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Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age‐dependent manner in all mouse models of LD. In this study, we applied home‐cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin‐deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6–7 months, and ∼12 months of age, malin‐deficient mice ("KO") and wild‐type (WT) littermates underwent a standardized home‐cage behavioral assessment designed to non‐obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel‐running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age‐related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel‐running. Neuropathological examinations in subsets of the same mice revealed expected age‐dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home‐cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse. [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]

The low capacity of Malin in carrying out his duties and functions is one of the obstacles in realizing the development of nagari in West Sumatra. The purpose of this research are to (1) describe and analyze the factual model of Malin's training in the nagari community, (2) design and develop the Malin training conceptual model, (3) determine the validity of the Malin training conceptual model, (4) test the effectiveness of Malin's training hypothetical model, and (5) describe the supporting and inhibiting factors in the Malin training implementation in the Rambatan Subdistrict, Tanah Datar District, West Sumatra Province. Research and Development (R&D) research method by following the steps of ADDIE (Analyze, Design, Development, Implementation, Evaluate) model was adopted. Data collection techniques using interviews, documentation studies, observations and questionnaires. Data were analyzed using qualitative techniques by describing empirical data from preliminary studies. Trial activities in addition to testing the implementation of the model and the device are also to determine the feasibility of the model used, so as to produce the expected product. The model evaluation results are used to show, benefit, practicality and feasibility of the model developed so that the final training model is obtained. The results showed that the development of training models for Malin basically included: needs analysis and designing training models, the development of conceptual models of training began: planning, implementing, evaluating and reflecting the results of research. The implementation of the Malin problem-based training model shows that (good category) means that it is feasible and can improve Malin's knowledge and skills as a strong influence from the implementation of the developed training model. Based on the results of the significance test analysis, it can be concluded that Malin's problem-based training model has proven effective in increasing Malin's knowledge and skills in carrying out his duties and functions in the Nagari community.

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]

Lafora disease (LD) is an autosomal recessive myoclonus epilepsy with onset in the teenage years leading to death within a decade of onset. LD is characterized by the overaccumulation of hyperphosphorylated, poorly branched, insoluble, glycogen-like polymers called Lafora bodies. The disease is caused by mutations in either EPM2A, encoding laforin, a dual specificity phosphatase that dephosphorylates glycogen, or EMP2B, encoding malin, an E3-ubiquitin ligase. While glycogen is a widely accepted laforin substrate, substrates for malin have been difficult to identify partly due to the lack of malin antibodies able to detect malin in vivo. Here we describe a mouse model in which the malin gene is modified at the C-terminus to contain the c-myc tag sequence, making an expression of malin-myc readily detectable. Mass spectrometry analyses of immunoprecipitates using c-myc tag antibodies demonstrate that malin interacts with laforin and several glycogen-metabolizing enzymes. To investigate the role of laforin in these interactions we analyzed two additional mouse models: malin-myc/laforin knockout and malin-myc/LaforinCS, where laforin was either absent or the catalytic Cys was genomically mutated to Ser, respectively. The interaction of malin with partner proteins requires laforin but is not dependent on its catalytic activity or the presence of glycogen. Overall, the results demonstrate that laforin and malin form a complex in vivo, which stabilizes malin and enhances interaction with partner proteins to facilitate normal glycogen metabolism. They also provide insights into the development of LD and the rescue of the disease by the catalytically inactive phosphatase., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. D. H., A. A. D.-R., and P. J. R. were consultants for Maze Therapeutics. T. D. H. is also a consultant for SAJE Pharma. The other authors declare that they have no competing interest. None of the work in this article was supported by these entities., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase‐inactive laforin rescues the laforin‐deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin‐ or malin‐deficient mouse lines expressing phosphatase‐inactive laforin. We find that: (i) in laforin‐deficient mice, phosphatase‐inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin‐deficient mice, phosphatase‐inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin‐dependent fashion, and that loss of this control underlies LD.

