RAPID EPILEPSY TESTING (EPIRAPID)

Emerging evidence shows that people with epilepsy who have certain genetic mutations may benefit from changes in their current treatment. EpiRapid allows for testing of a panel of genes with the potential to immediately alter treatment, with results available in 8-10 days*.

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Emerging evidence shows that people with epilepsy who have certain genetic mutations may benefit from changes in their current treatment. EpiRapid allows for testing of a panel of genes with the potential to immediately alter treatment, with results available in 8-10 days*.

Disease Name 
Epilepsy
Disease Information 

Epilepsy is characterized by recurrent, unprovoked seizures. It can develop in any person at any age, but is most common in children, particularly in the first year of life. 65-70% of all epilepsy is currently thought to have a genetic component,1 with single gene causes representing a growing portion of this total. Genetic testing can help determine the underlying cause of many epilepsy syndromes, which may allow clinicians to:

  • Select the appropriate anti-convulsant(s) or other intervention
  • Avoid alternative, potentially invasive, testing
  • End the diagnostic odyssey
  • Improve the understanding of prognosis
  • Refine genetic counseling, including recurrence risk in future pregnancies
  • Provide families the opportunity to connect with others in a similar situation

Test Information

EpiRapid is our fastest epilepsy test, with results available in 8-10 days*. If a causative mutation is not identified, testing can proceed to a broader epilepsy gene panel (EpilepsyNext). 

Testing Benefits & Indication 

Some epilepsy syndromes have effective treatments available. Early diagnosis can therefore lead to more customized and appropriate management. Recent advancements in clinical research have shown that particular genetic causes of epilepsy may be more or less responsive to certain types of therapy.  

While this area of precision medicine is still growing, some of the reported associations are listed below. All genes mentioned are included in EpiRapid.

Gene Therapy
ALDH7A12 Pyridoxine (vitamin B6), folinic acid
FOLR13 Folinic acid
KCNQ24,5 Carbamazepine, phenytoin, ezogabine
KCNQ36 Phenobarbitol, phenytoin, carbamazepine, valproate
KCNT17 Quinidine
MECP28 Memantine
PCDH199 Stiripentol
PNPO10 Pyridoxine (vitamin B6)
POLG11 Avoid: valproic acid
PRRT212,13 Carbamazepine
SCN1A14

Consider: diazepam, clonazepam, levetiracetam, topiramate, stiripentol, valproate, clobazam (for Lennox-Gastaut syndrome), ketogenic diet (for Doose syndrome)

Avoid: carbamazepine, lamotrigine, and vigabatrin

SCN8A15 Phenytoin
SLC2A116 Ketogenic diet
STXBP117 Levetiracetam
TSC118 Vigabatrin
TSC218 Vigabatrin

 

Genetic testing is useful for:

  • Diagnostic confirmation in symptomatic individuals 
  • Guiding recommendations for medical treatment and management 
  • Testing of at-risk asymptomatic family members (including prenatal diagnosis)
  • Molecular confirmation of a diagnosis to avoid unnecessary testing and procedures
Test Description 

EpiRapid includes 16 genes with reported therapeutic associations: ALDH7A1, FOLR1, KCNQ2, KCNQ3, KCNT1, MECP2, PCDH19, PNPO, POLG, PRRT2, SCN1A, SCN8A, SLC2A1, STXBP1, TSC1, and TSC2. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). 

Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.19 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Deletion/duplication analysis by MLPA is performed for MECP2.

Mutation Detection Rate 
Clinical Epilepsy Syndrome Mutation Detection Rate  (Clinical Sensitivity)
Alpers syndrome Up to 87%20-22 
Benign familial neonatal seizures (BFNS) Up to 57%23
Benign familial infantile seizures (BFIS) Up to 83% of individuals with a family history of this condition, up to 30% of individuals without a family history24,25 
Dravet syndrome Up to 80%23
Early-onset epileptic encephalopathies (other than Dravet syndrome, Ohtahara syndrome, infantile spasms/West syndrome) Up to 30%26-30
Genetic epilepsy with febrile seizures plus (GEFS+) At least 5-10%23
Infantile spasms (including West syndrome) up to 40%23,31,32
Ohtahara syndrome Up to 35%23
Pyridoxine-responsive epilepsy Up to 90%33
Tuberous sclerosis complex (TSC) Approximately 85%34

 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
7033 EpiRapid  8-10 days* 
7034 EpiRapid with reflex to EpilepsyNext 8-10 days* plus 4-6 weeks 

* Verbal results will be available at 8-10 days and will include all identified mutations/variant likely pathogenic results. A written report will be available at 10-14 days and will include variants of uncertain significance (VUS). It is possible that the written report will contain a mutation/variant likely pathogenic result that was not communicated verbally due to ongoing variant classification efforts in the intervening days.

