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Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.

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INTRODUCTION: Lafora disease is autosomal recessive progressive myoclonus epilepsy with late childhood-to teenage-onset caused by loss-of-function mutations in either EPM2A or EPM2B genes encoding laforin or malin, respectively. DEVELOPMENT: The main symptoms of Lafora disease, which worsen progressively, are: myoclonus, occipital seizures, generalized tonic-clonic seizures, cognitive decline, neuropsychiatric syptoms and ataxia with a fatal outcome. Pathologically, Lafora disease is characterized by the presence of polyglucosans deposits (named Lafora bodies), in the brain, liver, muscle and sweat glands. Diagnosis of Lafora disease is made through clinical, electrophysiological, histological and genetic findings. Currently, there is no treatment to cure or prevent the development of the disease. Traditionally, antiepileptic drugs are used for the management of myoclonus and seizures. However, patients become drug-resistant after the initial stage. CONCLUSIONS: Lafora disease is a rare pathology that has serious consequences for patients and their caregivers despite its low prevalence. Therefore, continuing research in order to clarify the underlying mechanisms and hopefully developing new palliative and curative treatments for the disease is necessary.

TITLE: Enfermedad de Lafora: revision de la bibliografia.Introduccion. La enfermedad de Lafora es una forma de epilepsia mioclonica progresiva de herencia autosomica recesiva, de inicio en la infancia tardia o en la adolescencia, y producida por mutaciones de perdida de funcion en los genes EPM2A o EPM2B, los cuales codifican para las proteinas laforina y malina, respectivamente. Desarrollo. Los principales sintomas de la enfermedad, que empeoran progresivamente, son mioclonias, crisis occipitales, crisis tonicoclonicas generalizadas, deterioro cognitivo, sintomas neuropsiquiatricos y ataxia. El curso es progresivo y fatal. Patologicamente, se caracteriza por la presencia de depositos de poliglucosanos (denominados cuerpos de Lafora) en el cerebro, el higado, el musculo y las glandulas sudoriparas. El diagnostico de enfermedad de Lafora se realiza mediante hallazgos clinicos, electrofisiologicos, histologicos y geneticos. En la actualidad no existe un tratamiento que erradique o prevenga su desarrollo. Tradicionalmente, se utilizan farmacos antiepilepticos para el tratamiento de las mioclonias y las convulsiones, aunque aparecen resistencias a estas. Conclusiones. La enfermedad de Lafora es una patologia rara que, pese a su baja prevalencia, supone graves consecuencias para los pacientes y sus cuidadores. Asi pues, resulta necesario continuar la investigacion para clarificar los mecanismos subyacentes y desarrollar nuevos tratamientos paliativos y curativos de la enfermedad.

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The progressive myoclonus epilepsies (PMEs) are a devastating group of rare disorders(1) that manifest with increasing action myoclonus, which is also present at rest but activates with stimuli such as noise, light, or touch. Ultimately, patients become wheelchair-bound and experience early death. Neurologic signs that frequently but not reliably coexist include other seizure types (particularly generalized tonic-clonic), progressive ataxia, and dementia. Typically, presentation is in late childhood or adolescence; however, all ages may be affected. Although distinction from more common forms of genetic generalized epilepsy, particularly juvenile myoclonic epilepsy, may be challenging early on, the presence or evolution of 1) progressive neurologic disability, 2) failure to respond to antiepileptic drug therapy, and 3) background slowing on EEG should suggest PME. Importantly, inappropriate therapy in the genetic generalized epilepsies may result in ataxia, impaired cognition, and uncontrolled seizures, which may mimic PME. PMEs should be distinguished from progressive encephalopathies with seizures (due to degenerative conditions such as GM2 gangliosidosis, nonketotic hyperglycinemia, Niemann-Pick type C, juvenile Huntington and Alzheimer disease) and progressive myoclonic ataxias, which affect predominantly adults with progressive ataxia, myoclonus, few if any tonic-clonic seizures, and without evidence of dementia.(2,3.)

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OBJECTIVE: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. METHODS: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. RESULTS: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. CONCLUSIONS: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

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Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The condition is characterized by epilepsy, myoclonus and dementia. Diagnostic findings on MRI and neurophysiological testing are not definitive and biopsy or genetic studies may be required. Therapy in Lafora disease is currently limited to symptomatic management of the epilepsy, myoclonus and intercurrent complications. With a greater understanding of the pathophysiological processes involved, there is justified hope for future therapies.

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PURPOSE: We observed three apparently unrelated and geographically separate Arab families with Lafora disease in Israel and the Palestinian territories. METHODS: We clinically evaluated the families and analyzed their DNA for EPM2A mutations. RESULTS: Of seven individuals with Lafora disease, the clinical onset varied from 13 to 20 years. All three families shared the same novel homozygous deletion in EPM2A. Haplotype analysis around the deletion showed that the families shared a common homozygous haplotype. The boundaries of this haplotype varied between families and even within one family. CONCLUSIONS: We conclude that considerable variability in the age at onset of Lafora disease can occur within families. Identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases. Haplotype analysis suggests that this EPM2A mutation arose many generations previously, so it may be of importance for cases distributed more widely in the Middle East.

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Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration. LD is caused by mutations in the EMP2A gene encoding a protein phosphatase. A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22. The LD is relatively common in southern Europe, the Middle East, and Southeast Asia. A few sporadic cases with typical LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new families from Japan and searched for mutations in EPM2A . All eight families were also screened for NHLRC1 mutations. We found five independent families having novel mutations in NHLRC1. Identified mutations include five missense mutations (p.I153M, p.C160R, p.W219R, p.D245N, and p.R253K) and a deletion mutation (c.897insA; p.S299fs13). We also found a family with a ten base pair deletion (c.822-832del10) in the coding region of EPM2A. In two families, no EPM2A or NHLRC1 mutation was found. Our study, in addition to documenting the genetic and molecular heterogeneity observed for LD, suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Japanese population.

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