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Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimethyl fumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethyl fumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests. [ABSTRACT FROM AUTHOR]

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]

Background and Purpose: Lafora disease (LD) is a very rare autosomal recessive disorder manifesting primarily as fatal, congenital, and neurodegenerative epilepsies. We aimed to describe the MRI characteristics due to gene mutations in a Chinese pedigree with LD. Methods: Whole‐exome sequencing, muscle biopsy, pedigree analysis, and MRI analysis were conducted. Five family members (two of whom were affected by LD) were whole‐genome sequenced. Longitudinal changes in brain MRI volumes were analyzed by Freesurfer. Results: We identified a new intron heterozygous mutation in the EMP2A gene c.71 (exon 1) G>A in a Chinese LD pedigree that was characterized by refractory seizures, progressive vision impairment, and declines in motor and cognitive functions. The patient suffered generalized tonic–clonic seizures since the age of 15 years and had severe forms of progressive myoclonic seizure. She eventually died after being admitted to the intensive care unit due to status epilepticus at the age of 24 years. Period acid Schiff staining showed positive polyglucosan particles in muscle biopsy specimens. Regions of atrophy in the whole brain, and especially in the hippocampus, were detected. Conclusions: We identified a new heterozygous mutation (c.71+1G>A) in a Chinese LD pedigree, which broadens the mutation spectrum of LD genes. We found that the patient exhibited brain volumetric atrophy along with rapidly worsening symptoms. These results contribute to our understanding of LD. [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]

Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease. [ABSTRACT FROM AUTHOR]

Abstract Background and Purpose Lafora disease (LD) is a very rare autosomal recessive disorder manifesting primarily as fatal, congenital, and neurodegenerative epilepsies. We aimed to describe the MRI characteristics due to gene mutations in a Chinese pedigree with LD. Methods Whole‐exome sequencing, muscle biopsy, pedigree analysis, and MRI analysis were conducted. Five family members (two of whom were affected by LD) were whole‐genome sequenced. Longitudinal changes in brain MRI volumes were analyzed by Freesurfer. Results We identified a new intron heterozygous mutation in the EMP2A gene c.71 (exon 1) G>A in a Chinese LD pedigree that was characterized by refractory seizures, progressive vision impairment, and declines in motor and cognitive functions. The patient suffered generalized tonic–clonic seizures since the age of 15 years and had severe forms of progressive myoclonic seizure. She eventually died after being admitted to the intensive care unit due to status epilepticus at the age of 24 years. Period acid Schiff staining showed positive polyglucosan particles in muscle biopsy specimens. Regions of atrophy in the whole brain, and especially in the hippocampus, were detected. Conclusions We identified a new heterozygous mutation (c.71+1G>A) in a Chinese LD pedigree, which broadens the mutation spectrum of LD genes. We found that the patient exhibited brain volumetric atrophy along with rapidly worsening symptoms. These results contribute to our understanding of LD.

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 (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of LD. However, despite the efforts made by different groups, the question of why PGBs accumulate in the brain is still unanswered. We have recently demonstrated that, in vivo, astrocytes accumulate most of the PGBs present in the brain, and this could lead to astrocyte dysfunction. To develop a deeper understanding of the defects present in LD astrocytes that lead to LD pathophysiology, we obtained pure primary cultures of astrocytes from LD mice from the postnatal stage under conditions that accumulate PGBs, the hallmark of LD. These cells serve as novel in vitro models for studying PGBs accumulation and related LD dysfunctions. In this sense, the metabolomics of LD astrocytes indicate that they accumulate metabolic intermediates of the upper part of the glycolytic pathway, probably as a consequence of enhanced glucose uptake. In addition, we also demonstrate the feasibility of using the model in the identification of different compounds that may reduce the accumulation of polyglucosan inclusions. [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. [ABSTRACT FROM AUTHOR]

PurposeTo evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD).MethodsWe investigated the electro-clinical longitudinal data and CSF Aβ42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families.ResultsThree 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 Aβ42, 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.ConclusionsThree electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the efficacy 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.

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 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.

