Polyglucosan Inclusion Bodies Research Articles

Intestinal involvement in amyloidosis is a sequential process.

Gastrointestinal amyloidosis causes dysmotility. A comprehensive histological analysis to explain these symptoms is lacking. Therefore, we systematically examined histological features of intestinal dysmotility in patients with AL and AA amyloidosis, compared to controls. Autopsy tissue material from small bowel and colon was used for histological (semiquantitative) evaluation of the mucosa, blood vessels, muscular layers, enteric nervous system (ENS) and the interstitial cells of Cajal (ICC), using hematoxylin and eosin, periodic acid Schiff, Elastic von Gieson and Congo red staining, and immunohistochemistry with α-smooth muscle actin, HuC/D, S100 and CD117 antibodies, according to guidelines of the Gastro 2009 International Working Group. Amyloid deposits were present in the vascular walls of all amyloidosis patients. In the mucosa, amyloid was found in 67% of AA patients. The muscular layers were involved in 64% of amyloidosis patients, most prominent in AA patients, associated with the presence of polyglucosan inclusion bodies, but not with either abnormal α-actin patterns or fibrosis. Amyloid in the muscularis propria surrounding the myenteric plexus was found, but not inside the myenteric plexus. These deposits might be related to loss of the ICC network, but there was no association with decreased neuronal or nerve fiber density. We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process: amyloid deposition starts in the vasculature, followed by involvement of the muscular layers, ICC loss, and potentially affect the myenteric plexus. This final stage may be accompanied by clinical symptoms of severe intestinal dysmotility.

Lafora Body Disease: A Rare Type of Progressive Myoclonic Epilepsy

Lafora body disease is one of the inherited progressive myoclonic epilepsy (PME) syndromes. It is an autosomal-recessive disorder with onset in late childhood or early adolescence. The disease is characterized by fragmentary, symmetric, or generalized myoclonic and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Pathologically polyglucosan inclusion bodies (Lafora body) are seen which are pathognomonic of the disease and are not seen in any other types of PMEs. Electroencephalogram (EEG) reveals slowing of background and generalized spike/polyspike-and-waves and photosensitivity. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Periodic electroencephalogram discharges in a case of Lafora body disease: An unusual finding.

Lafora body disease (LBD) is a form of progressive myoclonic epilepsy, characterized by seizures, myoclonic jerks, cognitive decline, ataxia, and intracellular polyglucosan inclusion bodies (Lafora bodies) in the neurons, heart, skeletal muscle, liver, and sweat gland duct cells. Electroencephalogram (EEG) findings in LBD may include multiple spikes and wave discharges, photosensitivity, multifocal epileptiform discharges, and progressive slowing in background activity. Periodicity in epileptiform discharges has not been frequently depicted in LBD. We herein report an unusual case of LBD who showed generalized periodic epileptiform discharges in EEG.

Mystery Case: Lafora periodic acid–Schiff inclusion bodies

A 16-year-old boy presented with a 5-year history of progressive cognitive decline and behavioral change followed by generalized tonic-clonic and myoclonic seizures refractory to many anticonvulsants (valproic acid, phenobarbital, clonazepam, and topiramate) and cerebellar ataxia a year later. The son of consanguineous parents, he had a family history of 2 cousins who both had epilepsy and died at the ages of 15 and 25 years. Laboratory screening tests, including lactic acid, fundus examination, brain neuroimaging, and CSF, were normal. Skin biopsy (figure) revealed periodic acid–Schiff-positive intracellular polyglucosan inclusion bodies in myoepithelial and sweat gland duct cells. These findings are typical of Lafora disease, a fatal autosomal recessive disorder caused by mutations in one of 2 known genes, both located at chromosome 6: EPM2A , which encodes the protein laforin, and EPM2B , which encodes the protein malin. Differential diagnosis must be made with other causes of progressive myoclonic epilepsies, most commonly Unverricht-Lundborg disease (Baltic myoclonus), myoclonus epilepsy and ragged-red fibers syndrome, neuronal ceroid lipofuscinosis, and type 1 sialidosis. There is no treatment, and therapy is mainly supportive and symptomatic.1,2

PP01.12 – 2602: Differential diagnosis of progressive myoclonic epilepsia: Five patients with Lafora disease

Objective Lafora disease (LD) is a rare, fatal, autosomal recessive hereditary disease characterized by epilepsy, myoclonus and progressive neurological deterioration. Diagnosis is made by polyglucosan inclusion bodies (Lafora bodies) shown in skin biopsy. Responsible mutations involves either the EPM2A or NHLRC1 (EPM2B) gene. Methods We report genetic mutations and clinical courses of Lafora disease in 5 adolescents with homozygote NHLRC1 mutation and homozygous EPM2A mutation. Results A total 5 patients (3 female, 2 male) were presented with progressive myoclonic epilepsy. In all cases there were no problems at birth, childhood, and their psychomotor development were normal and attended regular school. In general seizures began around at 13–14 years old. Over the time they demostrated ataxia, and significant deterioration occurred in mental functions, myoclonus of the extremities started, and 3 of all patients were unable to walk unassisted and one of them died at 15 years old. Axillary skin biopsies were performed to all and Lafora bodies in cytoplasm were demostrated. All patients parents are second-degree relatives. Routine blood test, cerebrospinal fluid analaysis were normal. In three patients cranial magnetic resonance imaging (MRI) were normal, but 2 patients had mild serebral and serebellar atrophy. There were multifocal, from time-to-time generalized spike-wave activity were observed in their electroencephalography (EEG). Genetic analaysis for Lafora was studied and 2 patients (sublings) had same mutation) homozygous (c.336 C>A) p.Y112X mutation in EPM2A gene, homozygous (c.199 G>T) p. E67X mutation (2 patient had same mutation) in NHLRC1 gene, homozygous L 180V (CTG>GTC) mutation in EPM2A gene were detected. Conclusion LD is characterized by progressive myoclonic epilepsy and neurodegenerative symptoms. Therefore early recognation is diffucult. If patient show progressive myoclonic seizures with progressive mental deterotation, as well as ataxi we should consider LD

