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{{Infobox medical condition
{{Infobox medical condition
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| Name = Lafora disease
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'''Lafora disease''', also called '''Lafora progressive myoclonic epilepsy''' or '''MELF''',<ref>http://www.rightdiagnosis.com/medical/melf.htm</ref> is a fatal [[autosomal]] [[recessive]]<ref name=lpme>{{cite journal |vauthors=Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA |title=Lafora progressive Myoclonus Epilepsy mutation database - EPM2A and NHLRC1 (EPM2B) genes |journal=Hum. Mutat. |volume=26 |issue=4 |pages=397 |year=2005 |pmid=16134145 | doi = 10.1002/humu.9376}}</ref> [[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.<ref name="Andrews">{{cite book |author=James, William D. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate= |last2=Berger |first2=Timothy G. }}</ref>{{rp|545}} In a later study, Lafora disease has been and is now viewed as a [[neurodegenerative disease]], since prior to the actual formation of Lafora bodies there has been seen to be an impairment in the development of cerebral cortical neurons. It was further concluded that Lafora disease is a complex neurodegenerative disease and also a glycogen metabolism disorder.<ref>Ortolano S, Vieitez I et al. Loss of cortical neurons underlies the neuropathology of Lafora disease. Mol Brain 2014;7:7 {{PMC|3917365}}</ref>
'''Lafora disease''', also called '''Lafora progressive myoclonic epilepsy''' or '''MELF''',<ref>http://www.rightdiagnosis.com/medical/melf.htm</ref> is a fatal [[autosomal]] [[recessive]]<ref name=lpme>{{cite journal |vauthors=Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA |title=Lafora progressive Myoclonus Epilepsy mutation database - EPM2A and NHLRC1 (EPM2B) genes |journal=Hum Mutat. |volume=26 |issue=4 |pages=397 |year=2005 |pmid=16134145 | doi = 10.1002/humu.9376}}</ref> [[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.<ref name="Andrews">{{cite book |author=James, William D. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate= |last2=Berger |first2=Timothy G. }}</ref>{{rp|545}} Lafora disease is also a [[neurodegenerative disease]] that causes impairment in the development of cerebral cortical [[Neuron|neurons]] and it is a [[glycogen]] metabolism disorder.<ref>Ortolano S, Vieitez I et al. Loss of cortical neurons underlies the neuropathology of Lafora disease. Mol Brain 2014;7:7 {{PMC|3917365}}</ref>


Individuals who suffer from Lafora disease are not limited to humans, dogs can suffer as well. Typically Lafora is rare in American children but has a high occurrence in children from Southern European descent (Italy, France, Spain) and can also be found in children from South Asian countries (Pakistan, India) and even as far south as North Africa<ref>{{Cite web|url=http://www.myhealthyfeeling.com/lafora-disease-symptoms-causes-treatment/|title=Lafora Disease-Symptoms, Causes, Treatment|website=www.myhealthyfeeling.com|language=en-US|access-date=2017-11-07}}</ref>. As for canines, Lafora disease can spontaneously occur in any breed but the Miniature Wire Haired [[Dachshund]], [[Basset Hound|Bassett Hound]], and the [[Beagle]] are predisposed to LD.<ref>{{Cite web|url=http://www.canineepilepsy.co.uk/lafora-disease-research.html|title=Lafora disease research|last=Kamm|first=Kurt|website=www.canineepilepsy.co.uk|language=en-GB|access-date=2017-11-07}}</ref>
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Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable.<ref name=1pme>{{cite journal |author=Minassan |title=Lafora's Disease:Towards a Clinical, Pathologic, and Molecular Synthesis |journal=Pediatr Neurol |volume=25 |pages=21–29 |year=2000 |doi=10.1016/S0887-8994(00)00276-9 |pmid=11483392 |issue=1}}</ref> At present, there is no cure or treatment for this disease.

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Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable.<ref name=1pme>{{cite journal |author=Minassan |title=Lafora's Disease:Towards a Clinical, Pathologic, and Molecular Synthesis |journal=Pediatr Neurol |volume=25 |pages=21–29 |year=2000 |doi=10.1016/S0887-8994(00)00276-9 |pmid=11483392 |issue=1}}</ref> At present, there is no cure for this disease but there are ways to deal with symptoms through treatments and medications.


