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Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a−/− mice by examining knockout (KO; Epm2a−/−) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a−/− mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models. [ABSTRACT FROM AUTHOR]

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions. [ABSTRACT FROM AUTHOR]

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.

Mammalian glycogen chain lengths are subject to complex regulation, including by seven proteins (protein phosphatase‐1 regulatory subunit 3, PPP1R3A through PPP1R3G) that target protein phosphatase‐1 (PP1) to glycogen to activate the glycogen chain‐elongating enzyme glycogen synthase and inactivate the chain‐shortening glycogen phosphorylase. Lafora disease is a fatal neurodegenerative epilepsy caused by aggregates of long‐chained, and as a result insoluble, glycogen, termed Lafora bodies (LBs). We previously eliminated PPP1R3C from a Lafora disease mouse model and studied the effect on LB formation. In the present work, we eliminate and study the effect of absent PPP1R3D. In the interim, brain cell type levels of all PPP1R3 genes have been published, and brain cell type localization of LBs clarified. Integrating these data we find that PPP1R3C is the major isoform in most tissues including brain. In the brain, PPP1R3C is expressed at 15‐fold higher levels than PPP1R3D in astrocytes, the cell type where most LBs form. PPP1R3C deficiency eliminates ~90% of brain LBs. PPP1R3D is quantitatively a minor isoform, but possesses unique MAPK, CaMK2 and 14‐3‐3 binding domains and appears to have an important functional niche in murine neurons and cardiomyocytes. In neurons, it is expressed equally to PPP1R3C, and its deficiency eliminates ~50% of neuronal LBs. In heart, it is expressed at 25% of PPP1R3C where its deficiency eliminates ~90% of LBs. This work studies the role of a second (PPP1R3D) of seven PP1 subunits that regulate the structure of glycogen, toward better understanding of brain glycogen metabolism generally, and in Lafora disease. [ABSTRACT FROM AUTHOR]

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At the beginning of the 20th century, in view of the growing international recognition of Santiago Ramón y Cajal, the Spanish authorities took some important steps to support Cajal’s scientific work. This recognition peaked in 1906, when Camillo Golgi and Santiago Ramón y Cajal shared the Nobel Prize in Physiology or Medicine. The Spanish government provided Cajal a state-of-the-art laboratory in Madrid to allow him to continue with his research and they funded salaries to pay his first tenured collaborators, the number of which increased further after the creation of the Junta para Ampliación de Estudios (JAE). The JAE was an organism set up to help promising researchers develop their careers in different ways, thereby contributing to the development of science in Spain. Although largely forgotten or relatively unknown, there has been a recent revival in the recognition of the school that developed around Cajal, collectively referred to as the Spanish Neurological School (or colloquially, as the Cajal School or School of Madrid). Almost all Cajal’s collaborators were men, although a limited number of female scientists spent part of their careers at the heart of the Cajal School. Here we discuss these women and their work in the laboratory in Madrid. We have tracked the careers of Laura Forster (from Australia/United Kingdom), Manuela Serra, María Soledad Ruiz-Capillas and María Luisa Herreros (all Spanish), through their scientific publications, both in the journal founded by Cajal and elsewhere, and from other documentary sources. To complete the picture, we also outline the careers of other secondary figures that contributed to the production and running of Cajal’s laboratory in Madrid. We show here that the dawn of Spanish neuroscience included a number of contributions from female researchers who to date, have received little recognition.

An abnormal structural form of glycogen (with less branching points or amylopectin-like polysaccharide) called polyglucosan (PG) may accumulate in various tissues such as striated and smooth muscles, brain, nerve, liver and skin, and cause a group of nine different genetic disorders manifesting with a variety of clinical phenotypes that affect mainly the nervous system (Lafora disease, adult PG body disease), the heart (glycogen storage disease type XV, hypertrophic cardiomyopathy type 6, PG body myopathy type 1) and the skeletal muscle (glycogen storage disease type IV, glycogen storage disease type VII, PG body myopathy type 2), depending on the organs which are mostly affected by the PG aggregates. The pathological feature of PG storage in tissues is a hallmark of these disorders. Whole-genome sequencing has allowed to obtain a diagnosis in a large number of patients with a previously unrecognized disorder. We describe the clinical, pathological and molecular features of these genetic disorders, for many of which the pathological mechanisms underlying the corresponding mutant gene have been investigated and, at least in part, understood. [ABSTRACT FROM AUTHOR]