Enhanced sensitivity of laforin- and malin-deficient mice to the convulsant agent pentylenetetrazole.

Lafora disease is a rare form of inherited progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin, or in the EPM2B gene, which encodes malin. It is characterized by the presence of polyglucosan inclusion bodies (Lafora bodies) in brain and other tissues. Genetically engineered mice lacking expression of either the laforin (Epm2a−/−) or malin (Epm2b−/−) genes display a number of neurological and behavioral abnormalities that resemble those found in patients suffering from Lafora disease; of these, both Epm2a−/− and Epm2b−/− mice have shown altered motor activity, impaired motor coordination, episodic memory deficits, and different degrees of spontaneous epileptic activity. In this study, we analyze the sensitivity of Epm2a−/− and Epm2b−/− mice to the convulsant drug pentylenetetrazol (PTZ), an antagonist of the γ-aminobutyric acid type A (GABAA) receptor, commonly used to induce epileptic tonic-clonic seizures in laboratory animals. PTZ-induced epileptic activity, including myoclonic jerks and tonic-clonic seizures, was analyzed in 2 age groups of mice comprising representative samples of young adult and aged mice, after administration of PTZ at sub-convulsive and convulsive doses. Epm2a−/− and Epm2b−/− mice showed a lower convulsive threshold after PTZ injections at sub-convulsive doses. A lower convulsive threshold and shorter latencies to develop epileptic seizures were observed after PTZ injections at convulsive doses. Different patterns of generalized seizures and of discharges were observed in Epm2a−/− and Epm2b−/− mice. Epm2a−/− and Epm2b−/− mice present an increased sensitivity to the convulsant agent PTZ that may reflect different degrees of increased GABAA receptor-mediated hyperexcitability.

Lafora progressive myoclonus epilepsy

Two disease mechanisms operate in Lafora progressive myoclonus epilepsy (Lafora PME) to produce 3 phenotypes (epilepsy, rapid neurologic deterioration, and Lafora polyglucosan inclusion bodies). These 2 disease mechanisms are 1) an error in glycogen metabolism and 2) neurodegeneration. The question is, which comes first and which is primary and more important in disease production?

Lafora Progressive Myoclonus Epilepsy: Recent Insights into Cell Degeneration

Lafora disease (LD) is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The review also outlines important patents related to Lafora disease.

Lafora Disease

Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The condition is characterized by epilepsy, myoclonus and dementia. Diagnostic findings on MRI and neurophysiological testing are not definitive and biopsy or genetic studies may be required. Therapy in Lafora disease is currently limited to symptomatic management of the epilepsy, myoclonus and intercurrent complications. With a greater understanding of the pathophysiological processes involved, there is justified hope for future therapies.

Laforin, the most common protein mutated in Lafora disease, regulates autophagy.

Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterized by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. However, it is unclear at the moment whether Lafora bodies are the cause of the disease, or whether they are secondary consequences of a primary metabolic alteration. Here we describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy. This phenomenon is confirmed in cell lines from human patients, mouse embryonic fibroblasts from laforin knockout mice and in tissues from such mice. Conversely, laforin expression stimulates autophagy. Laforin regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway. The changes in autophagy mediated by laforin regulate the accumulation of diverse autophagy substrates and would be predicted to impact on the Lafora body accumulation and the cell stress seen in this disease that may eventually contribute to cell death.

Advances in Lafora progressive myoclonus epilepsy

Abstract Lafora progressive myoclonus epilepsy is an autosomal recessive, fatal, generalized polyglucosan storage disorder that occurs in childhood or adolescence with stimulus sensitive epilepsy (resting and action myoclonias, grand mal, and absence), dementia, ataxia and rapid neurologic deterioration. Mutations in EPM2A/laforin cause 58% of cases and mutations in EPM2B/malin cause 35% of cases. Accumulating evidence points to Lafora disease as primarily a disorder of cell death with impaired clearance of misfolded proteins, as shown by ubiquitin-positive aggresomes in HeLa cells transfected with mutated laforin, ubiquitin-positive polyglucosan inclusion bodies, and malin/E3 ubiquitin ligase polyubiquitination of laforin. How polyglucosan inclusion bodies accumulate is still a mystery. Polyglucosan accumulates hypothetically because of an overactive polyglucosan biosynthetic pathway or a breakdown in polyglucosan degradation. Five separate laboratories are looking for the biochemical pathways that connect laforin and malin to polyglucosan synthesis or degradation. A curative therapy for human Lafora disease with laforin replacement therapy using neutral pegylated immunoliposomes is being investigated.