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Epilepsy is a long-term neurological disease characterized by convulsions that can be recurrent. It is mainly caused by an imbalance between excitation and inhibition in the central nervous system. Currently, the pathogenesis is still unclear, although it may be related to changes in ion channels, neurotransmitters and glial cells. In recent years, increasing attention has been paid to the role of autophagy in the development of epilepsy. This chapter focuses on the role of the mTOR pathway in epileptogenesis and the relationship between autophagy, glycogen metabolism and Lafora disease and discusses the potential role of autophagy as a target for the treatment of epilepsy.

Lafora disease is rare group of progressive myoclonic epilepsies, worldwide. It is more common in children and adolescents and is genetic, glycogen metabolism disorder. It has Autosomal recessive (AR) inheritance. Lafora bodies are inclusion bodies within cytoplasm of cells in heart, liver, muscle, and skin. Disease clinically has triad of seizures, myoclonus, and dementia. Lafora disease is a neurodegenerative disorder. In the absence of laforin function long glucose chains in specific glycogen molecules extrude water form double helices and drive precipitation of molecules which accumulate into Lafora bodies. That leads to impairment in development of cerebral cortical neurons. Clinical on set of disease is range in between 8-19 years of age and peaks around 15years of age. In our case, 16-year-old girl presented to emergency of tertiary care hospital with complain of episode of convulsions 40 minutes before admission. She is known case of generalized tonic-clonic seizures for past two years. Axillary skin biopsy on H&E staining showed pilosebaceous glandular unit with peri-adnexal and perivascular infiltrate. PAS-D stain showed round, globular, tiny PAS positive material noted within sweat glands. MRI brain was suggestive of right vertebral artery partial occlusion.

The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising. [ABSTRACT FROM AUTHOR]

Lafora disease is a rare genetic disorder characterized by a disruption in glycogen metabolism. It manifests as progressive myoclonus epilepsy and cognitive decline during adolescence. Pathognomonic is the presence of abnormal glycogen aggregates that, over time, produce large inclusions (Lafora bodies) in various tissues. This study aims to describe the clinical and histopathological aspects of a novel Lafora disease patient, and to provide an update on the therapeutical advancements for this disorder. A 20-year-old Libyan boy presented with generalized tonic–clonic seizures, sporadic muscular jerks, eyelid spasms, and mental impairment. Electroencephalography showed multiple discharges across both brain hemispheres. Brain magnetic resonance imaging was unremarkable. Muscle biopsy showed increased lipid content and a very mild increase of intermyofibrillar glycogen, without the polyglucosan accumulation typically observed in Lafora bodies. Despite undergoing three lines of antiepileptic treatment, the patient's condition showed minimal to no improvement. We identified the homozygous variant c.137G>A, p.(Cys46Tyr), in the EPM2B/NHLRC1 gene, confirming the diagnosis of Lafora disease. To our knowledge, the presence of lipid aggregates without Lafora bodies is atypical. Lafora disease should be considered during the differential diagnosis of progressive, myoclonic, and refractory epilepsies in both children and young adults, especially when accompanied by cognitive decline. Although there are no effective therapies yet, the development of promising new strategies prompts the need for an early and accurate diagnosis. [ABSTRACT FROM AUTHOR]

Epilepsy is categorized as third most common chronic brain disorder. It is regarded as an enduring tendency to produce seizures. A type of epilepsy known as lafora disease is autosomal recessive progressive myoclonus epilepsy (PME) with onset in teenage years of a progressively stubborn seizure disorder which brings declining mental function, dementia and finally death within ten years after the first symptoms. Lafora disease is defective in two well-known genes EPM2A and EPM2B. EPM2B (NHLRC1) consists of one large exon of 1188 bps. It encodes 395 amino acid protein called Malin comprising a zinc finger of the Ring-type in the N-terminal half and 6 NHL-repeat domains in C-terminal. In this study, four families were enrolled from Balochistan including two or more epileptic individuals aged between 10-24 years. Blood samples were collected and DNA extraction was performed by inorganic method. DNA was amplified by polymerase chain reaction and subsequently sequenced to confirm any genetic variability in the affected individuals of the families. As a result, two different missense mutations (c.830C>A resulting p.Ala277Glu and c.332C>T resulting p.Pro111Leu) in affected individuals in two of the families were identified. The nonexistence of mutations in EPM2B in the other two families could be due to presence of mutations in noncoding or non-tested loci/genes. This study may facilitate in finding prevalence of lafora disease in Balochistan province of Pakistan. [ABSTRACT FROM AUTHOR]

