Abstract & Commentary

By Cynthia L. Harden, MD, Associate Professor, Neurology and Neuroscience, Weill Cornell Medical, Center of Cornell University. Dr. Harden does research for Schwarz, GlaxoSmithKline, UCB, Ortho, and Ivax, is a consultant for Cyberonics and GlaxoSmithKline, and is on the speaker's bureau for Cyberonics, GlaxoSmithKline, UCB, Novartis, Pfizer, and Ortho.

Synopsis: Epilepsy could be a complex disorder and the hypothesis of a digenic transmission of the disease should be discussed.

Source: Combi R, et al. Two New Putative Susceptibility Loci for ADNFLE. Brain Res Bull. 2005;67:257-263.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is an idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. Mutations of the neuronal nicotinic acetylcholine receptor (nAChR) subunits 4 and 2 are associated with ADNFLE, and have been thought to be the pathogenesis of the disorder. However, the authors of this study found that the nAChR mutations were not present in 4 severely affected ADNFLE Italian families. In the search for potential new genetic mutations, a genome-wide linkage analysis was performed on these families. Two new potential loci were found on chromosomes 3p22-p24 and 8q11.2-q21.1. This study elaborated on the chromosome 8 site, as this site codes for the corticotropin-releasing hormone (CRH) promoter gene. CRH has a broad neuromodulatory effect on various behaviors, including anxiety, learning, food intake, sleep and arousal.

The authors also cite an association between seizures and CRH in rodent models, which could account for the development of epilepsy. CRH has an excitatory effect upon hippocampal CA3 cells, which in turn upregulate glutamate release, thereby augmenting a potential epileptogenic focus. The 2 transversion CRH mutations at this site have opposing effects on protein production; one mutation decreases it and the other mutation increases it. Although this finding confirms that production is altered by the mutation, it implies that an association between CRH and epilepsy is not related to under- or over-production of CRH. However, due to the widespread effects of CRH on the nervous system, any subtle dysfunction in its activity could have neurophysiologic consequences and, in turn, cause seizures and/or sleep disturbances.

Subjects with the mutation reported increased daytime sleepiness, which was supported by increased arousal instability found on neurophysiologic testing. Arousal instability is measured using the cyclic alternating pattern rate (CAP rate), a ratio of the cyclic alternating pattern of sleep over the total sleep time. Altered CRH levels provoke sleep dysfunction such as arousal instability. Therefore, abnormal CAP rates in mutation carriers may be a second clinical abnormality related to the mutated CRH site.


This study elucidates how little we know regarding the causes of idiopathic epilepsy, and points to the possibility that there are many, as yet undiscovered, genetically determined causes of epilepsy. Until now, the major pathogenesis was thought to be related to a genetically influenced channelopathy. The CRH transversion mutation is the first to emphasize an endocrine rather than a neuronal membrane dysfunction. More information is necessary to understand the mechanistic steps that occur between the mutation at the genomic level to the alteration of CRH function, and the development of epileptogenic foci. This study reiterates the concept that epilepsy may have multiple sites at which dysregulation may occur. This genetic mutation may also be a marker for sleep irregularities in patients with epilepsy. Perhaps neurophysiologic testing, such as the CAP rates, in epileptic patients with sleep complaints can help to identify a genetic etiology in this population.