== Signs and Symptoms ==
== Signs and Symptoms ==
Symptoms of Lafora disease begin to develop during early [[adolescence|adolescent]] years and symptoms progress to worsen as time passes. The first ten years of life there is generally no indication of the presence of the disease. <ref>{{Cite web|url=http://www.myhealthyfeeling.com/lafora-disease-symptoms-causes-treatment/|title=Lafora Disease-Symptoms, Causes, Treatment|website=www.myhealthyfeeling.com|language=en-US|access-date=2017-11-07}}</ref> The most common feature of Lafora disease is seizures that have been reported mainly as [[Occipital lobe|occipital]] seizures and [[Myoclonus|myoclonic]] seizures with some cases of generalized [[Generalised tonic-clonic seizure|tonic-clonic]] seizures, atypical absence seizures, and [[Atonic seizure|atonic]] and [[Complex partial seizure|complex partial]] seizures. <ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/8214/lafora-disease#diseaseSymptomsSection|title=Lafora disease {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2017-12-09}}</ref> <ref>{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK1389/|title=GeneReviews®|last=Jansen|first=Anna C.|last2=Andermann|first2=Eva|date=1993|publisher=University of Washington, Seattle|editor-last=Adam|editor-first=Margaret P.|location=Seattle (WA)|pmid=20301563|editor-last2=Ardinger|editor-first2=Holly H.|editor-last3=Pagon|editor-first3=Roberta A.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Bean|editor-first5=Lora JH|editor-last6=Mefford|editor-first6=Heather C.|editor-last7=Stephens|editor-first7=Karen|editor-last8=Amemiya|editor-first8=Anne|editor-last9=Ledbetter|editor-first9=Nikki}}</ref> Other symptoms common with the seizures are [[drop attack]]s, [[ataxia]], temporary blindness, visual [[Hallucination|hallucinations]], and a quickly-developing and dramatic [[dementia]].<ref name=lpme/><ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/8214/lafora-disease#diseaseSymptomsSection|title=Lafora disease {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2017-12-09}}</ref>
Patients develop the first [[symptoms]] mainly during [[adolescence]]. Major problems include seizures, [[drop attack]]s, [[myoclonus]], [[ataxia]], and, most significantly, a quickly-developing and dramatic [[dementia]].<ref name=lpme/>


Other common signs and symptoms associated with Lafora disease are behavioral changes because of the frequency of seizures. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref> Over time those affected with Lafora disease have brain changes that cause things such as confusion, speech difficulties, [[Depression (mood)|depression]], decline in intellectual function, and impaired judgement and memory. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref> If area's of the [[cerebellum]] are affected by seizures then it is common to see issues with speech, coordination, and balance in Lafora patients. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref>
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== Genetics ==
Lafora disease is an autosomal recessive disorder, caused by mutations in one of three known genes: EPM2A, EPM2B, and NHLRC1.<ref>Minassian, B. A.; Lee, J. R.; Herbrick, J.-A.; Huizenga, J.; Soder, S.; Mungall, A. J.; Dunham, I.; Gardner, R.; Fong, C. G.; Carpenter, S.; Jardim, L.; Satishchandra, P.; Andermann, E.; Snead, O. C., III; Lopes-Cendes, I.; Tsui, L.-C.; Delgado-Escueta, A. V.; Rouleau, G. A.; Scherer, S. W.: Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nature Genet. 20: 171-174, 1998.</ref><ref>Chan, E. M.; Bulman, D. E.; Paterson, A. D.; Turnbull, J.; Andermann, E.; Andermann, F.; Rouleau, G. A.; Delgado-Escueta, A. V.; Scherer, S. W.; Minassian, B. A.: Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22. J. Med. Genet. 40: 671-675, 2003.</ref><ref>(J Neurol Sci 2013;325:170, Brain 2012;135:2684)</ref>( edit : two genes: the EPM2A gene and the NHLRC1 gene which was previously known as the EPM2B gene. A third gene - PRDM8 gene- MAY cause an early onset form of the disease ). EPM2A codes for the protein [[laforin]], a [[dual-specificity phosphatase]] with a [[Carbohydrate-binding module|carbohydrate binding domain]] (CBM-20). Vertebrates have only one such protein with DSP domain as well as CBM-20 domain. EPM2B encodes the protein malin, an E3 [[ubiquitin ligase]]. All three discovered genes are present on [[chromosome 6p23-27]] in humans.


For dogs that are affected with Lafora disease, common symptoms are rapid shuddering, shaking, or jerking of the canine's head backwards, high pitched vocalizations that could indicate the dog is panicking, seizures, and as the disease progresses dementia, blindness, and loss of balance. <ref>{{Cite web|url=https://wagwalking.com/condition/lafora-disease|title=Lafora Disease in Dogs - Symptoms, Causes, Diagnosis, Treatment, Recovery, Management, Cost|website=WagWalking|language=en|access-date=2017-12-12}}</ref>
== Pathophysiology ==
[[Image:autorecessive.svg|thumb|right|Lafora disease has an [[autosomal recessive]] pattern of inheritance.]]
Current understanding of pathophysiology is largely restricted to understanding the generation of Lafora bodies, and their exclusive appearance in neurons and not in astrocytes.


