Phenotype Spectrum of TRPM3-Associated Disorders

Area of Science:

• Neurogenetics
• Epileptology
• Developmental Neuroscience

Background:

• Monoallelic variants in the transient receptor potential melastatin-related type 3 gene (TRPM3) are linked to neurodevelopmental disorders.
• Limited information exists regarding the full clinical spectrum and treatment efficacy for TRPM3-related conditions.

Purpose of the Study:

• To characterize the clinical manifestations of TRPM3 variants, focusing on epilepsy.
• To evaluate the effectiveness of various treatments, particularly for seizure control and developmental outcomes.

Main Methods:

• Retrospective analysis of phenotypes and genotypes from 43 individuals with pathogenic TRPM3 variants.
• Data sourced from GeneMatcher, collaborations, and a systematic literature search.

Main Results:

• The cohort (median age 10 years, 60% female) frequently presented with developmental delay/intellectual disability (93%), hypotonia (77%), ocular (70%), and musculoskeletal anomalies (65%).
• Epilepsy, specifically developmental and epileptic encephalopathy (DEE/DEE-SWAS), affected 72% of patients. The p.Val1002Met variant was associated with higher rates of developmental delay and epilepsy.
• Primidone demonstrated significant efficacy, improving seizure frequency and enhancing motor, speech, and learning capabilities in all treated patients.

Conclusions:

• Developmental delay/intellectual disability and epilepsy are hallmark features of TRPM3 variants.
• Early screening for neurological abnormalities and prompt intervention are crucial, given epilepsy's impact on development.
• Primidone, a TRPM3 channel blocker, shows promise and should be considered for managing TRPM3 gain-of-function variants.