Pdf lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. Lafora disease and congenital generalized lipodystrophy. In the case of lafora disease, disordered cell metabolism leads to the accumulation. Mutations in nhlrc1 cause progressive myoclonus epilepsy. Other signs and symptoms include difficulty walking, muscle spasms myoclonus and dementia. The results of genetic analysis for mutations in epm2a and epm2b genes were negative. Progressive myoclonus epilepsy with lafora inclusion bodies. Typical progression of myoclonic epilepsy of the lafora type. Lafora disease in dogs, though a rare inherited disease, is not generally fatal for your pet. 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 is a rare neurometabolic condition caused by a mutation in the epm2a andor epm2b genes. In humans, lafora disease ld is a severe, progressive form of epilepsy that begins in childhood. We studied biopsy results in a kindred with the lafora form of progressive myoclonic epilepsy. Lafora disease ld is the most severe form of progressive myoclonus epilepsy with teenage onset.
Dec 28, 2007 lafora disease ld is characterized by fragmentary, symmetric, or generalized myoclonus andor generalized tonicclonic seizures, visual hallucinations occipital seizures, and progressive neurologic degeneration including cognitive andor behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. Recently, a humanized antigenbinding fragment hfab derived from a murine systemic lupus erythematosus dna. Lafora disease was diagnosed based on skin biopsy results, which revealed pathognomonic lafora bodies. Lafora disease genetic and rare diseases information. Lafora disease, seizures and sugars pubmed central pmc. Lafora disease ld is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Jun 21, 2019 lafora disease ld is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. As seizures increase in frequency, cognitive function declines towards dementia, and. A form of stimulus sensitive myoclonic epilepsy inherited as an autosomal recessive condition. Lafora disease is fatal intractable progressive myoclonic epilepsy. Sep 29, 2015 lafora disease is an inherited, severe form of progressive myoclonus epilepsy. 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. Unusual course of lafora disease university of groningen.
Treatment with metformin in twelve patients with lafora disease. It is important to know that myoclonus is a clinical sign and not a disease. The mission of chelseas hope is to raise funds for research, treatment, and ultimately, a cure for those affected by lafora disease. The disease most commonly starts as epileptic seizures in adolescence. Pdf lafora disease ld is an autosomal recessive progressive myoclonus epilepsy due to mutations in the epm2a. Two of her bitches tested as carriers of the autosomal recessive condition that was first recognized in mini wirehairs in the u. What lafora disease is it is a progressive neurologic disease characterized by seizures, mioclonia, brain symptoms and psychic deterioration.
Blood samples were collected from 733 mwhds worldwide, mostly of uk origin, for canine lafora disease testing. The disease is due to a mutation in the epm2b gene which results in intracellular accumulation of abnormal glycogen lafora bodies. We chronicle here an unusual case of an asymptomatic young male soccer player who presented with elevated liver enzymes. Researchers coordinate efforts to find cure for lafora disease back chelsea gerber is the inspiration behind chelseas hope, an organization dedicated to supporting awareness, research, treatment, and cures for those affected by lafora disease. At the time of onset, lafora disease is difficult to distinguish from idiopathic generalized epilepsies 8. Lafora disease ld is an adolescenceonset, genetic, and fatal form of neurodegenerative disorder with disease defining symptoms such as progressive myoclonus epilepsy, ataxia, muscle wasting, and intellectual disabilities. Over time, insoluble starch platelets gradually build up in the central nervous system. Some diseases are acute, producing severe symptoms that terminate after a short time, e.
