{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:32:39Z","timestamp":1779363159955,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Canine Lafora disease is a recessively inherited, rapidly progressing neurodegenerative disease caused by the accumulation of abnormally constructed insoluble glycogen Lafora bodies in the brain and other tissues due to the loss of NHL repeat containing E3 ubiquitin protein ligase 1 (NHLRC1). Dogs have a dodecamer repeat sequence within the NHLRC1 gene, which is prone to unstable (dynamic) expansion and loss of function. Progressive signs of Lafora disease include hypnic jerks, reflex and spontaneous myoclonus, seizures, vision loss, ataxia and decreased cognitive function. We studied five dogs (one Chihuahua, two French Bulldogs, one Griffon Bruxellois, one mixed breed) with clinical signs associated with canine Lafora disease. Identification of polyglucosan bodies (Lafora bodies) in myocytes supported diagnosis in the French Bulldogs; muscle areas close to the myotendinous junction and the myofascial union segment had the highest yield of inclusions. Postmortem examination of one of the French Bulldogs revealed brain Lafora bodies. Genetic testing for the known canine NHLRC1 mutation confirmed the presence of a homozygous mutation associated with canine Lafora disease. Our results show that Lafora disease extends beyond previous known breeds to the French Bulldog, Griffon Bruxellois and even mixed-breed dogs, emphasizing the likely species-wide nature of this genetic problem. It also establishes these breeds as animal models for the devastating human disease. Genetic testing should be used when designing breeding strategies to determine the frequency of the NHLRC1 mutation in affected breeds. Lafora diseases should be suspected in any older dog presenting with myoclonus, hypnic jerks or photoconvulsions.<\/jats:p>","DOI":"10.3390\/life11070689","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T10:13:42Z","timestamp":1626257622000},"page":"689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Canine Lafora Disease: An Unstable Repeat Expansion Disorder"],"prefix":"10.3390","volume":"11","author":[{"given":"Thilo","family":"von Klopmann","sequence":"first","affiliation":[{"name":"Department of Neurology, Small Animal Clinic Hofheim, 65719 Hofheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saija","family":"Ahonen","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Espadas-Santiuste","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Chester High Road, Neston CH64 7TE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaspar","family":"Matiasek","sequence":"additional","affiliation":[{"name":"Section of Clinical and Comparative Neuropathology, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80539 M\u00fcnchen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3851-0631","authenticated-orcid":false,"given":"Daniel","family":"Sanchez-Masian","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Chester High Road, Neston CH64 7TE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Rupp","sequence":"additional","affiliation":[{"name":"Department of Neurology, Small Animal Clinic Hofheim, 65719 Hofheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helene","family":"Vandenberghe","sequence":"additional","affiliation":[{"name":"Highcroft Veterinary Referrals, Whitchurch, Bristol BS14 9BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Rose","sequence":"additional","affiliation":[{"name":"Lumbry Park Veterinary Specialists, Alton GU34 3HL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Travis","family":"Wang","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peixiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berge Arakel","family":"Minassian","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75201, USA"},{"name":"Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3366-2110","authenticated-orcid":false,"given":"Clare","family":"Rusbridge","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford GU2 7AL, UK"},{"name":"Fitzpatrick Referrals, Godalming GU7 2QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/2470","article-title":"Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy","volume":"20","author":"Minassian","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/hmg\/8.2.345","article-title":"A Novel Protein Tyrosine Phosphatase Gene Is Mutated in Progressive Myoclonus Epilepsy of the Lafora Type (EPM2)","volume":"8","author":"Serratosa","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/ng1238","article-title":"Mutations in NHLRC1 cause progressive myoclonus epilepsy","volume":"35","author":"Chan","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0887-8994(00)00276-9","article-title":"Lafora\u2019s disease: Towards a clinical, pathologic, and molecular synthesis","volume":"25","author":"Minassian","year":"2001","journal-title":"Pediatric Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Swain, L., Key, G., Tauro, A., Ahonen, S., Wang, P., Ackerley, C., Minassian, B.A., and Rusbridge, C. (2017). Lafora disease in miniature Wirehaired Dachshunds. