Abstract
The progressive myoclonic epilepsy of Lafora or Lafora disease (LD) is a neurodegenerative disorder characterized by recurrent seizures and cognitive deficits. With typical onset in the late childhood or early adolescence, the patients show progressive worsening of the disease symptoms, leading to death in about 10 years. It is an autosomal recessive disorder caused by the loss-of-function mutations in the EPM2A gene, coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an E3 ubiquitin ligase (malin). LD is characterized by the presence of abnormally branched water insoluble glycogen inclusions known as Lafora bodies in the neurons and other tissues, suggesting a role for laforin and malin in glycogen metabolic pathways. Mouse models of LD, developed by targeted disruption of the Epm2a or Nhlrc1 gene, recapitulated most of the symptoms and pathological features as seen in humans, and have offered insight into the pathomechanisms. Besides the formation of Lafora bodies in the neurons in the presymptomatic stage, the animal models have also demonstrated perturbations in the proteolytic pathways, such as ubiquitin-proteasome system and autophagy, and inflammatory response. This review attempts to provide a comprehensive coverage on the genetic defects leading to the LD in humans, on the functional properties of the laforin and malin proteins, and on how defects in any one of these two proteins result in a clinically similar phenotype. We also discuss the disease pathologies as revealed by the studies on the animal models and, finally, on the progress with therapeutic attempts albeit in the animal models.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguado C., Sarkar S., Korolchuk V. I., Criado O., Vernia S., Boya P. et al. 2010 Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum. Mol. Genet. 19, 2867–2876.
Annesi G., Sofia V., Gambardella A., Candiano I. C., Spadafora P., Annesi F. et al. 2004 A novel exon 1 mutation in a patient with atypical lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit. Epilepsia 45, 294–295.
Berthier A., Payá M., García-Cabrero A. M., Ballester M. I., Heredia M., Serratosa J. M. et al. 2015 Pharmacological interventions to ameliorate neuropathological symptoms in a mouse model of Lafora disease. Mol. Neurobiol. 53, 1296–1309.
Cardinali S., Canafoglia L., Bertoli S., Franceschetti S., Lanzi G., Tagliabue A. et al. 2006 A pilot study of a ketogenic diet in patients with Lafora body disease. Epilepsy Res. 69, 129–134.
Chan E. M., Bulman D. E., Paterson A. D., Turnbull J., Andermann E., Andermann F. et al. 2003a Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22. J. Med. Genet. 40, 671–675.
Chan E. M., Young E. J., Ianzano L., Munteanu I., Zhao X., Christopoulos C. C. et al. 2003b Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat. Genet. 35, 125–127.
Chan E. M., Ackerley C. A., Lohi H., Ianzano L., Cortez M. A., Shannon P. et al. 2004a Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Hum. Mol. Genet. 13, 1117–1129.
Chan E. M., Omer S., Ahmed M., Bridges L. R., Bennett C., Scherer S. W. et al. 2004b Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus. Neurology 63, 565–567.
Cheng A., Zhang M., Gentry M. S., Worby C. A., Dixon J. E. and Saltiel A. R. 2007 A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease. Genes Dev. 21, 2399–2409.
Collinge J., Sidle K. C., Meads J., Ironside J. and Hill A. F. 1996 Molecular analysis of prion strain variation and the aetiology of ’new variant’ CJD. Nature 383, 685–690.
Cornford E. M., Hyman S., Cornford M. E., Chytrova G., Rhee J., Suzuki T. et al. 2016 Non-invasive gene targeting to the fetal brain after intravenous administration and transplacental transfer of plasmid DNA using PEGylated immunoliposomes. J. Drug Target 24, 58–67.
Corti O. and Brice A. 2013 Mitochondrial quality control turns out to be the principal suspect in parkin and PINK1-related autosomal recessive Parkinson’s disease. Curr. Opin. Neurobiol. 23, 100–108.
Criado O., Aguado C., Gayarre J., Duran-Trio L., Garcia-Cabrero A. M., Vernia S. et al. 2012 Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum. Mol. Genet. 21, 1521–1533.
Delgado-Escueta A. V., Ganesh S. and Yamakawa K. 2001 Advances in the genetics of progressive myoclonus epilepsy. Am. J. Med. Genet. 106, 129–138.