Among different types of Progressive Myoclonic Epilepsy (PME), Lafora disease is an autosomal recessive disorder, with age of onset 6-19 years. It is quickly progressive, and death occurs within 10 years. It is a glycogen metabolism disorder characterized by the presence of inclusion bodies, known as Lafora bodies within the cytoplasm of the skin, liver, breast and muscle. Lafora disease presents as a neurodegenerative disorder with difficult to control seizures mostly like progressive myoclonic epilepsy. But the disease may also present with multiple types of seizures like generalized tonic clonic, focal with secondary generalization, myoclonic, absence etc. Patient may also present with psychomotor regression with ataxia, dysarthria, dementia, visual hallucination etc. Electroencephalogram (EEG) shows generalized spike/polyspikes and waves with photosensitivity and background slowing. Diagnosis is further confirmed by presence of inclusion bodies (Lafora body) with typical histological findings on skin biopsy and genetic testing. Here we present a case of Lafora disease that presented with progressive myoclonic epilepsy and generalized tonic clonic seizure. We took proper history, did meticulous clinical examination and investigated her at our institute. We confirmed the patient having Lafora disease with typical histological findings that is presence of Lafora body on skin biopsy taken from axilla. Then treatment was given to the patient accordingly and proper counseling was done about the disease and its prognosis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD). Methods: We investigated the electro-clinical longitudinal data and CSF Ab42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families. Results: Three progressive electro-clinical stages were identified. The early phase was characterized by rare, generalized tonic-clonic and focal visual seizures, followed by the occurrence of myoclonus after a period ranging from 2 to 12 months. The intermediate stage, usually occurring 2 years after the onset of epilepsy, is characterized by a worsening of epilepsy and myoclonus associated with progressive dementia and cerebellar signs. Finally, the late stage, evolving after a mean period of 7 ± 1.41 years from the onset of the disease, was characterized by gait ataxia resulting in bedriddenness, severe dementia, daily/pluri-daily myoclonus, drug-resistant epilepsy, clusters of seizures or status epilepticus, and medical complications. Amyloid (CSF Ab42, amyloid PET) and neurodegenerative (CSF p-tau181 and t-tauAg, FDG-PET) biomarkers indicate a pattern of cognitive impairment of the non-Alzheimer's disease type. A total of 80% of the LD patients showed more severe hypometabolism in the second FDG-PET scan compared to the first scan performed in a lower phase; the lateral temporal lobe and the thalamus hypometabolism were associated with the presence of intermediate or late phase. Conclusions: Three electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the effcacy of new disease-modifying treatments. The combination of traditional CSF biomarkers improves the diagnostic accuracy of cognitive decline in LD patients, indicating a cognitive impairment of the non-Alzheimer's disease type. [ABSTRACT FROM AUTHOR]

Abstract Background Lafora disease is a rare genetic disorder involving glycogen metabolism disorder. It is inherited by autosomal recessive pattern presenting as a progressive myoclonus epilepsy and neurologic deterioration beginning in adolescence. It is characterized by Lafora bodies in tissues such as brain, skin, muscle, and liver. Case presentation We report a rare case of Lafora disease in a 16-year-old Albanian girl who presented at a tertiary health care center with generalized tonic–clonic seizures, eyelid twitches, hallucinations, headache, and cognitive dysfunction. She was initially treated for generalized epilepsy and received an antiepileptic drug. However, owing to resistance of seizures to this antiepileptic drug, a second drug was introduced. However, seizures continued despite compliance with therapy, and general neurological status began to deteriorate. The child began to have hallucinations and decline of cognitive function. She developed dysarthria and unsteady gait. When admitted to the hospital, blood tests and imaging examinations were planned. The blood tests were unremarkable. There was no relevant family history and no consanguinity. Electroencephalography showed multifocal discharges in both hemispheres, and brain magnetic resonance imaging revealed no abnormality. Axillary skin biopsy revealed inclusion bodies in apocrine glands. Consequently, the child was referred to an advanced center for genetic testing, which also confirmed diagnosis of Lafora disease with a positive mutation on NHLRC1 gene. Conclusions Even though rare as a condition, Lafora disease should be considered on differential diagnosis in progressive and drug-refractory epilepsy in adolescents, especially when followed by cognitive decline.

