Lafora disease can be caused by defects in the epm2a gene, which encodes the laforin protein phosphatase, or in. Its etiopathological hallmark is the lafora body lb, present throughout the brain in profuse ever. With visceromegaly gm1 gangliosidosis sandhoffs disease gm2 gangliosidosis niemannepick c and related disorders sialidosis mucopolysaccharidosis mps gaucher type iii. Aug 29, 2012 lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. An unusual case of lafora body disease, european journal of. Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the epm2a and epm2b genes. Wpw syndrome brain glycogenoses adult polyglucosan body disease, lafora disease and other disorders associated with accumulation of polyglucosan bodies in the brain.
Concentric amyloid lafora bodies are found in neurons, liver, skin, bone, and muscle from menkes, textbook of childhood neurology, 5th ed, pp111110 synonyms. Adult polyglucosan body disease is a chronically progressive. Pmes by the presence of cytosolic polysaccharide inclusions known as lafora bodies. Canine epilepsy and lafora disease elsa beltran dvm, mrcvs, dipecvn. Ld is caused by mutations in the gene encoding the phosphatase laforin, which reportedly exists solely in vertebrates. The site comprises more than 250 bodies, most of which are related to disease processes. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes. Genotypes and phenotypes of patients with lafora disease. It will, however, likely cause significant debilitation to your canine family member as the disease progresses. Lafora bodies can be observed on skin biopsy, and the emp2a mutation of the laforin gene is detected in 80% of cases. The documents contained in this web site are presented for information purposes only. Jan 16, 2019 lafora disease ld is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. Frontiers the ketogenic diet as a treatment paradigm for.
Disease progression was aggressive, with multiple generalised tonicclonic, myoclonic. Lafora disease is an autosomal recessive disorder, caused by loss of function mutations in either laforin glycogen phosphatase gene epm2a or malin e3 ubiquitin ligase gene nhlrc1. Lafora disease omim 254780 is an autosomal recessive form of epilepsy with onset in late childhood or adolescence 1, 2, 3. Lafora disease is a fatal autosomal recessive, genetic disorder characterized by the presence of inclusion bodies, known as lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin 545 lafora disease is also a neurodegenerative disease that causes impairment in the development of cerebral cortical neurons and is a glycogen metabolism. Medical and mental health complications of lafora disease. Lafora disease ld is a progressive myoclonic epilepsy resulting in severe neurodegeneration followed by death. It is caused by mutations in the gene encoding glycogen phosphatase. A pilot study of a ketogenic diet in patients with lafora. Lafora disease in dogs symptoms, causes, diagnosis.
Research open access loss of gabaergic cortical neurons underlies the neuropathology of lafora disease saida ortolano1, irene vieitez1, roberto carlos agisbalboa2 and carlos spuch2 abstract background. Lafora disease ld is an autosomal recessive progressive myoclonus epilepsy due to mutations in the epm2a laforin and epm2b malin genes, with no. The disease usually manifests in previously healthy adolescents, and death commonly occurs within 10 years of. Sep 29, 2015 the signs and symptoms of lafora disease generally appear during late childhood or adolescence.
Genetics of lafora lafora is an inherited autosomal recessive condition. A hallmark of ld is the accumulation of intracellular, insoluble carbohydrate aggregates known as lafora bodies lbs in brain, muscle, and other tissues. Muscle in lafora disease jama neurology jama network. Due to the mutationsdefects with the laforin protein, lafora bodies begin to build up causing lafora disease. Described for the first time in 1911 by gonzalo rodriguez lafora 18861971 a spanish neurologist. Lafora progressive myoclonus epilepsy is a brain disorder characterized by recurrent seizures epilepsy and a decline in intellectual function. The disease usually manifests in previously healthy adolescents. Our data enable an approximation of the prevalence of manifest lafora disease in germany to 1,69 per 10 million people. Lafora bodies lbs are carbohydrate storage products that characterize ld and underlie the epileptic disorder.
Pdf lafora disease from pathogenesis to treatment strategies. Primary symptoms include seizures, ataxia, myoclonus, and the progressive development of severe dementia. The search to identify genes for rare neurodegenerative diseases. The signs and symptoms of the disorder usually appear in late childhood or adolescence and worsen with time. Like most gsds, ld is an autosomal recessive genetic disorder. However, lafora body disease, a rare pro gressive myoclonic epilepsy, is characterized by a pathological hallmark of cytoplasmic inclusions lafora bodies owing to mutation in laforin, a protein phosphatase. These structures are abundant in the cerebellum and. Earlyonset lafora body disease brain oxford academic. Washing in ethanol, drying, and manual application to carbon tape did not. Lafora disease from pathogenesis to treatment strategies.