== Lafora Bodies ==
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Normal [[glycogen]] is soluble in the cellular environment, which has been attributed to its fractal structure. By contrast, the "abnormal glycogen" in Lafora bodies has an excessive phosphate content and branches at abnormally long intervals. It has been shown that laforin [[Dephosphorylation|dephosphorylates]] glycogen and preserves its solubility. Hence, in a laforin mutation, glycogen would be hyperphosphorylated. This has been confirmed in laforin knock-out mice.<ref>{{cite journal|last1=Mathieu|first1=Cécile|last2=de la Sierra-Gallay|first2=Ines Li|last3=Duval|first3=Romain|last4=Xu|first4=Ximing|last5=Cocaign|first5=Angélique|last6=Léger|first6=Thibaut|last7=Woffendin|first7=Gary|last8=Camadro|first8=Jean-Michel|last9=Etchebest|first9=Catherine|last10=Haouz|first10=Ahmed|last11=Dupret|first11=Jean-Marie|last12=Rodrigues-Lima|first12=Fernando|title=Insights into Brain Glycogen Metabolism|journal=Journal of Biological Chemistry|date=26 August 2016|volume=291|issue=35|pages=18072–18083|doi=10.1074/jbc.M116.738898}}</ref>
Lafora disease is distinguished by the presence of inclusions called "Lafora bodies" within the [[cytoplasm]] of cells. Lafora bodies are aggregates of [[polyglucosan]]s or abnormally shaped glycogen molecules. <ref>{{Cite journal|last=Turnbull|first=Julie|last2=Girard|first2=Jean-Marie|last3=Lohi|first3=Hannes|last4=Chan|first4=Elayne M.|last5=Wang|first5=Peixiang|last6=Tiberia|first6=Erica|last7=Omer|first7=Salah|last8=Ahmed|first8=Mushtaq|last9=Bennett|first9=Christopher|date=2012-9|title=Early-onset Lafora body disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437029/|journal=Brain|volume=135|issue=9|pages=2684–2698|doi=10.1093/brain/aws205|issn=0006-8950|pmc=PMC3437029|pmid=22961547}}</ref> Glycogen in Lafora disease patients has abnormal chain lengths which directly causes them to be insoluble, accumulate, and have a neurotoxic effect. <ref>{{Cite journal|last=Nitschke|first=Felix|last2=Sullivan|first2=Mitchell A|last3=Wang|first3=Peixiang|last4=Zhao|first4=Xiaochu|last5=Chown|first5=Erin E|last6=Perri|first6=Ami M|last7=Israelian|first7=Lori|last8=Juana‐López|first8=Lucia|last9=Bovolenta|first9=Paola|date=2017-7|title=Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494504/|journal=EMBO Molecular Medicine|volume=9|issue=7|pages=906–917|doi=10.15252/emmm.201707608|issn=1757-4676|pmc=PMC5494504|pmid=28536304}}</ref>


For glycogen to be soluble, there must be short chains and a high frequency of branching points, but this is not found in the glycogen in Lafora patients. LD patients have longer chains that have clustered arrangment of branch points that form crystalline areas of double helices making it harder for them to clear the blood-brain barrier. <ref>{{Cite journal|last=Nitschke|first=Felix|last2=Sullivan|first2=Mitchell A|last3=Wang|first3=Peixiang|last4=Zhao|first4=Xiaochu|last5=Chown|first5=Erin E|last6=Perri|first6=Ami M|last7=Israelian|first7=Lori|last8=Juana‐López|first8=Lucia|last9=Bovolenta|first9=Paola|date=2017-7|title=Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494504/|journal=EMBO Molecular Medicine|volume=9|issue=7|pages=906–917|doi=10.15252/emmm.201707608|issn=1757-4676|pmc=PMC5494504|pmid=28536304}}</ref> The glycogen in LD patients is also has higher phosphate levels and they are present in greater quantities. <ref>{{Cite journal|last=Nitschke|first=Felix|last2=Sullivan|first2=Mitchell A|last3=Wang|first3=Peixiang|last4=Zhao|first4=Xiaochu|last5=Chown|first5=Erin E|last6=Perri|first6=Ami M|last7=Israelian|first7=Lori|last8=Juana‐López|first8=Lucia|last9=Bovolenta|first9=Paola|date=2017-7|title=Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494504/|journal=EMBO Molecular Medicine|volume=9|issue=7|pages=906–917|doi=10.15252/emmm.201707608|issn=1757-4676|pmc=PMC5494504|pmid=28536304}}</ref>
Research literature suggests that over-activity of [[glycogen synthase]], the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans. Glycogen synthase can be inactivated by phosphorylation at various amino acid residues by many molecules, including GSK-3beta. [[Protein phosphatase 1]] can take out these phosphate moieties and make glycogen synthase active. However, PP-1 needs other proteins, like PTG (Protein Targeted to Glycogen), to assist. Malin, another protein mutated in Lafora disease, aids in the degradation of PTG, with assistance from laforin via the ubiquitin proteasome system (UPS). Hence in a malin mutation, PTG might accumulate and cause excessive glycogen synthase activity, leading to abnormal glycogen production. However, this supposition has not been confirmed by animal models.