Lafora disease is a rare disorder caused by loss of function mutations in either the EPM2A or NHLRC1 gene. The initial symptoms of this condition are most commonly epileptic seizures, but the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and has a fatal outcome within 5–10 years after onset. The hallmark of the disease is the accumulation of poorly branched glycogen in the form of aggregates known as Lafora bodies in the brain and other tissues. Several reports have demonstrated that the accumulation of this abnormal glycogen underlies all the pathologic traits of the disease. For decades, Lafora bodies were thought to accumulate exclusively in neurons. However, it was recently identified that most of these glycogen aggregates are present in astrocytes. Importantly, astrocytic Lafora bodies have been shown to contribute to pathology in Lafora disease. These results identify a primary role of astrocytes in the pathophysiology of Lafora disease and have important implications for other conditions in which glycogen abnormally accumulates in astrocytes, such as Adult Polyglucosan Body disease and the buildup of Corpora amylacea in aged brains. [ABSTRACT FROM AUTHOR]

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a‐/− and Epm2b−/− mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a−/− knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a−/− and Epm2b−/− knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities. [ABSTRACT FROM AUTHOR]

Background: Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and molecular alterations, neuroinflammation has emerged as another key histopathological feature of LD. Methods: To investigate the role of astrocytes and microglia in LD, we performed a systematic review according to the PRISMA statement. PubMed, Scopus, and Web-of-Science database searches were performed independently by two reviewers. Results: Thirty-five studies analyzing the relationship of astrocytes and microglia with LD and/or the effects of anti-inflammatory treatments in LD animal models were identified and included in the review. Although LD has long been dominated by a neuronocentric view, a growing body of evidence suggests a role of glial cells in the disease, starting with the finding that these cells accumulate PBs. We discuss the potential meaning of glial PB accumulations, the likely factors activating glial cells, and the possible contribution of glial cells to LD neurodegeneration and epilepsy. Conclusions: Given the evidence for the role of neuroinflammation in LD, future studies should consider glial cells as a potential therapeutic target for modifying/delaying LD progression; however, it should be kept in mind that these cells can potentially assume multiple reactive phenotypes, which could influence the therapeutic response. [ABSTRACT FROM AUTHOR]

Epilepsy develops related to a complex genetic heredity as many diseases in society. Lafora disease (LD) is an autosomal recessive inheritance. It is localized at EPM2A gen 6q23-25 and encodes tyrosine phosphatase (Laforin protein). About 80% of the patients have mutations in this gene. In a case of LD, rapid and progressive dementia and frequent occipital seizures are clinical symptoms. For definitive diagnosis, through genetical study, EPM2A and EPM2B genes should be analyzed. A male at the age of 18, with a medical history of meningitis and seizures with high temperature. Starting from the age of 10, there have been symptoms such as generalized tonic-clonic (GTC) seizures, startles in the whole body, and forgetfulness. In genetical tests, homozygote deletion of adenine nucleotide in the position of 468 at codon 156 and guanine nucleotide in the position of 469 at codon 157 is found. In other words, there has been dinucleotide deletion which is compatible with LD. A 20-year-old male was examined because of such symptoms as forgetfulness, myoclonia, hallucinations, and GTC clonic seizures. He was diagnosed with LD because of the heterozygote transformation of CCC to CTC at codon 111. Even though genetic disorders have many different reasons, it is advised that every society should have their own advanced studies on gene mutation. In Turkish cases, both of these genes were found mutated, each in different patients through various studies.

