Why Doesn't "Genetic" Epilepsy Seem to Run in Families?
Abstract & Commentary
By Cynthia L. Harden, MD Professor of Neurology, Weill Medical College of Cornell University Dr. Harden reports that she is involved with grant/research support for UCB and Eisai; is a retained consultant for GlaxoSmithKline; and is on the speaker's bureau for UCB, GlaxoSmithKline, and Pfizer.
Synopsis: Genetic susceptibility to epilepsy is a complex, polygenetic matrix that is heavily influenced by environmental factors.
Source: Heron SE, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 2007;62:560-568.
Genetic variations in the T-type calcium channel gene CACNA1H are known to be associated with childhood absence epilepsy. T-type channel gene CACNA1H variations may be associated with a broad range of epilepsy types, not as genes that impart epilepsy in a dominant Mendelian fashion, but clearly as permissive or susceptibility genes. This concept is supported by the observation that autosomal dominant epilepsies are extremely rare and have varied phenotypes even within families, and that some families with recurrent epilepsy have inheritance patterns that are difficult to sort out. Therefore, the genetic component of a familial epilepsy syndrome appears to be polygenic or complex, and the phenotype may be influenced by environmental factors.
Heron et al sought to explore the range of epilepsy syndromes associated with variations within this gene in a mixed group of epilepsy patients, and to determine what types of electrophysiological abnormalities were associated with the genetic variations. The investigators searched for variations in the gene CACNA1H among a group of 240 epilepsy patients (and 95 controls) with a broad mix of seizure types and epilepsy syndromes, including: generalized epilepsies such as juvenile myoclonic epilepsy, myoclonic/astatic epilepsy, focal epilepsies including temporal lobe epilepsy, febrile seizures, and generalized epilepsy with febrile seizures. Some patients were inter-related both within a generation and across generations; control subjects were anonymous blood donors. By direct gene sequencing, more than 100 amino acid variations were found, including 19 novel variants. The investigators determined that a subset of 11 of these variants could possibly result in a clinical effect. If the altered amino acid was a highly conserved site, this variation was thought to be an important genetic variation. Further, if the variation was partially co-segregated with an affected family member, absent in all control subjects, or in a region of known functional significance, it was chosen for further study. These 11 genetic variants were transfected into human embryo kidneys cells and the neurophysiologic characteristics of these cells were evaluated. Nine of the 11 genetic variants altered channel properties in a manner that would increase channel current; therefore, they elevated neuronal excitability and potentially permitted seizures. A range of phenotypes was associated with the same gene variant within a single family, with a trend toward more severe epilepsy in the presence of more than one variant within an individual.
The authors conclude that CACNA1H variations contribute to the manifestations of epilepsy, but are not sufficient to cause it. These susceptibility genetic variants, therefore, are an important influence on epilepsy occurrence; however, they would not be identified readily in a standard genome-wide case control study.
Commentary
The investigators in this study embarked on a well-guided fishing expedition for CACNA1H variations among persons with epilepsy, some of whom were members of large families that had multiple members with epilepsy. Variations in CACNA1H are intriguing candidates for epilepsy susceptibility since they can cause channelopathies, the most promising and validated avenue for the pathogenesis of genetic epilepsy. In cells in which the gene variation was present, the majority of the candidate variations were associated with alterations in calcium currents.
The investigators performed a remarkable experiment that goes "from the clinic to the lab" and discovered that CACNA1H variations present in epilepsy patients may cause calcium current alterations that could be associated with epilepsy. One problem with this report is that the epilepsy population studied appears to be enriched for the occurrence of candidate epilepsy genes, in that there are multiple families with multiple phenotypes who previously have been studied for other epilepsy genes. Therefore, the study population is not representative of a general epilepsy population. One could not extrapolate from this investigation and deduce that so many candidate CACNA1H variations would be found in a population of consecutive epilepsy clinic patients.
What do these findings mean for the practitioner? This complicated and open-ended report raises more questions than it answers about the genetics of epilepsy. It points out, first of all, that epilepsy is not a simple disease imparted by one errant gene. There are many susceptibility genes, many of which relate to channelopathies, that influence the occurrence of epilepsy. These genes are not sufficient to cause epilepsy, but may be necessary to permit epilepsy in some individuals. This explains why some epilepsies can be "genetic" but not familial. Parents may carry the susceptibility genes, but this is not enough to cause epilepsy in them, while the combination (or further mutation) in the offspring may permit epilepsy.
Patients often ask "why" about their epilepsy, because in more than 50% of incident cases there is no known environmental risk factor or cause. For generalized epilepsies such as juvenile myoclonic epilepsy, the neurologist may reply that the epilepsy is likely to have a genetic component; this evidence has been emerging for the past two decades. But it is conceptually incongruous to the lay person that an illness could be both "genetic" and not "familial." Information from investigations such as this report demonstrate the complexity of epilepsy genetics, and the variability and ubiquity of epilepsy-influencing genes. This polygenic plus environmental matrix fits with the phenotype of variability of epilepsy even within families, and the broad range of susceptibility to seizures within families that in most cases appears sporadic.
Practitioners should accept and understand this complexity and share it with patients when they ask "why?" Such a conversation could start with the lack of known causes for epilepsy in an individual, and proceed to the likely presence of genetic influences that are complex and require multiple gene variations. Evidence suggests that this complexity applies to both generalized and partial epilepsies. Finally, the occurrence of epilepsy requires that multiple genes be present within an individual; therefore, the illness may not manifest in any other family members, although some may be carriers for susceptibility genes in subsequent generations
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