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== Genetics and Mechanism ==
Neurons, though having a capacity to express glycogen synthase, lack capacity to degrade it. They seem not to have glycogen phosphorylase, which is present in astrocytes to degrade glycogen. Astrocytes contribute almost exclusively to brain glycogen storage yet do not develop Lafora bodies, which might highlight the importance of the capacity to degrade glycogen. In a laforin or malin mutation, a laforin–malin complex would cease to exist and drive neurons to make glycogen. This could be detrimental to neuronal function and possibly result in the manifestation of dementia.
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). <ref>{{Cite journal|last=Kecmanović|first=Miljana|last2=Keckarević-Marković|first2=Milica|last3=Keckarević|first3=Dušan|last4=Stevanović|first4=Galina|last5=Jović|first5=Nebojša|last6=Romac|first6=Stanka|date=2016-05-02|title=Genetics of Lafora progressive myoclonic epilepsy: current perspectives|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859416/|journal=The Application of Clinical Genetics|volume=9|pages=49–53|doi=10.2147/TACG.S57890|issn=1178-704X|pmc=PMC4859416|pmid=27194917}}</ref><ref>{{Cite web|url=https://ghr.nlm.nih.gov/condition/lafora-progressive-myoclonus-epilepsy#inheritance|title=Lafora progressive myoclonus epilepsy|last=Reference|first=Genetics Home|website=Genetics Home Reference|language=en|access-date=2017-12-12}}</ref> These mutations in either of these two genes leads to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin.<ref>{{Cite journal|last=Kecmanović|first=Miljana|last2=Keckarević-Marković|first2=Milica|last3=Keckarević|first3=Dušan|last4=Stevanović|first4=Galina|last5=Jović|first5=Nebojša|last6=Romac|first6=Stanka|date=2016-05-02|title=Genetics of Lafora progressive myoclonic epilepsy: current perspectives|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859416/|journal=The Application of Clinical Genetics|volume=9|pages=49–53|doi=10.2147/TACG.S57890|issn=1178-704X|pmc=PMC4859416|pmid=27194917}}</ref>


EPM2A codes for the protein [[laforin]], a [[dual-specificity phosphatase]] that acts on carbohydrates by taking phosphates off. <ref>{{Cite journal|last=Kecmanović|first=Miljana|last2=Keckarević-Marković|first2=Milica|last3=Keckarević|first3=Dušan|last4=Stevanović|first4=Galina|last5=Jović|first5=Nebojša|last6=Romac|first6=Stanka|date=2016-05-02|title=Genetics of Lafora progressive myoclonic epilepsy: current perspectives|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859416/|journal=The Application of Clinical Genetics|volume=9|pages=49–53|doi=10.2147/TACG.S57890|issn=1178-704X|pmc=PMC4859416|pmid=27194917}}</ref>
Removal of PTG in mice resulted in the near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy.<ref name=Turnbull2011>Turnbull J, Depaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, Piliguian M, Roach PJ, Wang P, Ackerley CA, Minassian BA (2011) PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. PLoS Genet 7(4):e1002037</ref>

NHLRC1 encodes the protein malin, an E3 [[ubiquitin ligase]], that regulates the amount of laforin.<ref>{{Cite journal|last=Kecmanović|first=Miljana|last2=Keckarević-Marković|first2=Milica|last3=Keckarević|first3=Dušan|last4=Stevanović|first4=Galina|last5=Jović|first5=Nebojša|last6=Romac|first6=Stanka|date=2016-05-02|title=Genetics of Lafora progressive myoclonic epilepsy: current perspectives|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859416/|journal=The Application of Clinical Genetics|volume=9|pages=49–53|doi=10.2147/TACG.S57890|issn=1178-704X|pmc=PMC4859416|pmid=27194917}}</ref>

Laforin is essential for making the right structure of glycogen. When the mutation occurs on the EPM2A gene, laforin protein is downregulated and less amount of this protein is present or none is made at all. If there is also a mutation in the NHLRC1 gene that makes the protein malin, then laforin cannot be regulated and thus less of it is made.

Less Laforin means more phosphorylation of glycogen, causing conformational changes rendering it insoluble and that is why it builds up and accumulates having neurotoxic effects. [[Image:autorecessive.svg|thumb|right|Lafora disease has an [[autosomal recessive]] pattern of inheritance.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/condition/lafora-progressive-myoclonus-epilepsy#inheritance|title=Lafora progressive myoclonus epilepsy|last=Reference|first=Genetics Home|website=Genetics Home Reference|language=en|access-date=2017-12-12}}</ref> EPM2A gene found on chromosome 6q24 and NHLRC1 gene found on chromosome 6p22.3. <ref>{{Cite journal|last=Ianzano|first=Leonarda|last2=Zhang|first2=Junjun|last3=Chan|first3=Elayne M.|last4=Zhao|first4=Xiao-Chu|last5=Lohi|first5=Hannes|last6=Scherer|first6=Stephen W.|last7=Minassian|first7=Berge A.|date=October 2005|title=Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes|url=https://www.ncbi.nlm.nih.gov/pubmed/16134145|journal=Human Mutation|volume=26|issue=4|pages=397|doi=10.1002/humu.9376|issn=1098-1004|pmid=16134145}}</ref>]]
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In other words, in a laforin mutation, glycogen would be hyperphosphorylated and this has been confirmed in laforin knock-out mice.<ref>{{cite journal|last1=Mathieu|first1=Cécile|last2=de la Sierra-Gallay|first2=Ines Li|last3=Duval|first3=Romain|last4=Xu|first4=Ximing|last5=Cocaign|first5=Angélique|last6=Léger|first6=Thibaut|last7=Woffendin|first7=Gary|last8=Camadro|first8=Jean-Michel|last9=Etchebest|first9=Catherine|last10=Haouz|first10=Ahmed|last11=Dupret|first11=Jean-Marie|last12=Rodrigues-Lima|first12=Fernando|title=Insights into Brain Glycogen Metabolism|journal=Journal of Biological Chemistry|date=26 August 2016|volume=291|issue=35|pages=18072–18083|doi=10.1074/jbc.M116.738898}}</ref>

