Introductory Overview
Epilepsy is a common neurological disorder characterized by recurrent seizures. It has an estimated prevalence of about 0.08% and a lifetime cumulative incidence of about 3% [1].
Approximately 60% of epilepsy cases have no cause other than a genetic predisposition, while the rest are due to a major acquired cause [2] (See pie chart).
However, the probability of a genetic cause of epilepsy is often underestimated in routine clinical practice [3]. Thus, genetic testing can be useful in order to facilitate appropriate counseling. In some patients, it can also help guiding the treatment and predict the risk of being affected for asymptomatic relatives [5,6].
Causes of common epilepsies:
Adapted from [3,4]
Repeat Animation
Prescription Guidance
Clinical Indication
- Individuals with a confirmed diagnosis of epilepsy and/or suspected genetic cause of epilepsy (epileptic seizures occurring at a young age, family history, etc.)
- Relatives of an index case tested positive for a mutation-causing disease
Test Benefits & Risk Management
Benefits of this test are:
- The diagnosis confirmation of a specific genetic syndrome of epilepsy
- The diagnosis refinement, e.g. determination of an unequivocal genetic cause in case of inconclusive clinical picture / atypical phenotype, discrimination between syndromic and non-syndromic form of epilepsy, etc.
- Treatment guidance and targeted management
- The subsequent identification of affected relatives in families where a disease causing mutation has already been found. This would allow an earlier management of at-risk family members.
Risk and treatment management includes, but is not limited to [6]:
For ALDH7A1 related pyridoxine-dependent epilepsy and PNPO related pyridoxamine 5′-phosphate oxidase deficiency:
Treatment
- Pyridoxine should be used
For KCNQ2 related early infantile epileptic encephalopathy / neonatal benign seizures:
Treatment
- Retigabine (or Ezogabine) specifically targets and modulates the opening of the involved potassium channels. However its safety and efficacy in children still need to be assessed.
For PRRT2 related infantile convulsions with paroxysmal choreoathetosis/ episodic kinesigenic dyskinesia / infantile benign seizures:
Treatment
- Carbamazepine or oxcarbazepine might be effective
Management
- Patients should be monitored for other neurological manifestations
For SCN1A related Dravet syndrome / GEFSP2 / familial hemiplegic migraine:
Treatment
- Some sodium channel agents such as phenytoin, carbamazepin and lamotrigine should be avoided
Management
- Monitoring and management of progressive changes in gait
- Awareness of risk of sudden unexplained death in epilepsy
For SLC2A1 related GLUT1 deficiency syndrome:
Treatment
- Ketogenic diet should be tried
Management
- Patients should be monitored for movement disorder
Test Characteristics
Panel Composition
| Gene | MIM Gene | Related Disorder/Phenotype | MIM Phenotype |
|---|---|---|---|
| ALDH7A1 | 107323 | Epilepsy, pyridoxine-dependent | 266100 |
| ALG13 | 300776 | Congenital disorder of glycosylation, type Is | 300884 |
| ARHGEF9 | 300429 | Epileptic encephalopathy, early infantile, 8 | 300607 |
| CDKL5 | 300203 | Epileptic encephalopathy, early infantile, 2 | 300672 |
| CHD2 | 602119 | Epileptic encephalopathy, childhood-onset | 615369 |
| CPA6 | 609562 | Epilepsy, familial temporal lobe, 5 | 614417 |
| DEPDC5 | 614191 | Epilepsy, familial focal, with variable foci | 604364 |
| GABRA1 | 137160 | Epileptic encephalopathy, early infantile, 19 | 615744 |
| GABRB3 | 137192 | Epilepsy, childhood absence, susceptibility to, 5 | 612269 |
| GABRD | 137163 | Epilepsy, idiopathic generalized, susceptibility to, 10 | 613060 |
| GABRG2 | 137164 | Febrile seizures, familial, 8 | 611277 |
