User:Drostinatorr/Lafora disease

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Epidemiology:

All the reports that have been published on Lafora Disease have shown that the overall prevalence of the disease is about 4 cases per million individuals around the world. Due to Lafora's disease (LD) being so rare, there have been very few case series documented. The prevalence of Lafora Disease varies throughout the world because of the differing customs of each country that it is present in. It is much more prevalent in countries that have higher cases of inbreeding. Usually, these locations are generally more isolated from the world at large. In the western countries the prevalence of Lafora Disease is much lower because of the greater city size and less isolated communities that would participate in inbreeding.

Genetics:

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). These mutations in either of these two genes lead to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin.

Graph 1 shows the data for 250 families that have been affected by Lafora Disease and the distribution of cases around the world. The graph shows that there is a very large number of cases in Italy because of the EPM2A gene mutation compared to any other country in the world.

'Graph 1' Represents data that shows how Lafora disease has been distributed throughout not just the United States but the world as a whole. This particular graph shows 250 families that have been affected by Lafora Disease.

'Graph 2' Represents data that shows how the gene mutation for both EPM2A and EPM2B has been distributed around the world. The data goes to show that there are more cases caused by EPM2B than there are for EPM2B (NHLRC1).

Graph 2 shows the percentage distribution of the cases from either an EPM2A gene mutation or an EPM2B (NHLRC1) gene mutation. 42% of the cases are caused by EPM2A and 58% are caused by EPM2B (NHLRC1). The most common mutation on the EPM2A gene is the R241X mutation. This genetic mutation is the cause for 17% of the EPM2A caused Lafora Disease cases.

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

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

Laforin is essential for making the normal structure of a glycogen molecule. When the mutation occurs on the EPM2A gene, laforin protein is down-regulated 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, leading to an accumulation of misformed glycogen, which has neurotoxic effects.

Signs and Symptoms:

Symptoms of Lafora disease begin to develop during the early adolescent years, and symptoms progress as time passes. In the years before then, there is generally no indication of the presence of the disease, though in a few cases, the disease presents as a learning disorder around 5 years of age. In extremely rare cases, symptoms may not show at all until as late as the 3rd decade of life, though these cases have slower progression than typical LD. 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. Other symptoms common with the seizures are drop attacks, ataxia, temporary blindness, visual hallucinations, and a quickly-developing and dramatic dementia.

Other common signs and symptoms associated with Lafora disease are behavioral changes due to the frequency of seizures. Over time those affected with Lafora disease have brain changes that cause confusion, speech difficulties, depression, decline in intellectual function, impaired judgement and impaired memory. If areas of the cerebellum are affected by seizures, it is common to see problems with speech, coordination, and balance in Lafora patients.

Within ten years of developing symptoms, life expectancy has known to go down. People who advance to adulthood tend to lose their ability to do daily tasks by themselves, which can lead them to having to have comprehensive care. If their symptoms have become onset extremely fast or at an early age, comprehensive care allows one to get treatment in ways that are not only regarding receiving their medication, but it also includes both physical and mental health towards the daily activities that one would normally perform by themselves.

Treatment:

Unfortunately there is no cure for Lafora Disease with treatment being limited to controlling seizures through anti-epileptic and anti-convulsant medications. 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. 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. 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 living, but not necessarily functioning. Recently Metformin is approved for the treatment.

Due to the severity of Lafora's disease being exceedingly rare, it is recommended to contact a specialist, such as one specialized in genetics, as well as looking into universities and other medical centers around because they will have the most up to date technology.

Research:

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

An approach to studying this rare disease would be performing a case-control study. This is done by following a group of people to accrue person years to evaluate historical associated factors. These historical factors can then help researchers deduce new cases and consider the discrepancies of various risk factors. This leads to potentially faster recognition of exposures when there are outbreaks of the disease. The added benefits of a case control study are that they take less time to complete, and cost quite a bit less to facilitate, with no follow-up necessary. They can also be used to establish association between different variables, which can then lead into more focused, long-term studies.

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. The adipocyte hormone Leptin is what this research targeted by blocking the leptin signaling to reduce glucose uptake and stop Lafora bodies from forming.