Lafora disease is a rare refractory epilepsy that results in death. This report highlights two cases of lafora disease and introduces a novel mutation in the patients. A review of the pathophysiology and future therapies is reviewed. [ABSTRACT FROM AUTHOR]

We report a case of progressive myoclonic epilepsy caused by a novel mutation in EPM2A. The female patient experienced abnormal jerky movements of the involving all four limbs and several generalized seizures, degeneration of cognition, and unsteadiness. Genetic analysis identified two rare, deleterious mutations in exon4: chr6: 145,948,751(c.G797G > A) and chr6: 145,948,761(c.T787C > T). The mutations at these two loci were from the genomes of their mother and father, respectively, which were compound heterozygous variations. This report updates the mutation sites of gene EPM2A and extends genotype-phenotype correlations in Lafora disease. [ABSTRACT FROM AUTHOR]

Lafora disease is a rare disorder caused by loss of function mutations in either the EPM2A or NHLRC1 gene. The initial symptoms of this condition are most commonly epileptic seizures, but the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and has a fatal outcome within 5–10 years after onset. The hallmark of the disease is the accumulation of poorly branched glycogen in the form of aggregates known as Lafora bodies in the brain and other tissues. Several reports have demonstrated that the accumulation of this abnormal glycogen underlies all the pathologic traits of the disease. For decades, Lafora bodies were thought to accumulate exclusively in neurons. However, it was recently identified that most of these glycogen aggregates are present in astrocytes. Importantly, astrocytic Lafora bodies have been shown to contribute to pathology in Lafora disease. These results identify a primary role of astrocytes in the pathophysiology of Lafora disease and have important implications for other conditions in which glycogen abnormally accumulates in astrocytes, such as Adult Polyglucosan Body disease and the buildup of Corpora amylacea in aged brains.

INTRODUCCTION: Lafora's disease is a rare and fatal entity that usually presents in adolescence as progressive myoclonic epilepsy, with an estimated worldwide prevalence of 4 per million inhabitants. The deterioration is so severe that patients die an average of 10 years after the onset of symptoms. CASE REPORT: We present a 15-year-old female patient who began with frequent falls, tremors, and decreased visual acuity. She was diagnosed with myoclonus and treated with levetiracetam. She showed a gradual loss of short-term memory and intermittent amaurosis events. Generalized tonic-clonic seizures and cognitive impairment were added. She was approached comprehensively, finding visual acuity of the right eye 20/100, the left eye 20/60, and bitemporal hemianopia. WISC-IV evaluation reported a total IQ of 65. EEG with disorganized baseline activity, generalized polyspikes, intermingling of spikes and waves; electroretinogram with alteration in wave A; and brain MRI with bifrontal atrophy. Axillary biopsy with special PAS staining showed intensely positive Lafora bodies. Genetic study reported mutation in gene EPM2A c.721C> T (p.Arg241 *) and EPM2A c.92_124del (p.Arg31_Arg41del). Managed with valproic acid, levetiracetam, and a low glycemic index diet. CONCLUSIONS: Diagnosis of progressive myoclonic epilepsies is challenging. The progression of Lafora disease invariably leads to death and there is no specific treatment, so efforts should be focused on establishing more aggressive management of epilepsy from the early stages to provide a better quality of life to the patient and family. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain. [ABSTRACT FROM AUTHOR]

Epilepsy develops related to a complex genetic heredity as many diseases in society. Lafora disease (LD) is an autosomal recessive inheritance. It is localized at EPM2A gen 6q23-25 and encodes tyrosine phosphatase (Laforin protein). About 80% of the patients have mutations in this gene. In a case of LD, rapid and progressive dementia and frequent occipital seizures are clinical symptoms. For definitive diagnosis, through genetical study, EPM2A and EPM2B genes should be analyzed. A male at the age of 18, with a medical history of meningitis and seizures with high temperature. Starting from the age of 10, there have been symptoms such as generalized tonic-clonic (GTC) seizures, startles in the whole body, and forgetfulness. In genetical tests, homozygote deletion of adenine nucleotide in the position of 468 at codon 156 and guanine nucleotide in the position of 469 at codon 157 is found. In other words, there has been dinucleotide deletion which is compatible with LD. A 20-year-old male was examined because of such symptoms as forgetfulness, myoclonia, hallucinations, and GTC clonic seizures. He was diagnosed with LD because of the heterozygote transformation of CCC to CTC at codon 111. Even though genetic disorders have many different reasons, it is advised that every society should have their own advanced studies on gene mutation. In Turkish cases, both of these genes were found mutated, each in different patients through various studies. [ABSTRACT FROM AUTHOR]