DePaoli-Roach A. A., Tagliabracci V. S., Segvich D. M., Meyer C. M., Irimia J. M. and Roach P. J. 2010 Genetic depletion of the malin E3 ubiquitin ligase in mice leads to lafora bodies and the accumulation of insoluble laforin. J. Biol. Chem. 285, 25372–25381.
Dubey D. and Ganesh S. 2008 Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in lafora progressive myoclonus epilepsy. Hum. Mol. Genet. 17, 3010–3020.
Dubey D., Parihar R. and Ganesh S. 2012 Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy. Genomics 99, 36–43.
Duran J., Gruart A., García-Rocha M., Delgado-García J. M. and Guinovart J. J. 2014 Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum. Mol. Genet. 23, 3147–3156.
Ferlazzo E., Canafoglia L., Michelucci R., Gambardella A., Gennaro E., Pasini E. et al. 2014 Mild Lafora disease: clinical, neurophysiologic, and genetic findings. Epilepsia 55, e129–e133.
Fernández-Sánchez M. E., Criado-García O., Heath K. E., García-Fojeda B., Medraño-Fernández I., Gomez-Garre P. et al. 2003 Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum. Mol. Genet. 12, 3161–3171.
Field E. J., Farmer F., Caspary E. A. and Joyce G. 1969 Susceptibility of scrapie agent to ionizing radiation. Nature 222, 90–91.
Ganesh S., Agarwala K. L., Ueda K., Akagi T., Shoda K., Usui T. et al. 2000 Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum. Mol. Genet. 9, 2251–2261.
Ganesh S., Shoda K., Amano K., Uchiyama A., Kumada S., Moriyama N. et al. 2001 Mutation screening for Japanese Lafora’s disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene. Mol. Cell Probes. 15, 281–289.
Ganesh S., Delgado-Escueta A. V., Suzuki T., Francheschetti S., Riggio C., Avanzini G. et al. 2002a Genotype-phenotype correlations for EPM2A mutations in Lafora’s progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum. Mol. Genet. 11, 1263–1271.
Ganesh S., Suzuki T. and Yamakawa K. 2002b Alternative splicing modulates subcellular localization of laforin. Biochem. Biophys. Res. Commun. 291, 1134–1137.
Ganesh S., Delgado-Escueta A. V., Sakamoto T., Avila M. R., Machado-Salas J., Hoshii Y. et al. 2002c Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum. Mol. Genet. 11, 1251–1262.
Ganesh S., Tsurutani N., Suzuki T., Ueda K., Agarwala K. L., Osada H. et al. 2003 The Lafora disease gene product laforin interacts with HIRIP5., a phylogenetically conserved protein containing a NifU-like domain. Hum. Mol. Genet. 12, 2359–2368.
Ganesh S., Tsurutani N., Suzuki T., Hoshii Y., Ishihara T., Delgado-Escueta A. V. et al. 2004 The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies. Biochem. Biophys. Res. Commun. 313, 1101–1109.
Ganesh S., Puri R., Singh S., Mittal S. and Dubey D. 2006 Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy. J. Hum. Genet. 51, 1–8.
García-Cabrero A. M., Marinas A., Guerrero R., de Córdoba S. R., Serratosa J. M. and Sánchez M. P. 2012 Laforin and malin deletions in mice produce similar neurologic impairments. J. Neuropathol. Exp. Neurol. 71, 413–421.
Garyali P., Segvich D. M., DePaoli-Roach A. A. and Roach P. J. 2014 Protein degradation and quality control in cells from laforin and malin knockout mice. J. Biol. Chem. 289, 20606–20614.
Garyali P., Siwach P., Singh P. K., Puri R., Mittal S., Sengupta S. et al. 2009 The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum. Mol. Genet. 18, 688–700.
Gayarre J., Duran-Trío L., Criado Garcia O., Aguado C., Juana-López L., Crespo I. et al. 2014 The phosphatase activity of laforin is dispensable to rescue Epm2a-/- mice from Lafora disease. Brain 137, 806–818.
Gentry M. S., Worby C. A. and Dixon J. E. 2005 Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc. Natl. Acad. Sci. USA 102, 8501–8506.
