Lafora disease

Lafora disease
Gonzalo Rodríguez Lafora, discoverer of the disease
Classification and external resources
Specialty	neurology
ICD-10	G40.3
ICD-9-CM	333.2
OMIM	254780
DiseasesDB	30834
MeSH	D020192
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Lafora disease, also called Lafora progressive myoclonic epilepsy or MELF, is a fatal autosomal recessivegenetic disorder characterized by the presence of inclusion bodies, known as Lafora bodies, within the cytoplasm of the cells of the heart, liver, muscle, and skin. In a later study, Lafora disease has been and is now viewed as a neurodegenerative disease, since prior to the actual formation of Lafora bodies there has been seen to be an impairment in the development of cerebral cortical neurons. It was further concluded that Lafora disease is a complex neurodegenerative disease and also a glycogen metabolism disorder.

Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable. At present, there is no cure or treatment for this disease.

Patients develop the first symptoms mainly during adolescence. Major problems include seizures, drop attacks, myoclonus, ataxia, and, most significantly, a quickly-developing and severe dementia.

Lafora disease is an autosomal recessive disorder, caused by mutations in one of three known genes: EPM2A, EPM2B, and NHLRC1.( edit : two genes: the EPM2A gene and the NHLRC1 gene which was previously known as the EPM2B gene. A third gene - PRDM8 gene- MAY cause an early onset form of the disease ). EPM2A codes for the protein laforin, a dual-specificity phosphatase with a carbohydrate binding domain (CBM-20). Vertebrates have only one such protein with DSP domain as well as CBM-20 domain. EPM2B encodes the protein malin, an E3 ubiquitin ligase. All three discovered genes are present on chromosome 6p23-27 in humans.

Current understanding of pathophysiology is largely restricted to understanding the generation of Lafora bodies, and their exclusive appearance in neurons and not in astrocytes.

Normal glycogen is soluble in the cellular environment, which has been attributed to its fractal structure. By contrast, the "abnormal glycogen" in Lafora bodies has an excessive phosphate content and branches at abnormally long intervals. It has been shown that laforin dephosphorylates glycogen and preserves its solubility. Hence, in a laforin mutation, glycogen would be hyperphosphorylated. This has been confirmed in laforin knock-out mice.

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Wikipedia