Lafora disease is caused by mutations in at least two genes, epm2a and epm2b, he explains. Canine epilepsy and lafora disease the dachshund breed. These mutations in either of these two genes lead to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin. It will not become clinically affected by the disease but, if bred to. An unusual case of lafora body disease, european journal. These neurological disorders, usually, involve neuronal excitability through the modulating of ion channels, receptors and intracellular signaling pathways, and are the targets of the aeds. Lafora disease can be caused by defects in the epm2a gene, which. Lafora disease ld is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. Certainly, this appears to be the case in a small pilot study of kd treatment in patients with lafora body disease cardinali et al. Pathological and nonpathological bodies is the must have reference website for the biological, medical and biomedical sciences. Pdf lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. Genedx believes in responsible testing that is based on established medical guidelines, and we aim to be completely transparent with our pricing so that patients, clinicians, and payers know the cost of the test. Structural biochemistrylafora disease wikibooks, open.
Skin biopsy specimens from the midcalf area confirmed earlier findings by showing numerous periodic acidschiffpositive inclusion bodies in eccrine sweat gland duct cells. Lafora disease ubiquitin ligase malin regulates neuronatin level and neuronatininduced glycogen synthesis. In these cases,the affected person often begins showing signs and symptoms of lafora disease between ages 21 and 28. Typical progression of myoclonic epilepsy of the lafora type. Pdf lafora disease ld is an autosomal recessive progressive myoclonus epilepsy due to mutations in the epm2a laforin and epm2b malin genes, with. As discussed above, lafora disease is primarily a neurodegenerative disease, and the symptoms are caused by lafora body accumulation in the brain due to deficiency in either laforin or malin 87. Affected individuals experience an initial seizure during adolescence, followed by severe neurological decline until the patients death approximately ten years after the first seizure 1, 4. Neurological disorders in late stages of progression may have such extreme neuronal dysfunction and death to allow a refueling with metabolic substrates to help recover integrity and function. The objective of this retrospective case series is to characterize the genotypes and. The onset of ncse was temporally related to the withdrawal of sodium valproate and. Lafora disease is a metabolic disorder resulting in insoluble glucan accumulation in the cytoplasm, and manifests as a debilitating neurodegeneration that ends with the death of the patient. Lafora disease is a hereditary epilepsy that is considered to be one of the progressive myoclonic epilepsies. Lafora disease in dogs, though a rare inherited disease, is not generally fatal for your pet.
Lafora s disease see epilepsy, generalized, idiopathicsee. Lafora disease genetic and rare diseases information. Lafora disease ld is a fatal childhood epilepsy caused by recessive mutations in either the epm2a or epm2b gene. It is this debilitation which frequently brings the parents of a lafora disease afflicted canine to a decision concerning possible euthanasia. Lafora is a progressive and eventually fatal form of epilepsy. This case study describes in detail a case of lafora disease, from its earliest stages through the clinical progression, including detailed neurophysiological studies, diagnostic biopsy and autopsy. The phosphatase laforin crosses evolutionary boundaries. Lafora disease epilepsy, progressive myoclonic, lafora. Many studies investigated the use of antiepileptic drugs aeds in several neurological diseases other than epilepsy.
Laforin, a dualspecificity phosphatase involved in lafora. These structures were frequently intermingled and stained intensely with silver proteinate, a specific stain for polysaccharides. It is characterised by the presence of lafora bodies polyglucosan inclusions in neurons and other body tissue. Lafora disease frequently develops at 1018 years of age and tranmission is autosomal recessive. Neuronatin might be implicated in the lafora body formation. Lafora progressive myoclonus epilepsy lafora disease is a rare, usually childhoodonset, fatal neurodegenerative disease caused by biallelic mutations in epm2a laforin or epm2b nhlrc1. Ultrastructural studies of muscle from a patient with lafora disease showed sheets of glycogen particles and fine granularfilamentous material between myofibrils.
Lafora body disease definition of lafora body disease by. A hallmark of ld is the accumulation of insoluble polyglucosans called lafora bodies lbs. Malin knockout ko mice present polyglucosan accumulations in several brain areas, as do patients of ld. For instance, in lafora disease ld, deficiencies in an e3 ubiquitin ligase malin or a phosphotyrosineglycogen phosphatase laforin also cause abnormal. Kudos is a free service that helps authors explain, share and measure their article for maximum impact. Lafora disease, is a fatal autosomal recessive genetic disorder characterized by the presence of inclusion bodies, known as lafora bodies, within neurons and the cells of the heart, liver, muscle, and skin. Through this website, the gerber family has been able to help raise awareness about disease, connect with other lafora families, and to help fund research to try to find a cure. Several works report that photoinhibition of ps ii is inversely proportional. Aug 29, 2012 we have identified a new progressive myoclonus epilepsy with lafora bodies, earlyonset lafora body disease, 101 years after lafora disease was first described. Abstractintroductionlafora body disease lbd is a rare autosomal recessive disorder characterized by progression to inexorable dementia and frequent occipital seizures, in addition to myoclonus and generalized tonicclonic seizures gtcss. Unusual course of lafora disease zutt 2016 epilepsia open.
