Management

All patients with TRPM3-related disorders must undergo in-depth neurological examination and developmental evaluation. Cognitive and neuropsychological testing are recommended. Video EEG monitoring, including sleep EEG monitoring to identify Spike-Wave Activation in Sleep (SWAS) patterns are advised, as well as brain MRI to evaluate for structural changes, which may be normal or show findings such as ventriculomegaly or cerebellar atrophy. In case the patient’s TRPM3-variant has not yet been described, functional characterisation of channel activity of the variant using established (electro)physiological approaches is recommended to establish pathogenicity and sensitivity to TRPM3 antagonists such as primidone.

Since TRPM3-related disorders are caused by a gain of channel function, therapies to reduce TRPM3 activity can be beneficial. The FDA-approved drug primidone inhibits TRPM3 at therapeutic levels, and thereby currently represents the only targeted pharmacotherapy for patients. Patients taking primidone often become seizure free and show improvements in development and learning capabilities. Therefore, early initiation of primidone in confirmed gain-of-function variants, even in the absence of seizures, may potentially improve the developmental trajectory. To avoid side effects, it is recommended to slowly titrate primidone, starting at 0.1mg/kg/day, towards a dosage of 0.1mg/kg/day. Combining primidone with fluvoxamine to limit its conversion to the barbiturate phenobarbital has been described to reduce sedation in some patients. Notably, some patients have TRPM3 mutations affecting the primidone binding site on the channel, which may reduce the drug's efficacy.

In addition, early developmental intervention is important and includes therapies targeting motor, speech, and cognitive skills. For individuals with limited or absent speech, alternative communication strategies such as sign language or picture‑based systems may be beneficial. Behavioural and psychiatric support should be offered when autism spectrum features, aggression, or sleep disturbances are present. Regular orthopedic follow‑up is recommended to monitor for hip dysplasia, scoliosis, and foot deformities. Ophthalmologic assessment is also advised to detect and manage strabismus, refractive errors, and other visual abnormalities.

Support group:
TRPM3 foundation: www.trpm3.org