Laforin and Malin are two proteins that are encoded by the genes EPM2A and EPM2B, respectively. Laforin is a glucan phosphatase and Malin is an E3-ubiquitin ligase, and these two proteins function as a complex. Mutations occurring at the level of one of the two genes lead to the accumulation of an aberrant form of glycogen meant to cluster in polyglucosans that go under the name of Lafora bodies. Individuals affected by the appearance of these polyglucosans, especially at the cerebral level, experience progressive neurodegeneration and several episodes of epilepsy leading to the manifestation of a fatal form of a rare disease called Lafora disease (LD), for which, to date, no treatment is available. Despite the different dysfunctions described for this disease, many molecular aspects still demand elucidation. An effective way to unknot some of the nodes that prevent the achievement of better knowledge of LD is to focus on the substrates that are ubiquitinated by the E3-ubiquitin ligase Malin. Some substrates have already been provided by previous studies based on protein-protein interaction techniques and have been associated with some alterations that mark the disease. In this work, we have used an unbiased alternative approach based on the activity of Malin as an E3-ubiquitin ligase. We report the discovery of novel bonafide substrates of Malin and have characterized one of them more deeply, namely PIP3-dependent Rac exchanger 1 (P-Rex1). The analysis conducted upon this substrate sets the genesis of the delineation of a molecular pathway that leads to altered glucose uptake, which could be one of the origin of the accumulation of the polyglucosans present in the disease.

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]

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Lafora disease is a rare genetic disease caused by the accumulation of malformed glycogen products in the tissues. The disease usually manifests with idiopathic generalized tonic colonic seizures with poor response to antiepileptic drugs (AEDs). We report the case of a 19-year-old girl with the chief complaint of generalized refractory seizures, jerky movement, and cognitive deterioration with a positive history of epilepsy in her younger brother. The disease onset was at the age of 16 with jerky movement and blurred vision. She was admitted to our ward to have a long-term video EEG monitoring for further evaluation. Clinical presentation accompanied with abnormal EEG characteristics for Lafora disease, and the positive familial history were highly suggestive of Lafora disease. The disease was confirmed with genetic testing by which the mutation of EPM2A was detected.

Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy (prevalence

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]

Purpose: The aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD). Methods: We investigated the electro-clinical data andmedical complications of three LD patients withmutations in EPM2A and two in NHLRC1 genes during the LD late stage. Results: The late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic-clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations. Conclusion: Status epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications. [ABSTRACT FROM AUTHOR]

Lafora disease is a rare inherited neurodegenerative disease with onset in adolescence. Patients present with progressive myoclonic seizures and cognitive decline. The disease is linked to mutations in either of the two genes encoding malin and laforin, and it is associated with the accumulation of polyglucosan inclusions (Lafora bodies [LBs]) in various tissues, such as brain, liver, muscle, and skin, with the skin being particularly accessible for biopsy. Histopathologic examination of affected tissue with demonstration of LBs, together with the presence of pathologic mutation in EPM2A or NHLRC1 genes, is sufficient for diagnosis of this neurologic disorder when clinically suspected. Here, we report the case of a 16‐year‐old female with progressive neurologic symptoms and homozygous mutation in the NHLRC1 gene encoding malin. The skin biopsy was instrumental in reaching the final diagnosis by showing LBs in sweat glands by histopathologic and electron microscopic examination. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is a fatal rare neurodegenerative disorder that affects young adolescents and has no treatment yet. The hallmark of LD is the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), in the brain and peripheral tissues. LD is caused by mutations in either EPM2A or EPM2B genes, which, respectively, encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, with identical clinical features. LD knockout mouse models (Epm2a − / − and Epm2b − / −) recapitulate PG body accumulation, as in the human pathology, and display alterations in glutamatergic transmission and neuroinflammatory pathways in the brain. In this work, we show the results of four pre-clinical trials based on the modulation of glutamatergic transmission (riluzole and memantine) and anti-neuroinflammatory interventions (resveratrol and minocycline) as therapeutical strategies in an Epm2b − / − mouse model. Drugs were administered in mice from 3 to 5 months of age, corresponding to early stage of the disease, and we evaluated the beneficial effect of the drugs by in vivo behavioral phenotyping and ex vivo histopathological brain analyses. The behavioral assessment was based on a battery of anxiety, cognitive, and neurodegenerative tests and the histopathological analyses included a panel of markers regarding PG accumulation, astrogliosis, and microgliosis. Overall, the outcome of ameliorating the excessive glutamatergic neurotransmission present in Epm2b − / − mice by memantine displayed therapeutic effectiveness at the behavioral levels. Modulation of neuroinflammation by resveratrol and minocycline also showed beneficial effects at the behavioral level. Therefore, our study suggests that both therapeutical strategies could be beneficial for the treatment of LD patients. A mouse model of Lafora disease (Epm2b-/-) was used to check the putative beneficial effect of different drugs aimed to ameliorate the alterations in glutamatergic transmission and/or neuroinflammation present in the model. Drugs in blue gave a more positive outcome than the rest. [ABSTRACT FROM AUTHOR]

