Conference Coverage
If a genetic disorder is suspected as the cause of treatment-resistant epilepsy, appropriate genetic tests may lead to timely diagnosis and targeted therapy, as well as reduce overall costs and limit anxiety to families, said Anup Patel, MD, in a review paper published online ahead of print September 8 in Epilepsia. In a literature review, Dr. Patel and Margie A. Ream, MD, PhD, discussed the genetic methods available, along with their advantages and disadvantages.
“Interpretation of complicated results should be performed only in collaboration with geneticists and genetic counselors unless the ordering neurologist has a strong background in and understanding of genetics,” the authors advised. Drs. Ream and Patel are Assistant Professors in the Department of Pediatrics at Nationwide Children’s Hospital and Ohio State University in Columbus.
Generally, genetic testing is not recommended for patients with drug-responsive epilepsy or at epilepsy onset, although comparative genomic hybridization can be useful at first evaluation of a patient with global developmental delay. Metabolic testing should be undertaken at the onset of epilepsy in infants without a structural or syndromic cause of their seizures.
For children with drug-resistant epilepsy, Drs. Ream and Patel proposed a diagnosis algorithm. Biochemical testing should be the first line of action to uncover treatable metabolic disorders such as inborn errors of metabolism, which often cause seizures. Metabolic testing gives quicker results than targeted genetic studies or gene panels, thus allowing for more rapid treatment initiation. In most cases, there are several phenotypic variations of genetic epilepsy, and many genes would need to be tested for a given phenotype. This situation often makes targeted gene sequencing costlier than a gene panel.
Drug-resistant epilepsy, especially when associated with developmental delay or congenital anomalies, should prompt comparative genomic hybridization analysis, which detects copy number variations (ie, DNA deletions or duplications). The analysis’s sensitivity of 23.5% increases when multiple abnormalities are present. Aneuploidy and balanced translocations not detectable by comparative genomic hybridization can be found with karyotype.
The next test in the algorithm is a gene panel. This broad genetic test is useful in identifying specific genes and may be the most cost-effective way to approach diagnosing a broad phenotype.
Beyond gene panel testing, an even broader genetic evaluation is whole exome sequencing. This method tests all exons in the genome, is not limited to known epilepsy genes, and has 39% sensitivity. Whole exome sequencing is indicated in genetically heterogeneous disorders, when there is a suspected genetic disease lacking a specific test, when other genetic tests are negative for suspected disorders, and, in some cases, for prenatal testing. The disadvantage of whole exome sequencing is that it results in complex data, but it holds the potential for gene discovery in patients with similar phenotypes or if gene mutations occur in a common biochemical pathway. Whole exome sequencing costs in the range of $5,000 to $14,000 but sometimes can be less costly than traditional molecular diagnostic approaches.
Drs. Ream and Patel recommended “reserving whole exome sequencing for the most elusive cases” until it becomes more cost-effective. Ideally, they said, in the future, “whole exome sequencing could be tailored for epilepsy patients by optimizing coverage of known epilepsy genes.”
—Evelyn Tran
