TRPM3‐related disorders encompass a broad phenotypic spectrum ranging from global neurodevelopmental impairment to multisystem involvement affecting the eyes and musculoskeletal system. Not all individuals with a TRPM3variant display the full constellation of symptoms, and severity can vary widely between patients.
Neurodevelopmental delay is one of the core clinical features. Most affected individuals present with global developmental delay and intellectual disability, ranging from mild to severe. Speech development is particularly impacted, with many patients showing markedly delayed speech acquisition or complete absence of expressive language. Hypotonia is frequently observed, contributing to delays in motor milestones; approximately half of individuals are unable to achieve independent walking.
Epilepsy is present in the majority of patients. Seizures often meet criteria for developmental and epileptic encephalopathy (DEE), including DEE-SWAS in some cases. Age at seizure onset has a median of 24 months, but can range from as early as 1 month to 7 years. Common seizure types include absence seizures and generalized tonic–clonic seizures. In the majority of cases, seizures are resistant to standard anti-epileptic drugs. In rare cases, drug-resistant epilepsy is the only symptom.
Other neurological/psychiatric features reported in patients with TRPM3variants include cerebral palsy, autism spectrum traits, aggression, sleep problems, altered sensitivity to heat and pain-insensitivity.
Ophthalmologic abnormalities are frequently described, including strabismus, refractive errors, and nystagmus.
Musculoskeletal anomalies are present in about half of affected individuals, most commonly hip dysplasia, scoliosis, and various foot deformities. Craniofacial dysmorphisms (broad forehead, short philtrum, micrognathia) have also been described.
TRPM3