Phenotype Spectrum of TRPM3-Associated Disorders

Abstract

Objective: Monoallelic variants in the transient receptor potential melastatin-related type 3 gene (TRPM3) have been associated with neurodevelopmental manifestations, but knowledge on the clinical manifestations and treatment options is limited. We characterized the clinical spectrum, highlighting particularly the epilepsy phenotype, and the effect of treatments.

Methods: We analyzed retrospectively the phenotypes and genotypes of 43 individuals with TRPM3 variants, acquired from GeneMatcher and collaborations (n = 21), and through a systematic literature search (n = 22). We included all patients with a pathogenic TRPM3 variant.

Results: The median age at the time of the study was 10 years, with a preponderance of girls (60%) versus boys (40%). Frequent findings were developmental delay and/or intellectual disability (93%), global or axial hypotonia (77%), ocular involvement (70%), musculoskeletal anomalies (65%), and dysmorphic features (58%). Epilepsy was diagnosed in 31 patients (72%), classified in all as developmental and epileptic encephalopathy with or without spike wave activation in sleep (DEE/DEE-SWAS). Patients with the variant p.Val1002Met (n = 24) significantly more often had developmental delay and epilepsy. The most effective anti-seizure medication was primidone. All treated patients showed an improvement in seizure frequency, motor and speech development, and/or learning capability with this drug.

Interpretation: Developmental delay/intellectual disability and epilepsy are dominant phenotypic features in patients with TRPM3 variants. Given that epilepsy can negatively impact development, screening for awake and sleep electroencephalogram abnormalities and other manifestations are essential to offer early intervention. The TRPM3 channel blocker primidone has shown promising effects and should be considered in every child with a TRPM3 gain-of-function variant. ANN NEUROL 2025;97:561-570.

FIGURE 1

Anti‐seizure medication (ASM) in patients with TRPM3 variants. (A) Effects of ASM on seizure frequency and/or developmental profile. Green marks seizure freedom, light green marks improvement, red indicates no improvement or termination because of side effects. Primidone was the most effective ASM, and 9 patients had improvement in electroencephalogram (EEG), developmental skills, and/or seizure frequency. In 1 further patient, the effect of primidone could not be evaluated because of the short treatment period. Levetiracetam had no positive effect in 8 patients. One further patient became free of seizures when primidone was started in addition to levetiracetam, and another patient took levetiracetam prophylactically for 6 months after an abnormal EEG. Not included ASMs in this figure are topiramate, ethosuximide, phenobarbital, zonisamide, oxcarbazepine and diazepam, because each of them was only taken by a single patient. (B) Proposal on how to gradually introduce primidone treatment. The shown dosages were effective in 7 patients and 1 patient took up to 11.5mg/kg/d. In general, for children 8 years or older, primidone as monotherapy was recommended in doses up to 2,000mg/d, and in combination with other ASMs, up to 1,500mg/d. However, in our experience patients with TRPM3‐associated neurodevelopmental disorder need very little primidone dosages to achieve an improvement in seizure frequency, EEG, and psychomotor development, and therefore, we recommend a dosage up to 10mg/kg/d. High dosages in the beginning were more likely to be associated with side effects in 3 patients of our cohort. Common adverse effects were sedation and drowsiness. In the initial phase, ataxia, diplopia, and nystagmus are possible. Three patients took fluvoxamine to reduce phenobarbital levels and were less sleepy. Generally, we recommend close monitoring of the clinical picture of the patient and to increase primidone dependent on the clinical improvement, seizure frequency and EEG results.

FIGURE 2

Variants in TRPM3. (A) The figure shows all variants with their chromosomal position and in relation to their position on the protein. We merged all variants to the reference sequence NM_001366145.2 via ClinGen. The associated TRPM3 protein isoform on UniProt is Q9HCF6–3, which is also called isoform m. We generated the protein level based on the positions for Q9HCF6–3 on NextProt (N‐terminus 1–3; 1st transmembrane region 4–24; cytoplasmic topological domain 25–781; 2nd transmembrane region 782–802; extracellular topological domain 803–884; 3rd transmembrane region 885–905; cytoplasmic topological domain 906–951; 4th transmembrane region 952–972; extracellular topological domain 973–982; 5th transmembrane region 983–1,003; cytoplasmic topological domain 1,004–1,015; 6th transmembrane domain 1,016–1,036; extracellular topological domain 1,037–1,103; 7th transmembrane domain 1,104–1,124; cytoplasmic topological domain 1,125–1719). Gain of function was revealed by functional analysis for 8 variants., , (B) Missense‐tolerance‐ratio‐score (MTR‐score) generated by MTR‐Viewer37 on 2024‐03‐16 and the settings were: canonical form of TRPM3, ENST00000377110, MTRv2, all populations and window size 21. Because it was technically not possible to calculate the score for the Ensemble Transcript ID ENST00000677713.2 we diverted all variants to the Ensemble Transcript ID ENST00000377110 by ClinGen (Table S3). “Horizontal lines show gene‐specific MTR centiles 5th (green), 25th (yellow), 50th (black) and neutrality (MTR = 1.0 in blue). MTR calculated using whole exome sequencing component of gnomAD v.2.0.”

FIGURE 3

Phenotype characteristics correlated to the TRPM3 variant position. (A) Bubble chart of all patients distributed to the different protein domains their variant affects, which are N‐terminus (n = 2), transmembrane (n = 27), cytoplasmic (n = 13), and extracellular (n = 1) domain. The color applies to the frequency of phenotypic manifestations and the bubble size to the number of patients in relation to the number of patients, in whom the item was reported. (B) Bubble chart of all patients with the recurrent variant p.Val1002Met (n = 24), which is located in the transmembrane region. The color applies to the frequency of phenotype manifestations and the bubble size to the number of patients in relation to the number of patients, in whom the item is reported.