Background: Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and molecular alterations, neuroinflammation has emerged as another key histopathological feature of LD. Methods: To investigate the role of astrocytes and microglia in LD, we performed a systematic review according to the PRISMA statement. PubMed, Scopus, and Web-of-Science database searches were performed independently by two reviewers. Results: Thirty-five studies analyzing the relationship of astrocytes and microglia with LD and/or the effects of anti-inflammatory treatments in LD animal models were identified and included in the review. Although LD has long been dominated by a neuronocentric view, a growing body of evidence suggests a role of glial cells in the disease, starting with the finding that these cells accumulate PBs. We discuss the potential meaning of glial PB accumulations, the likely factors activating glial cells, and the possible contribution of glial cells to LD neurodegeneration and epilepsy. Conclusions: Given the evidence for the role of neuroinflammation in LD, future studies should consider glial cells as a potential therapeutic target for modifying/delaying LD progression; however, it should be kept in mind that these cells can potentially assume multiple reactive phenotypes, which could influence the therapeutic response.

Lafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in mouse models of the disease. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene (Gys1). We administered Gys1-ASO by intracerebroventricular injection and analysed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy. [ABSTRACT FROM AUTHOR]

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons. [ABSTRACT FROM AUTHOR]

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A , encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a -/- knock-out and Epm2a R240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a -/- and Epm2a R240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a -/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease. • Single ICV injection or infusion of alglucosidase alfa do not remove Lafora bodies in the mouse brain. • Single ICV injection or infusion of alglucosidase alfa do not revert neurological alterations in the mouse model of Lafora disease. • There is no evidence from animal studies to support the use of alglucosidase alfa for the treatment of Lafora disease. [ABSTRACT FROM AUTHOR]

Lafora disease is a severe form of progressive myoclonic epilepsy with autosomal recessive inheritance diagnosed by inclusion body in biopsy. A 26-year-old woman was admitted due to complaints of frequent twitches and fainting. The 0.5x0.3x0.3 cm axillary skin punch biopsy was subjected to routine histopathological evaluation. Cytoplasmic PAS-positive inclusion bodies were observed at the basal side of the eccrine and apocrine glands. The diagnosis of Lafora disease can also be made by the observation of the polyglycosan cytoplasmic inclusion bodies in the brain, liver and skeletal muscle biopsies. Although we need more work to understand the etiopathogenesis of Lafora disease, we would like to draw attention to the importance of skin biopsy in the differential diagnosis of young patients with clinically refractory epilepsy, myoclonus, and cognitive decline.

We report a long-lived patient with Lafora disease (LD). A 34-year-old woman experienced onset of seizures at the age of 11 years. She was bedridden in her early twenties due to frequent generalized tonic-clonic seizures, myoclonus, and progressive mental deterioration. Her seizures occurred all the time despite administration of multiple anticonvulsants at high doses. At the age of 31, she started perampanel, which resulted in reduction of anticonvulsants after her visible myoclonus and convulsions disappeared. Brain magnetic resonance imaging showed marked cerebral and cerebellar atrophy, and single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed significant hypoperfusion of the frontal lobe and cerebellum. We identified a W219R homozygous mutation in exon 1 of the NHLRC1 gene. Because perampanel may not only control seizures but also prevent mental deterioration in LD, we propose that perampanel should be administered from the early stage of LD. [ABSTRACT FROM AUTHOR]

EPM2A has been certified as a causative gene in patients with Lafora disease (LD), which is a rare autosomal recessive and severe form of progressive myoclonus epilepsy. LD classically starts in adolescence, characterized by various types of seizure with myoclonic seizure as the main type. Typically within 10 years, intractable seizure attack, rapidly progressing dementia, and a vegetative state were present. LD is particularly frequently found in Mediterranean countries. Here, we report a Chinese family with a novel compound heterozygous mutation in the EPM2A gene, characterized by recurrent vomiting, intractable epilepsy, and progressive cognitive decline. [ABSTRACT FROM AUTHOR]