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182024"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/emmm.201200241","article-title":"Deleterious effects of neuronal accumulation of glycogen in flies and mice","volume":"4","author":"Duran","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Duran, J., Hervera, A., Markussen, K.H., Varea, O., L\u00f3pez-Soldado, I., Sun, R.C., Del R\u00edo, J.A., Gentry, M.S., and Guinovart, J.J. (2021). Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease. Brain A J. Neurol.","DOI":"10.1093\/brain\/awab110"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s12035-019-01842-z","article-title":"Reactive Glia-Derived Neuroinflammation: A Novel Hallmark in Lafora Progressive Myoclonus Epilepsy That Progresses with Age","volume":"57","author":"Lahuerta","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1093\/hmg\/ddu024","article-title":"Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease","volume":"23","author":"Duran","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Turnbull, J., DePaoli-Roach, A.A., Zhao, X., Cortez, M.A., Pencea, N., Tiberia, E., Piliguian, M., Roach, P.J., Wang, P., and Ackerley, C.A. (2011). PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002037"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/ana.23899","article-title":"Inhibiting glycogen synthesis prevents Lafora disease in a mouse model","volume":"74","author":"Pederson","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1126\/science.1102832","article-title":"Expanded repeat in canine epilepsy","volume":"307","author":"Lohi","year":"2005","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/jsap.12593","article-title":"NHLRC1 repeat expansion in two beagles with Lafora disease","volume":"57","author":"Hajek","year":"2016","journal-title":"J. Small Anim. Pract."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1101\/gr.3736605","article-title":"The canine genome","volume":"15","author":"Ostrander","year":"2005","journal-title":"Genome Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1748-5827.2003.tb00113.x","article-title":"Progressive myoclonus epilepsy in a beagle","volume":"44","author":"Gredal","year":"2003","journal-title":"J. Small Anim. Pract."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/age.12756","article-title":"NHLRC1 dodecamer repeat expansion demonstrated by whole genome sequencing in a Chihuahua with Lafora disease","volume":"50","author":"Barrientos","year":"2019","journal-title":"Anim. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/age.12795","article-title":"NHLRC1 dodecamer expansion in a Welsh Corgi (Pembroke) with Lafora disease","volume":"50","author":"Kehl","year":"2019","journal-title":"Anim. Genet."},{"key":"ref_18","first-page":"509","article-title":"Lafora\u2019s disease in the dog. A comparative study","volume":"58","author":"Holland","year":"1970","journal-title":"Am. J. Pathol."},{"key":"ref_19","first-page":"518","article-title":"Canine neuronal glycoproteinosis--Lafora\u2019s disease in the dog [Hereditary diseases]","volume":"12","author":"Cusick","year":"1976","journal-title":"J. Am. Anim. Hosp. Assoc."},{"key":"ref_20","unstructured":"Whitenack, D.L. (1978, January 22\u201326). Neuronal glycoproteinosis (Lafora\u2019s disease) in the dog. Proceedings of the American Association of Veterinary Laboratory Diagnosticians, Madison, WI, USA."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rusbridge, C., Long, S., Jovanovik, J., Milne, M., Berendt, M., Bhatti, S.F., De Risio, L., Farqhuar, R.G., Fischer, A., and Matiasek, K. (2015). International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol. BMC Vet. Res., 11.","DOI":"10.1186\/s12917-015-0466-x"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Matiasek, K., Pumarola i Batlle, M., Rosati, M., Fern\u00e1ndez-Flores, F., Fischer, A., Wagner, E., Berendt, M., Bhatti, S.F.M., De Risio, L., and Farquhar, R.G. (2015). International veterinary epilepsy task force recommendations for systematic sampling and processing of brains from epileptic dogs and cats. BMC Vet. Res., 