There are approximately 300,000 pediatric epilepsy cases in the US, with 45,000 newly diagnosed cases each year. Understanding the etiology (i.e. underlying cause) of epilepsy is essential for properly treating patients. Until recently, the etiology of epilepsy was regarded as unknown in about 75% of patients. However, because of new developments in sequencing technologies, genetic studies are yielding new discoveries every year that are helping patients unlock the underlying cause of their disease, allowing them and their care givers to make more informed decisions about their treatment.
More than 50% of all epilepsies have a genetic cause
As recently as 2011, only 30% of epilepsies were considered to have a genetic cause.1 Now, it is widely accepted that most epilepsies have a genetic cause2—a spectrum from a variant in a single gene, to variants in multiple genes, to an interaction of genetics with environmental factors.
Genetic testing can help establish a correct diagnosis
There is considerable overlap in the symptoms of many epilepsy syndromes, making a precise diagnosis difficult. Recent discoveries in the genetics of epilepsy have highlighted two important patterns:
- One gene can be associated with multiple epilepsy syndromes, and
- One epilepsy syndrome can be associated with multiple genes.
Taken together, these findings support that the most efficient and cost effective way to confirm a diagnosis in a patient is to perform a genetic test.
Genetic testing can shorten the diagnostic odyssey
A 2013 study queried physicians who had identified patients with a variant in the SCN1A gene, which is known to cause a type of epilepsy called Dravet syndrome.3 Of the 163 physicians who responded, 48% reported that a positive genetic test facilitated diagnosis earlier than with clinical and EEG data alone. Furthermore, the genetic diagnosis prevented additional investigations in 67% of patients, altered treatment approach in 69%, influenced education choice in 74%, and improved seizure control in 42% through a change in medication.
Genetics can impact treatment
One of the biggest misconceptions in the use of genetic tests for diagnosing epilepsy is that genetics cannot direct treatment. There are, in fact, many examples in which the results from a genetic test will impact treatment (see below). These examples show that a patient’s genetics can be used not only to show which therapies to consider, but also which therapies to avoid.
- Treat GLUT1 (glucose transporter 1) deficiency due to SLC2A1 variants with ketogenic diet.4,5 Early diagnosis is very important in GLUT1 deficiency because early intervention can prevent irreversible neuronal damage that can occur due to prolonged, severe hypoglycorrhacia (low glucose in the cerebral spinal fluid). 6,7
- Avoid use of valproic acid in POLG-related disorder due to the potential for fatal hepatotoxicity.8
- Treat creatine deficiency syndrome (deficiencies caused by variants in the GAMT and GATM genes) with oral creatine, ornithine, and arginine supplementation due to low cerebral spinal fluid creatine.9 Treating asymptomatic newborns with siblings with GAMT or GATM variants have prevented disease manifestations in the newborns, showing that early treatment at the asymptomatic stage of the disease can be beneficial.10
- Treat SCN1A related Dravet syndrome with valproate, clobazam, or stiripentol and avoid sodium channel blocking medications such as lamotrigine, carbamzepine, and phenytoin which may exacerbate epileptic developmental outcome.11 Avoiding sodium-blocking agents could prevent status epilepticus and unnecessary, expensive ER visits and hospitalizations.12
- Treat pydridoxal 5’ phosphate dependent epilepsy (caused by variants in the ALDH7A1 gene) with pyridoxal phosphate and pyridoxine (vitamin B6) and folinic acid.13 Patients with ALDH7A1 variants may not initially respond but may respond if left on treatment over time.14,15
- Avoid sodium channel blocking medications for progressive myoclonic epilepsy associated with Lafora Body Disease, caused by variants in the genes EMP2A and NHLRC1 (also known as EMP2B).16
- Avoid treating Unverricht Lundborg disease (caused by variants in the gene CSTB) with sodium channel blockers and GABAergic drugs but use zonisamide, topiramate or levetiracetam.17
- Treat autosomal dominant nocturnal frontal lobe epilepsy with CHRNA4 variants with zonisamide for better response than carbamazepine.18
- Treat GRIN2A variant-associated epilepsy syndromes with memantine.19
- Treat KCNQ2 or KCNQ3 variant-associated epilepsy syndromes with ezogabine.14
- Treat KCNT1 variant-associated epilepsy with quinidine.14
- Avoid carbamezapine, vigabatrin, and tigabine in patients with pathogenic variants in UBE3A and Angelman syndrome (AS). Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled.20,21 A genetic test can confirm AS and avoid overmedication.