Research literature also suggests that over-activity of [[glycogen synthase]], the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans and it can be inactivated by phosphorylation at various amino acid residues by many molecules, including GSK-3beta, Protein phosphatase 1, and malin. <ref>{{Cite journal|last=Wang|first=Wei|last2=Lohi|first2=Hannes|last3=Skurat|first3=Alexander V.|last4=DePaoli-Roach|first4=Anna A.|last5=Minassian|first5=Berge A.|last6=Roach|first6=Peter J.|date=2007-01-15|title=Glycogen metabolism in tissues from a mouse model of Lafora disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577384/|journal=Archives of biochemistry and biophysics|volume=457|issue=2|pages=264–269|doi=10.1016/j.abb.2006.10.017|issn=0003-9861|pmc=PMC2577384|pmid=17118331}}</ref><ref>{{Cite journal|last=Sullivan|first=Mitchell A.|last2=Nitschke|first2=Silvia|last3=Steup|first3=Martin|last4=Minassian|first4=Berge A.|last5=Nitschke|first5=Felix|date=2017-08-11|title=Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578133/|journal=International Journal of Molecular Sciences|volume=18|issue=8|doi=10.3390/ijms18081743|issn=1422-0067|pmc=PMC5578133|pmid=28800070}}</ref> <ref>{{Cite journal|last=Ianzano|first=L|last2=Zhao|first2=XC|last3=Minassian|first3=BA|last4=Scherer|first4=SW|date=2003/06|title=Identification of a novel protein interacting with laforin, the EPM2a progressive myoclonus epilepsy gene product.|url=http://europepmc.org/abstract/MED/12782127|journal=Genomics|language=en|volume=81|issue=6|doi=10.1016/S0888-7543(03)00094-6|issn=0888-7543}}</ref>

So as mutations arise in the production of these molecules (GSK-3beta, PP1, and malin), excessive glycogen synthase activity occurs in combination with mutations in laforin that phosphorylates the excess of glycogen being made rendering the large amount of them insoluble. The key player missing is ubiquitin. It is not able to degrade the excess amount of the insoluble lafora bodies. Since mutations arise in malin, an e3 ubiquitin ligase, this directly interferes with the degradation of laforin causing the laforin not to be degraded and it can then hyperphosphorylate. <ref>{{Cite journal|last=Gentry|first=Matthew S.|last2=Worby|first2=Carolyn A.|last3=Dixon|first3=Jack E.|date=2005-06-14|title=Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin|url=http://www.pnas.org/content/102/24/8501|journal=Proceedings of the National Academy of Sciences of the United States of America|language=en|volume=102|issue=24|pages=8501–8506|doi=10.1073/pnas.0503285102|issn=0027-8424|pmid=15930137}}</ref>


== Diagnosis ==
== Diagnosis ==
{{Unreferenced section|date=April 2013}}
{{Unreferenced section|date=April 2013}}
Lafora Disease is diagnosed by doing a series of tests by a neurologist, epileptologist (person who specializes in epilepsy), or geneticist. To confirm the diagnosis, an EEG, MRI, and genetic testing are needed to detect the activity of the brain and potential genetic relation to Lafora Disease. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref> A biopsy may be necessary as well to detect and confirm the presence of Lafora bodies in the skin. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref> Typically, if a patient comes to a doctor and has been having seizures, like patients with LD characteristically have, these are the common tests that would happen right away to figure out areas of the brain where the seizures are occurring. Whole genome or exome testing is necessary to have with anyone who suffers from epilepsy. <ref>{{Cite web|url=https://www.epilepsy.com/article/2017/2/researchers-coordinate-efforts-find-cure-lafora-disease|title=Researchers Coordinate Efforts to Find Cure for Lafora Disease|website=Epilepsy Foundation|language=en|access-date=2017-12-12}}</ref>
Diagnosis is based on the clinical picture including history and EEG findings. The demonstration of Lafora bodies within the [[apocrine sweat gland]] of the skin by an [[axilla]]ry skin [[biopsy]] examination is a classic approach that may now be substituted by genetic testing. The inclusion bodies, which seem to contain high levels of carbohydrates, are typically labeled by a specific stain called PAS ([[Periodic acid-Schiff]]) which is resistant to [[diastase]] treatment. Under strong clinical suspicion, liver and brain biopsies may be undertaken. Currently the preferred method of certain diagnosis is [[DNA sequencing]].


