Assessing the Safety and Efficacy of Lamotrigine as Anti-myotonic Agent in Myotonic Dystrophy Type 1 (DM1): A Longitudinal, Open-Label, Pilot Study

Neurol Ther (2025) 14:2249–2260 https://doi.org/10.1007/s40120-025-00804-z BRIEF REPORT Assessing the Safety and Efficacy of Lamotrigine as Anti‑myotonic Agent in Myotonic Dystrophy Type 1 (DM1): A Longitudinal, Open‑Label, Pilot Study Barbara Risi · Nesaiba Ait Allali · Stefano Cotti Piccinelli Beatrice Labella · Enrica Bertella Roberto Carugati · Lucia Ferullo · Filomena Caria · Simona Damioli · · Giorgia Giovanelli · Francesca Garofali · Giuseppina Margollicci · · Emanuele Olivieri · Loris Poli · Alessandro Padovani · Massimiliano Filosto Received: May 16, 2025 / Accepted: July 21, 2025 / Published online: August 2, 2025 © The Author(s) 2025 ABSTRACT Introduction: Myotonia, defined as impaired relaxation of skeletal muscles after voluntary contraction or electrical stimulation, is a core feature of myotonic dystrophy type 1 (DM1) and can be highly disabling. The most used anti-myotonic drug, mexiletine, has limited availability and is associated with several side effects. Lamotrigine (LTG), an anti-epileptic drug that reduces voltage-sensitive sodium channel Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s40120-025-00804-z. B. Risi · N. Ait Allali · S. Cotti Piccinelli · F. Caria · S. Damioli · E. Bertella · G. Giovanelli · F. Garofali · G. Margollicci · R. Carugati · M. Filosto (*) NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy e-mail: B. Risi Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy B. Labella · L. Ferullo · E. Olivieri · L. Poli · A. Padovani Unit of Neurology, ASST Spedali Civili, Brescia, Italy B. Labella · L. Ferullo · E. Olivieri · A. Padovani · M. Filosto Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy activity, has shown efficacy in treating myotonia in both in vitro models and patients with nondystrophic myotonias. We aimed to investigate in a cohort of patients with DM1 the use of LTG as an anti-myotonic treatment in a real-world setting. Methods: We enrolled 14 consecutive adult patients with genetically confirmed DM1 and clinically significant myotonia impacting daily living (Myotonia Behaviour Scale, MBS > 1). LTG was administered in escalating doses, starting from 50 mg/day up to 200 mg/day. Efficacy was assessed using a linear mixed-effects model. Two functional timed tests [the 9-Hole Peg Test (9HPT) and the preparation of a coffee pot, devised by us and called the “Coffee Task” test] were performed at baseline (pre-treatment) and at each dose level. Safety data was also collected. Results: The mean age at enrollment was 40 years, and the mean disease duration was 12 years. LTG dosage had a significant positive effect on 9HPT performance at the maximum dose compared to baseline. Age and disease duration significantly influenced 9HPT results. No significant changes were observed in the other functional timed test. No serious adverse events were reported. Conclusion: This pilot, open-label study provides preliminary evidence for the efficacy and safety of LTG as an anti-myotonic treatment in Vol.:(0123456789) 2250 Neurol Ther (2025) 14:2249–2260 patients with DM1. These findings support the need for larger, placebo-controlled trials to confirm its clinical utility. Keywords: Myotonic dystrophy; Lamotrigine; Myotonia; Therapy DM1; Key Summary Points Why carry out this study? Myotonia is a hallmark of myotonic dystrophy type 1 (DM1), which is characterized by delayed relaxation of the skeletal muscles following voluntary contraction or electrical stimulation. This disabling symptom impacts daily activities, mobility, and social interaction. The only approved drug targeting this condition, mexiletine, is poorly available and has numerous side effects. New diseasemodifying drugs under development can also act on the myotonic phenomenon, but they probably will not be available to all patients worldwide. Considering the effectiveness of lamotrigine in reducing myotonia in patients with nondystrophic myotonias as emerged in recent clinical trials, this pilot study aimed to evaluate for the first time the effect and safety of this drug in a cohort of patients with DM1. What was learned from this study? Patients treated with lamotrigine performed the 9-Hole Peg Test, which is used as a measure of manual dexterity, more quickly than at baseline when they were treatment-naïve. The change was significant at the maximum dosage of lamotrigine. The safety profile was satisfactory. These results demonstrate the potential value of lamotrigine as a treatment for myotonia. This drug is already on the market, inexpensive, and well tolerated. The results should pave the way for future placebo-controlled trials. INTRODUCTION Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults [1]. It is an autosomal dominant disorder caused by the expansion (ranging from 50 to 4000 repeats) of an unstable CTG trinucleotide repeat in the DMPK gene on chromosome 19, which encodes a myosin kinase expressed in skeletal muscle [2–4]. A hallmark of DM1 is myotonia, defined as delayed relaxation of skeletal muscle following voluntary contraction or electrical stimulation. This phenomenon typically improves with repeated contractions, known as the warm-up phenomenon [5]. Myotonia can affect nearly any muscle, but it is particularly disabling when it involves the hand muscles (leading to handgrip myotonia) or the bulbar, tongue, or facial muscles, resulting in difficulties with speaking, chewing, and swallowing [6]. These features significantly impair patients’ quality of life. The etiopathogenesis of myotonia in DM1 has been extensively studied. One early hypothesis suggested that DMPK dysfunction might impair the fast inactivation of sodium channels—a time-dependent mechanism that physiologically halts sodium influx and cell depolarization [7]. Delayed closing of inactivation gates results in increased muscle fiber excitability and susceptibility to sustained, repetitive discharges, causing myotonia [8, 9]. However, studies in both DMPK loss-of-function (knockout mice) and gain-of-function (kinase overexpression) models failed to show muscle hyperexcitability, arguing against this as the primary mechanism [10, 11]. Subsequent research highlighted the role of reduced chloride channel conductance. Under normal conditions, chloride conductance stabilizes the resting membrane potential and counteracts depolarization induced by extracellular potassium (K+) accumulation in the T tubules— events that can trigger myotonic discharges [12]. When chloride conductance is impaired, K+ builds up in these invaginations, as demonstrated in both animal and human studies [13–15]. In DM1, impaired chloride conductance results from dysregulation of alternative splicing Neurol Ther (2025) 14:2249–2260 [16]. RNA transcripts from the expanded allele form nuclear foci containi (...truncated)