Girard J. M., Lê K. H. and Lederer F. 2006 A dual-specificity protein phosphatase implicated in Lafora disease. Biochimie 88, 1961–1971.
Goedert M. 2015 Neurodegeneration. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled A\(\upbeta \), tau, and \(\upalpha \)-synuclein. Science 349, 1255555.
Goldsmith D. and Minassian B. A. 2016 Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy Behav. 62, 132–135.
Gómez-Garre P., Sanz Y., Rodríguez De Córdoba S. R. and Serratosa J. M. 2000 Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur. J. Hum. Genet. 8, 946–954.
Guerrero R., Vernia S., Sanz R., Abreu-Rodríguez I., Almaraz C., García-Hoyos M. et al. 2011 A PTG variant contributes to a milder phenotype in Lafora disease. PLoS One 6, e21294.
Ianzano L., Zhao X. C., Minassian B. A. and Scherer S. W. 2003 Identification of a novel protein interacting with laforin., the EPM2a progressive myoclonus epilepsy gene product. Genomics 81, 579–587.
Ianzano L., Young E. J., Zhao X. C., Chan E. M., Rodriguez M. T., Torrado M. V. et al. 2004 Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum. Mutat. 23, 170–176.
Inoue M., Iwai R., Yamanishi E., Yamagata K., Komabayashi-Suzuki M., Honda A. et al. 2015 Deletion of Prdm8 impairs development of upper-layer neocortical neurons. Genes Cells 20, 758–770.
Irimia J. M., Tagliabracci V. S., Meyer C. M., Segvich D. M., DePaoli-Roach A. A., and Roach P. J. 2015 Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. J. Biol. Chem. 290, 22686–22698.
Iwai R., Tabata H., Inoue M., Nomura K. I., Okamoto T., Ichihashi M. et al. 2018 A Prdm8 target gene Ebf3 regulates multipolar-to-bipolar transition in migrating neocortical cells. Biochem. Biophys. Res. Commun. 495, 388–394.
Jain N., Mishra R. and Ganesh S. 2016 FoxO3a-mediated autophagy is down-regulated in the laforin deficient mice, an animal model for Lafora progressive myoclonus epilepsy. Biochem. Biophys. Res. Commun. 474, 321–327.
Jain N., Rai A., Mishra R. and Ganesh S. 2017 Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock. Cell Stress Chaperones. 22, 307–315.
Jara-Prado A., Ochoa A., Alonso M. E., Lima Villeda G. A., Fernández-Valverde F., Ruano-Calderón L. et al. 2014 Late onset Lafora disease and novel EPM2A mutations: breaking paradigms. Epilepsy Res. 108, 1501–1510.
Jung C. C., Atan D., Ng D., Ploder L., Ross S. E., Klein M. et al. 2015 Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity. Proc. Natl. Acad. Sci. USA 112, E3010–E30109.
Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S. et al. 1998 Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608.
Knecht E., Aguado C., Sarkar S., Korolchuk V. I., Criado-García O., Vernia S. et al. 2010 Impaired autophagy in Lafora disease. Autophagy 6, 991–993.
Knecht E., Criado-García O., Aguado C., Gayarre J., Duran-Trio L., Garcia-Cabrero A. M. et al. 2012 Malin knockout mice support a primary role of autophagy in the pathogenesis of Lafora disease. Autophagy 8, 701–703.
Kossoff E. H., Veggiotti P., Genton P. and Desguerre I. 2014 Transition for patients with epilepsy due to metabolic and mitochondrial disorders. Epilepsia 3, 37–40.
Lagier-Tourenne C., Polymenidou M. and Cleveland D. W. 2010 TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19, R46–64.
Lattante S., Rouleau G. A. and Kabashi E. 2013 TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum. Mutat. 34, 812–826.
Lesca G., Boutry-Kryza N., de Toffol B., Milh M., Steschenko D., Lemesle-Martin M. et al. 2010 Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia. 51, 1691–1698.
Liu Y., Wang Y., Wu C., Liu Y. and Zheng P. 2006 Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling. J. Biol. Chem. 281, 34768–34774.
Liu Y., Zeng L., Ma K., Baba O., Zheng P., Liu Y. et al. 2013 Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase. Mol. Neurobiol. 49, 645–657.