Le tératome sacro coccygien malin est une tumeur embryonnaire congénitale rare à forte potentialité de dégénérescence maligne. Nous rapportons un cas chez un nourrisson de 20 mois, de sexe féminin. Quatrième enfant du couple dont la mère est âgée de 29 ans avec quatre grossesses, quatre parités, quatre vivants et zéro avortement. Il s'agissait d'une grossesse mal suivie, à terme, accouchement par voie basse, une PEV correcte avec un BCG positif et une marche autonome à 13 mois, chez la patiente on retrouve une tuméfaction inguinale et de la grande lèvre gauche, douloureuse, fluctueuse (A), un abdomen distendu avec une plaie suintante de 4cm/3cm de la fesse droite (A). Au cliche ASP on retrouve un abdomen distendu flasque avec surcroit d'opacité de la région péri-ombilicale et de l'hypogastre (B), l'échographie montre une volumineuse masse tissulaire sous vésicale finement calcifiée de 87*54mm (C). Une TDM thoraco abdominale réalisée, objective une masse tissulaire sacro- coccygienne de 83*59 mm, calcifiée avec une discrète lyse du pubis gauche et une formation kystique abdominale sans paroi propre (D,E), il existe également des images nodulaires de taille variable sur les poumons et le foie (F,G). Le nourrisson a été pris en charge par une équipe d'onco-pediatre.

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

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]

Résumé Introduction Le kyste trichilemmal proliférant (KTP) est une tumeur annexielle rare, d’évolution généralement bénigne, se développant principalement au cuir chevelu des femmes âgées. Seulement une cinquantaine de cas malins sont rapportés dans la littérature. Nous décrivons une nouvelle observation illustrant toute l’agressivité de cette entité rendant sa prise en charge particulièrement complexe. Observation Une patiente de 70 ans, consultait pour une augmentation de la taille d’un kyste occipital évoluant depuis 6 ans. Un scanner céphalique et une excision chirurgicale large ont confirmé le diagnostic d’un KTP malin. Quatre mois plus tard, la patiente a présenté des métastases régionales et une invasion intracérébrale. Discussion À travers notre cas et en analysant la littérature, nous discutons le cadre nosologique du KTP ainsi que ses éléments clinico-histologiques et pronostiques distinctifs. Conclusion Des études larges sont nécessaires pour mieux cerner les particularités du KTP, notamment la forme maligne, mais cela reste difficile de par sa rareté. Summary Background Proliferating trichilemmal cyst (PTC) is a rare adnexal tumor, generally benign, primarily sitting on the scalp of elderly women. About fifty cases are reported in the literature. Herein, we describe another one particularly aggressive. Observation A 70-year-old woman had been showing an increase in the size of an occipital cyst for 6 years. A cephalic scan and wide surgical excision had confirmed the diagnosis of a malignant PTC. Four months later, the tumor recurred with regional metastases and intracerebral invasion. Discussion Through our case and based on the literature analyzing, we discuss the nosology of PTC and its clinical and histological distinctive elements. Conclusion Large studies are needed to better understand the specificities of PTC, specially malignant form, but it remains difficult because of its rarity. [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]

Lafora disease ( LD) is a fatal progressive epilepsy essentially caused by loss-of-function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies ( LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase-inactive laforin rescues the laforin-deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin- or malin-deficient mouse lines expressing phosphatase-inactive laforin. We find that: (i) in laforin-deficient mice, phosphatase-inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin-deficient mice, phosphatase-inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is the inherited progressive myoclonus epilepsy caused by mutations in either EPM2A gene, encoding the protein phosphatase laforin or the NHLRC1 gene, encoding the ubiquitin ligase malin. Since malin is an ubiquitin ligase and its mutations cause LD, it is hypothesized that improper clearance of its substrates might lead to LD pathogenesis. Here, we demonstrate for the first time that neuronatin is a novel substrate of malin. Malin interacts with neuronatin and enhances its degradation through proteasome. Interestingly, neuronatin is an aggregate prone protein, forms aggresome upon inhibition of cellular proteasome function and malin recruited to those aggresomes. Neuronatin is found to stimulate the glycogen synthesis through the activation of glycogen synthase and malin prevents neuronatin-induced glycogen synthesis. Several LD-associated mutants of malin are ineffective in the degradation of neuronatin and suppression of neuronatin-induced glycogen synthesis. Finally, we demonstrate the increased levels of neuronatin in the skin biopsy sample of LD patients. Overall, our results indicate that malin negatively regulates neuronatin and its loss of function in LD results in increased accumulation of neuronatin, which might be implicated in the formation of Lafora body or other aspect of disease pathogenesis.

Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD.

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]

Covalent phosphorylation of glycogen, first described 35 years ago, was put on firm ground through the work of the Whelan laboratory in the 1990s. But glycogen phosphorylation lay fallow until interest was rekindled in the mid 2000s by the finding that it could be removed by a glycogen-binding phosphatase, laforin, and that mutations in laforin cause a fatal teenage-onset epilepsy, called Lafora disease. Glycogen phosphorylation is due to phosphomonoesters at C2, C3 and C6 of glucose residues. Phosphate is rare, ranging from 1:500 to 1:5000 phosphates/glucose depending on the glycogen source. The mechanisms of glycogen phosphorylation remain under investigation but one hypothesis to explain C2 and perhaps C3 phosphate is that it results from a rare side reaction of the normal synthetic enzyme glycogen synthase. Lafora disease is likely caused by over-accumulation of abnormal glycogen in insoluble deposits termed Lafora bodies in neurons. The abnormality in the glycogen correlates with elevated phosphorylation (at C2, C3 and C6), reduced branching, insolubility and an enhanced tendency to aggregate and become insoluble. Hyperphosphorylation of glycogen is emerging as an important feature of this deadly childhood disease [ABSTRACT FROM AUTHOR]

Lafora disease (LD, OMIM 254780 , ORPHA501) is a rare neurodegenerative form of epilepsy related to mutations in two proteins: laforin, a dual specificity phosphatase, and malin, an E3-ubiquitin ligase. Both proteins form a functional complex, where laforin recruits specific substrates to be ubiquitinated by malin. However, little is known about the mechanism driving malin–laforin mediated ubiquitination of its substrates. In this work we present evidence indicating that the malin–laforin complex interacts physically and functionally with the ubiquitin conjugating enzyme E2-N (UBE2N). This binding determines the topology of the chains that the complex is able to promote in the corresponding substrates (mainly K63-linked polyubiquitin chains). In addition, we demonstrate that the malin–laforin complex interacts with the selective autophagy adaptor sequestosome-1 (p62). Binding of p62 to the malin–laforin complex allows its recognition by LC3, a component of the autophagosomal membrane. In addition, p62 enhances the ubiquitinating activity of the malin–laforin E3-ubiquitin ligase complex. These data enrich our knowledge on the mechanism of action of the malin–laforin complex as an E3-ubiquitin ligase and reinforces the role of this complex in targeting substrates toward the autophagy pathway. [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.

Lafora disease (LD; OMIM 254780, ORPHA501) is a devastating neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in most cases, by mutations in either the EPM2A or the EPM2B gene, encoding respectively laforin, a phosphatase with dual specificity that is involved in the dephosphorylation of glycogen, and malin, an E3-ubiquitin ligase involved in the polyubiquitination of proteins related to glycogen metabolism. Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis). Regarding this last function, it has been shown that cells are more sensitive to ER stress and show defects in proteasome and autophagy activities in the absence of a functional laforin–malin complex. More recently, we have demonstrated that oxidative stress accompanies these proteostasis defects and that various LD models show an increase in reactive oxygen species and oxidative stress products together with a dysregulated antioxidant enzyme expression and activity. In this review we discuss possible connections between the multiple defects in protein homeostasis present in LD and oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Lafora disease (LD, OMIM 254780) is a fatal neurodegenerative disorder produced mainly by mutations in two genes: EPM2A, encoding the dual specificity phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. Although it is known that laforin and malin may form a functional complex, the underlying molecular mechanisms of this pathology are still far from being understood. Methods: In order to gain information about the substrates of the laforin/malin complex, we have carried out a yeast substrate-trapping screening, originally designed to identify substrates of protein tyrosine phosphatases. Results: Our results identify the two muscular isoforms of pyruvate kinase (PKM1 and PKM2) as novel interaction partners of laforin. Conclusions: We present evidence indicating that the laforin/malin complex is able to interact with and ubiquitinate both PKM1 and PKM2. This post-translational modification, although it does not affect the catalytic activity of PKM1, it impairs the nuclear localization of PKM2. [ABSTRACT FROM AUTHOR]