It is caused by mutations in the gene encoding glycogen phosphatase epm2a or the e3 ubiquitin ligase. Diagnosis of lafora body disease by axillary skin biopsy dergipark. Lafora disease, progressive myoclonus epilepsy, genetic study, prdm8, lafora bodies. Progressive myoclonic epilepsies are characterized by the following. Use of antiepileptic drugs for hyperkinetic movement. A dog that has only one mutated lafora gene is a carrier. Ld leads to accumulation of insoluble, abnormal, glycogenlike structures called lafora bodies lbs. Lafora bodies are aggregates of polyglucosans, poorly constructed glycogen molecules with inordinately long. An unusual case of lafora body disease an unusual case of lafora body disease corkill, robin g hardie, richard j. Create codetable from scratch show conversion to icd9cm contact. This is the first larger case series of lafora patients in germany. Symptoms begin in the second decade with progressive myoclonic epilepsy and survival is unusual beyond the age of 30.
A case report abstract lafora disease is a type of progressive myoclonic epilepsy with poor prognosis, characterized by myoclonus, seizures, cerebellar ataxia and mental disorder. Lafora disease definition of lafora disease by medical. Lafora body disease is a rare neurometabolic disorder of autosomal recessive inheritance. A dog must inherit two of the mutated genes, one from each parent to be classified affected. Neuronatin level is increased in the skin biopsy sample of lafora disease patients. These polyglucosan accumulations are called lafora bodies lbs and are profuse in all brain regions and in the majority of neurons, specifically in their cell. Progressive myoclonus epilepsy pme is a rare epilepsy syndrome caused by a variety of genetic disorders. Lafora disease in miniature wirehaired dachshunds plos. Loss of cortical neurons underlies the neuropathology musxular lafora disease. Laforas disease article about laforas disease by the free. Prior to the onset of symptoms, affected children appear to have normal development although some may have isolated febrile or nonfebrile convulsions in infancy or early childhood. Today during the plenary session, he provides a stepbystep description of the pathogenesis of the lafora body and lafora disease. Previously, we and others showed that laforin and malin form a functional.
In lbd patients, typical polyglucosan accumulations result from alterations of proteins involved in the regulation of glycogen metabolism. Case study by mental health aspects of developmental disabilities. Targeting pathogenic lafora bodies in lafora disease using. Lafora disease neurology michigan medicine confluence. Laforin has been shown to stimulate autophagy in an mtordependent fashion, suggest. Only comments seeking to improve the quality and accuracy of information on the orphanet website are accepted. Lafora body disease lbd is severe and rapidly worsening progressive myoclonus epilepsy pme, not treatable with specific therapy. In our patient, however, inclusion bodies were more. The disease is hallmarked not only by seizures, of which jess has all types tc, myoclonic, absence, atonic, complex partial, but also intellectual decline, dementia, trouble speaking, walking and generally doing anything fullfunctioning teens can do. Lafora disease ld is an autosomal recessive progressive myoclonus epilepsy due to mutations in the epm2a laforin and epm2b malin genes, with no substantial genotypephenotype differences. Aug 01, 2015 skin inflammatory nontumor lafora body disease ld this website is intended for pathologists and laboratory personnel, who understand that medical information is imperfect and must be interpreted using reasonable medical judgment. We have identified a new progressive myoclonus epilepsy with lafora bodies, earlyonset lafora body disease, 101 years after lafora disease was first described. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia.
Lafora progressive myoclonus epilepsy ld lafora disease is a fatal autosomal recessive neurodegenerative disorder caused by lossoffunction mutations in either the epm2a gene, encoding the dualspecificity phosphatase laforin, or the epm2b gene, encoding the e3ubiquitin ligase malin. Lafora body is a rarely seen and progressive disease which is characterized by mental decline, myoclonus and generalized epilepsy. Lafora disease ld is a recessively inherited teenage. Epilepsy, progressive myoclonic, lafora progressive myoclonic epilepsy, lafora type lafora body disease lafora body disease, late onset. Mini wires should be dna tested for lafora disease. An approach to developmental regression pdf free download. 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. A hallmark of ld is the intracellular accumulation of insoluble polysaccharide deposits known as lafora bodies lbs in the brain and other tissues. Research open access loss of gabaergic cortical neurons. The disease is due to a mutation in the epm2b gene which results in intracellular accumulation of abnormal glyco gen lafora bodies. Lafora progressive myoclonus epilepsy genetics home.
