Amitriptyline use in individuals with KCNQ2/3 gain-of-function variants: A retrospective cohort study.

Steffen Syrbe, Kern Olofson, Katrijn Arts, Robin Cloarec, Elisabeth Cats, Joost Nicolai, Charissa Millevert, Matthias De Wachter, Cathrine Elisabeth Gjerulfsen, Magdalena Krygier, Robert Smigiel, Berten Ceulemans, Allan Bayat, Stephane Auvin, Rikke S Møller, Gerhard Kluger, Sarah Weckhuysen, Mathieu Milh, Katrien Jansen

Journal: Epilepsia 2025;66(5):1628-1640

PMID: 39962862

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Abstract

OBJECTIVE

Heterozygous gain-of-function (GOF) variants in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channel subunits Kv7.2 and Kv7.3, lead to neurodevelopmental disorders for which no established treatments are available. Amitriptyline, an antidepressant, blocks Kv7.2/Kv7.3 and has previously been reported to be effective in a single individual with a KCNQ2 GOF variant. We designed a retrospective, single-arm, multicenter study to investigate the effects of amitriptyline in a real-world setting.

METHODS

We used a 7-point Likert scale to measure seizure frequency, clinical examination, motor function, alertness, skill acquisition, communication, mood, behavior, self-care, sleep, tiredness, and electroencephalogram at baseline, after a minimum of 6 weeks of intervention, and, if applicable, after discontinuation. Adverse events were assessed in all participants, and the effectiveness of the treatment was evaluated in 11 individuals who received a minimum dosage of .5 mg/kg/day for at least 6 weeks. Data were collected from October 2023 to August 2024.

RESULTS

Thirteen individuals, eight with a pathogenic KCNQ2 GOF variant and five with a pathogenic KCNQ3 GOF variant, were included. Nine were female, and the median age at start of amitriptyline was 7.1 years (range = 1.5-20 years). Eleven individuals received a minimum dosage of .5 mg/kg/day for at least 6 weeks. The median dosage of amitriptyline administered was 1 mg/kg/day, with a median treatment duration of 29 weeks. Although amitriptyline was ineffective in two individuals (18%), eight (72%) demonstrated at least minimal improvement in two or more domains, with improvements in alertness and communication being the most frequently reported. In those with reported improvements, amitriptyline was discontinued in four individuals, but continued improvements were seen, to the same or greater extent compared to treatment. The remaining five individuals are on continued treatment because of perceived benefits.

SIGNIFICANCE

Overall, the effect of amitriptyline remains unclear, and formal n-of-1 trials are needed to investigate the precise effects of amitriptyline in KCNQ GOF-related neurodevelopmental disorders.

Address: Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center (EpiCARE member), Dianalund, Denmark.; Department of Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.; Vlaams Instituut voor Biotechnologie (VIB) Center for Molecular Neurology, Antwerp, Belgium.; Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.; Gelre Hospitals, Apeldoorn, the Netherlands.; Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.; Research Institute for Rehabilitation, Transition, and Palliation, Paracelsus Medical University Salzburg, Salzburg, Austria.; Department of Child Neurology, Aix-Marseille University, AP-HM, La Timone Children's Hospital, Marseille, France.; Center de Référence Déficiences Intellectuelles et Polyhandicaps de Causes Rares, APHM, Hôpital de la Timone-Enfants, Marseille, France.; Center for Child and Adolescent Medicine, Clinic 1, Division of Pediatric Epileptology, Heidelberg University, Medical Faculty of Heidelberg, Heidelberg, Germany.; Department of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium.; Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland.; Department of Pediatrics, Endocrinology, Diabetology, and Metabolic Diseases, Wrocław Medical University, Wrocław, Poland.; Pediatric Neurology Department, CRMR Epilepsies Rares (EpiCARE member), APHP, Robert Debré University Hospital, Paris, France.; Université Paris Cité, INSERM NeuroDiderot, Paris, France.; Institut Universitaire de France, Paris, France.; Department of Child Neurology, Danish Epilepsy Center, Dianalund, Denmark.; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center (EpiCARE member), Dianalund, Denmark.; Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center (EpiCARE member), Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center (EpiCARE member), Dianalund, Denmark.; Department of Child Neurology, Danish Epilepsy Center, Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.; Department of Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.; Vlaams Instituut voor Biotechnologie (VIB) Center for Molecular Neurology, Antwerp, Belgium.; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.; μNEURO Research Center of Excellence, University of Antwerp, Antwerp, Belgium.

DOI: 10.1111/epi.18310

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MeSH Terms: Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Young Adult, Amitriptyline, Cohort Studies, Gain of Function Mutation, KCNQ2 Potassium Channel, KCNQ3 Potassium Channel, Retrospective Studies, Treatment Outcome