Polyglucosan bodies are accumulations of insoluble glucose polymers and proteins that form intracytoplasmic inclusions in the brain, large numbers of which can be indicative of neurodegenerative diseases such as Lafora disease. Montserrat orioles ( Icterus oberi ) are an icterid passerine endemic to Montserrat with conservation populations maintained in captivity abroad. We demonstrate that polyglucosan bodies are unusually abundant in the cerebellar molecular and Purkinje cell layers and cerebellar peduncles of captive-bred and wild-caught Montserrat orioles. The bodies are periodic acid-Schiff positive and diastase resistant and label with concanavalin A and for ubiquitin, consistent with those seen in humans. We found no association of the polyglucosan bodies with concurrent neurological lesions or clinical signs, nor with EPM2 A and EPM2B gene mutations associated with Lafora disease. We conclude that an abundance of cerebellar polyglucosan bodies may be a normal finding in aged Montserrat orioles and not a threat to the captive breeding population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

PurposeThe aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD).MethodsWe investigated the electro-clinical data and medical complications of three LD patients with mutations in EPM2A and two in NHLRC1 genes during the LD late stage.ResultsThe late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic–clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations.ConclusionStatus epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications.

Background: Lafora disease (LD) is a neurodegenerative disorder featuring action and stimulus-sensitive myoclonus, epilepsy, and cognitive deterioration. Mutations in the EPM2A/EPM2B genes classically prove causative for the disease in most cases. Since full-field electroretinogram (ffERG) may reveal early-stage changes in a wide spectrum of diseases, we aimed to evaluate retinal cones and rods dysfunction in a cohort of Italian LD patients. Methods: Patients with genetically confirmed LD were recruited and subjected to ffERG analysis following the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol. Results: Six patients aged between 13 and 26 years (mean 19.5 years) were included. The mean age at disease onset was 12.5 years with a mean disease duration of 7 years. The ffERG analysis revealed a global mild to severe generalized cones dysfunction in all patients. Linear correlation was identified between disease stage and the degree of cones and rods dysfunction, as well as between the type of mutation and the cones and rods dysfunction. Conclusions: This study brings further evidence of early retinal alterations in LD patients. The cones and rods dysfunction grade is related to disease duration. The ffERG is an important tool to determine the disease stage, allowing to evaluate either natural or treatment-related disease progression in a minimally invasive way. [ABSTRACT FROM AUTHOR]