== Lafora bodies ==
== Treatment and Prognosis ==
Unfortunately there is no cure for Lafora Disease with treatment being limited to controlling seizures through anti-epileptic and anti-convulsant medications. <ref>{{Cite journal|last=Striano|first=Pasquale|last2=Zara|first2=Federico|last3=Turnbull|first3=Julie|last4=Girard|first4=Jean-Marie|last5=Ackerley|first5=Cameron A.|last6=Cervasio|first6=Mariarosaria|last7=De Rosa|first7=Gaetano|last8=Del Basso-De Caro|first8=Maria Laura|last9=Striano|first9=Salvatore|date=February 2008|title=Typical progression of myoclonic epilepsy of the Lafora type: a case report|url=https://www.ncbi.nlm.nih.gov/pubmed/18256682|journal=Nature Clinical Practice. Neurology|volume=4|issue=2|pages=106–111|doi=10.1038/ncpneuro0706|issn=1745-8358|pmid=18256682}}</ref> The treatment is usually based on the individual's specific symptoms and the severity of those symptoms. Some examples of medications include [[valproate]], [[levetiracetam]], [[topiramate]], [[Benzodiazepine|benzodiazepines]], or [[perampanel]]. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-13}}</ref> Although the symptoms and seizures can be controlled for a long period by using anti-epileptic drugs, the symptoms will progress and patients lose their ability to perform daily activities leading to the survival rate of approximately 10 years after symptoms begin. <ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-13}}</ref> Quality of life worsens as the years go on, with some patients requiring a feeding tube so that they can get the nutrition and medication they need in order to keep functioning, but not necessarily living.<ref>{{Cite web|url=https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy|title=Lafora Progressive Myoclonus Epilepsy|website=Epilepsy Foundation|language=en|access-date=2017-12-13}}</ref>
Lafora disease is distinguished by the presence of inclusions called "Lafora bodies" within the [[cytoplasm]]. Lafora bodies are composed of abnormal glycogen called [[polyglucosan]]s. These [[amylopectin]]-like polyglucosans are insoluble and hence precipitate inside cells.


== Recent Research ==
Polyglucosan bodies appear with age; in Lafora disease, their numbers have increased enormously. Lafora bodies have been observed in virtually all organs of patients with the disease. In the brain, their presence appears to be restricted to neurons; they do not seem to present in [[astrocytes]]. Their morphology varies from tissue to tissue, but they generally contain a central core and have a peripheral fluffy appearance.<ref name=2pme>{{cite journal |vauthors=Striano P, Zara F, Turnbull J, Girard JM, Ackerley CA, Cervasio M, De Rosa G, Del Basso-De Caro L, Striano S, Minassian BA |title=Typical Progression of myoclonic epilepsy of the Lafora type |journal=Nat Clin Pract Neurol |volume=4|pages=106–111 |year=2008 |doi=10.1038/ncpneuro0706 |pmid=18256682 |issue=2}}</ref>
⚫
The disease is named after [[Gonzalo Rodríguez Lafora]] (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients.<ref>{{WhoNamedIt|synd|3290|Lafora's disease}}</ref> Since the discovery of Lafora Disease in early to mid 1900's there has not been too much research into it, until more recent years.


Recent research is looking into how inhibition of glycogen synthesis, since increased glucose uptake causes increased glycogen, could potentially stop the formation of the Lafora Bodies in neurons in laforin-deficient mice models while also reducing the chances of [[Epileptic seizure|seizures]]. <ref>{{Cite journal|last=Rai|first=Anupama|last2=Mishra|first2=Rohit|last3=Ganesh|first3=Subramaniam|date=2017-12-15|title=Suppression of leptin signaling reduces polyglucosan inclusions and seizure susceptibility in a mouse model for Lafora disease|url=https://academic.oup.com/hmg/article/26/24/4778/4158144|journal=Human Molecular Genetics|volume=26|issue=24|pages=4778–4785|doi=10.1093/hmg/ddx357|issn=0964-6906}}</ref> The adipocyte hormone Leptin is what this research targeted by blocking the leptin signaling to reduce glucose uptake and stop Lafora bodies from forming. <ref>{{Cite journal|last=Rai|first=Anupama|last2=Mishra|first2=Rohit|last3=Ganesh|first3=Subramaniam|date=2017-12-15|title=Suppression of leptin signaling reduces polyglucosan inclusions and seizure susceptibility in a mouse model for Lafora disease|url=https://academic.oup.com/hmg/article/26/24/4778/4158144|journal=Human Molecular Genetics|volume=26|issue=24|pages=4778–4785|doi=10.1093/hmg/ddx357|issn=0964-6906}}</ref>
== Prognosis ==
There is no treatment, and therapy is mainly supportive and [[symptomatic treatment|symptomatic]]. Although seizure and myoclonus can be controlled for a long period by using [[antiepileptic drugs]], patients rarely survive beyond one or two decades due to the devastating effects of dementia and ataxia. One medication, [[Zonisamide]], has been shown to lengthen the life of those with the disease.{{citation needed|date=December 2012}} This medication helps control and decrease the severity of the seizures affected patients often experience. Gene therapy strategies are being tried in a mouse model.