At the beginning of the 20th century, in view of the growing international recognition of Santiago Ramón y Cajal, the Spanish authorities took some important steps to support Cajal's scientific work. This recognition peaked in 1906, when Camillo Golgi and Santiago Ramón y Cajal shared the Nobel Prize in Physiology or Medicine. The Spanish government provided Cajal a state-of-the-art laboratory in Madrid to allow him to continue with his research and they funded salaries to pay his first tenured collaborators, the number of which increased further after the creation of the Junta para Ampliación de Estudios (JAE). The JAE was an organism set up to help promising researchers develop their careers in different ways, thereby contributing to the development of science in Spain. Although largely forgotten or relatively unknown, there has been a recent revival in the recognition of the school that developed around Cajal, collectively referred to as the Spanish Neurological School (or colloquially, as the Cajal School or School of Madrid). Almost all Cajal's collaborators were men, although a limited number of female scientists spent part of their careers at the heart of the Cajal School. Here we discuss these women and their work in the laboratory in Madrid. We have tracked the careers of Laura Forster (from Australia/United Kingdom), Manuela Serra, María Soledad Ruiz-Capillas and María Luisa Herreros (all Spanish), through their scientific publications, both in the journal founded by Cajal and elsewhere, and from other documentary sources. To complete the picture, we also outline the careers of other secondary figures that contributed to the production and running of Cajal's laboratory in Madrid. We show here that the dawn of Spanish neuroscience included a number of contributions from female researchers who to date, have received little recognition. [ABSTRACT FROM AUTHOR]

Introduction: Lafora disease is a rare and severe form of progressive myoclonus epilepsy. It is an autosomal recessive disease, genetically heterogeneous. Aim: Our aims is to study the clinic-pathological features of this rare entitie We report a case of Lafora disease. Case Report: We report the case of a 16 year old girl, which shows from the age of 14 myoclonus epilepsy. Neurological examination showed cerebellar syndrome and intellectual deterioration. Skin biopsy was needed to guide the diagnosis. The Lafora disease has a constantly fatal prognosis. Histological examination confirms the diagnosis and molecular study may help to establish a genetic counseling. Conclusion: Lafora disease has significant clinical and evolutionary characteristics that should guide the clinician to achieve axillary skin biopsy to find Lafora bodies.

The history of the progressive myoclonus epilepsies (PMEs) spans more than a century. However, the recent history of PMEs begins with a consensus statement published in the wake of the Marseille PME workshop in 1989 (Marseille Consensus Group, ). This consensus helped define the various types of PME known at the time and set the agenda for a new era of genetic research which soon lead to the discovery of many PME genes. Prior to the Marseille meeting, and before the molecular era, there had been much confusion and controversy. Because investigators had but limited and biased experience with these rare disorders due to the uneven, skewed distribution of PMEs around the world, opinions and nosologies were based on local expertise which did not match well with the experiences of other researchers and clinicians. The three major areas of focus included: (1) the nature and limits of the concept of PME in varying scopes, which was greatly debated; (2) the description of discrete clinical entities by clinicians; and (3) the description of markers (pathological, biological, neurophysiological, etc.) which could lead to a precise diagnosis of a given PME type, with, in the best cases, a reliable correlation with clinical findings. In this article, we shall also examine the breakthroughs achieved in the wake of the 1989 Marseille meeting and recent history in the field, following the identification of several PME genes. As in other domains, the molecular and genetic approach has challenged some established concepts and has led to the description of new PME types. However, as may already be noted, this approach has also confirmed the existence of the major, established types of PME, which can now be considered as true diseases. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy due to mutations in the EPM2A (laforin) and EPM2B (malin) genes, with no substantial genotype-phenotype differences between the two. Founder effects and recurrent mutations are common, and mostly isolated to specific ethnic groups and/or geographical locations. Pathologically, LD is characterized by distinctive polyglucosans, which are formations of abnormal glycogen. Polyglucosans, or Lafora bodies (LB) are typically found in the brain, periportal hepatocytes of the liver, skeletal and cardiac myocytes, and in the eccrine duct and apocrine myoepithelial cells of sweat glands. Mouse models of the disease and other naturally occurring animal models have similar pathology and phenotype. Hypotheses of LB formation remain controversial, with compelling evidence and caveats for each hypothesis. However, it is clear that the laforin and malin functions regulating glycogen structure are key. With the exception of a few missense mutations LD is clinically homogeneous, with onset in adolescence. Symptoms begin with seizures, and neurological decline follows soon after. The disease course is progressive and fatal, with death occurring within 10 years of onset. Antiepileptic drugs are mostly non-effective, with none having a major influence on the progression of cognitive and behavioral symptoms. Diagnosis and genetic counseling are important aspects of LD, and social support is essential in disease management. Future therapeutics for LD will revolve around the pathogenesics of the disease. Currently, efforts at identifying compounds or approaches to reduce brain glycogen synthesis appear to be highly promising. [ABSTRACT FROM AUTHOR]

