Lafora Disease: A fatal form of Epilepsy

Lafora disease (LD) is a rare, fatal genetic disorder, which remains unknown to many people. Gonzalo Rodrίguez Lafora first described it as a progressive myoclonic epilepsy, but it is also considered a neurodegenerative and a glycogen metabolism disorder. The extent of LD is devastating, with affected people losing their ability to carry out daily activities and eventually requiring comprehensive care. Unfortunately, there is no prevention or cure, and therefore it’s important to educate others about this condition to create awareness and to encourage fundraising to enhance the scientific research in this area . 


LD begins to manifest in late childhood or early adolescence, and the prognosis is poor. The first noticeable features are seizures, often myoclonic seizures which cause involuntary jerking movements. These gradually worsen after onset of the disease, becoming more frequent and less responsive to anticonvulsant medication, making them difficult to treat. Hallucinations also start to appear, and the individual may experience partial loss of vision (scotomata). Eventually, cognitive decline and dementia follows. Towards the end of the disease the individual enters a vegetative state, and death occurs around 10 years post-onset. Death is often due to status epilepticus, where the individual experiences a continuous epileptic fit over several minutes, without recovery of consciousness (Turnbull et al., 2012).  


A pathological hallmark of LD is the presence of Lafora bodies, which are aggregations of intracellular polyglucosans. These lack glycogen’s normal branching structure, rendering them insoluble (Kecmanovic et al., 2016). They are commonly found within several tissues such as the brain, muscle and liver; all of which have a high glucose metabolism. However, clinical manifestations of LD are solely within the central nervous system (CNS) (Ganesh et al., 2005). The formation of Lafora bodies within neurones are thought to be the cause of epilepsy and neurodegeneration, although the mechanism behind this is still not fully understood.  


LD is an autosomal recessive disorder, and therefore 2 mutated alleles must be inherited for the disease to be expressed in the phenotype. So far, research has determined that 90% of cases are caused by mutations in either the EPM2B or the EPM2A gene, and it is thought that another unidentified gene may also play a role (Couarch et al., 2011). Evidence shows that LD is more prevalent in areas that have a high rate of consanguinity, such as India and Pakistan. However, exact prevalence figures are not available due to rarity of the condition (Jansen and Andermann, 2015).  

Mutations and mechanisms  

EPM2A encodes laforin, and EPM2B encodes malin. Both of these are proteins that form a complex which is thought to prevent a dangerous build-up of glycogen within tissues that do not normally store it, such as the CNS. Loss-of-function mutations in either EPM2A or EMP2B prevent the formation of malin or laforin, respectively. Therefore, these proteins cannot form a complex and evidence has suggested that this leads to glycogen accumulation, hence the formation of Lafora bodies (Ganesh et al., 2002).


Figure 1: The mechanisms involved in the formation of nsoluble Lafora bodies, leading to Lafora disease. Taken from  

Management of LD 

Currently, there remains no cure for LD and we are still unable to slow its progression. Medications are prescribed to manage seizures, although anticonvulsant drugs, such as phenytoin, can actually worsen myoclonus. Recent research has identified that perampanel can improve seizure frequency and decrease spontaneous myoclonus (Dirani et al., 2014), and clinical trials in 2016 have shown that it has some efficacy in treating LD myoclonus specifically (Goldsmith and Minassian, 2016). Although this offers a promising step forward for sufferer’s, there remains no treatment for loss of cognition, which also plays a huge role in this disabling condition.  

LD in canines  

LD is naturally occurring within canine breeds such as Bassett Hounds, Beagles and miniature Wirehaired Dachshunds (MWHDs). In 2005, it was first reported that 5% of MWHDs suffered from LD due to autosomal recessive inheritance caused by a single loss-of-function mutation in the canine EPM2B gene. More recent research has also demonstrated that the disease process of LD in canines is similar to its development in humans. This is of great importance to researchers as these animals can be used as models in the search for a better understanding of LD, and for possible therapeutic treatments (Swain et al., 2017).     

Lafora Epilepsy Cure Initiative (LECI) 

The LECI was created in an effort to search for a cure for LD, and improve its diagnosis and treatment. Researchers from the U.S., Canada and Europe are all working together within a team directed by Professor Matthew Gentry at the University of Kentucky College of Medicine. Currently, each lab is focusing on different aspects of the disease, and they have already made progress by discovering that reducing glycogen synthesis can cure LD in mouse models.  


For more information on Lafora disease: 

Epilepsy foundation:  

Chelsea Gerber’s LD research fund:  


Author: Abbie Houghton

Edited by: Molly Campbell


Couarch, P., Vernia, S., Gourfinkel-An, I., Lesca, G., Gataullina, S., Fedirko, E., Trouillard, O., Depienne, C., Dulac, O., Steschenko, D., Leguern, E., Sanz, P. and Baulac, S. 2011. Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism. Journal of Molecular Medicine. 89(9), pp.915-925. 

Dirani, M., Nasreddine, W., Abdulla, F. and Baydoun, A. 2014. Seizure control and improvement of neurological dysfunction in Lafora disease with perampanel. Epilepsy and Behaviour Case Reports. 2(1), pp.164-166. 

Ganesh, S., Delgado-Escueta, A., Sakamoto, T., Avila, M., Machado-Sala, J., Hoshii, Y., Akagi, T., Gomi, H., Suzuki, T., Amano, K., Agarwala, K., Hasegawa, Y., Bai, D., Ishihara, T., Hashikawa, T., Itohara, S., Cornford, E., Niki, H. and Yamakawa, K. 2002. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myclonus epilepsy and impaired behavioural response in mice. Oxford University Press. 11(11), pp.1251-1262. 

Ganesh, S., Puri, R., Singh, S., Mittal, S. and Dubey, D. 2005. Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy. Journal of Human Genetics. 51(1), pp.1-8. 

Goldsmith, D. and Minassian, B. 2016. Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy & Behaviour. 62(1), pp.132-135. 

Jansen, A. and Andermann, E. 2015. Progressive Myoclonus Epilepsy, Lafora Type. Gene Reviews. [Online]. [Accessed 21 October 2017]. Available from: 

Kecmanovic, M., Keckarevic-Markovic, M., Keckarevic, D., Stevanovic, G., Jovic, N. and Romac, S. 2016. Genetics of Lafora progressive myoclonic epilepsy: current perspectives. The Application of Clinical Genetics. 9(1), pp.49-53. 

Swain, L., Key, G., Tauro, A., Ahonen, S., Wang, P., Ackerley, C., Minassian, B. and Rusbridge, C. 2017. Lafora disease in miniature Wirehaired Dachshunds. PLOS. 12(8), pp.1-13. 

Turnbull, J., Girard, J., Lohi, H., Chan, E., Wang, P., Tiberia, E., Omer, S., Ahmed, M., Bennett, C., Chakrabarty, A., Tyagi, A., Liu, Y., Pencea, N., Zhao, X., Scherer, S., Ackerley, C. and Minassian, B. 2012. Early-onset Lafora body disease. Brain. 135(9), pp. 2684-2698


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