Phenotype Spectrum of TRPM3-Associated Disorders

Laura Jolitz; Ingo Helbig; Mark P Fitzgerald; Sarah McKeown Ruggiero; Stacey Cohen; Chloe Angelini; Elena Vallespin; Vincent Michaud; Anna Gerasimenko; Benjamin Cogne; Bertrand Isidor; Boris Keren; David Dyment; Delphine Heron; Helena Gásdal Karstensen; Inge Cuppen; John Christodoulou; Meredith Wilson; Nicole J Lake; Saskia Biskup; Steffen Syrbe; Takayasu Mori; Lena-Luise Becker; Angela M Kaindl

doi:10.1002/ana.27141

Phenotype Spectrum of TRPM3-Associated Disorders

Ann Neurol. 2025 Jan 3. doi: 10.1002/ana.27141. Online ahead of print.

Authors

Laura Jolitz^{1

2

3

4}, Ingo Helbig⁵, Mark P Fitzgerald^{5

6

7}, Sarah McKeown Ruggiero⁵, Stacey Cohen⁸, Chloe Angelini⁹, Elena Vallespin¹⁰, Vincent Michaud^{11

12}, Anna Gerasimenko^{13

14}, Benjamin Cogne^{15

16}, Bertrand Isidor¹⁵, Boris Keren¹⁷, David Dyment¹⁸, Delphine Heron¹⁴, Helena Gásdal Karstensen¹⁹, Inge Cuppen²⁰, John Christodoulou²¹, Meredith Wilson^{22

23}, Nicole J Lake²⁴, Saskia Biskup²⁵, Steffen Syrbe²⁶, Takayasu Mori²⁷, Lena-Luise Becker^#^{1

2

3

4}, Angela M Kaindl^#^{1

2

3

4}

Affiliations

¹ Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ Institute for Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Section CNS Development and Neurologic Disease, German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Germany.
⁵ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁷ Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Medical Genetics, Groupe Hospitalier Pellegrin, CHU Bordeaux, Bordeaux Cedex, France.
¹⁰ Medical and Molecular Genetics Institute (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, Madrid, Spain.
¹¹ Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France.
¹² INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France.
¹³ Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne Université, Paris, France.
¹⁴ Département de Génétique, Centre de référence "déficiences intellectuelles de causes rares", APHP Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Paris, France.
¹⁵ Service de Génétique Médicale, Nantes Université, CHU de Nantes, Nantes, France.
¹⁶ Laboratoire de Biologie Médicale Multi-Sites SeqOIA (laboratoire-seqoia.fr), Paris, France.
¹⁷ Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
¹⁹ Dept. of Genetics, Center of Diagnostics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
²⁰ Department of Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
²¹ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Australia.
²² Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia.
²³ Discipline of Genomic Medicine, University of Sydney, Sydney, Australia.
²⁴ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
²⁵ Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany.
²⁶ Heidelberg University, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Division of Pediatric Epileptology, Heidelberg, Germany.
²⁷ Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan.

^# Contributed equally.

PMID: 39749750
DOI: 10.1002/ana.27141

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.

Abstract

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