Lohi H., Ianzano L., Zhao X. C., Chan E. M., Turnbull J., Scherer S. W. et al. 2005a Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum. Mol. Genet. 14, 2727–2736.
Lohi H., Young E. J., Fitzmaurice S. N., Rusbridge C., Chan E. M., Vervoort M. et al. 2005b Expanded repeat in canine epilepsy. Science 307, 81.
López-González I., Viana R., Sanz P. and Ferrer I. 2017 Inflammation in Lafora disease: Evolution with disease progression in Laforin and Malin knock-out mouse models. Mol. Neurobiol. 54, 3119–3130.
Lourenco G. F., Janitz M., Huang Y. and Halliday G. M. 2015 Long noncoding RNAs in TDP-43 and FUS/TLS-related frontotemporal lobar degeneration (FTLD). Neurobiol. Dis. 82, 445–454.
Lynch D. S., Wood N. W. and Houlden H. 2016 Late-onset Lafora disease with prominent parkinsonism due to a rare mutation in EPM2A. Neurol. Genet. 16, e101.
Machado-Salas J., Avila-Costa M. R., Guevara P., Guevara J., Durón R. M., Bai D. et al. 2012 Ontogeny of lafora bodies and neurocytoskeleton changes in laforin-deficient mice. Exp. Neurol. 236, 131–140.
Michelucci R., Pasini E., Riguzzi P., Andermann E., Kälviäinen R. and Genton P. 2016 Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials. Epileptic Disord. 18, 145–153.
Minassian B. A., Lee J. R., Herbrick J. A., Huizenga J., Soder S., Mungall A. J. et al. 1998 Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat. Genet. 20, 171–174.
Minassian B. A., Sainz J., Serratosa J. M., Gee M., Sakamoto L. M., Bohlega S. et al. 1999 Genetic locus heterogeneity in Lafora’s progressive myoclonus epilepsy. Ann. Neurol. 45, 262–265.
Minassian B. A., Ianzano L., Meloche M., Andermann E., Rouleau G. A., Delgado-Escueta A. V. et al. 2000 Mutation spectrum and predicted function of laforin in Lafora’s progressive myoclonus epilepsy. Neurology 55, 341–346.
Minassian B. A. 2001 Lafora’s disease: towards a clinical, pathologic, and molecular synthesis. Pediatr. Neurol. 25, 21–29.
Minassian B. A., Andrade D. M., Ianzano L., Young E. J., Chan E., Ackerley C. A. et al. 2001 Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase. Ann. Neurol. 49, 271–275.
Mittal S., Dubey D., Yamakawa K. and Ganesh S. 2007 Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. Hum. Mol. Genet. 16, 753–762.
Mittal S., Upadhyay M., Singh P. K., Parihar R. and Ganesh S. 2015 Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease. J. Biosci. 40, 863–871.
Moreno D., Towler M. C., Hardie D. G., Knecht E. and Sanz P. 2010 The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. Mol. Biol. Cell. 21, 2578–2588.
Nanduri A. S., Kaushal N., Clusmann H. and Binder D. K. 2008 The maestro don Gonzalo Rodríguez-Lafora. Epilepsia 49, 943–947.
Navarro-Sastre A., Tort F., Stehling O., Uzarska M. A., Arranz J. A., Del Toro M. et al. 2011 A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am. J. Hum. Genet. 89, 656–667.
Nasri A., Mansour M., Kacem A., Derbali H., Yahya M., Riahi A. et al. 2017 Pediatric obsessive compulsive disorder: an unusual form of Lafora disease. Encephale 43, 90–94.
Nitschke F., Sullivan M. A., Wang P., Zhao X., Chown E. E., Perri A. M. et al. 2017 Abnormal glycogen chain length pattern., not hyperphosphorylation, is critical in Lafora disease. EMBO Mol. Med. 9, 906–917
Pederson B. A., Turnbull J., Epp J. R., Weaver S. A., Zhao X., Pencea N. et al. 2013 Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Ann. Neurol. 74, 297–300.
Puri R. and Ganesh S. 2010 Laforin in autophagy: a possible link between carbohydrate and protein in Lafora disease? Autophagy 6, 1229–1231.
