Treatment with metformin in twelve patients with Lafora disease.

LaFora disease (LD) is a rare, lethal, progressive myoclonus epilepsy which no targeted therapies currently available. Studies in mouse models of LD showed a good response to metformin, a drug with neuroprotective effects famous.

For this reason, in 2016, the European Medicines Agency granted orphan designation for metformin for the treatment of LD. However, no clinical data available far.We retrospective data so collected in patients treated with metformin LD called three centres.Twelve Italy epilepsy patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) in the middle stage / final illness is treated with add -on metformin for an average period of 18 months (range: 6-36). Metformin titrated with average maintenance dose 1167 mg / day (range: 500-2000 mg). In four patients the dose is limited by gastrointestinal side effects.

No serious adverse events occurred. Three patients had a clinical response, which while two, characterized by a decrease in seizure frequency and a secure global clinical improvement.Metformin overall in our small cohort of patients with LD. Despite the poor clinical outcome, this may be associated with an advanced stage of the disease in our case and we can not exclude the role of metformin in slowing the progression of LD. Therefore, on the basis of preclinical data, we believe that treatment with metformin can be tried as early as possible in the course of LD.

LaFora disease (LD) is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by neurological continuous decline, culminating in death within 10 years. LD leads to the accumulation of soluble, not normal, glycogen-like structures called LaFora body (LBS). It is caused by mutations in the gene encoding glycogen phosphatase (EPM2A) or E3 ubiquitin ligase master (EPM2B / NHLRC1).

Both proteins are involved in a complicated, however, not fully described pathway that regulates the metabolism of glycogen. EPM2A and complex formation master signal promoting protein ubiquitination participate in glycogen metabolism, in which mutations lead to the formation LBS dysfunctional.

 Treatment with metformin in twelve patients with Lafora disease.
Treatment with metformin in twelve patients with Lafora disease.

In vivo glutamate clearance defect in a mouse model LaFora disease.

LaFora disease (LD) is a neurodegenerative disorder that is rarely fatal characterized by epilepsy, neurodegeneration and accumulation of insoluble polyglucosan in the brain and other peripheral tissues. Although in the last two decades we have increased our knowledge on the molecular basis of the underlying pathophysiology of LD, only a small fraction of research on LD have paid attention to the mechanisms triggering one of the features of the most deadly of diseases: epilepsy.

Recent studies in our laboratory suggest that dysfunction in mouse activity astrocytic glutamate transporter 1 (GLT-1) may contribute to epilepsy in LD. In this work, we present a new in vivo evidence of dysfunction of GLT-1, contribute to increased extracellular glutamate levels in the hippocampus of a mouse model of disease LaFora (Epm2b – / -, lacking E3-ubiquitin ligase master). According to our results, Epm2b – / – mice showed increased neuronal activity, as assessed by expression of c-fos, in the hippocampus, an area directly related to epileptogenesis.

This brain area is presented lower ability to remove after a local synaptic glutamate GLT-1 blockade with dihydrokainate (DHK), compared with Epm2b + / + animals, indicating that these animals have permission glutamate compromised when the challenging conditions presented. These results correlated with upregulation of isoform minor hippocampus of GLT-1 gene, called GLT-1b, which has been associated with the compensation mechanism is activated in response to neuronal stress.

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In conclusion, the hippocampus of Epm2b – / – mice presents an in vivo decrease in glutamate uptake that may contribute to epileptogenesis.