Join researchgate to discover and stay uptodate with the latest research from leading experts in lafora disease and many other. Genotypes and phenotypes of patients with lafora disease. Lafora disease ld, omim254780 is a rare and fatal form of progressive myoclonus epilepsy pme. Lafora bodies have also been described in the central nervous system of dogs with neurologic disease and in the skeletal muscle fibers and peripheral nerves of dogs with familial myoclonic epilepsy. What lafora disease is it is a progressive neurologic disease characterized by seizures. Download our lafora disease information leaflet or visit the whdc list of lafora screening test results and their lafora news page. Among pmes, ld is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogenlike polyglucosan inclusions, named lafora bodies lbs. Typical progression of myoclonic epilepsy of the lafora. Unfortunately, the field of rare diseases as a whole suffers from a shortage of medical and scientific knowledge, largely due to lack of awareness and funding sources. Lafora disease ld, an autosomal recessive neurodegenerative disorder, is characterized by the presence of cytoplasmic polyglucosan inclusions known as lafora bodies in several tissues including the brain. Mar 27, 2007 lafora disease ld can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. The epm2a gene encodes a protein having an active catalytic site of a protein tyrosine phosphatase. Listing a study does not mean it has been evaluated by the u.
The symptoms usually start in the teenage years, and development. It causes severe seizures, leading to dementia and eventually death in early adulthood. If you have problems viewing pdf files, download the latest version of adobe reader. Several different types of seizures have been reported. Malin is an e3ubiquitin ligase that is mutated in lafora disease, a fatal form of. Lafora disease is the principal form of adolescenceonset progressive myoclonus epilepsy. Locus heterogeneity led us to search for a second gene. 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. Earlyonset lafora body disease brain oxford academic. Lafora disease ld is a fatal, autosomal recessive glycogen storage disease that results in progressive neurodegeneration with epilepsy, dementia, and myoclonus. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Lafora disease ld is an autosomal recessive progressive myoclonus epilepsy due to mutations in the epm2a laforin and epm2b malin genes, with no substantial. Several types of seizure typically occur in patients with lafora disease, including myoclonic, occipital. Lafora disease is a neurodegenerative disorder, like alzheimers, parkinsons and huntingtons. Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. Pdf lafora disease from pathogenesis to treatment strategies. Genetic mapping of a new lafora progressive myoclonus. 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 cure for all diseases with many case histories of diabetes, high blood pressure, seizures, chronic fatigue syndrome, migraines, alzheimers, parkinsons, multiple sclerosis, and others showing that all of these can be simply investigated and cured. The most common feature of lafora disease is recurrent seizures. Mutations in two genes, epm2a encoding laforin and nhlrc1 encoding malin, account for the majority of mutations causing lafora disease and are. Lafora disease causes seizures, muscle spasms, difficulty walking, dementia, and eventually death. Genedx 207 perry parkway gaithersburg, md 20877 toll free. Patients present with an epileptic event in their early to midteen years, and these episodes along with the cognitive decline and myoclonus progressively increase until death approximately 10 years later because of respiratory. Myoclonus is a term used to describe episodes of sudden, involuntary muscle jerking or. The signs and symptoms of lafora disease generally appear during late childhood or adolescence. Genotypes and phenotypes of patients with lafora disease living in. Laforin and malin play a critical role in the survival of nerve cells neurons in the brain studies suggest that laforin and malin work together and may have several functions. 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. In humans also, another gene, laforin epm2a causes the disease, but epm2a has not been associated with it in dogs 17. The disorder is neurologically progressive, and the disease is eventually fatal.
Lafora disease in dogs is caused by a repeat expansion mutation in the nhl repeat containing e3 ubiquitin protein ligase 1 nhlrc1 gene 6, 8, a gene known to cause lafora disease in humans. Seizure control and improvement of neurological dysfunction in. Chelseas hope, post office box 348626, sacramento, ca 95834. Progression of electroencephalography eeg changes in a patient with lafora disease.
Lafora disease ld is an autosomal recessive late onset, progressive myoclonic epilepsy with a high prevalence in the miniature wirehaired dachshund. Central nervous system delivery and biodistribution. Lafora disease is a rare, autosomal recessive, progressive myoclonic epilepsy with onset typically in the second decade of life and uniformly fatal outcome. 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 ld is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called lafora bodies lbs. For this reason, in 2016, the european medicines agency granted orphan designation to metformin for the treatment of ld. Apparently healthy older children or teenagers start having seizures, which can initially be controlled with antiepileptic drugs aeds 8,9. A recurrent homozygous nhlrc1 variant in siblings with lafora. Icd10cmpcs codes version 201620172018, icd10 data search engine. It will, however, likely cause significant debilitation to your canine family member as the disease progresses. Lafora disease is a hereditary disorder and is known to be transmitted as an autosomal recessive pattern. The signs and symptoms of the disorder usually appear in late childhood or adolescence and worsen with time.