The storage polymer glycogen normally contains small amounts of covalently attached phosphate as phosphomonoesters at C2, C3 and C6 atoms of glucose residues. In the absence of the laforin phosphatase, as in the rare childhood epilepsy Lafora disease, the phosphorylation level is elevated and is associated with abnormal glycogen structure that contributes to the pathology. Laforin therefore likely functions in vivo as a glycogen phosphatase. The mechanism of glycogen phosphorylation is less well-understood. We have reported that glycogen synthase incorporates phosphate into glycogen via a rare side reaction in which glucose-phosphate rather than glucose is transferred to a growing polyglucose chain (Tagliabracci et al. (2011) Cell Metab 13 , 274–282). We proposed a mechanism to account for phosphorylation at C2 and possibly at C3. Our results have since been challenged (Nitschke et al. (2013) Cell Metab 17 , 756–767). Here we extend the evidence supporting our conclusion, validating the assay used for the detection of glycogen phosphorylation, measurement of the transfer of 32 P from [β- 32 P]UDP-glucose to glycogen by glycogen synthase. The 32 P associated with the glycogen fraction was stable to ethanol precipitation, SDS-PAGE and gel filtration on Sephadex G50. The 32 P-signal was not affected by inclusion of excess unlabeled UDP before analysis or by treatment with a UDPase, arguing against the signal being due to contaminating [β- 32 P]UDP generated in the reaction. Furthermore, [ 32 P]UDP did not bind non-covalently to glycogen. The 32 P associated with glycogen was released by laforin treatment, suggesting that it was present as a phosphomonoester. The conclusion is that glycogen synthase can mediate the introduction of phosphate into glycogen, thereby providing a possible mechanism for C2, and perhaps C3, phosphorylation. [ABSTRACT FROM AUTHOR]

The transition of adolescents with refractory epilepsy to the care of adult neurologists can be challenging. For those patients with epilepsy due to mitochondrial disorders, Lafora disease, Unverricht- Lundborg disease, and GLUT1 deficiency syndrome, a successful transition can be even more problematic for both caregivers and neurologists. Many of these patients require dietary treatments (ketogenic and modified Atkins diets) for long-term management of their epilepsy. For these patients, coordinating transfer of their dietary management is necessary. [ABSTRACT FROM AUTHOR]

La maladie de Lafora (ML) represente une forme rare et grave d�epilepsie myoclonique progressive. C�est une affection a transmission autosomique recessive, heterogene sur le plan genetique. Nous rapportons le cas d�une adolescente de 16 ans, issue de parents consanguins de premier degre, qui presente depuis l�age de 14 ans des crises d�epilepsie et des myoclonies. L'examen neurologique a montre un syndrome cerebelleux et une deterioration intellectuelle. La biopsie cutanee etait indispensable pour orienter le diagnostic. La ML a un pronostic constamment fatal. L�etude histologique confirme le diagnostic et l�etude moleculaire peut aider a etablir un conseil genetique.

The objective of this study is to determine the long-term outcome of children with intractable epilepsy who have diffuse cortical hypometabolism on 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (FDG-PET) scans. Seventeen children with intractable epilepsy showing bilateral, diffuse cortical hypometabolism on FDG-PET were followed up through telephone interview from 1 year 4 months to 11 years 4 months (mean: 5 years 7 months ± 2 years 1 month) after their PET scans. One child succumbed to Sanfilippo disease at age 20 years. Only 2 children were seizure free. Fifty percent had walking difficulties, 56.25% were not toilet trained, all had speech difficulties, 43.75% had behavioral problems, 37.5% had poor eye contact, 75% had socialization difficulties, and 87.5% attended special schools. Three children were found to have genetic causes, including a 4-MB deletion of the mitochondrial genome, MECP2 duplication, and Lafora disease. In conclusion, the long-term outcome in this patient population is poor, and they tend to suffer from genetic/neurodegenerative diseases. [ABSTRACT FROM PUBLISHER]

