Pathophysiology
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, a fact that 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.
Research literature suggests that overactivity of glycogen synthase, the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans. Glycogen synthase can be inactived by phosphorylation at various amino acid residues by many molecules including GSK-3beta. Protein Phosphatase-1 can take out these phosphate moieties and make glycogen synthase active. However, PP-1 needs other proteins like PTG (Protein Targeted to Glycogen) to assist. Malin, another protein mutated in Lafora disease, aids in the degradation of PTG, with assistance from laforin via the ubiquitin proteasome system (UPS). Hence in a malin mutation, PTG might accumulate and cause excessive glycogen synthase activity leading to abnormal glycogen production. However, this supposition has not been confirmed by animal models.
Neurons, though having a capacity to express glycogen synthase, lack capacity to degrade it. They seem not to have glycogen phosphorylase, which is present in astrocytes to degrade glycogen. Astrocytes contribute almost exclusively to brain glycogen storage yet do not develop Lafora bodies, a fact which might highlight the importance of the capacity to degrade glycogen. In a laforin or malin mutation, a laforin-malin complex would cease to exist and drive neurons to make glycogen. This could be detrimental to neuronal function and possibly result in the manifestation of dementia.
Removal of PTG in mice resulted in the near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy.
Read more about this topic: Lafora Disease