Lafora disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b−/−mice, we observed an increase in a modified form of peroxiredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD. [ABSTRACT FROM AUTHOR]

In Lafora disease (LD), the deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase, respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. The biochemical mechanism underlying the PB accumulation, however, remains undefined. We recently demonstrated that laforin is a phosphatase of muscle glycogen synthase (GS1) in PBs, and that laforin recruits malin, together reducing PBs. We show here that accomplishment of PB degradation requires a protein assembly consisting of at least four key enzymes: laforin and malin in a complex, and the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase (GPBB). Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan. Without fountional laforin-malin complex assembled on PBs, GPBB and AGL1 together are unable to efficiently breakdown polyglucosan. All these events take place on PBs and in cytoplasm. Deficiency of each of the four enzymes causes PB accumulation in the cytoplasm of affected cells. Demonstration of the molecular mechanisms underlying PB degradation lays a substantial biochemical foundation that may lead to understanding how PB metabolizes and why mutations of either EPM2A or NHLRC1 in humans cause LD. Mutations in AGL1 or GPBB may cause diseases related to PB accumulation. [ABSTRACT FROM AUTHOR]

Le schwannome malin est une tumeur très rare chez l'enfant (1 à 2% des tumeurs des tissus mous), elle se développe au dépend des cellules de Schwanne. Dans ce travail, les auteurs rapportent un cas de schwannome malin développé au dépend du nerf grand sciatique. La radiographie de la cuisse de face et de profil était normale. L'imagerie par résonance magnétique a identifié une lésion le long du trajet du nerf grand sciatique. La tumeur a été réséquée en totalité emportant le nerf grand sciatique. L'examen antomo-pathologique a confirmé le diagnostic.

Lafora body disease (LBD) is one of the inherited progressive myoclonus epilepsy syndromes. It is an autosomal- recessive disorder with onset in late childhood or early adolescence. The characteristic features are seizures and progressive deterioration of neurological function. Seizures which include myoclonic and occipital lobe seizures with visual hallucinations and photosensitive seizures. The course of the disease consists of worsening seizures and progressive decline in mental and other neurologic functions that result in death within a decade of its onset. Pathology reveals pathognomonic polyglucosan inclusions that are not seen in any other types of progressive myoclonus epilepsies. Electro physiologically, EEG in LBD reveals slowing of background activity with recurrent epileptiform discharges and photosensitivity. Giant somatosensory evoked potential and visual evoked potential have been documented. LBD is one of the several neurologic disorders associated with brain polyglucosan bodies. Up to 80% of patients with LBD have mutations in the EPM2A and EPM2B genes. Although common mutations are rare, simple genetic tests to identify these mutations have been established. The EPM2A and EPM2B genes codes for the protein laforin and malin, which localizes at the plasma membrane and the rough endoplasmic reticulum and functions as a dual-specificity phosphatase. The pathogenetic role of the protein is being established. [ABSTRACT FROM AUTHOR]