Other researchers are looking into the ways in which Lafora bodies are being regulated at the level of gene expression. There is specific research looking into how Laforin, a glycogen dephosphatase, gene expression is potentially being downregulated or mutations are arising in the DNA in LD allowing more phosphates to be present helping to render glycogen insoluble. <ref>{{Cite journal|last=Raththagala et al., 2015|first=|date=January 22, 2015|title=Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease|url=http://www.cell.com/molecular-cell/pdf/S1097-2765(14)00915-0.pdf|journal=Molecular Cell|volume=|pages=|via=}}</ref>
== Epidemiology ==
{{Unreferenced section|date=April 2013}}
Epilepsy occurs in one percent of all humans. [[Progressive myoclonus epilepsy|Progressive myoclonic epilepsies]] (PME) account for about one percent of all epilepsies. Lafora disease is one of the common PMEs. Symptoms of Lafora disease begin to manifest themselves in children from 10 to 17 years old. Males and females are equally affected.{{Citation needed|date=June 2015}}
There are only 200 reported cases in the world <ref>{{cite web|url=http://abc7news.com/archive/6843090/|title=FAMILY TURNS DISEASE INTO SUPPORT FOR OTHERS}}</ref> but the exact prevalence is unknown. Most patients affected with this condition have ancestry from the [[Mediterranean]], the [[Middle East]], and [[India]].<ref>{{cite web|url=http://ghr.nlm.nih.gov/condition/lafora-progressive-myoclonus-epilepsy|title=Lafora progressive myoclonus epilepsy}}</ref>


During the past two years (2015-2017), researchers in U.S., Canada, and Europe have formed the (LECI) [[Lafora Epilepsy Cure Initiative]] to try and find a cure for Lafora Disease with funding from the National Institutes of Health (NIH) led by Dr. Matthew Gentry at the University of Kentucky. Since researchers have found the two genes that cause LD, they are currently aiming to interrupt the process of how these mutations in those genes interfere with normal carbohydrate metabolism in mice models. They predict they will have one or more drugs ready for human clinical trials within the next few years.<ref>{{Cite web|url=https://www.epilepsy.com/article/2017/2/researchers-coordinate-efforts-find-cure-lafora-disease|title=Researchers Coordinate Efforts to Find Cure for Lafora Disease|website=Epilepsy Foundation|language=en|access-date=2017-12-13}}</ref>
== History ==
⚫
The disease is named after [[Gonzalo Rodríguez Lafora]] (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients.<ref>{{WhoNamedIt|synd|3290|Lafora's disease}}</ref>


== References ==
== References ==

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Lafora disease
SpecialtyNeurology Edit this on Wikidata

Lafora disease, also called Lafora progressive myoclonic epilepsy or MELF,[1] is a fatal autosomal recessive[2] 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.[3]: 545  Lafora disease is also a neurodegenerative disease that causes impairment in the development of cerebral cortical neurons and it is a glycogen metabolism disorder.[4]

Individuals who suffer from Lafora disease are not limited to humans, dogs can suffer as well. Typically Lafora is rare in American children but has a high occurrence in children from Southern European descent (Italy, France, Spain) and can also be found in children from South Asian countries (Pakistan, India) and even as far south as North Africa[5]. As for canines, Lafora disease can spontaneously occur in any breed but the Miniature Wire Haired Dachshund, Bassett Hound, and the Beagle are predisposed to LD.[6]

Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable.[7] At present, there is no cure for this disease but there are ways to deal with symptoms through treatments and medications.

Signs and Symptoms

Symptoms of Lafora disease begin to develop during early adolescent years and symptoms progress to worsen as time passes. The first ten years of life there is generally no indication of the presence of the disease. [8] The most common feature of Lafora disease is seizures that have been reported mainly as occipital seizures and myoclonic seizures with some cases of generalized tonic-clonic seizures, atypical absence seizures, and atonic and complex partial seizures. [9] [10] Other symptoms common with the seizures are drop attacks, ataxia, temporary blindness, visual hallucinations, and a quickly-developing and dramatic dementia.[2][11]

Other common signs and symptoms associated with Lafora disease are behavioral changes because of the frequency of seizures. [12] Over time those affected with Lafora disease have brain changes that cause things such as confusion, speech difficulties, depression, decline in intellectual function, and impaired judgement and memory. [13] If area's of the cerebellum are affected by seizures then it is common to see issues with speech, coordination, and balance in Lafora patients. [14]

For dogs that are affected with Lafora disease, common symptoms are rapid shuddering, shaking, or jerking of the canine's head backwards, high pitched vocalizations that could indicate the dog is panicking, seizures, and as the disease progresses dementia, blindness, and loss of balance. [15]

Lafora Bodies

Lafora disease is distinguished by the presence of inclusions called "Lafora bodies" within the cytoplasm of cells. Lafora bodies are aggregates of polyglucosans or abnormally shaped glycogen molecules. [16] Glycogen in Lafora disease patients has abnormal chain lengths which directly causes them to be insoluble, accumulate, and have a neurotoxic effect. [17]

