Lafora Disease was originally described over 100 years ago by Dr. Gonzalo Rodriquez-Lafora as a ?myoclonus epilepsy with dementia.? A hallmark of the disease identified by Lafora are inclusions in the brain, now known as Lafora bodies (LBs). LD is a rapidly progressing invariably fatal epilepsy. Onset is in adolescence, in apparently healthy teenagers of both sexes, with headaches and insidious decline in cognitive function. Myoclonic seizures, staring spells, and generalized convulsions follow and all escalate over time. Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absence begins. The young person then develops dementia, often disinhibited, and seizes with increased frequency. The patient becomes bedridden and death comes after a protracted decade of unceasing myoclonus in the form of a particularly massive seizure, status epilepticus, or aspiration pneumonitis. Identification of the genetic basis for LD by members of our group has ushered in a new era in our understanding of the formation of LBs leading to LD. We have made rapid progress, and have now demonstrated that eliminating LBs wholly cures LD in mouse models, opening up the real possibility of a cure. To that end, we propose the establishment of the Lafora Epilepsy Cure Initiative (LECI) Center. We have assembled an international group of pioneers and leaders in the field. We propose to attack the disease from multiple angles, targeting the full spectrum of molecular and cellular causes of LD and believe that we are uniquely positioned to realize the dream of treating and curing LD patients. The overall focus of this Program Project Grant is to: Diagnose, Treat, and eventually Cure LD. Four complimentary projects and three integrated core facilities form the basis of this proposal. Our projects are: Project #1: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD. Project #2: Genome editing, mRNA suppression and glycogen chain termination to inhibit glycogen storage as therapy for LD. Project #3: Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD. Project #4: Defining the therapeutic window for the treatment of LD. LD offers a unique window into both normal neuronal glycogen metabolism and epileptic disease when the process is perturbed. While this project aims at defining the basic mechanisms of LD and translating this work into therapeutics and cures, our work is likely to reveal pathogenic mechanisms common to other epilepsies. The collective effort of the LD experts will both define LD therapy options and generate abundant new collateral data that will uncover pathways connecting the bioenergetics of the brain with the generation of seizures and epilepsy. These insights may be particularly informative to the most daunting aspect of epilepsy, namely intractability that afflicts over 30% of patients.

Public Health Relevance

Lafora disease is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever-worsening seizures until it results in death after 10 years. The collaboration in this Program Project Grant brings together the clinician-scientists and researchers who discovered the causes of this disease: the shape of glycogen becomes abnormal in this disease, in fact it becomes similar to plant starch, and builds up in the patients' brain cells. We will utilize state of the art technologies including techniques to manipulate genes, introducing biological agents to interfere with gene expression, utilization of hormones and carbohydrate-poor dies, small molecules, and sugar-mimics to down-regulate glycogen production. Our research is in a state where we see a clear track to develop effective methods to diagnose, treat, and ultimately cure LD. Our vision is that one day a physician having diagnosed a child with this horrendous epilepsy would have the medicines and technologies to stop the disease in its tracks so that the child is able to resume development and life a healthy and normal life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Neurological Sciences and Disorders C (NSD-C)
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Stewart, Randall R
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University of Kentucky
Schools of Medicine
United States
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Sánchez-Elexpuru, Gentzane; Serratosa, José M; Sánchez, Marina P (2017) Sodium selenate treatment improves symptoms and seizure susceptibility in a malin-deficient mouse model of Lafora disease. Epilepsia 58:467-475
Mishra, Navin; Wang, Peixiang; Goldsmith, Danielle et al. (2017) Everolimus does not prevent Lafora body formation in murine Lafora disease. Neurol Genet 3:e127
Solmesky, Leonardo J; Khazanov, Netaly; Senderowitz, Hanoch et al. (2017) A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease. Biochem J 474:3403-3420
Sánchez-Elexpuru, Gentzane; Serratosa, José M; Sanz, Pascual et al. (2017) 4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease. Neuroreport 28:268-271
Villalba-Orero, María; Sánchez-Elexpuru, Gentzane; López-Olañeta, Marina et al. (2017) Lafora Disease Is an Inherited Metabolic Cardiomyopathy. J Am Coll Cardiol 69:3007-3009
Swain, Lindsay; Key, Gill; Tauro, Anna et al. (2017) Lafora disease in miniature Wirehaired Dachshunds. PLoS One 12:e0182024
Sullivan, Mitchell A; Nitschke, Silvia; Steup, Martin et al. (2017) Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan. Int J Mol Sci 18:
Nitschke, Felix; Sullivan, Mitchell A; Wang, Peixiang et al. (2017) Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease. EMBO Mol Med 9:906-917
López-González, Irene; Viana, Rosa; Sanz, Pascual et al. (2017) Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models. Mol Neurobiol 54:3119-3130
Genton, Pierre; Striano, Pasquale; Minassian, Berge A (2016) The history of progressive myoclonus epilepsies. Epileptic Disord 18:3-10

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