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 . 

Characteristics  

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).  

Pathology  

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.  

Inheritance 

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).

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Figure 1: The mechanisms involved in the formation of nsoluble Lafora bodies, leading to Lafora disease. Taken from http://researchfeatures.com/2017/06/30/plants-provide-hope-epilepsy-initiative/  

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: https://www.epilepsy.com/learn/types-epilepsy-syndromes/lafora-progressive-myoclonus-epilepsy  

Chelsea Gerber’s LD research fund: https://chelseashope.org/  

 

Author: Abbie Houghton

Edited by: Molly Campbell

References 

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: https://www.ncbi.nlm.nih.gov/books/NBK1389/ 

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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Can you trick yourself into being confident? The big debate.

After watching a TED Talk by Amy Cuddy about how our body language affects our confidence (which I highly recommend for anyone interested), I wanted to look at the chemical changes that occur within the brains neurotransmitter levels (the chemicals that transmit information in our brain and body) in relation to the content of her talk.

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Firstly, what was the summary of her research? She found that by standing tall with your arms outstretched – in a “high-power” pose – neurotransmitter levels are altered in the body. The hormone testosterone (responsible for giving us confidence) increases and the neurotransmitter cortisol (the stress hormone) decreases. When a “low-power” pose was adopted (when subjects hunched over and hugged themselves) the opposite effect occurred –  testosterone levels decreased and cortisol levels rose.

What I found really fascinating was her claim that this change was perceivable to other people. In her experiment, a group of subjects underwent a fake job interview presentation. They were split into two groups; one group performed “high-power” poses prior to the interview, and the other performed “low-power” poses. The interviewers were not aware which candidates had adopted which pose. Despite not knowing which candidate did what, they preferably chose to hire those who had adopted the “high-power” pose before the interview, despite that fact that the prior body position had no effect on body language during the presentation.

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Top Line “High-power” poses. Bottom Line “Low-power” poses. (Amy Cuddy, Harvard University).

Is this really true? Can you really trick your body into being confident when you don’t feel it? As a neuroscientist, I was interested in the chemical changes that were claimed to occur – could this simple act of standing tall really change the chemicals released by the body?

Upon further investigation, I found a furious debate between researchers on whether “high-power” posing actually works, or whether it was just a placebo effect with no change in neurotransmitter levels. A lot of research has been conducted attempting to replicate the results found by Amy Cuddy’s team – with very little success. The overwhelming evidence has shown that while these power poses make people feel more powerful, the biological and behavioural translation is minimal. In fact, one of the original co-authors to Cuddy’s work, Dana Carney, has since spoken out about the conflicting scientific evidence, stating it shows that the effects of “high-power” posing cannot be replicated and therefore cannot have a biological cause.

In studies that replicate the methodology of the original study (but with larger sample sizes), the results were disappointing. Several studies showed that interviewees performed no differently, and “high-power” posers were not hired at a greater rate than “low-power” posers. Studies that examined the changes in hormone levels were consistent with the evidence that “high-power” posing has no effect on confidence, or neurotransmitter levels.

Despite this, the TED talk is really convincing and does pose a dilemma for me. I wanted to believe this was true – that I could change the way I act and feel just by posing by myself for 2 minutes. There have also been millions of viewers to this TED talk that have self-reported the miraculous effect that “high-power” posing has had for them. For me, I have had to accept that while I may wish it to be true, there is little evidence to prove that “high-power” posing effects your neurochemistry. But despite this, I think if you’re going for that job interview, or a big meeting, or you’re just not feeling great that day, take two minutes to adopt some power poses – tell yourself you can do it, and trick your body into being confident. It may not have a chemical basis behind it, but who doesn’t love a good old placebo effect?

Author: Rosie Porter

Edited by Molly Campbell

References

Cuddy, Amy J.C., Caroline A. Wilmuth, and Dana R. Carney. “The Benefit of Power Posing Before a High-Stakes Social Evaluation.” Harvard Business School Working Paper, No. 13-027, September 2012.

The link to Amy Cuddy’s TED talk: https://www.ted.com/talks/amy_cuddy_your_body_language_shapes_who_you_are

Michigan State University “‘Power Poses’ Don’t Work, Studies Suggest.” NeuroscienceNews. 11 September 2017. [http://neurosciencenews.com/power-poses-psychology-7458/]

To read more about Dana Carney’s viewpoint you can read this statement released by her:

http://faculty.haas.berkeley.edu/dana_carney/pdf_my%20position%20on%20power%20poses.pdf

Zika Fever

The recent observed link between the Zika virus and neurodevelopmental disorders in Latin America has forced the world health organisation to place the outbreak as a public health emergency. So what is Zika and what are its effects on the nervous system?

Zika

The first reported infection from the Zika virus occurred in Uganda in 1947. Although the virus does show a wide geographical distribution, the outbreaks remained small and narrowly distributed until 2007 when there was a large epidemic, effecting 75% of the population on Yap Island. Zika, a mosquito-borne virus, belongs to the Flaviviridae family, which also includes the virus yellow fever. The species of Mosquito thought to be the main vector of the virus in South and South East Asia is the Aedes aegypti (Yssel et al., 2015). Studies have shown that there is a widespread distribution in North Africa as well as countries in Southeast Asia, including India and the Phillipines. These large outbreaks are characterised by mild flu like symptoms such as fever, rash, arthralgia, muscle and joint pain, malaise, headache and conjunctivitis (Yssel et al., 2015). Recent reports have suggested that the virus can also be spread through sexual transmission, however only two reported cases suggest this, and so the main focus of research remains on transmission via mosquito bite. The Zika virus is particularly a concern for pregnant mothers who are infected with the virus, as it can give rise to microcephaly.