Simple Summary: Reports of behavioral signs, such as blindness and circling in free-ranging moose from different parts of the world, have spurred comprehensive pathological investigation to find the causes of the disease that have clinical relevance. In this case study, brains collected from two adult free-ranging moose (Alces alces) cows that were seemingly blind and found walking in circles were examined by light and electron microscopy with further ancillary testing. Here, we report for the first time Lafora disease and alpha-synucleinopathy in two wild free-ranging moose cows who presented with abnormal behavior and blindness, with similar neuronal polyglucosan body (PGB) accumulations identified in humans and other animals. Microscopic analysis of the hippocampus of brain revealed inclusion bodies resembling PGBs (Lafora disease) in the neurons with ultrastructural findings of aggregates of branching filaments, consistent with polyglucosan bodies. Furthermore, α-synuclein immunopositivity was noted in the hippocampus, with accumulations of small granules ultrastructurally distinct from PGBs and morphologically compatible with alpha-synucleinopathy (Lewy body). The apparent blindness found in these moose could be related to an injury associated with secondary bacterial invasion; however, an accumulation of neurotoxicants (PGBs and α-synucleins) in retinal ganglion cells could also be the cause. Lafora disease and alpha-synucleinopathy were considered in the differential diagnosis of the young adult moose who presented with signs of blindness and behavioral signs such as circling. Lafora disease is an autosomal recessive glycogen-storage disorder resulting from an accumulation of toxic polyglucosan bodies (PGBs) in the central nervous system, which causes behavioral and neurologic symptoms in humans and other animals. In this case study, brains collected from two young adult free-ranging moose (Alces alces) cows that were seemingly blind and found walking in circles were examined by light and electron microscopy. Microscopic analysis of the hippocampus of the brain revealed inclusion bodies resembling PGBs in the neuronal perikaryon, neuronal processes, and neuropil. These round inclusions measuring up to 30 microns in diameter were predominantly confined to the hippocampus region of the brain in both animals. The inclusions tested α-synuclein-negative by immunohistochemistry, α-synuclein-positive with PAS, GMS, and Bielschowsky's staining; and diastase-resistant with central basophilic cores and faintly radiating peripheral lines. Ultrastructural examination of the affected areas of the hippocampus showed non-membrane-bound aggregates of asymmetrically branching filaments that bifurcated regularly, consistent with PGBs in both animals. Additionally, α-synuclein immunopositivity was noted in the different regions of the hippocampus with accumulations of small granules ultrastructurally distinct from PGBs and morphologically compatible with alpha-synucleinopathy (Lewy body). The apparent blindness found in these moose could be related to an injury associated with secondary bacterial invasion; however, an accumulation of neurotoxicants (PGBs and α-synuclein) in retinal ganglions cells could also be the cause. This is the first report demonstrating Lafora disease with concurrent alpha-synucleinopathy (Lewy body neuropathy) in a non-domesticated animal. [ABSTRACT FROM AUTHOR]

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a−/− zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities. [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]

Glycogen is a glucose polymer that plays a crucial role in glucose homeostasis by functioning as a short-term energy storage reservoir in animals and bacteria. Abnormalities in its metabolism and structure can cause several problems, including diabetes, glycogen storage diseases (GSDs) and muscular disorders. Defects in the enzymes involved in glycogen synthesis or breakdown, resulting in either excessive accumulation or insufficient availability of glycogen in cells seem to account for the most common pathogenesis. This review discusses glycogen metabolism and structure, including molecular architecture, branching dynamics, and the role of associated components within the granules. The review also discusses GSD type XV and Lafora disease, illustrating the broader implications of aberrant glycogen metabolism and structure. These conditions also impart information on important regulatory mechanisms of glycogen, which hint at potential therapeutic targets. Knowledge gaps and potential future research directions are identified. [Display omitted] [ABSTRACT FROM AUTHOR]

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.

Lafora disease (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of LD. However, despite the efforts made by different groups, the question of why PGBs accumulate in the brain is still unanswered. We have recently demonstrated that, in vivo, astrocytes accumulate most of the PGBs present in the brain, and this could lead to astrocyte dysfunction. To develop a deeper understanding of the defects present in LD astrocytes that lead to LD pathophysiology, we obtained pure primary cultures of astrocytes from LD mice from the postnatal stage under conditions that accumulate PGBs, the hallmark of LD. These cells serve as novel in vitro models for studying PGBs accumulation and related LD dysfunctions. In this sense, the metabolomics of LD astrocytes indicate that they accumulate metabolic intermediates of the upper part of the glycolytic pathway, probably as a consequence of enhanced glucose uptake. In addition, we also demonstrate the feasibility of using the model in the identification of different compounds that may reduce the accumulation of polyglucosan inclusions.

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]