Puri R. and Ganesh S. 2012 Autophagy defects in lafora disease: cause or consequence? Autophagy 8, 289–290.
Puri R., Suzuki T., Yamakawa K. and Ganesh S. 2009 Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease. J. Biol. Chem. 284, 22657–22663.
Puri R., Suzuki T., Yamakawa K. and Ganesh S. 2012 Dysfunctions in endosomal-lysosomal and autophagy pathways underlie neuropathology in a mouse model for Lafora disease. Hum. Mol. Genet. 21, 175–184.
Rai A., Mishra R. and Ganesh S. 2017 Suppression of leptin signaling reduces polyglucosan inclusions and seizure susceptibility in a mouse model for Lafora disease. Hum. Mol. Genet. 26, 4778–4785.
Rai A., Singh P. K., Singh V., Kumar V., Mishra R., Thakur A. K. et al. 2018 Glycogen synthase protects neurons from cytotoxicity of mutant huntingtin by enhancing the autophagy flux. Cell Death Dis. 9, 201.
Rao S. N., Maity R., Sharma J., Dey P., Shankar S. K., Satishchandra P. et al. 2010a Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum. Mol. Genet. 19, 4726–4734.
Rao S. N., Sharma J., Maity R. and Jana N. R. 2010b Co-chaperone CHIP stabilizes aggregate-prone malin, a ubiquitin ligase mutated in Lafora disease. J. Biol. Chem. 285, 1404–1413.
Raththagala M., Brewer M. K., Parker M. W., Sherwood A. R., Wong B. K., Hsu S. et al. 2015 Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease. Mol. Cell 57, 261–272.
Roach P. J. 2011 Are there errors in glycogen biosynthesis and is laforin a repair enzyme? FEBS Lett. 585, 3216–3218.
Roach P. J. 2015 Glycogen phosphorylation and Lafora disease. Mol. Aspects Med. 46, 78–84.
Roemer M. I. 1990 Public and private sectors in health system development. Asia Pac. J. Public Health 4, 164–168.
Romá-Mateo C., Aguado C., García-Giménez J. L., Ibáñez-Cabellos J. S., Seco-Cervera M., Pallardó F. V. et al. 2014 Increased oxidative stress and impaired antioxidant response in Lafora disease. Mol. Neurobiol. 51, 932–946.
Romá-Mateo C., Aguado C., García-Giménez J. L., Knecht E., Sanz P. and Pallardó F. V. 2015 Oxidative stress, a new hallmark in the pathophysiology of Lafora progressive myoclonus epilepsy. Free Radic. Biol. Med. 88, 30–41.
Rubio-Villena C., Garcia-Gimeno M. A. and Sanz P. 2013 Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int. J. Biochem. Cell Biol. 45, 1479–1488.
Rubio-Villena C., Viana R., Bonet J., Garcia-Gimeno M. A., Casado M., Heredia M. et al. 2018 Astrocytes: new players in progressive myoclonus epilepsy of Lafora type. Hum. Mol. Genet. 27, 1290–1300.
Sainz J., Minassian B. A., Serratosa J. M., Gee M. N., Sakamoto L. M., Iranmanesh R. et al. 1997 Lafora progressive myoclonus epilepsy: narrowing the chromosome 6q24 locus by recombinations and homozygosities. Am. J. Hum. Genet. 61, 1205–1209.
Saez I., Duran J., Sinadinos C., Beltran A., Yanes O., Tevy M. F. et al. 2014 Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia. J. Cereb. Blood Flow Metab. 34, 945–955.
Sánchez-Elexpuru G., Serratosa J. M. and Sánchez M. P. 2017a Sodium selenate treatment improves symptoms and seizure susceptibility in a malin-deficient mouse model of Lafora disease. Epilepsia 58, 467–475.
Sánchez-Elexpuru G., Serratosa J. M., Sanz P. and Sánchez M. P. 2017b 4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease. Neuroreport. 28, 268–271.
Sánchez-Martín P., Romá-Mateo C., Viana R. and Sanz P. 2015 Ubiquitin conjugating enzyme E2-N and sequestosome-1 (p62) are components of the ubiquitination process mediated by the malin-laforin E3-ubiquitin ligase complex. Int. J. Biochem. Cell Biol. 69, 204–214.