Abstract: Protein phosphatase type 1 (PP1) plays a major role in the regulation of glycogen biosynthesis. PP1 is recruited to sites of glycogen formation by its binding to specific targeting subunits. There, it dephosphorylates different enzymes involved in glycogen homeostasis leading to an activation of glycogen biosynthesis. Regulation of these targeting subunits is crucial, as excess of them leads to an enhancement of the action of PP1, which results in glycogen accumulation. In this work we present evidence that PPP1R3D (R6), one of the PP1 glycogenic targeting subunits, interacts physically with laforin, a glucan phosphatase involved in Lafora disease, a fatal type of progressive myoclonus epilepsy. Binding of R6 to laforin allows the ubiquitination of R6 by the E3-ubiquitin ligase malin, what targets R6 for autophagic degradation. As a result of the action of the laforin–malin complex on R6, its glycogenic activity is downregulated. Since R6 is expressed in brain, our results suggest that the laforin–malin complex downregulates the glycogenic activity of R6 present in neuron cells to prevent glycogen accumulation. [Copyright &y& Elsevier]

Disorders of glycogen metabolism are inborn errors of energy homeostasis affecting primarily skeletal muscle, heart, liver, and, less frequently, the central nervous system. These rare diseases are quite variable in age of onset, symptoms, morbidity, and mortality. This review provides an update on disorders of glycogen metabolism affecting skeletal muscle exclusively or predominantly. From a pathogenetic perspective, we classify these diseases as primary, if the defective enzyme is directly involved in glycogen/glucose metabolism, or secondary, if the genetic mutation affects proteins which indirectly regulate glycogen or glucose processing. In addition to summarizing the most recent clinical reports in this field, we briefly describe animal models of human glycogen disorders. These experimental models are greatly improving the understanding of the pathogenetic mechanisms underlying the muscle degenerative process associated to these diseases and provide in vivo platforms to test new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is a rare, fatal neurodegenerative disorder characterized by the accumulation of glycogen-like inclusions in the cytoplasm of cells from most tissues of affected patients. One hundred years after the first description of these inclusions, the molecular bases underlying the processes involved in LD physiopathology are finally being elucidated. The main cause of the disease is related to the activity of two proteins, the dual-specificity phosphatase laforin and the E3-ubiquitin ligase malin, which form a functional complex. Laforin is unique in humans, as it is composed of a carbohydrate-binding module attached to a cysteine-based catalytic dual-specificity phosphatase domain. Laforin directly dephosphorylates glycogen, but other proteinaceous substrates, if they exist, have remained elusive. Recently, an emerging set of laforin-binding partners apart from malin have been described, suggestive of laforin roles unrelated to its catalytic activity. Further investigations based on different transgenic mouse models have shown that the laforin-malin complex is also involved in other cellular processes, such as response to endoplasmic reticulum stress and misfolded protein clearance by the lysosomal pathway. However, controversial data and some missing links still make it difficult to assess the concrete relationship between glycogen deregulation and neuronal damage leading to the fatal symptoms observed in LD patients, such as myoclonic seizures and epilepsy. Consequently, clinical treatments are far from being achieved. In the present review, we focus on the knowledge of laforin biology, not only as a glucan phosphatase, but also as an adaptor protein involved in several physiological pathways. [ABSTRACT FROM AUTHOR]

Lafora disease (LD) is a fatal, autosomal recessive neurodegenerative disorder that results in progressive myoclonus epilepsy. A hallmark of LD is the accumulation of insoluble, aberrant glycogen-like structures called Lafora bodies. LD is caused by mutations in the gene encoding the E3 ubiquitin ligase malin or the glucan phosphatase laforin. Although LD was first described in 1911, its symptoms are still lacking a consistent molecular explanation and, consequently, a cure is far from being achieved. Some data suggest that malin forms a functional complex with laforin. This complex promotes the ubiquitination of proteins involved in glycogen metabolism and misregulation of pathways involved in this process results in Lafora body formation. In addition, recent results obtained from both cell culture and LD mouse models have highlighted a role of the laforin-malin complex in the regulation of endoplasmic reticulum-stress and protein clearance pathways. These results suggest that LD should be considered as a novel member of the group of protein clearance diseases such as Parkinson's, Huntington's, or Alzheimer's, in addition to being a glycogen metabolism disease. Herein, we review the latest results concerning the role of malin in LD and attempt to decipher its function. © 2012 IUBMB IUBMB Life, 64(10): 801-808, 2012 [ABSTRACT FROM AUTHOR]