La maladie de Lafora (ML) représente une forme rare et grave d'épilepsie myoclonique progressive. C'est une affection à transmission autosomique récessive, hétérogène sur le plan génétique. Nous rapportons le cas d'une adolescente de 16 ans, issue de parents consanguins de premier degré, qui présente depuis l'âge de 14 ans des crises d'épilepsie et des myoclonies. L'examen neurologique a montré un syndrome cérébelleux et une détérioration intellectuelle. La biopsie cutanée était indispensable pour orienter le diagnostic. La ML a un pronostic constamment fatal. L'étude histologique confirme le diagnostic et l'étude moléculaire peut aider à établir un conseil génétique. [ABSTRACT FROM AUTHOR]

The progressive myoclonic epilepsies (PME) are a rare group of inherited neurodegenerative diseases with debilitating evolution, resistance to treatment and poor prognosis. However, advances in molecular genetics have enabled better understanding of the pathogenesis of these diseases, bringing hope for improved treatment options in the future. This manuscript is an overview of the clinical and molecular findings in patients with PME. Furthermore, it describes therapeutic approaches that are currently recommended in the literature. [ABSTRACT FROM AUTHOR]

Introduction: Lafora disease is a rare and severe form of progressive myoclonus epilepsy. It is an autosomal recessive disease, genetically heterogeneous. Aim: Our aims is to study the clinic-pathological features of this rare entitie We report a case of Lafora disease. Case Report: We report the case of a 16 year old girl, which shows from the age of 14 myoclonus epilepsy. Neurological examination showed cerebellar syndrome and intellectual deterioration. Skin biopsy was needed to guide the diagnosis. The Lafora disease has a constantly fatal prognosis. Histological examination confirms the diagnosis and molecular study may help to establish a genetic counseling. Conclusion: Lafora disease has significant clinical and evolutionary characteristics that should guide the clinician to achieve axillary skin biopsy to find Lafora bodies. [ABSTRACT FROM AUTHOR]

Autosomal recessively inherited progressive myoclonus epilepsies (PMEs) include Lafora disease, Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, type I sialidosis (cherry-red spot myoclonus), action myoclonus–renal failure syndrome, and type III Gaucher disease. Almost all the autosomal recessively inherited PMEs are lysosomal diseases, with the exception of Lafora disease in which neither the accumulating material nor the gene products are in lysosomes. Progress in identifying the causative defects of PME is near-complete. Much work lies ahead to resolve the pathobiology and neurophysiology of this group of devastating disorders. [ABSTRACT FROM AUTHOR]

Glycogen, a branched polymer of glucose, serves as an energy reserve in many organisms. The degree of branching likely reflects the balance between the activities of glycogen synthase and branching enzyme. Mice overexpressing constitutively active glycogen synthase in skeletal muscle (GSL30) have elevated muscle glycogen. To test whether excess glycogen synthase activity affected glycogen branching, we examined the glycogen from skeletal muscle of GSL30 mice. The absorption spectrum of muscle glycogen determined in the presence of iodine was shifted to higher wavelengths in the GSL30 animals, consistent with a decrease in the degree of branching. As judged by Western blotting, the levels of glycogenin and the branching enzyme were also elevated. Branching enzyme activity also increased approximately threefold. However, this compared with an increase in glycogen synthase of some 50-fold, so that the increase in branching enzyme in response to overexpression of glycogen synthase was insufficient to synthesize normally branched glycogen. [Copyright &y& Elsevier]

We have identified an interacting partner protein (encoded by the human EPM2AIP1 gene (approved symbol)) for laforin, the product of the EPM2A gene, which is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The EPM2AIP1 gene was identified in a screen for laforin-interacting proteins with a human brain cDNA library using the yeast two-hybrid system. The specificity of the interaction was confirmed by coimmunoprecipitation of in vivo-transfected protein and by using EPM2A deletion constructs. Subcellular colocalization of laforin and EPM2AIP1 protein was also demonstrated. The human EPM2AIP1 gene, corresponding to the KIAA0766 cDNA clone in the databases, was characterized and shown, like EPM2A, to be ubiquitously expressed. The gene, which comprises one large exon 1824 nucleotides in length and has alternative 3′ untranslated regions, maps to human chromosome 3p22.1. The function is currently not known and extensive analyses do not reveal any homology to other proteins or any obvious structural motifs. Because genetic heterogeneity in Lafora disease has been described, mutational analysis of the EPM2AIP1 gene was performed on non-EPM2A patients, but no mutations were found. The identification of this first binding partner for laforin promises to be an important step toward unraveling the underlying pathogenesis of this severest form of teenage-onset epilepsy. [Copyright &y& Elsevier]

