63 research outputs found
Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data
The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population
Off-label psychopharmacologic prescribing for children: History supports close clinical monitoring
The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring
Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
The epilepsies affect around 65 million people worldwide and have a substantial missing
heritability component. We report a genome-wide mega-analysis involving 15,212 individuals
with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11
are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at
these loci, with the majority in genetic generalized epilepsies. These genes have diverse
biological functions, including coding for ion-channel subunits, transcription factors and a
vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants
associated with epilepsy play a role in epigenetic regulation of gene expression in the brain.
The results show an enrichment for monogenic epilepsy genes as well as known targets of
antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and
overlapping genetic basis to seven different epilepsy subtypes. Together, these findings
provide leads for epilepsy therapies based on underlying pathophysiology
- …