Mutations in either EPM2A, the gene encoding a dual-specificity phosphatase named laforin, or NHLRC1, the gene encoding an E3 ubiquitin ligase named malin, cause Lafora disease in humans. Lafora disease is a fatal neurological disorder characterized by progressive myoclonus epilepsy, severe neurological deterioration and accumulation of poorly branched glycogen inclusions, called Lafora bodies or polyglucosan bodies, within the cell cytoplasm. The molecular mechanism underlying the neuropathogenesis of Lafora disease remains unknown. Here, we present data demonstrating that in the cells expressing low levels of laforin protein, overexpressed malin and its Lafora disease-causing missense mutants are stably polyubiquitinated. Malin and malin mutants form ubiquitin-positive aggregates in or around the nuclei of the cells in which they are expressed. Neither wild-type malin nor its mutants elicit endoplasmic reticulum stress, although the mutants exaggerate the response to endoplasmic reticulum stress. Overexpressed laforin impairs the polyubiquitination of malin while it recruits malin to polyglucosan bodies. The recruitment and activities of laforin and malin are both required for the polyglucosan body disruption. Consistently, targeted deletion of laforin in brain cells from Epm2a knockout mice increases polyubiquitinated proteins. Knockdown of Epm2a or Nhlrc1 in neuronal Neuro2a cells shows that they cooperate to allow cells to resist ER stress and apoptosis. These results reveal that a functional laforin-malin complex plays a critical role in disrupting Lafora bodies and relieving ER stress, implying that a causative pathogenic mechanism underlies their deficiency in Lafora disease. Structured digital abstract ;with and by () and by () with by (View Interaction: , , , , , , , , , , ) [ABSTRACT FROM AUTHOR]

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Le schwannome malin est une tumeur très rare chez l'enfant (1 à 2% des tumeurs des tissus mous), elle se développe au dépend des cellules de schwanne. Dans ce travail, les auteurs rapportent un cas de schwannome malin développé au dépend du nerf grand sciatique. La radiographie de la cuisse de face et de profil était normale. L'imagerie par résonance magnétique a identifié une lésion le long du trajet du nerf grand sciatique. La tumeur a été réséquée en totalité emportant le nerf grand sciatique. L'examen anatomo-pathologique a confirmé le diagnostic. [ABSTRACT FROM AUTHOR]

Summary: Lafora disease (LD) is a type of autosomal recessive, progressive myoclonus epilepsy resulting mostly from mutations in the EPM2A and NHLRC1 genes. Mutational analysis in both genes was initiated with the aim of establishing LD DNA diagnosis in Turkey. Four novel NHLRC1 (p.G131X, p.P69S and p.D82H) and EPM2A (p.V7A) and two recurrent NHLRC1 (p.D146N) and EPM2A (p.R241X) mutations were identified in six families. The delineation of causative mutations in patients provided early disease diagnosis for other family members and contributed to the knowledge of LD pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Lafora disease (LD) is the inherited progressive myoclonus epilepsy caused by mutations in either EPM2A gene, encoding the protein phosphatase laforin or the NHLRC1 gene, encoding the ubiquitin ligase malin. Since malin is an ubiquitin ligase and its mutations cause LD, it is hypothesized that improper clearance of its substrates might lead to LD pathogenesis. Here, we demonstrate for the first time that neuronatin is a novel substrate of malin. Malin interacts with neuronatin and enhances its degradation through proteasome. Interestingly, neuronatin is an aggregate prone protein, forms aggresome upon inhibition of cellular proteasome function and malin recruited to those aggresomes. Neuronatin is found to stimulate the glycogen synthesis through the activation of glycogen synthase and malin prevents neuronatin-induced glycogen synthesis. Several LD-associated mutants of malin are ineffective in the degradation of neuronatin and suppression of neuronatin-induced glycogen synthesis. Finally, we demonstrate the increased levels of neuronatin in the skin biopsy sample of LD patients. Overall, our results indicate that malin negatively regulates neuronatin and its loss of function in LD results in increased accumulation of neuronatin, which might be implicated in the formation of Lafora body or other aspect of disease pathogenesis. [Copyright &y& Elsevier]

