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Juvenile myoclonic epilepsy ( JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME ( CAE/ JME; pedigree 1), JME with adolescent onset pyknoleptic absence ( JME/ pA; pedigree 2), and classic JME ( cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5-6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two-point parametric linkage analyses were performed with 5185 single-nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/ EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2-q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage ( Zmax = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3-q31.2 ( Zmax = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease-causing genes, favoring the concept of JME as several distinct diseases. Whole-exome sequencing will likely identify a CAE/ JME gene in 2q21.2-2q31.1, a JME/ pA gene in 13q13.3-q31.2, and a cJME gene in 17q12. [ABSTRACT FROM AUTHOR]

The development of new pharmaceutical products has successfully addressed a multitude of disease states; however, new product development for treating disorders of the central nervous system (CNS) has lagged behind other therapeutic areas. This is due to several factors including the complexity of the diseases and the lack of technologies for delivery through the blood-brain barrier (BBB). This article examines the current state of six major CNS disease states: depression, epilepsy, multiple sclerosis (MS), neurodegenerative diseases (specifically Alzheimer's disease [AD]), neuropathic pain, and schizophrenia. Discussion topics include analysis of the biological mechanisms underlying each disease, currently approved products, and available animal models for development of new therapeutic agents. Analysis of currently approved therapies shows that all products depend on the molecular properties of the drug or prodrug to penetrate the BBB. Novel technologies, capable of enhancing BBB permeation, are also discussed relative to improving CNS therapies for these disease states. [ABSTRACT FROM AUTHOR]

Summary: Purpose: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12. Methods: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype–genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10–20 years. Results: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups. Conclusions: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample. [ABSTRACT FROM AUTHOR]