Genetics of Lafora progressive myoclonic epilepsy: current perspectives

Abstract

Lafora disease (LD) is a fatal neurodegenerative disorder caused by loss-of-function mutations in either laforin glycogen phosphatase gene (EPM2A) or malin E3 ubiquitin ligase gene (NHLRC1). LD is associated with gradual accumulation of Lafora bodies (LBs). LBs are aggregates of polyglucosan, a long, linear, poorly branched, hyperphosphorylated, insoluble form of glycogen. Loss-of-function mutations either in the EPM2A or in the NHLRC1 gene lead to polyglucosan formation. One hypothesis on LB formation is based on findings that laforin–malin complex downregulates glycogen synthase (GS) through malin-mediated ubiquitination, and the other one is based on findings that laforin dephosphorylates glycogen. According to the first hypothesis, polyglucosan formation is a result of increased GS activity, and according to the second, an increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan, while GS remains bound to the precipitating glycogen. In this review, we summarize all the recent findings that have important implications for the treatment of LD, all of them showing that partial inhibition of GS activity may be sufficient to prevent the progression of the disease. The current perspective in LD is high-throughput screening for small molecules that act on the disease pathway, that is, partial inhibitors of GS, which opens a therapeutic window for potential treatment of this fatal disease.

SERPINI1 pathogenic variants: An emerging cause of childhood‐onset progressive myoclonic epilepsy

“…A subset of these entities involves the intracellular accumulation of certain molecules that evade degradation and result in cellular dysfunction and loss. This is the case in Lafora disease with polyglucosan bodies forming in neuronal perikarya and dendrites (Kecmanovic et al, ) and in neuronal ceroid lipofuscinoses (NCL) with the characteristic periodic acid‐Schiff (PAS)—and Luxol fast Blue‐positive intracellular ceroid material in neurons and astrocytes (Jadav et al, ). Despite these pathological stigmata, the broad spectrum of clinical presentations necessitates genetic testing to confirm the diagnosis and understand the molecular pathophysiology of the resulting phenotypes.…”

Enfermedad de Lafora: revisión de la bibliografía

“…Por ello se propone la realización de un análisis genético con el fin de confirmar LD. En el caso de que no se confirmase el diagnóstico en un paciente que presenta las características de la LD después de analizar los exones de los genes EPM2A y EPM2B, se debe considerar un análisis genómico en el que se incluya las secuenciaciones completas del genoma [45]. Turnbull et al [2] proponen realizar el diagnóstico en base a tres niveles diferentes de evidencia, que se recogen representados en el esquema de la Figura 2.…”

“…Por tanto, la regulación a la baja de la síntesis de glucógeno podría ser un tratamiento potencial para la LD. En humanos no se puede eliminar completamente la GS, ya que causaría otro tipo de patologías, pero podría considerarse como una posibilidad terapéutica la reducción parcial de la GS[45].Laforina y malinaTras la identificación del gen de la laforina en 1998, la investigación se centró en descubrir cuál era el sustrato de la laforina y cómo la ausencia de esta proteína se relaciona con la LD. Se ha propuesto que la laforina funciona como regulador de la GS[46], así como glucano fosfatasa[27], aunque recientemente se ha descrito que la…”

Lafora Disease: A Ubiquitination-Related Pathology

“…However, in some cases, there is a late-onset or a slow progression of the disease. In these cases, it is assumed either that the mutation present in EPM2A or in EPM2B only partially affects the function of the corresponding protein, or that the presence of genetic or environmental modifiers influences the regular progression of the disease [ 13 , 14 , 15 , 16 ].…”