Treatment with metformin in twelve patients with Lafora disease
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(2019) 14:149
LETTER TO THE EDITOR
Open Access
Treatment with metformin in twelve patients with Lafora disease Francesca Bisulli1,2*† , Lorenzo Muccioli2†, Giuseppe d’Orsi3, Laura Canafoglia4, Elena Freri5, Laura Licchetta1,2, Barbara Mostacci1, Patrizia Riguzzi1, Federica Pondrelli2, Carlo Avolio3, Tommaso Martino3, Roberto Michelucci1 and Paolo Tinuper1,2
Abstract Background: Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far. Methods: We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres. Results: Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6–36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500–2000 mg). In four patients dosing was limited by gastrointestinal sideeffects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement. Conclusions: Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD. Keywords: Metformin, Lafora disease, Progressive myoclonus epilepsy, EPM2A, EPM2B, NHLRC1
Introduction Lafora disease (LD) is a lethal, autosomal recessive, progressive myoclonus epilepsy. LD is caused by mutations in EPM2A or NHLRC1, encoding laforin and malin, respectively. With loss of function of either, structurally abnormal glycogen becomes insoluble and accumulates as Lafora bodies, responsible for disease progression [1]. Disruptions in cell homeostasis such as proteasomal dysfunction, oxidative stress, autophagy impairment, and mitochondrial dysfunction, also play a role in the pathophysiology of LD [2]. Symptoms typically begin in adolescence, and death * Correspondence: [email protected] † Francesca Bisulli and Lorenzo Muccioli contributed equally to this work. 1 IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy 2 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Full list of author information is available at the end of the article
commonly occurs within 10 years of onset. Antiepileptic drugs (AED) are partially effective on myoclonus and seizures but don’t have a major influence on the prog
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