Lafora disease affects a small number of people compared to the general population and is considered rare in many parts of the world. Lafora disease can be made by detection of polyglucosan. In total, he published approximately 200 papers covering a wide range of. It is classified as lafora disease by the presence of lafora bodies, a specific type of inclusion bodies that are present in all organs, and current research shows that it is caused by a mutation of three genes on the sixth chromosome. Most patients are completely normal in childhood, with the exception of early learning difficulties in some ganesh et al. Many different sequence mutations as well as several microdeletions in epm2a have been found that cosegregate with lafora s disease. Rarely, it begins in 5 to 6 year old children as a learning disorder. Lafora disease myoclonic epilepsy omim 254780 is a familial, degenerative disorder with the clinical triad of seizures, myoclonus, and dementia. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous epm2a mutation and patients with apparently homozygous epm2b mutations where one parent is not a. Lafora disease is an inherited form of epilepsy that affects miniature wirehaired dachshunds. Lafora disease presents as a neurodegenerative disorder that causes impairment in the development of cerebral cortical neurons. Lafora progressive myoclonus epilepsy is a brain disorder characterized by recurrent seizures epilepsy and a decline in intellectual function.
Wed like to understand how you use our websites in order to improve them. Ld leads to accumulation of insoluble, abnormal, glycogenlike structures called lafora bodies lbs. This is the first case report describing an association between congenital generalized lipodystrophy and lafora disease. Lafora s aforas disease is a rare form of myoclonus epilepsy. Mar 27, 2018 canine lafora disease is caused by a dodecamer repeat expansion mutation in the nhlrc1 gene and a dna test is available to identify homozygous dogs at risk, carriers and dogs free of the mutation. Recent breedwide testing suggests that the carrier plus affected rate may be as high as 20%. One lafora disease gene, epm2a, has been identified on chromosome 6q24. Miniature wirehaired dachshund breeder dianne graham of pulaski, virginia, learned about lafora disease five years ago when she discovered an english dog in her dogs pedigree was affected. Nationwide genetic testing towards eliminating lafora. Lafora is a progressive and eventually fatal form of epilepsy. Symptoms develop because the dog cannot efficiently process starch into sugar. Lafora progressive myoclonus epilepsy can be caused by mutations in either the epm2a gene or the nhlrc1 gene. Lafora disease ld is a severe form of progressive myoclonic epilepsy, which typically begins in adolescents between ages 12 to 17 with an apparently normal developmental process. The condition is characterised by a late onset of epilepsy, myoclonus and dementia.
If your dog shows symptoms, alert the breeder of your dog now and get your dog tested as soon as possible. Most of the current literature focuses on diagnosis, genetic basis, neurological signs, and possible treatment of this currently incurable disease. A form of progressive myoclonic epilepsy, it can produce a variety of complications including intellectual disability, various seizure disorders, mental health. Researchers coordinate efforts to find cure for lafora disease. Myoclonus is a brief, involuntary twitching of a muscle or a group of muscles. Treatment with metformin in twelve patients with lafora. Biopsies of other organs can also be diagnostic but are more invasive. These genes provide instructions for making proteins called laforin and malin, respectively.
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. A collection of disease information resources and questions answered by our genetic and rare diseases information specialists for lafora disease. It is frequently characterized by epileptic seizures, difficulty walking, muscle spasms, and dementia in late childhood or adolescence. He was best known now for describing in 1911 the intracytoplasmic inclusion bodies in lafora disease. Founder effects and recurrent mutations are common, and mostly isolated to specific ethnic groups andor geographical locations. Nationwide genetic testing towards eliminating lafora disease. Lafora disease also known as lafora body disease is a rare neurometabolic disorder of autosomal recessive inheritance, which is generally caused by a mutation in epm2a 4,8, or epm2b genes. Lafora disease from pathogenesis to treatment strategies.
