Genetic causes of early-onset epileptic encephalopathy

Gürsoy S, Erçal D. Diagnostic Approach to Genetic Causes of Early-Onset
Epileptic Encephalopathy. J Child Neurol. 2015 Aug 13. [Epub ahead of print]

Abstract

Epileptic encephalopathies are characterized by recurrent clinical seizures and prominent interictal epileptiform discharges seen during the early infantile period. Although epileptic encephalopathies are mostly associated with structural brain defects and inherited metabolic disorders, pathogenic gene mutations may also be involved in the development of epileptic encephalopathies even when no clear genetic inheritance patterns or consanguinity exist. The most common epileptic encephalopathies are Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome and Dravet syndrome, which are usually unresponsive to traditional antiepileptic medication. Many of the diagnoses describe the phenotype of these electroclinical syndromes, but not the underlying causes. To date, approximately 265 genes have been defined in epilepsy and several genes including STXBP1, ARX, SLC25A22, KCNQ2, CDKL5, SCN1A, and PCDH19 have been found to be associated with early-onset epileptic encephalopathies. In this review, we aimed to present a diagnostic approach to primary genetic causes of early-onset epileptic encephalopathies.

From the article:

Molecular Genetic Testing in Epileptic Encephalopathies

Molecular-based studies on early-onset epileptic encephalopathies should be performed, necessitating programmed genetical algorithms. If the phenotype could be determined with clinical findings, spesific gene testing would be helpful in diagnosis. However, if the phenotype could not be determined because of overlapping phenotypes of different syndromes and the spectrum of phenotypes seen in different mutations, the use of gene panels for epilepsy would increase the probability of correct diagnosis. In a recent study, the rate of diagnosis with targeted single gene sequencing has been reported as 15.4%, whereas the rate has increased to 46.2% with the utility of epilepsy gene panels. In another very recent study, the authors have reported that targeted next-generation sequencing panels for epileptic encephalopathies has increased the diagnostic yield from <10% to >25% in patients with epileptic encephalopathy. Therefore, gene panels for epilepsy would be a cost-effective alternative to Sanger sequencing of individual genes for the genetic diagnosis of epilepsy. Furthermore, whole-exome sequencing can be used to perform next-generation sequencing of exon-enriched samples. This technology only sequences approximately 1% of the genome that is in the coding-protein area and forms modest bioinformatic data, whereas almost 85% of mutations for diseases are in gene-coding regions. In a large-scaled study, results from clinical diagnostic exome sequencing demonstrated that a molecular diagnosis could be achieved in 35% of the people with epilepsy. Whole exome, or other next-generation, sequencing is not currently available in most centers, but when it becomes more widely available, it will provide major improvements on the management of epilepsy syndromes.                  

Conclusion

Data regarding the etiopathogenesis and the genetical basis of early-onset epileptic encephalopathies has been progressively improved and enlarged. The detection of responsible genes carries importance in management of the disorder and assisting in selection of therapy. Furthermore, the prognosis of the diseases can be estimated and may help identify families who may benefit from a referral to genetic counseling. Knowledge of the clinical profile, seizure types, and EEG features of the disease phenotype associated with the specific mutation could help the clinician improve diagnostic precision and management. If the electroclinical findings are obscure, targeted gene panels for epilepsy would be a cost-effective alternative to Sanger sequencing of individual genes for the genetic diagnosis of epilepsy. But when whole exome, or other next-generation, sequencing becomes available worldwide in the near future, it will absolutely increase the diagnostic yield and reveal novel epileptic encephalopathy genes.