11.","DOI":"10.1186\/s12917-015-0467-9"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.cmet.2013.04.006","article-title":"Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease","volume":"17","author":"Nitschke","year":"2013","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cmet.2011.01.017","article-title":"Phosphate incorporation during glycogen synthesis and Lafora disease","volume":"13","author":"Tagliabracci","year":"2011","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1074\/jbc.M114.607796","article-title":"Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease","volume":"290","author":"Contreras","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"906","DOI":"10.15252\/emmm.201707608","article-title":"Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease","volume":"9","author":"Nitschke","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_27","unstructured":"Fitzmaurice, S.N., Rusbridge, C., Shelton, G.D., Minassian, B.A., and Scherer, S.W. (2000, January 21\u201323). Familial myoclonic epilepsy in the Miniature Wirehaired Dachshund. Proceedings of the European Society of Veterinary Neurology 14th Annual Symposium, Philadelphia, PA, USA."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/s41582-018-0057-0","article-title":"Lafora disease-from pathogenesis to treatment strategies","volume":"14","author":"Nitschke","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1002\/mds.20530","article-title":"Levetiracetam in patients with cortical myoclonus: A clinical and electrophysiological study","volume":"20","author":"Striano","year":"2005","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11940-016-0404-7","article-title":"Myoclonus: Pathophysiology and Treatment Options","volume":"18","author":"Levy","year":"2016","journal-title":"Curr. Treat. Opt. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1093\/hmg\/ddy044","article-title":"Astrocytes: New players in progressive myoclonus epilepsy of Lafora type","volume":"27","author":"Viana","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.freeradbiomed.2015.01.034","article-title":"Oxidative stress, a new hallmark in the pathophysiology of Lafora progressive myoclonus epilepsy","volume":"88","author":"Aguado","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/erm.2020.5","article-title":"Neuroinflammation and progressive myoclonus epilepsies: From basic science to therapeutic opportunities","volume":"22","author":"Sanz","year":"2020","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.18632\/aging.101211","article-title":"An epigenetic aging clock for dogs and wolves","volume":"9","author":"Thompson","year":"2017","journal-title":"Aging"},{"key":"ref_35","unstructured":"Rusbridge, C., Fitzmaurice, S.N., Lohi, H., Young, E.J., and Minassian, B.A. (2004, January 24\u201325). Treatment of Lafora disease (inherited myoclonic epilepsy) in dogs. Proceedings of the European Society of Veterinary Neurology 18th Annual Symposium, Glasgow, UK."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.eplepsyres.2006.01.007","article-title":"A pilot study of a ketogenic diet in patients with Lafora body disease","volume":"69","author":"Cardinali","year":"2006","journal-title":"Epilepsy Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e533","DOI":"10.1212\/NXG.0000000000000533","article-title":"Ketogenic diet reduces Lafora bodies in murine Lafora disease","volume":"6","author":"Israelian","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1017\/S0007114510000097","article-title":"Dietary supplementation with medium-chain TAG has long-lasting cognition-enhancing effects in aged dogs","volume":"103","author":"Pan","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.yebeh.2015.11.014","article-title":"Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy","volume":"55","author":"Packer","year":"2016","journal-title":"Epilepsy Behav."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fnut.2018.00127","article-title":"Efficacy of a Therapeutic Diet on Dogs With Signs of Cognitive Dysfunction Syndrome (CDS): A Prospective Double Blinded Placebo Controlled Clinical Study","volume":"5","author":"Pan","year":"2018","journal-title":"Front. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1089\/can.2019.0005","article-title":"Cannabidiol-Enriched Extract Reduced the Cognitive Impairment but Not the Epileptic Seizures in a Lafora Disease Animal Model","volume":"5","author":"Aso","year":"2020","journal-title":"Cannabis Cannabinoid Res."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/689\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:30:19Z","timestamp":1760164219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["life11070689"],"URL":"https:\/\/doi.org\/10.3390\/life11070689","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]}}}