Advances in the genetics of progressive myoclonus epilepsy

The genetic progressive myoclonus epilepsies (PMEs) are clinically characterized by the triad of stimulus sensitive myoclonus (segmental lightning like muscular jerks), epilepsy (grand mal and absences) and progressive neurologic deterioration (dementia, ataxia, and various neurologic signs depending on the cause). Etiologically heterogenous, PMEs are rare and mostly autosomal recessive disorders, with the exception of autosomal dominant dentatorubral-pallidoluysian atrophy and mitochondrial encephalomyopathy with ragged red fibers (MERRF). In the last five years, specific mutations have been defined in Lafora disease (gene for laforin or dual specificity phosphatase in 6q24), Unverricht-Lundborg disease (cystatin B in 21q22.3), Jansky-Bielschowsky ceroid lipofuscinoses (CLN2 gene for tripeptidyl peptidase 1 in 11q15), Finnish variant of late infantile ceroid lipofuscinoses (CLN5 gene in 13q21-32 encodes 407 amino acids with two transmembrane helices of unknown function), juvenile ceroid lipofuscinoses or Batten disease (CLN3 gene in 16p encodes 438 amino acid protein of unknown function), a subtype of Batten disease and infantile ceroid lipofuscinoses of the Haltia-Santavuori type (both are caused by mutations in palmitoyl-protein thiosterase gene at 1p32), dentadorubropallidoluysian atrophy (CAG repeats in a gene in 12p13.31) and the mitochondrial syndrome MERRF (tRNA Lys mutation in mitochondrial DNA)

Drug resistance

Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure frequency before onset of therapy predicts a poor outcome of pharmacotherapy. Based on this observation the ‘intrinsic severity hypothesis’ has been proposed. This hypothesis implies that neurobiological factors which contribute to increased disease severity correlate with drug resistance. Further hypotheses propose specific mechanisms of resistance. The mechanisms discussed include alterations in drug targets as well as alterations at the blood-brain barrier including the up-regulation of efflux transporters. Respective data that render experimental support for the hypotheses, pose the question whether these constitute a basis for the development of novel treatment strategies. However, any strategy aiming to outwit one of the suggested mechanisms is challenged by paucity of convincing clinical support for the hypotheses as well as the fact that drug resistance is generally considered as a multi-factorial problem. Future studies are necessary to explore whether the mechanisms have any clinical relevance, and if so, to explore whether selected mechanisms might predominate in patient subgroups