Microcephaly

Approximately 3 million babies are born in Brazil every year. In a normal scenario an estimated 150 babies would be diagnosed with microcephaly, whereas now Brazil are said to be investigating around 4000 cases. Many post mortems of infants who died with microcephaly have been shown to present the Zika virus within their brains, and it has also been detected in the placenta and amniotic fluid.

Microcephaly is a disorder that affects neurological development. New-borns with the disorder tend to have smaller than average intracranial brain volume. There are two main types of microcephaly; primary microcephaly: when the brain is smaller at birth, and secondary microcephaly: when the brain is of normal size at birth but there is failure of the brain to develop normally post-natal (Woods 2004). The face develops at a normal rate which leads to an infant with a receding hair line and in many cases a wrinkled scalp. The cerebral cortex is particularly reduced which leads to a simplified gyral pattern and MRI studies have shown the frontal lobes to be particularly affected. Primary microcephaly is thought to be caused by a decrease in neurones produced by neurogenesis, whereas secondary microcephaly is characterised by a reduced amount of dendritic endings and synaptic connections (Woods,2004). Primary usually occurs before 32 weeks of gestation. The majority of neurones are formed by week 21 of foetal development, whereas dendritic connections and myelination mainly occur after birth; this explains the differences in the two variations of the disorder. Abnormalities are not just seen in regards to the brain and skull, later in life the body is usually seen to be underweight and dwarfed. Seizures severely impair intellectual development and disturbances in motor functions may also develop later due to the demyelination and reduced connectivity.

It is important to note that genetic factors, alcohol consumption of the mother during the pregnancy, maternal syphilis infections and poor pre-natal care can all be the cause of microcephaly. Thus further investigations are required to determine whether this causal link between Zika infection and microcephaly is directly related.

The infection is also thought to affect adults, resulting in temporary paralysis known as Guillain- Barré syndrome.

17256

(Kaneshiro and Black, 2013)

 

Guillain- Barré syndrome

During the recent outbreak in French Polynesia (2013 and 2015) the reports of individuals with Guillain- Barré syndrome (GBS) increased 20-fold (Yssel et al., 2015). GBS is a disorder in which the immune system begins to attack part of the peripheral nervous system. These immune cells begin to destroy the myelin sheath and in some cases the axons also. When demyelination occurs the speed of electrical transmission is greatly reduced. This causes problems with both motor and sensory transmission, as the limbs receive and transmit information over longer distances, and thus are more susceptible to the adverse effects of demyelination. Initial symptoms of the disorder include myasthenia (weakness) and tingling sensations known as paraesthesia in the lower limbs. These go on to spread to the upper limbs. Because there is reduced sensory afferent feedback the individual becomes unable to detect and respond to mechanical, thermal and nociceptive stimuli efficiently. These effects increase in intensity until the point of paralysis, where specific muscles can no longer be used. If this syndrome progresses then there is a high risk of mortality as the paralysis can affect respiratory muscles and the cardiovascular system. Research suggests that when a virus like Zika causes this syndrome it may be due to the virus changing the cells of the nervous system In such a way that the immune system begins to recognise them as foreign, or removes the ability of the immune system to distinguish between its own cells and those that are foreign. This leads to immune cells such as macrophages phagocytosing and destroying cells of the peripheral nervous system, particularly the Schwann cells, which lay the myelin sheath.

Prognosis for the disease is fairly good: most individuals recover fully with only a few (around 30%) suffering from prolonged weakness. This may pose the question as to why there is such a panic over the Zika outbreak. However, regions where there is the highest number of cases do not have efficient access to healthcare, and therefore there is an increased risk of mortality, which must be considered.

Conclusion

Brazilian authorities are currently investigation other potential causes of microcephaly, but it seems that there is an increasing amount of evidence linking the virus with these disorders. The greatest problem is that 80% of Zika cases are asymptomatic; therefore pregnant women may not be aware that they’ve even contracted the infection. If there is a confirmed link between the virus and microcephaly, then research developments are required that enable efficient and prompt diagnosis, in addition to preventing the disease infecting pregnant women and those of childbearing age in the first place.

References

Kaneshiro, N.K. and Black, B. (2013) Microcephaly: MedlinePlus medical encyclopedia image. Available at: https://www.nlm.nih.gov/medlineplus/ency/imagepages/17256.htm (Accessed: 8 February 2016).

Woods, C.G. (2004) ‘Human microcephaly’, Current Opinion in Neurobiology, 14(1), pp. 112–117. doi: 10.1016/j.conb.2004.01.003

Yssel, H., Dejarnac, O., Wichit, S., Ekchariyawat, P., Neyret, A., Natthanej, L., Perera-Lecoin, M., Hamel, R., Talignani, L., Thomas, F., Cao-Lormeau, V.-M., Choumet, V., Briant, L., Desprès, P., Amara, A., Surasombatpattana, P., Missé, D., (2015) ‘biology of zika virus infection in human skin cells’, Journal of Virology, pp. 15–354.

 

Article by: Kate Pearman

Edited by Molly Campbell