| GNAO1 | 139311 | Epileptic encephalopathy, early infantile, 17 | 615473 |
| GRIN2A | 138253 | Epilepsy, focal, with speech disorder and with or without mental retardation | 245570 |
| HCN1 | 602780 | Epileptic encephalopathy, early infantile, 24 | 615871 |
| HDAC4 | 605314 | Brachydactyly-mental retardation syndrome | 600430 |
| IQSEC2 | 300522 | Mental retardation, X-linked 1 | 309530 |
| KCNQ2 | 602235 | Seizures, benign neonatal, 1 / Epileptic encephalopathy, early infantile, 7 | 121200, 613720 |
| KCNQ3 | 602232 | Seizures, benign neonatal, type 2 | 121201 |
| KCNT1 | 608167 | Epilepsy, nocturnal frontal lobe, 5 / Epileptic encephalopathy, early infantile, 14 | 615005, 614959 |
| KCTD7 | 611725 | Epilepsy, progressive myoclonic 3, with or without intracellular inclusions | 611726 |
| LGI1 | 604619 | Epilepsy, familial temporal lobe, 1 | 600512 |
| MBD5 | 611472 | Mental retardation, autosomal dominant 1 | 156200 |
| PCDH19 | 300460 | Epileptic encephalopathy, early infantile, 9 | 300088 |
| PLCB1 | 607120 | Epileptic encephalopathy, early infantile, 12 | 613722 |
| PNPO | 603287 | Pyridoxamine 5′-phosphate oxidase deficiency | 610090 |
| PRRT2 | 614386 | Episodic kinesigenic dyskinesia 1 / Seizures, Benign familial infantile, 2 | 128200, 602066 |
| SCN1A | 182389 | Dravet syndrome / Epilepsy, generalized, with febrile seizures plus, type 2 / Migraine, familial hemiplegic, 3 | 607208, 604403, 609634 |
| SCN1B | 600235 | Epilepsy, generalized, with febrile seizures plus, type 1 | 604233 |
| SCN2A | 182390 | Epileptic encephalopathy, early infantile, 1 / Seizures, benign familial infantile, 3 | 613721, 607745 |
| SCN8A | 600702 | Epileptic encephalopathy, early infantile, 13 | 614558 |
| SLC25A22 | 609302 | Epileptic encephalopathy, early infantile, 3 | 609304 |
| SLC2A1 | 138140 | GLUT1 deficiency syndrome 1&2; Epilepsy, idiopathic generalized, susceptibility to, 12 | 606777, 612126, 614847 |
| SLC35A3 | 605632 | Arthrogryposis, mental retardation, and seizures | 615553 |
| SPTAN1 | 182810 | Epileptic encephalopathy, early infantile, 5 | 613477 |
| STXBP1 | 602926 | Epileptic encephalopathy, early infantile, 4 | 612164 |
| SYNGAP1 | 603384 | Mental retardation, autosomal dominant 5 | 612621 |
| TBC1D24 | 613577 | Epileptic encephalopathy, early infantile, 16 / Myoclonic epilepsy, infantile, familial | 615338, 605021 |
Technical Details
Methodology
- Targeted capture of all coding exons and exon-intron boundaries followed by NGS.
- Confirmatory Sanger sequencing of potentially pathogenic variants.
- Deletion and duplication assessed by MLPA (Multiplex ligation-dependent probe amplification)
TAT
4-5 weeks in average. Urgent testing is available upon request.
References
- Banerjee P, Hauser W. Incidence and prevalence. In: Engel J, Pedley T, eds. Epilepsy: a comprehensive textbook. 2nd edn. Philadelphia: Wolters Kluwer, Lippincott, Williams & Wilkins, 2008:45–56.
- Johnson MR (2011) The genetic contribution to epilepsy: the known and missing heritability. In: The Causes of Epilepsy, eds S.D. Shorvon et al, pp 63-67. Cambridge University Press, Cambridge.
- Hildebrand MS, Dahl HH, Damiano JA, Smith RJ, Scheffer IE, Berkovic SF. Recent advances in the molecular genetics of epilepsy. J Med Genet. 2013 May;50(5):271-9. PubMed PMID: 23468209.
- Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014 May;10(5):283-92. PubMed PMID: 24733163
- Ottman R, Hirose S, Jain S, Lerche H, Lopes-Cendes I, Noebels JL, Serratosa J, Zara F, Scheffer IE. Genetic testing in the epilepsies–report of the ILAE Genetics Commission. Epilepsia. 2010 Apr;51(4):655-70. PubMed PMID: 20100225.
- Poduri A, Sheidley BR, Shostak S, Ottman R. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014 May;10(5):293-9. PubMed PMID: 24733164