Treatment with metformin in twelve patients with Lafora disease

Francesca Bisulli, Lorenzo Muccioli, Giuseppe D'Orsi, Laura Canafoglia, Elena Freri, Laura Licchetta, Barbara Mostacci, Patrizia Riguzzi, Federica Pondrelli, Carlo Avolio, Tommaso Martino, Roberto Michelucci, Paolo Tinuper

Research output: Contribution to journalArticle

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 side-effects. 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.

Original languageEnglish
Article number149
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
Publication statusPublished - Jun 21 2019

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Lafora Disease
Metformin
Therapeutics
Progressive Myoclonic Epilepsy
Orphaned Children
Neuroprotective Agents
Disease Progression
Epilepsy
Seizures

Keywords

  • EPM2A
  • EPM2B
  • Lafora disease
  • Metformin
  • NHLRC1
  • Progressive myoclonus epilepsy

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

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Treatment with metformin in twelve patients with Lafora disease. / Bisulli, Francesca; Muccioli, Lorenzo; D'Orsi, Giuseppe; Canafoglia, Laura; Freri, Elena; Licchetta, Laura; Mostacci, Barbara; Riguzzi, Patrizia; Pondrelli, Federica; Avolio, Carlo; Martino, Tommaso; Michelucci, Roberto; Tinuper, Paolo.

In: Orphanet Journal of Rare Diseases, Vol. 14, No. 1, 149, 21.06.2019.

Research output: Contribution to journalArticle

Bisulli, Francesca ; Muccioli, Lorenzo ; D'Orsi, Giuseppe ; Canafoglia, Laura ; Freri, Elena ; Licchetta, Laura ; Mostacci, Barbara ; Riguzzi, Patrizia ; Pondrelli, Federica ; Avolio, Carlo ; Martino, Tommaso ; Michelucci, Roberto ; Tinuper, Paolo. / Treatment with metformin in twelve patients with Lafora disease. In: Orphanet Journal of Rare Diseases. 2019 ; Vol. 14, No. 1.
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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 side-effects. 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.",
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AU - Bisulli, Francesca

AU - Muccioli, Lorenzo

AU - D'Orsi, Giuseppe

AU - Canafoglia, Laura

AU - Freri, Elena

AU - Licchetta, Laura

AU - Mostacci, Barbara

AU - Riguzzi, Patrizia

AU - Pondrelli, Federica

AU - Avolio, Carlo

AU - Martino, Tommaso

AU - Michelucci, Roberto

AU - Tinuper, Paolo

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Y1 - 2019/6/21

N2 - 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 side-effects. 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.

AB - 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 side-effects. 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.

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