Even if there is no specific treatment for a patient today, there may be one in the future. A patient’s genome does not change over time. So, as new therapies are developed and research makes new associations between disease and genetics, a patient may find new personalized therapeutic options tailored to their genetic profile in the future.
Genetics can inform risks to other family members
The inheritance patterns of epilepsy are complex. The signs and symptoms of inherited epilepsies have a great deal of overlap, and symptoms are often variable within the same family. This makes an accurate clinical diagnosis very difficult without a genetic test. Genetic testing can help distinguish between inherited epilepsies that may broadly impact other members of a family from those that arise from de novo variations. (A de novo variation is an alteration in a gene that is present for the first time in one family member.)
Understanding the cause of a patient’s epilepsy is critical to effectively treating this disease. Genetic testing will speed up the diagnostic process and provide a more accurate diagnosis. This will enable:
- Health care providers to tailor treatment
- Patients to get the most appropriate treatment sooner
- Patients and families to get appropriate counseling
- Avoid unnecessary, costly and often further invasive diagnostic testing such as skin biopsies and expensive imaging techniques
Because genetics plays such a large and important role in the etiology and treatment of epilepsy, everyone with epilepsy should have a genetic test performed as early as possible.
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- Ingrid E. Scheffer. Genetic Testing in Epilepsy: What Should You Be Doing?. Epilepsy Currents: July/August 2011; 11(4): 107-111.
- Thomas RH, Berkovic SF. The hidden genetics of epilepsy: A clinically important new paradigm. Nat Rev Neurol. 2014; 10(5): 283-292.
- Brunklaus et al. The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy. Dev Med Child Neurol. 2013; 55: 154-161.
- Kassa H, Winesett S, Bessoneb S, Turner Z, Kossoff E. Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure. 2016; 35: 83-87.
- Vigevano F, Arzimanoglou A, Plouin P, Specchio N. Therapeutic approach to epileptic encephalopathies. Epilepsia. 2013; 54 (Suppl 8): 45-50.
- Maiorana A, Manganozzi L, Barbetti , Bernabei S, Gallo G, Cusmai R, Caviglia S, Dionisi-Vici C. Ketogenic diet in a patient with congenital hyperinsulinism: A novel approach to prevent brain damage. Orphanet J Rare Dis. 2015; 10: 120.
- Akman C, Yu J, Alter A, Engelstad K, De Vivo D. Diagnosing Glucose Transporter 1 Deficiency at Initial Presentation Facilitates Early Treatment. J Pediatr. 2016; 171: 220–226.
- Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. 2010 Mar 16 [Updated 2014 Dec 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK26471/
- Mercimek-Mahmutoglu S, Salomons GS. Creatine Deficiency Syndromes. 2009 Jan 15 [Updated 2015 Dec 10]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK3794/
- Battini R, Alessandrì MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni G. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr. 2006; 148: 828–30.
- Plecko B. Pyridoxine and pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol. 2013; 113: 1811-7.
- Miller IO, Sotero de Menezes MA. SCN1A-Related Seizure Disorders. 2007 Nov 29 [Updated 2014 May 15]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1318/
- Plecko B. Pyridoxine and pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol. 2013; 113: 1811-7.
- Mills PB, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1deficiency). Brain. 2010; 133: 2148-2159.
- Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL. Pyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011; 104(1-2): 48-60.
- Jansen AC, Andermann E. Progressive Myoclonus Epilepsy, Lafora Type. 2007 Dec 28 [Updated 2015 Jan 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1389/
- Lehesjoki AE, Kälviäinen R. Unverricht-Lundborg Disease. 2004 Jun 24 [Updated 2014 Nov 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1142/
- Kurahashi H, Hirose S. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. 2002 May 16 [Updated 2015 Feb 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1169/
- Hani AJ, Mikati HM, Mikati MA. Genetics of pediatric epilepsy. Pediatr Clin North Am. 2015; 62(3): 703-22.
- Dagli AI, Mueller J, Williams CA. Angelman Syndrome. 1998 Sep 15 [Updated 2015 May 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1144/
- Fiumara A, Pittalà A, Cocuzza M, Sorge G. Epilepsy in patients with Angelman syndrome. Ital J Pediatr. 2010; 36: 31.