Sankhala R. S., Koksal A. C., Ho L., Nitschke F., Minassian B. A. and Cingolani G. 2015 Dimeric quaternary structure of human laforin. J. Biol. Chem. 290, 4552–4559.
Sengupta S., Badhwar I., Upadhyay M., Singh S. and Ganesh S. 2011 Malin and laforin are essential components of a protein complex that protects cells from thermal stress. J. Cell Sci. 124, 2277–2286.
Serratosa J. M., Delgado-Escueta A. V., Posada I., Shih S., Drury I., Berciano J. et al. 1995 The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q. Hum. Mol. Genet. 4, 1657–1663.
Serratosa J. M., Gómez-Garre P., Gallardo M. E., Anta B., de Bernabé D. B., Lindhout D. et al. 1999 A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum. Mol. Genet. 8, 345–352.
Sharma J., Rao S. N., Shankar S. K., Satishchandra P. and Jana N. R. 2011 Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis. Neurobiol. Dis. 44, 133–141.
Sharma J., Mulherkar S., Mukherjee D. and Jana N. R. 2012 Malin regulates Wnt signaling pathway through degradation of dishevelled2. J. Biol. Chem. 287, 6830–6839.
Sharma J., Mukherjee D., Rao S. N., Iyengar S., Shankar S. K., Satishchandra P. et al. 2013 Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease. J. Biol. Chem. 288, 9482–9490.
Singh S., Sethi I., Francheschetti S., Riggio C., Avanzini G., Yamakawa K. et al. 2006 Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora’s progressive myoclonic epilepsy. J. Med. Genet. 43, e48.
Singh S. and Ganesh S. 2009 Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Hum. Mutat. 30, 715–723.
Singh P. K., Singh S. and Ganesh S. 2012a The laforin-malin complex negatively regulates glycogen synthesis by modulating cellular glucose uptake via glucose transporters. Mol. Cell Biol. 32, 652–663.
Singh S. and Ganesh S. 2012b Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers? J. Hum. Genet. 57, 283–285.
Singh S., Singh P. K., Bhadauriya P. and Ganesh S. 2012c Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a. RNA Biol. 9, 1440–1449.
Singh P. K., Singh S. and Ganesh S. 2013 Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease. Mol. Biol. Cell. 24, 3776–3786.
Singh S., Suzuki T., Uchiyama A., Kumada S., Moriyama N., Hirose S. et al. 2005 Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. J. Hum. Genet. 50, 347–352.
Solaz-Fuster M. C., Gimeno-Alcañiz J. V., Ros S., Fernandez-Sanchez M. E., Garcia-Fojeda B., Criado Garcia O. et al. 2007 Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Hum. Mol. Genet. 17, 667–678.
Solmesky L. J., Khazanov N., Senderowitz H., Wang P., Minassian B. A., Ferreira I. M. et al. 2017 A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease. Biochem. J. 474, 3403–3420.
Striano P., Zara F., Turnbull J., Girard J. M., Ackerley C. A., Cervasio M. et al. 2008 Typical progression of myoclonic epilepsy of the Lafora type: a case report. Nat. Clin. Pract. Neurol. 4, 106–111.
Sun T., Yi H., Yang C., Kishnani P. S. and Sun B. 2016 Starch binding domain-containing protein 1 plays a dominant role in glycogen transport to lysosomes in Liver. J. Biol. Chem. 291, 16479–16484.
Tagliabracci V. S., Girard J. M., Segvich D., Meyer C., Turnbull J., Zhao X. et al. 2008 Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J. Biol. Chem. 283, 33816–33825.
Tiberia E., Turnbull J., Wang T., Ruggieri A., Zhao X. C., Pencea N. et al. 2012 Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease. J. Biol. Chem. 287, 25650–25659.
Turnbull J., Girard J. M., Lohi H., Chan E. M., Wang P., Tiberia E. et al. 2012 Early-onset Lafora body disease. Brain. 135, 2684–2698.
Turnbull J., Tiberia E., Pereira S., Zhao X., Pencea N., Wheeler A. L. et al. 2013 Deficiency of a glycogen synthase-associated protein, Epm2aip1, causes decreased glycogen synthesis and hepatic insulin resistance. J. Biol. Chem. 288, 34627–34637.