Progressive myoclonus epilepsies (PMEs) are a group of genetic neurological disorders characterised by the occurrence of epileptic seizures, myoclonus and progressive neurological deterioration including cerebellar involvement and dementia. The primary cause of PMEs is variable and alterations in the corresponding mutated genes determine the progression and severity of the disease. In most cases, they lead to the death of the patient after a period of prolonged disability. PMEs also share poor information on the pathophysiological bases and the lack of a specific treatment. Recent reports suggest that neuroinflammation is a common trait under all these conditions. Here, we review similarities and differences in neuroinflammatory response in several PMEs and discuss the window of opportunity of using anti-inflammatory drugs in the treatment of several of these conditions. [ABSTRACT FROM AUTHOR]

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients. [ABSTRACT FROM AUTHOR]

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal autosomal recessive neurodegenerative disorder (with an onset in teenage years in previously normal adolescents). This paper represents a view of a patient diagnosed with Lafora progressive myoclonus epilepsy, over a course of seven years. A description of the initial manifestation of symptoms, doctors' attempts to combat the symptoms with drug treatment, further attempts towards reaching the correct diagnosis, the final confirmation of the Lafora diagnosis (mutation in the NHLRC1 gene), and the current state of the patient is presented. The absence of a positive family history, the lack of staff specialized in dealing with this or similar pathology, and the diagnostic inability to characterize this type of disorder in Bosnia and Herzegovina have led to a fair delay in diagnosing and beginning of an adequate pharmacological treatment. Overall, recent identification of LD cases in Bosnia and Herzegovina warrants an establishment of a Centre for Genetic Testing in order to ensure more humane counseling of an entire family whose family member(s) might be diagnosed with this devastating and currently an incurable disorder. [ABSTRACT FROM AUTHOR]

Lafora disease (LD, OMIM 254780) is a rare disorder characterized by epilepsy and neurodegeneration leading patients to a vegetative state and death, usually within the first decade from the onset of the first symptoms. In the vast majority of cases LD is related to mutations in either the EPM2A gene (encoding the glucan phosphatase laforin) or the EPM2B gene (encoding the E3-ubiquitin ligase malin). In this work, we characterize the mutations present in the EPM2A gene in a patient displaying a slow progression form of the disease. The patient is compound heterozygous with Y112X and N163D mutations in the corresponding alleles. In primary fibroblasts obtained from the patient, we analyzed the expression of the mutated alleles by quantitative real time PCR and found slightly lower levels of expression of the EPM2A gene respect to control cells. However, by Western blotting we were unable to detect endogenous levels of the protein in crude extracts from patient fibroblasts. The Y112X mutation would render a truncated protein lacking the phosphatase domain and likely degraded. Since minute amounts of laforin-N163D might still play a role in cell physiology, we analyzed the biochemical characteristics of the N163D mutation. We found that recombinant laforin N163D protein was as stable as wild type and exhibited near wild type phosphatase activity towards biologically relevant substrates. On the contrary, it showed a severe impairment in the interaction profile with previously identified laforin binding partners. These results lead us to conclude that the slow progression of the disease present in this patient could be either due to the specific biochemical properties of laforin N163D or to the presence of alternative genetic modifying factors separate from pathogenicity. [ABSTRACT FROM AUTHOR]

Canine Lafora disease (LD) is an autosomal recessive genetic disorder causing nonfatal structural epilepsy, mainly affecting miniature wirehaired dachshunds. Repeat expansion in the EPM2B gene causes a functional impairment of the ubiquitin ligase malin which regulates glycogen metabolism. Abnormally structured glycogen accumulates and develop polyglucosan bodies predominantly in the central nervous system. The authors performed a comprehensive clinical, genetic, and pathological study of 4 LD cases affecting miniature wirehaired dachshund dogs with EPM2B repeat expansions, with systemic distribution of polyglucosan bodies and accumulation of laforin and other functionally associated proteins in the polyglucosan bodies. Myoclonic seizures first appeared at 7-9 years of age, and the dogs died at 14-16 years of age. Immunohistochemistry for calbindin revealed that the polyglucosan bodies were located in the cell bodies and dendritic processes of Purkinje cells. Polyglucosan bodies were also positive for laforin, hsp70, α/β-synuclein, ubiquitin, LC3, and p62. Laforin-positive polyglucosan bodies were located in neurofilament-positive neurons but not in GFAP-positive astrocytes. In nonneural tissues, periodic acid-Schiff (PAS)-positive polyglucosan bodies were observed in the heart, skeletal muscle, liver, apocrine sweat gland, and smooth muscle layer of the urinary bladder. In the skeletal muscle, polyglucosan bodies were observed only in type 1 fibers and not in type 2 fibers. The results indicate that although the repeat expansion of the EPM2B gene is specific to dogs, the immunohistochemical properties of polyglucosan body in canine LD are comparable to human LD. However, important phenotypic variations exist between the 2 species including the affected skeletal muscle fiber type. [ABSTRACT FROM AUTHOR]

