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Seizure Oct 2019Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and... (Review)
Review
Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.
Topics: Humans; Myoclonic Epilepsies, Progressive; Precision Medicine
PubMed: 31476531
DOI: 10.1016/j.seizure.2019.08.012 -
The Biochemical Journal Feb 2012Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been... (Review)
Review
Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.
Topics: Amino Acid Sequence; Animals; Biology; Carbohydrate Metabolism; Concept Formation; Gluconeogenesis; Glycogen; Glycogenolysis; Humans; Metabolic Networks and Pathways; Mice; Models, Biological; Models, Molecular; Molecular Sequence Data; Sequence Homology, Amino Acid
PubMed: 22248338
DOI: 10.1042/BJ20111416 -
Epileptic Disorders : International... Sep 2016Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy due to mutations in the EPM2A (laforin) and EPM2B (malin) genes, with no substantial... (Review)
Review
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.
Topics: Animals; Disease Models, Animal; Genetic Counseling; Glycogen; Humans; Lafora Disease; Mice; Protein Tyrosine Phosphatases, Non-Receptor
PubMed: 27702709
DOI: 10.1684/epd.2016.0842 -
European Child & Adolescent Psychiatry Jul 2023COVID-19 was declared a pandemic in March 2020, resulting in many countries worldwide calling for lockdowns. This study aimed to review the existing literature on the... (Review)
Review
COVID-19 was declared a pandemic in March 2020, resulting in many countries worldwide calling for lockdowns. This study aimed to review the existing literature on the effects of the lockdown measures established as a response to the COVID-19 pandemic on the mental health of children and adolescents. Embase, Ovid, Global Health, PsycINFO, Web of Science, and pre-print databases were searched in this PRISMA-compliant systematic review (PROSPERO: CRD42021225604). We included individual studies reporting on a wide range of mental health outcomes, including risk and protective factors, conducted in children and adolescents (aged ≤ 19 years), exposed to COVID-19 lockdown. Data extraction and quality appraisal were conducted by independent researchers, and results were synthesised by core themes. 61 articles with 54,999 children and adolescents were included (mean age = 11.3 years, 49.7% female). Anxiety symptoms and depression symptoms were common in the included studies and ranged 1.8-49.5% and 2.2-63.8%, respectively. Irritability (range = 16.7-73.2%) and anger (range = 30.0-51.3%), were also frequently reported by children and adolescents. Special needs and the presence of mental disorders before the lockdown, alongside excessive media exposure, were significant risk factors for anxiety. Parent-child communication was protective for anxiety and depression. The COVID-19 lockdown has resulted in psychological distress and highlighted vulnerable groups such as those with previous or current mental health difficulties. Supporting the mental health needs of children and adolescents at risk is key. Clinical guidelines to alleviate the negative effects of COVID-19 lockdown and public health strategies to support this population need to be developed.
Topics: Humans; Adolescent; Female; Child; Male; COVID-19; Mental Health; Pandemics; SARS-CoV-2; Communicable Disease Control; Anxiety; Depression
PubMed: 34406494
DOI: 10.1007/s00787-021-01856-w -
Revue Neurologique Apr 2022The ubiquitin system impacts most cellular processes and is altered in numerous neurodegenerative diseases. However, little is known about its role in neurodegenerative... (Review)
Review
The ubiquitin system impacts most cellular processes and is altered in numerous neurodegenerative diseases. However, little is known about its role in neurodegenerative diseases due to disturbances of glycogen metabolism such as Lafora disease (LD). In LD, insufficiently branched and long-chained glycogen forms and precipitates into insoluble polyglucosan bodies (Lafora bodies), which drive neuroinflammation, neurodegeneration and epilepsy. LD is caused by mutations in the gene encoding the glycogen phosphatase laforin or the gene coding for the laforin interacting partner ubiquitin E3 ligase malin. The role of the malin-laforin complex in regulating glycogen structure remains with full of gaps. In this review we bring together the disparate body of data on these two proteins and propose a mechanistic hypothesis of the disease in which malin-laforin's role to monitor and prevent over-elongation of glycogen branch chains, which drive glycogen molecules to precipitate and accumulate into Lafora bodies. We also review proposed connections between Lafora bodies and the ensuing neuroinflammation, neurodegeneration and intractable epilepsy. Finally, we review the exciting activities in developing therapies for Lafora disease based on replacing the missing genes, slowing the enzyme - glycogen synthase - that over-elongates glycogen branches, and introducing enzymes that can digest Lafora bodies. Much more work is needed to fill the gaps in glycogen metabolism in which laforin and malin operate. However, knowledge appears already adequate to advance disease course altering therapies for this catastrophic fatal disease.
Topics: Glycogen; Humans; Lafora Disease; Protein Tyrosine Phosphatases, Non-Receptor; Ubiquitin-Protein Ligases
PubMed: 34301405
DOI: 10.1016/j.neurol.2021.06.006 -
Molecular Aspects of Medicine Dec 2015Covalent 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... (Review)
Review
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.
Topics: Animals; Glycogen; Glycogen Synthase; Humans; Lafora Disease; Neurons; Phosphorylation
PubMed: 26278984
DOI: 10.1016/j.mam.2015.08.003 -
Animals : An Open Access Journal From... Jun 2022Lafora disease is an autosomal recessive glycogen-storage disorder resulting from an accumulation of toxic polyglucosan bodies (PGBs) in the central nervous system,...
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 () 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.
PubMed: 35804532
DOI: 10.3390/ani12131633 -
Cells Jul 2018Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological... (Review)
Review
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 gene, encoding the dual phosphatase laforin, or the 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.
PubMed: 30050012
DOI: 10.3390/cells7080087