For glycogen to be soluble, there must be short chains and a high frequency of branching points, but this is not found in the glycogen in Lafora patients. LD patients have longer chains that have clustered arrangment of branch points that form crystalline areas of double helices making it harder for them to clear the blood-brain barrier. [18] The glycogen in LD patients is also has higher phosphate levels and they are present in greater quantities. [19]

Genetics and Mechanism

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). [20][21] These mutations in either of these two genes leads to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin.[22]

EPM2A codes for the protein laforin, a dual-specificity phosphatase that acts on carbohydrates by taking phosphates off. [23]

NHLRC1 encodes the protein malin, an E3 ubiquitin ligase, that regulates the amount of laforin.[24]

Laforin is essential for making the right structure of glycogen. When the mutation occurs on the EPM2A gene, laforin protein is downregulated and less amount of this protein is present or none is made at all. If there is also a mutation in the NHLRC1 gene that makes the protein malin, then laforin cannot be regulated and thus less of it is made.

Less Laforin means more phosphorylation of glycogen, causing conformational changes rendering it insoluble and that is why it builds up and accumulates having neurotoxic effects.

Lafora disease has an autosomal recessive pattern of inheritance.[25] EPM2A gene found on chromosome 6q24 and NHLRC1 gene found on chromosome 6p22.3. [26]

In other words, in a laforin mutation, glycogen would be hyperphosphorylated and this has been confirmed in laforin knock-out mice.[27]

Research literature also suggests that over-activity of glycogen synthase, the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans and it can be inactivated by phosphorylation at various amino acid residues by many molecules, including GSK-3beta, Protein phosphatase 1, and malin. [28][29] [30]

So as mutations arise in the production of these molecules (GSK-3beta, PP1, and malin), excessive glycogen synthase activity occurs in combination with mutations in laforin that phosphorylates the excess of glycogen being made rendering the large amount of them insoluble. The key player missing is ubiquitin. It is not able to degrade the excess amount of the insoluble lafora bodies. Since mutations arise in malin, an e3 ubiquitin ligase, this directly interferes with the degradation of laforin causing the laforin not to be degraded and it can then hyperphosphorylate. [31]

Diagnosis

Lafora Disease is diagnosed by doing a series of tests by a neurologist, epileptologist (person who specializes in epilepsy), or geneticist. To confirm the diagnosis, an EEG, MRI, and genetic testing are needed to detect the activity of the brain and potential genetic relation to Lafora Disease. [32] A biopsy may be necessary as well to detect and confirm the presence of Lafora bodies in the skin. [33] Typically, if a patient comes to a doctor and has been having seizures, like patients with LD characteristically have, these are the common tests that would happen right away to figure out areas of the brain where the seizures are occurring. Whole genome or exome testing is necessary to have with anyone who suffers from epilepsy. [34]

Treatment and Prognosis

Unfortunately there is no cure for Lafora Disease with treatment being limited to controlling seizures through anti-epileptic and anti-convulsant medications. [35] The treatment is usually based on the individual's specific symptoms and the severity of those symptoms. Some examples of medications include valproate, levetiracetam, topiramate, benzodiazepines, or perampanel. [36] Although the symptoms and seizures can be controlled for a long period by using anti-epileptic drugs, the symptoms will progress and patients lose their ability to perform daily activities leading to the survival rate of approximately 10 years after symptoms begin. [37] Quality of life worsens as the years go on, with some patients requiring a feeding tube so that they can get the nutrition and medication they need in order to keep functioning, but not necessarily living.[38]

Recent Research

The disease is named after Gonzalo Rodríguez Lafora (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients.[39] Since the discovery of Lafora Disease in early to mid 1900's there has not been too much research into it, until more recent years.

Recent research is looking into how inhibition of glycogen synthesis, since increased glucose uptake causes increased glycogen, could potentially stop the formation of the Lafora Bodies in neurons in laforin-deficient mice models while also reducing the chances of seizures. [40] The adipocyte hormone Leptin is what this research targeted by blocking the leptin signaling to reduce glucose uptake and stop Lafora bodies from forming. [41]

Other researchers are looking into the ways in which Lafora bodies are being regulated at the level of gene expression. There is specific research looking into how Laforin, a glycogen dephosphatase, gene expression is potentially being downregulated or mutations are arising in the DNA in LD allowing more phosphates to be present helping to render glycogen insoluble. [42]

During the past two years (2015-2017), researchers in U.S., Canada, and Europe have formed the (LECI) Lafora Epilepsy Cure Initiative to try and find a cure for Lafora Disease with funding from the National Institutes of Health (NIH) led by Dr. Matthew Gentry at the University of Kentucky. Since researchers have found the two genes that cause LD, they are currently aiming to interrupt the process of how these mutations in those genes interfere with normal carbohydrate metabolism in mice models. They predict they will have one or more drugs ready for human clinical trials within the next few years.[43]

References

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External links

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