Silence. You might wonder why you hear very little about ARX in exome studies these days. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Mutations in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, it’s on the differential list for patients with Infantile Spasms without a known cause. Let me tell you about the problems that the ARX gene poses for exome sequencing. Continue reading
EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading
A growing number of genes have been identified to be causative for genetic forms of epilepsy, which are neither ion channels, receptors nor other classical epilepsy genes but epigenetic players. The epigenetic enzymes and effector proteins described to be mutated in inherited genetic epilepsies as well as epileptic encephalopathies, intellectual disability syndromes and autism spectrum disorders with associated severe or occasional seizure phenotype are of various function. Since this function never seems to be sufficiently discussed in the respective publications and little is to be found on how these genes may be linked to the phenotype, here comes a little overview summarizing how epigenetics is contributing not only to symptomatic focal epilepsy but may also help to explain the phenotypic heterogeneity of genetic epilepsies.
G proteins. Intracellular signaling in neurons can occur through various mechanisms including so-called second messengers. G proteins constitute an important part of the signaling cascade that translates the signal from membrane-bound receptors. On neurons, GABA-B receptors or alpha-2 adrenergic receptors use signal transduction through the so-called G alpha-o proteins, which are particularly abundant in the CNS and encoded by the GNAO1 gene. Now a recent paper in the American Journal of Human Genetics describes de novo mutations in Ohtahara Syndrome and movement disorders. Continue reading
Exome no more. Over the last 15 months, we have repeatedly discussed how exome sequencing or genome sequencing is applied to neurodevelopmental disorders in order to discover new candidate genes and to assess the role of known candidate genes. We have also wondered sometimes whether exome sequencing is the most straightforward approach. Now – outpacing the two large international consortia using exome sequencing in epileptic encephalopathies – a recent study in Nature Genetics uses a different approach to uncover the genetic basis in 10% of patients with epileptic encephalopathies. Targeted resequencing or gene panel analysis is a hybrid technology between candidate gene sequencing and next generation sequencing and focuses only on a subset of candidate genes. While their study provides a comprehensive overview over the genetics of rare epilepsy syndromes, it raises the question whether the era of large-scale exome sequencing is coming to a natural end. Continue reading