Lafora body disease is one cause of progressive myoclonus epilepsy. It typically presents in the second decade with generalized seizures, myoclonus and then intellectual decline. Death is usual within 10 years. Diagnosis may be made by biopsy of skin, muscle, liver or brain. We present four siblings who were normal until their mid-twenties, but then developed intellectual decline, followed by myoclonus. Although a rare form of Lafora body disease has been described that follows a more benign course, may be of later onset, and whose pathology is subtly different, this family is so far unique in terms of the late presentation of otherwise typical Lafora body disease. [ABSTRACT FROM AUTHOR]

An abnormal structural form of glycogen (with less branching points or amylopectin-like polysaccharide) called polyglucosan (PG) may accumulate in various tissues such as striated and smooth muscles, brain, nerve, liver and skin, and cause a group of nine different genetic disorders manifesting with a variety of clinical phenotypes that affect mainly the nervous system (Lafora disease, adult PG body disease), the heart (glycogen storage disease type XV, hypertrophic cardiomyopathy type 6, PG body myopathy type 1) and the skeletal muscle (glycogen storage disease type IV, glycogen storage disease type VII, PG body myopathy type 2), depending on the organs which are mostly affected by the PG aggregates. The pathological feature of PG storage in tissues is a hallmark of these disorders. Whole-genome sequencing has allowed to obtain a diagnosis in a large number of patients with a previously unrecognized disorder. We describe the clinical, pathological and molecular features of these genetic disorders, for many of which the pathological mechanisms underlying the corresponding mutant gene have been investigated and, at least in part, understood.

The progressive myoclonus epilepsies (PME) are neurodegenerative diseases with prominent myoclonus and epilepsy. They are mostly, though not exclusively, diseases of children, and are mostly, though not exclusively, fatal. This review includes only those PME where more than one family has been described. The largest group of PME is the neuronal ceroid lipofuscinoses (NCL). The genetics of the NCL is representative of the larger group. Most, but not all, are monogenic, autosomal recessive inherited diseases, and most diseases genes, but not all, encode lysosomal proteins. One of the major questions in PME is "why PME"? That is, why do these neurodegenerative diseases result in so much epileptogenesis? Perhaps, the answers to "why epilepsy?" underlying this entire volume on genetics of epilepsy, will be aided by this group of the severest of epilepsies, where most, probably almost all, genes are already known. As therapies go, while not much is available yet, most of the PME start from a point of initial normalcy, and have a period of minimal symptoms close to onset, and most are relatively simple metabolic diseases. Hence, among the intractable epilepsies, hope for treatments and cures is likely the strongest in this group of diseases., (© 2014 Elsevier B.V. All rights reserved.)

Aim: The aim of this report is to provide initial evidence that add-on treatment with perampanel might be highly effective in progressive myoclonic epilepsy such as Lafora disease., Case Report: We report on a 21-year-old woman suffering from persistent myoclonus and generalized tonic-clonic seizures for more than seven years. Additionally, ataxia, a disturbance in speech and gait, as well as a cognitive decline were rapidly progressing. Subsequently, the diagnosis of Lafora disease was confirmed by the identification of a novel homozygous missense mutation in exon 3 of the EPM2A gene (c.538C>G; p.L180V). Adjunctive therapy with perampanel was started in this patient with advanced Lafora disease and was titrated up to 8 mg/day. A sustained and reproducible remission of myoclonus and GTCS could be achieved for a follow-up of three months. After dosage reduction to 6 mg/day, seizures recurred; however, on increasing the daily dose to 10 mg, seizures stopped for another three months. The patient also regained her ability to walk with help and the aid of a walker., Conclusions: Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptors and recently licensed as adjunctive therapy for the treatment of refractory focal onset seizures. There is evidence for its effectiveness in generalized epilepsies, and phase III studies for this indication are on the way. Our case illustrates the possibility that perampanel might be a valuable option for treatment in PME. Considering its impressive efficacy in this case, we suggest a prospective, multicenter study evaluating perampanel in PME.