Myoclonic Epilepsy With Lafora Bodies

Mauro, Salvatore Di; Hirt, Lieselotte; Blume, Robert P.

doi:10.1001/archneur.1971.00490060017002

Cited by 63 publications

(8 citation statements)

References 28 publications

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“…Error bars, S.E. agreement with multiple studies that have failed to find any changes in the activities of enzymes associated with glycogen metabolism in LD patients (47)(48)(49).…”

Section: Figure 4 Laforin Is Unique In Its Ability To Dephosphorylatsupporting

confidence: 90%

Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates

Worby

Gentry

Dixon

2006

Journal of Biological Chemistry

194

236

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Laforin is the only phosphatase in the animal kingdom that contains a carbohydrate-binding module. Mutations in the gene encoding laforin result in Lafora disease, a fatal autosomal recessive neurodegenerative disorder, which is diagnosed by the presence of intracellular deposits of insoluble complex carbohydrates known as Lafora bodies. We demonstrate that laforin interacts with proteins known to be involved in glycogen metabolism and rule out several of these proteins as potential substrates. Surprisingly, we find that laforin displays robust phosphatase activity against a phosphorylated complex carbohydrate. Furthermore, this activity is unique to laforin, since several other phosphatases are unable to dephosphorylate polysaccharides. Finally, fusing the carbohydrate-binding module of laforin to the dual specific phosphatase VHR does not result in the ability of this phosphatase to dephosphorylate polysaccharides. Therefore, we hypothesize that laforin is unique in its ability to utilize a phosphorylated complex carbohydrate as a substrate and that this function may be necessary for the maintenance of normal cellular glycogen.

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“…Error bars, S.E. agreement with multiple studies that have failed to find any changes in the activities of enzymes associated with glycogen metabolism in LD patients (47)(48)(49).…”

Section: Figure 4 Laforin Is Unique In Its Ability To Dephosphorylatsupporting

confidence: 90%

Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates

Worby

Gentry

Dixon

2006

Journal of Biological Chemistry

194

236

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show abstract

“…Lafora bodies and corpora amylacea consist of filamentous and granular materials; the core consists of densely aggregated granular material and the outer rim is composed of irregularly branched filaments 3,21,22 . This has been confirmed by the present study.…”

Section: Discussionsupporting

confidence: 90%

Distribution and electron microscopical and immunohistochemical aspects of Lafora bodies in a Lafora patient with a 17‐year clinical course

Yoshimura¹,

Kaneko

Yohimura

et al. 1999

Neuropathology

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Autopsy was performed on a 30‐year‐old man who died of Lafora disease. This patient, one of two siblings with Lafora disease, had onset of symptoms at age 13 years and a clinical course of 17 years. He had frequent tonic‐clonic convulsions and myoclonus, followed by dementia. Due to dysphagia resulting from strong spasms of the pharyngo‐esophageal muscles, he underwent gastrostomy. Routine laboratory data, including liver function tests and an electrocardiogram (ECG), were within the normal range. The autopsy revealed degeneration with polyglucosan accumulations in myocardiac muscle cells, liver cells, and smooth muscle cells of the esophago‐gastrointestinal tract, urinary system, and blood vessels, as well as in striated muscle cells in the skeletal muscles and neurons in the nervous system. In the central nervous system (CNS), numerous intraneuronal polyglucosan accumulations (Lafora bodies) were present in the following structures (listed in decreasing order of density): the substantia nigra, olivary nuclei (superior and inferior), vestibular nucleus (medial and lateral), thalamus, globus pallidus (lateral segment), dentate nucleus, gracile and cuneate nuclei, cerebral cortex (frontal, temporal, parietal and occipital), amygdala, nucleus basalis of Meynert, neostriatum, hypothalamus, reticular formation of the brain stem, locus ceruleus, red nucleus, mesencephalic central gray, solitary nucleus, ambiguus nucleus, dorsal vagal nucleus, and some other cranial nerve nuclei. In the mammillary bodies or subthalamic nucleus no perikaryonal Lafora bodies were found, although a considerable number of intraneuritic Lafora bodies were noted. Electron microscopically, Lafora bodies were composed of granular material and irregular filaments (about 6 nm in diameter), which were immunohistochemically positive for ubiquitin and tau. No Lafora bodies were reactive with Gallyas stain. This study is the first to have revealed that in Lafora disease smooth muscle cells can be systemically involved in specific degeneration for Lafora disease. In this patient, severe myoclonus could potentially spread over the pharynx and esophagus and cause pharyngo‐esophageal spasm and dysphagia. Because of the very long clinical course, the histopathology of this patient may represent the full extension of the degeneration that is specific for Lafora disease.

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“…Lafora disease (LD) is a fatal teenage-onset neurological disorder characterized by progressive myoclonic epilepsy (PME), neurodegeneration, and neuronal accumulation of a poorly branched and insoluble amylopectin-like form of glycogen, called polyglucosan, into inclusion bodies termed Lafora bodies (LBs) or polyglucosan bodies (PBs) (6, 11, 23, 27). Loss-of-function mutations in either of two genes cause LD: EPM2A , which encodes the dual-specificity phosphatase laforin, and NHLRC1 , which encodes the E3 ubiquitin ligase malin (9, 24).…”

Section: Introductionmentioning

confidence: 99%

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

Wang

et al. 2013

Mol Neurobiol

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Glycogen, the largest cytosolic macromolecule, is soluble because of intricate construction generating perfect hydrophilic-surfaced spheres. Little is known about neuronal glycogen function and metabolism, though progress is accruing through the neurodegenerative epilepsy Lafora disease (LD) proteins laforin and malin. Neurons in LD exhibit Lafora bodies (LBs), large accumulations of malconstructed insoluble glycogen (polyglucosans). We demonstrated that the laforin-malin complex reduces LBs and protects neuronal cells against endoplasmic reticulum stress-induced apoptosis. We now show that stress induces polyglucosan formation in normal neurons in culture and in brain. This is mediated by increased glucose-6-phosphate allosterically hyperactivating muscle glycogen synthase (GS1), and is followed by activation of the glycogen digesting enzyme glycogen phosphorylase. In the absence of laforin, stress-induced polyglucosans are undigested and accumulate into massive LBs, and in laforin-deficient mice stress drastically accelerates LB accumulation and LD. The mechanism through which laforin-malin mediates polyglucosan degradation remains unclear but involves GS1 dephosphorylation by laforin. Our work uncovers the presence of rapid polyglucosan metabolism as part of the normal physiology of neuroprotection. We propose that deficiency in the degradative phase of this metabolism, leading to LB accumulation and resultant seizure predisposition and neurodegeneration, underlies LD.

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Myoclonic Epilepsy With Lafora Bodies

Cited by 63 publications

References 28 publications

Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates

Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates

Distribution and electron microscopical and immunohistochemical aspects of Lafora bodies in a Lafora patient with a 17‐year clinical course

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

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