Diabetes mellitus in a patient with lafora disease. The lafora bodies contain more phosphate and its branching is discontinuous compared to glycogen, which make lafora bodies insoluble in water. Lafora disease is an inherited, severe form of progressive myoclonus epilepsy. Gene therapy to deliver a functional copy of the defective gene would thus be an obvious option for lafora disease treatment fig. Lafora disease ld is an autosomal recessive, neurodegenerative disorder resulting in myoclonus, epilepsy, dementia, and death. The most common feature of lafora disease is recurrent seizures.
Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in. Vagus nerve stimulation in lafora body disease core. Adult polyglucosan body disease apbd is a lateonset disease caused by intracellular. The hallmark of the disease is the accumulation of polyglucosan inclusions called lafora bodies lbs. Other signs and symptoms include difficulty walking, muscle spasms myoclonus and dementia. Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. Nonprofit public benefit california corporation ein. The syndrome includes myoclonic seizures and tonicclonic seizures together with progressive neurological decline.
Although the diet was welltolerated by patients, it did not stop disease progression or improve symptoms. Unlike most metabolic disorders, the link between lafora disease and metabolism has not been defined in almost 100 years. Genotypes and phenotypes of patients with lafora disease living in. Lafora disease is a fatal autosomal recessive, genetic disorder characterized by the presence of inclusion bodies, known as lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin 545 lafora disease is also a neurodegenerative disease that causes impairment in the development of cerebral cortical neurons and is a glycogen metabolism disorder. This disease typically begins between six and nineteen years after apparently normal development and generally results in death within ten years. The impact of a longterm ketogenic diet was studied in five people with lafora disease. The epidemiology of lafora disease in germany is largely unknown.
What lafora disease is it is a progressive neurologic disease characterized by seizures, mioclonia, brain symptoms and psychic deterioration. Targeting pathogenic lafora bodies in lafora disease. Merrf lafora body disease unverrichtelundborg disease juvenile ncl sialidoses. We report an electroencephalographic study in four cases of histologically proven lafora body disease. With loss of function of either, structurally abnormal glycogen becomes insoluble and accumulates as lafora bodies, responsible for disease. However, there are reports of later onset forms of the condition. Apr 01, 2015 group 6 glycogen metabolism in lafora disease. Vagus nerve stimulation in lafora body disease core reader. Some diseases are acute, producing severe symptoms that. Use of antiepileptic drugs for hyperkinetic movement disorders. Expression, purification and characterization of soluble. Lbs are a type of polyglucosan body, an insoluble aggregate of aberrant glycogen found in some gsds and neurodegenerative disorders. Lafora disease genetic and rare diseases information center. The condition most commonly begins with epileptic seizures in late childhood or adolescence.
Also without the laforin protein malin would not be able to locate ptg, gs, and gde. Lafora disease myoclonic epilepsy omim 254780 is a familial, degenerative disorder with the clinical triad of seizures, myoclonus, and dementia. Polyglucosans, or lafora bodies lb are typically found in the brain, periportal hepatocytes of the liver, skeletal and cardiac myocytes, and in the. Senior clinician in neurology neurosurgery the animal health trust, lanwades park, kenford, newmarket introduction epileptic seizures are one of the most common chronic neurological diseases in the canine species.
Jci insight guaiacol as a drug candidate for treating. Sep 29, 2015 lafora disease typically begins between ages 12 and 17 years, after a period of apparently normal development. Lafora disease ld is caused by mutations in either the laforin or malin gene. The results to date suggest that prdm8, the earlyonset lafora body disease protein, regulates the cytoplasmic quantities of the lafora disease enzymes. Nov 12, 2019 lafora progressive myoclonus epilepsy lafora disease is a rare, usually childhoodonset, fatal neurodegenerative disease caused by biallelic mutations in epm2a laforin or epm2b nhlrc1. Neurodegeneration and functional impairments associated. However, given the small study population, the researchers could not exclude the possibility that a ketogenic diet has the potential to slow down the disease progression. The objective of this retrospective case series is to characterize the genotypes and phenotypes of patients with lafora disease. The link between glycogen synthesis, lafora body formation and lafora disease development is further supported by the observation that lowering glycogen synthesis by ptg or glycogen synthase depletion reduces the presence of lafora bodies and ameliorates the pathological manifestations that characterize lafora disease turnbull et al. Lafora disease ubiquitin ligase malin promotes proteasomal.
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