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