Lafora disease is a rare, genetic, glycogen metabolism disorder inherited as autosomal recessive characterized by the presence of inclusion bodies, known as lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin. It is this debilitation which frequently brings the parents of a lafora disease afflicted canine to a decision concerning possible euthanasia. It is caused by mutations in the gene encoding glycogen phosphatase epm2a or the e3 ubiquitin ligase. Check the status of your dogs dam, sire and known littermates on the kennel club test. Described for the first time in 1911 by gonzalo rodriguez lafora 18861971 a spanish neurologist. Biopsy results in a kindred with lafora disease jama. Publishers pdf, also known as version of record publication date. A novel gene epm2a that is deleted or mutated in people with lafora s disease is described. Studies on a mouse model of ld showed a good response to metformin, a drug with a well known neuroprotective effect. Disease bioinformatics lafora disease lafora progressive myoclonic epilepsy is a rare recessive genetic form of epilepsy.
The objective of this retrospective case series is to characterize the genotypes and phenotypes of patients with lafora disease. Lafora disease is a progressive myoclonus epilepsy with polyglucosan accumulations and a peculiar neurodegeneration with generalised organellar disintegration. Ld is characterized by myoclonus involuntary muscle contractions of diverse typology, as well as tonicclonic seizures stiffening and jerking movements. Lafora disease in miniature wirehaired dachshunds plos. Novel therapeutic strategy for treating lafora disease.
Laforin, a protein phosphatase, and malin, an ubiquitin ligase, are two of the proteins that are known to be defective in ld. Lafora progressive myoclonus epilepsy genetics home. Lafora disease definition of lafora disease by medical. Cancer, other pathologies, inflammation, immunity, infection, and aging, 2016. There is more information about lafora disease in our health information library. The signs and symptoms of lafora disease generally appear during late. It has an autosomal recessive mode of inheritance and is almost universally fatal by the second or third decade of life. Medical and mental health complications of lafora disease. Lafora disease genetic and rare diseases information center. Death within four to ten years has been the inevitable outcome in all reported cases.
After the diagnosis was established by brain biopsy in the first patient, many. Ld is caused by mutations in the epm2a gene, encoding the dual phosphatase. Lafora disease epilepsy, progressive myoclonic, lafora. Diabetes mellitus in a patient with lafora disease. Dr rodriguez lafora was the first to describe lafora disease in 1911. Four members of a family with known consanguinity presented as teenagers with seizures, myoclonus, dementia, and ataxia. The epidemiology of lafora disease in germany is largely unknown. 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. Lafora disease in dogs lafora disease is a hereditary disorder and is known to be transmitted as an autosomal recessive pattern. Lafora disease is an inherited myoclonus epilepsy syndrome. Laforas disease article about laforas disease by the. Delivery of proteinbased therapeutics to the central nervous system cns for the clearance of lbs remains a unique challenge in the field. Chelseas hope lafora children research fund is an irs 501c3 nonprofit organization. A at the time of disease onset age 17 years there is normal to slightly slowed background activity.
The condition most commonly begins with epileptic seizures in late childhood or adolescence. Lafora disease e3ubiquitin ligase malin is related to. The inclusion bodies found in lafora disease are not present in unaffected parents and siblings carriers. Editor jul 25 2019 a team of scientists have designed and tested in mice a novel and promising therapeutic strategy for treating lafora disease. Lafora disease proteins malin and laforin are recruited to. Lafora disease in dogs symptoms, causes, diagnosis. 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. Earliest symptoms are headaches, decline in school performance, spontaneous and induced myoclonus, and convulsive seizures, with eeg showing. Other than for strictly personal use, it is not permitted to download or to forwarddistribute the text or part of it without the consent of the. The condition is characterized by epilepsy, myoclonus and dementia. 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.
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