Turnbull J., Epp J. R., Goldsmith D., Zhao X., Pencea N., Wang P. et al. 2014 PTG protein depletion rescues malin-deficient Lafora disease in mouse. Ann. Neurol. 75, 442–446.
Turnbull J., Tiberia E., Striano P., Genton P., Carpenter S., Ackerley C. A. et al. 2016 Lafora disease. Epileptic Disord. 18, 38–62.
Upadhyay M., Gupta S., Bhadauriya P. and Ganesh S. 2015 Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway. Biochem. Biophys. Res. Commun. 464, 106–111.
Upadhyay M., Agarwal S., Bhadauriya P. and Ganesh S. 2017 Loss of laforin or malin results in increased Drp1 level and concomitant mitochondrial fragmentation in Lafora disease mouse models. Neurobiol. Dis. 100, 39–51.
Valles-Ortega J., Duran J., Garcia-Rocha M., Bosch C., Saez I., Pujadas L. et al. 2011 Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Mol. Med. 3, 667–681.
Vernia S., Rubio T., Heredia M., Rodríguez de Córdoba S. and Sanz P. 2009 Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS One 4, e5907.
Viana R., Lujan P. and Sanz P. 2015 The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2. BMC Biochem. 16, 24.
Vilchez D., Ros S., Cifuentes D., Pujadas L., Vallès J., García-Fojeda B. et al. 2007 Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat. Neurosci. 10, 1407–1413.
Villalba-Orero M., Sánchez-Elexpuru G., López-Olañeta M., Campuzano O., Bello-Arroyo E., García-Pavía P. et al. 2017 Lafora Disease is an inherited metabolic cardiomyopathy. J. Am. Coll. Cardiol. 69, 3007–3009.
Wang J., Stuckey J. A., Wishart M. J. and Dixon J. E. 2002 A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J. Biol. Chem. 277, 2377–2380.
Wang Y., Liu Y., Wu C., Zhang H., Zheng X. and Zheng Z. 2006 Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling. Cancer Cell 10, 179–190.
Wang Y., Ma K., Wang P., Baba O., Zhang H., Parent J. M. et al. 2013 Laforin prevents stress-induced polyglucosan body formation and Lafora disease progression in neurons. Mol. Neurobiol. 48, 49–61.
Worby C. A., Gentry M. S. and Dixon J. E. 2006 Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J. Biol. Chem. 281, 30412–30418.
Worby C. A., Gentry M. S. and Dixon J. E. 2008 Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J. Biol. Chem. 283, 4069–4076.
Yildiz E. P., Yesil G., Ozkan M. U., Bektas G., Caliskan M. and Ozmen M. 2017 A novel EPM2A mutation in a patient with Lafora disease presenting with early parkinsonism symptoms in childhood. Seizure 51, 77–79.
Zeng L., Wang Y., Baba O., Zheng P., Liu Y. and Liu Y. 2012 Laforin is required for the functional activation of malin in endoplasmic reticulum stress resistance in neuronal cells. FEBS J. 279, 2467–2478.
Zhu Y., Zhang M., Kelly A. R. and Cheng A. 2014 The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein-protein interactions. Biosci. Rep. 34, pii: e00117.
Acknowledgements
We apologize to the authors whose papers we could not cite in this review due to space limitations. We thank the group members (past and present) for their immense contributions towards the LD projects in the laboratory. The work on LD is currently supported by a research grant from the Science and Engineering Research Board, Department of Science and Technology, Government of India, to SG (SB/S5/AB/05/2016) and to RP (YSS/2015/001818). SG is also supported by the Tata Innovation Fellowship of the Department of Biotechnology, Government of India (BT/HRD/35/01/01/2017), and the P. K. Kelkar Endowed Chair at IIT Kanpur.
Author information
Authors and Affiliations
Corresponding author
Additional information
We dedicate this review article to our mentor and teacher Professor Rajiva Raman as a tribute to his constant encouragements and immense contributions to the field of genetics in the country.
Rights and permissions
About this article
Cite this article
Parihar, R., Rai, A. & Ganesh, S. Lafora disease: from genotype to phenotype. J Genet 97, 611–624 (2018). https://doi.org/10.1007/s12041-018-0949-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12041-018-0949-1