Summary: Lafora disease (LD) clinically appears in previously healthy teenagers as progressively worsening seizures, myoclonus, dementia, and ultimately a vegetative state leading to death within a decade of its onset. Here we present a typical case of LD in which the patient survived until the age of 40. Although the patient's brain was severely affected, other organs remained functional until her death. The field of LD research is approaching potentially curative therapies (eg, with antisense oligonucleotides or gene replacement) targeting only the central nervous system (CNS). Our case provides anecdotal evidence suggesting that a patient with typical LD can retain full bodily health aside from the effects of neurological damage. [ABSTRACT FROM AUTHOR]

Lafora disease (LD), also known as progressive myoclonic epilepsy-2 (EPM2), is a rare, fatal autosomal recessive disorder typically starting during adolescence in otherwise neurologically normal individuals. It is clinically characterized by insidious of progressive neurological features including seizures, action myoclonus, visual hallucination, ataxia and dementia. Mutations in the laforin (EPM2A) gene on chromosome 6q24 or in the malin gene (NHLRC1) on chromosome 6p22 are responsible of LD phenotype. Diagnostic workup includes genetic analysis as well as axillary skin biopsy with evidence of typical periodic acid-Schiff (PAS)-positive polyglucosan inclusion bodies (Lafora bodies) in the apocrine glands and/or in the eccrine duct. Usually, genotype–phenotype correlations do not reveal substantial differences between patients carrying EPM2A and NHLRC1 mutations, but a few specific NHLRC1 mutations appear to correlate with a late onset and slow progressing LD. We report a case of LD due to compound heterozygote NHLRC1 mutation in an adolescent presenting with severe and atypical electro-clinical features, mimicking an autoimmune encephalopathy, and a rapidly progressive clinical course. [ABSTRACT FROM AUTHOR]

Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD. [ABSTRACT FROM AUTHOR]

Introduction: Lafora disease (LD) is a severe form of progressive epilepsy characterized by myoclonic seizures, cerebellar ataxia, progressive dementia and poor prognosis. In treatment-resistant epilepsies as LD, seizures are tried to be controlled with methods such as vagus nerve stimulation (VNS). Case: Twenty-seven-year-old male patient was transferred from emergency department to intensive care unit intubated with status epilepticus and aspiration pneumonia. Our patient was receiving sodyum valproate, levetiracetam, clonazepam, lacosamide, topiramate as quintuple anti-epileptic treatment for LD and had VNS pacemaker. The patient was diagnosed with epilepsy at the age of 15 years with nocturnal myoclonic epileptic attacks. Axillary sweat gland biopsy was performed with pre-diagnosis of LD and result was negative. Two years after first epileptic attack, patient’s school achievement declined. Sweat gland biopsy was repeated and pathognomonic Lafora inclusion bodies were observed. Genetic analysis revealed EPM2A and EPM2B gene mutation in 6th chromosome. There was no family history. The attacks couldn’t be controlled with midazolam and were partially suppressed with propofol. However, epileptic attacks persisted in situations such as fever and bright light. Patient was followed up in isolation room with dim light to minimize environmental stimuli. In addition to anti-epileptic treatments, the epileptic attacks were well controlled after pacemaker recalibration and voltage was increased from 1.25 mA to 1.75 mA. Discussion: VNS is surgical treatment alternative for refractory epilepsy and allows treatment revision according to progression of disease with voltage and frequency regulation. VNS aims to produce an anti-epileptic effect as a result of activation of amygdala and thalamocortical pathways by intermittent stimulation of left vagal nerve with pulse width of 130- 500 microseconds, 30 Hz and 0.25-3.5 mA. Considering that VNS may be useful in treatment of refractory status epilepticus and more effective management may be achieved by modifying voltage, pulse width and frequency after administration to patient. [ABSTRACT FROM AUTHOR]