Lafora Progressive Myoclonus Epilepsy: Recent Insights into Cell Degeneration

Spuch, Carlos; Ortolano, Saida; Navarro, Carmen

doi:10.2174/187221412800604617

Cited by 5 publications

(3 citation statements)

References 72 publications

(107 reference statements)

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“…It is likely therefore that LBs and neurological damage are independent consequences of the same defect in a common physiological pathway and it is possible that only some Lafora disease symptoms are a consequence of LBs formation. Because Lafora disease has been traditionally classified as a glycogen metabolism disorder, only a few reports described the neurodegenerative changes in the neuropile [3,11,64-66]. Nevertheless, our data strongly support the idea that Lafora disease is both a complex neurodegenerative disease and a glycogen metabolism disorder.…”

Section: Discussionsupporting

confidence: 76%

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Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

et al. 2014

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BackgroundLafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease EPM2A-/- mouse.ResultsIn this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old EPM2A-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling.ConclusionsHere, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis.

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Section: Discussionsupporting

confidence: 76%

“…Lafora disease (OMIM 254780) is an autosomal recessive form of epilepsy with onset in late childhood or adolescence [ 1 - 3 ]. Primary symptoms include seizures, ataxia, myoclonus, and the progressive development of severe dementia.…”

Section: Introductionmentioning

confidence: 99%

Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

et al. 2014

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“…The laforin-malin complex mediates the continual proteasome-dependent degradation of abnormal glycogen particles and the associated enzymes necessary for glycogen synthesis (Liu et al, 2013; Vilchez et al, 2007). Mutations in either laforin- or malin-encoding genes, as it occurs in Lafora Disease (LD), results in synthesis of malformed glycogen-like polymer named polyglucosans (Spuch et al, 2012). Polyglucosans contain large quantity of phosphate esters, where biosynthetic errors of glycogen synthase are normally removed by laforin (Roach, 2011).…”

Section: Synthesis Of Unmetabolizable Glycogen Is Correlated With Epimentioning

confidence: 99%

Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

et al. 2014

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Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K+ by astrocytes, thereby leading to increased extracellular K+ and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K+ homeostasis and increased susceptibility to seizures in epilepsy.

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The progressive myoclonic epilepsies

2015

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Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a part of the phenotype. This umbrella term encompasses many diverse conditions, ranging from Lafora body disease to Gaucher's disease. These diseases as a group are important because of a generally poor response to antiepileptic medication, an overall poor prognosis and inheritance risks to siblings or offspring (where there is a proven genetic cause). A correct diagnosis also helps patients and their families to accept and understand the nature of their disease, even if incurable. Here, we discuss the phenotypes of these disorders and summarise the relevant specific investigations to identify the underlying cause.

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Lafora Progressive Myoclonus Epilepsy: Recent Insights into Cell Degeneration

Cited by 5 publications

References 72 publications

Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

The progressive myoclonic epilepsies

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