Despite decades of studying muscle glycogen in many metabolic situations, surprisingly little is known regarding its regulation. Glycogen is a dynamic and vital metabolic fuel that has very limited energetic capacity. Thus its regulation is highly complex and multifaceted. The stores in muscle are not homogeneous and there appear to be various metabolic pools. Each granule is capable of independent regulation and fundamental aspects of the regulation appear to be associated with a complex set of proteins (some are enzymes and others serve scaffolding roles) that associate both with the granule and with each other in a dynamic fashion. The regulation includes altered phosphorylation status and often translocation as well. The understanding of the roles and the regulation of glycogenin, protein phosphatase 1, glycogen targeting proteins, laforin and malin are in their infancy. These various processes appear to be the mechanisms that give the glycogen granule precise, yet dynamic regulation. [ABSTRACT FROM AUTHOR]

Abstract: We report the case of a 66-year-old patient with a pilomatrix carcinoma from the right submandibular region with pulmonary and cerebral metastases. The histological confirmation of the diagnosis has been based on the biopsy of the submandibular tumefaction which was rapidly growing. We tried at first a doxorubicine and cisplatine chemotherapy because of the considerable locoregional extension and the existence of pulmonary metastases. The patient response to three cures of chemotherapy was spectacular with a partial clinical response (75%) and a partially cleaned-up chest observed in the radiological evaluation. In the 5th cycle of chemotherapy following the same protocol, the patient presented a relapse with cerebral metastases. The patient received hypofractionated radiotherapy on the brain followed by etoposide and cisplatine chemotherapy, then oral vinorelbine. The patient died of progressive disease after 32 weeks. [Copyright &y& Elsevier]

While scientists have routinely measured muscle glycogen in many metabolic situations for over 4 decades, there is surprisingly little known regarding its regulation. In the past decade, considerable evidence has illustrated that the carbohydrate stores in muscle are not homogeneous, and it is very likely that metabolic pools exist or that each granule has independent regulation. The fundamental aspects appear to be associated with a complex set of proteins that associate with both the granule and each other in a dynamic fashion. Some of the proteins are enzymes and others play scaffolding roles. A number of the proteins can translocate, depending on the metabolic stimulus. These various processes appear to be the mechanisms that give the glycogen granule precise yet dynamic regulation. This may also allow the stores to serve as an important metabolic regulator of other metabolic events. [ABSTRACT FROM AUTHOR]

Abstract: Frequently found in kidney, angiomyolipoma is a rare mesenchymal tumor when diagnosed in the liver and usually benign composed of proliferative blood vessels, fatty tissue and smooth muscle. We report the case of a 67-year-old woman who underwent a left hepatectomy for a 4th segment tumor unidentified after imaging and fine needle biopsy. Final anatomopathologic examination revealed an epithelioïd hepatic angiomyolipoma with signs of malignant behaviour as vascular and lymphatics embolus and invaded left portal vein thrombosis. During the subsequent 24-month follow-up, no recurrence was observed. A review of the literature found only two cases of malignant hepatic angiomyolipoma with fatal issue, however, their incidence must be underrated because of their scarcity and the difficulty of their diagnosis, which needs immunohistochemical confirmation with HMB 45 in particularly. Advances in imaging and anatomopathology in particular with the concept of PEComa (Perivascular-Epithelioïd Cell) as the unifying feature should lead to the recognition of the various variant patterns and cell types. The latter which are important for a correct diagnosis, in order to obtain reliable data about frequency, possible malignant behaviour and therefore consensus management for hepatic angiomyolipoma. [Copyright &y& Elsevier]