Specialty 
Genes 
ALDH7A1
FOLR1
KCNQ2
KCNQ3
KCNT1
MECP2
PCDH19
PNPO
POLG
PRRT2
SCN1A
SCN8A
SLC2A1
STXBP1
TSC1
TSC2
References 
  1. Nordii DR. Epileptic encephalopathies in infants and children. J Clin Neurophysiol. 2012; 29(5):420-424.
  2. Mills PB, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010; 133:2148-2159.
  3. Delmelle F, et al. Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR1 mutation. Eur J Paediatr Neurol. 2016;20(5):709-713.
  4. Bellini G, et al. KCNQ2-Related Disorders. April 27, 2010 [Last Update: April 11, 2013]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  5. Hani AJ, et al. Genetics of pediatric epilepsy. Pediatr Clin North Am. 2015;62(3): 703-722.  
  6. Bellini G, et al. KCNQ3-Related Disorders. May 22, 2014. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  7. Mikati MA, et al. Quinidine in the treatment of KCNT1 positive epilepsies. Ann Neurol. 2015; Sep 15. 
  8. Bello O, et al. Is memantine a potential therapeutic for Rett syndrome? Front Neurosci. 2013;7(245):1-3.
  9. Trivisano M, et al. Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19-related epilepsy. Eur J Paediatr Neurol. 2015; 19(2):248-50. 
  10. Riikonen R, et al. Long-term outcome in pyridoxine-responsive infantile epilepsy. Eur J Paediatr Neurol. 2015;19(6):647-651.
  11. Saneto RP, et al. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure. 2010;19(3):140-146.
  12. Dale RC, et al. Benefit of carbamazepine in a patient with hemiplegic migraine associated with PRRT2 mutation. Dev Med Child Neurol. 2014; 56(9):910.
  13. Chou IC, et al. Successful control with carbamazepine of family with paroxysmal kinesigenic dyskinesia of PRRT2 mutation. Biomedicine. 2014;4:15. 
  14. GeneReviews. SCN1A-Related Seizure Disorder. Accessed September 20, 2015.
  15. Boerma RS, et al. Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach. Neurotherapeutics. 2015; Aug 9.
  16. Ramm-Pettersen A, et al. Good outcome in patient with early dietary treatment of GLUT-1 deficiency syndrome: results form a retrospective Norwegian study. Dev Med Child Neurol. 2013;55(5):440-447.
  17. Dilena R, et al. Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation. Brain Dev. 2015; Jul 23. 
  18. Wang S, Fallah A. Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options. Neuropsychiatr Dis Treat. 2014; 10: 2021-2030.
  19. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.
  20. Nguyen KV, et al. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45(1):108-116. 
  21. Isohanni P, et al. POLG1 manifestations in childhood. Neurology. 2011;76(9):811-815. 
  22. Hunter MF, et al. Alpers syndrome with mutations in POLG: clinical and investigative features. Pediatr Neurol. 2011;45(5):311-318. 
  23. Ottman R, et al. Genetic testing in the epilepsies--report of the ILAE Genetics Commission. Epilepsia. 2010; 51(4):655-670.
  24. Heron SE, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 2012;90(1):152-160. 
  25. Schubert J, et al. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat. 2012;33(10):1439-1443. 
  26. Zucca C, et al. Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified. Arch Neurol. 2008; 65(4):489-494.
  27. Harkin LA, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007; 130:843-852.
  28. Weckhuysen S, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012; 71(1):15-25.
  29. Kamiya K, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci. 2004; 24(11):2690-2698.
  30. Ogiwara I, et al. De novo mutations of voltage-gated sodium channel alpha(II) gene SCN2A in intractable epilepsies. Clin Genet. 2009; 73(13):1046-1053.
  31. Staley et al. Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatr. 2011;127:e117-e125. 
  32. Au KS, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9:88–100.
  33. Mills PB, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010; 133:2148-2159.
  34. Au KS, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9:88–100.