When should genetic testing be performed in epilepsy patients?

Annapurna Poduri (2017) When Should Genetic Testing Be Performed in Epilepsy Patients?. Epilepsy Currents: January/February, Vol. 17, No. 1, pp. 16-22.

This review is a summary of a talk presented at the 2015 American Epilepsy Society Annual Meeting. Its purposes are 1) to review developments in epilepsy genetics, 2) to discuss which groups of patients with epilepsy might benefit from genetic testing, and 3) to present a rational approach to genetic testing in epilepsy in the rapidly evolving era of genomic medicine.

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From the article

Who might benefit from genetic testing? And why should we embark on the process of seeking approval and coverage for genetic testing in the realm of epilepsy, when we are also managing medications, side effects, and developmental and behavioral concerns in ever more complex healthcare systems? Genetic testing can be time-consuming, particularly when done with proper pretest counseling about the range of effects that may ensue and their meaning (see below). Follow-up of results, parental testing in some cases, and return of positive results often demand additional visits and can be logistically challenging. Why then pursue genetic testing in the epilepsy clinic? The two main reasons for seeking a genetic diagnosis in epilepsy are 1) diagnostic certainty, which may aid in prognosis, and 2) potential impact on treatment (see examples in Table 1). So, it would make sense to focus testing at this time on those in whom there is a high likelihood of a diagnostic finding and on those whose refractory epilepsy may be influenced by a precise genetic diagnosis that can guide treatment. In most cases, we cannot answer the question of whether treatment will be affected until after we perform genetic testing and have the results. For patients with refractory epilepsy, particularly infants and young children, if there is any chance of that occurring, parents and physicians alike are naturally compelled to undertake all possible testing that could in any way ameliorate the clinical situation. This is the case regardless of the likelihood of the availability of a rational therapy based on the diagnosis. In this group, we seek an end to a “diagnostic odyssey” for families and a removal of a sense of blame that many of them report prior to a conclusive molecular diagnosis.

The highest yield group of patients for genetic testing to date can be summarized as “epilepsy plus,” consisting of epilepsy with accompanying dysmorphic features (though a specific genetic syndrome may not be evident early on), intellectual disability, autism, and cognitive regression  . In these groups, the yield of CMA is about 5% and sequencing via panel testing or exome sequencing, 20 to 50 percent. This group is also highly likely to experience refractory epilepsy. There are some conditions, the inherited metabolic epilepsies, that are treatable and simply should not be missed; these include pyridoxine-dependent epilepsy caused by recessive variants in ALDH7A1. There is a growing list of genes that suggest a modification in treatment (e.g., SCN1A—avoid phenytoin and lamotrigine, in general though not always; SCN2A and SCN8A—high-dose sodium channel-affecting agents such as phenytoin may be effective). There are others for which observations across many centers may have a role in suggesting treatment (e.g., PCDH19) but for which prospective trials are still needed to know if there is a clear specific response to particular treatments. For some genes, there is a hope of “precision” medicine, or treatment based on the biology of the genetic dysfunction. This includes KCNT1, GRIN2A, and DEPDC5 and other mTORopathies, including focal cortical dysplasia. Two major caveats should be mentioned here: 1) the presence of any variant in an epilepsy-associated gene does not automatically mean that the variant is pathogenic, nor does it inform us as to the type of functional change that may be present (e.g., gain vs loss of function), and 2) while case reports are helpful in establishing proof of principle and pointing to potential treatments, we need as a community to come together to conduct clinical trials with clear, uniform outcomes to study the effects of rational, target medications for each rare genetic epilepsy. Both careful vetting of variants and consultation with colleagues with expertise in specific genes are often needed to aid in the most accurate determination of whether or not to pursue gene-based treatment…

Genetics plays a major role in epilepsy, particularly in patients with refractory epilepsy. The well-informed neurologist can triage who most needs and could benefit from genetic testing, choose the appropriate testing, and explain the findings in the context of the ever-important clinical scenario. What is needed is a thoughtful genetic approach incorporated into the overall clinical evaluation of a patient with epilepsy. The ability to access and incorporate new information about types of testing, specific genes, and possible treatments can augment the success of this approach. Depending on the practice setting, a neurologist can address all of these issues and stay current by partnering with a colleague in genetics or by seeking epilepsy genetics expertise from physicians and genetic counselors in a specialized epilepsy genetics program.