among these, Marsili syndrome is caused by a dominant point mutation in the transcription factor ZFHX2, and it is characterized by markedly reduced sensitivity to noxious heat, mechanical injury, while other functions remain intact. this project aims to establish the first integrated, system-level characterization of Marsili syndrome by combining human sensory phenotyping with neurophysiological and molecular analyses. The study will be conducted in two sessions of approximately 4 hours each, 24 hours apart from each other

Inclusion Criteria: * Healthy men and women aged 18-80 years * Marsili syndrome * Speak and understand English Exclusion Criteria: * Pregnant or breastfeeding * Current regular use of cannabis, opioids, cocaine, amphetamines, MDMA/ecstasy, benzodiazepines, barbiturates, hallucinogens, or other central nervous system-active recreational drugs. * Current use of prescription medication that may significantly affect pain perception, itch perception, cortical excitability, or inflammatory responses, including opioids, antiepileptic drugs, antidepressants, antipsychotics, systemic corticosteroids, or immunosuppressive medication. * Current or previous neurological disease, including epilepsy, stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Parkinson's disease, or other degenerative neurological disorders. * Current or previous severe psychiatric disorder, including major depression, psychosis, bipolar disorder, or severe anxiety disorder. * Current or previous clinically significant musculoskeletal, cardiovascular, pulmonary, inflammatory, autoimmune, or dermatological disease that may interfere with study procedures or outcome measures. * Lack of ability to understand study information, provide informed consent, or cooperate with study procedures. * Abnormally disrupted sleep during the 24 hours before the experiment. * Contraindications to TMS, including previous epileptic seizure, implanted electronic medical devices, metal implants in the head or jaw, implanted hearing aids, facial metal implants, permanent makeup, or tattoos in the facial area. * Inability to pass the Transcranial Magnetic Stimulation Adult Safety Screen. * Abnormally disrupted sleep in the 24 hours preceding the experiment