Genetic basis of pediatric epilepsy syndromes (Review)

Zhang,Dongli; Liu,Xiaoming; Deng,Xingqiang

doi:10.3892/etm.2017.4267

Genetic basis of pediatric epilepsy syndromes (Review)

Authors:
- Dongli Zhang
- Xiaoming Liu
- Xingqiang Deng
View Affiliations

Affiliations: Department of Neurology, Xuzhou Children's Hospital, Xuzhou, Jiangsu 221002, P.R. China
Published online on: March 27, 2017 https://doi.org/10.3892/etm.2017.4267
Pages: 2129-2133
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Childhood epilepsy affects ~0.5-1% in the general population worldwide. Early‑onset epileptic encephalopathies are considered to be severe neurological disorders, which lead to impaired motor, cognitive, and sensory development due to recurrence of seizures. Many of the observed epilepsy phenotypes are associated with specific chromosomal imbalances and thus display gene dosage effects, and also specific mutations of a variety of genes ranging from ion channels to transcription factors. High throughput sequencing technologies and whole exome sequencing have led to the recognition of several new candidate genes with a possible role in the pathogenesis of epileptic encephalopathies. The mutations causing channelopathies can be either a gain or a loss of ion channel function and contribute to the pathogenesis of epilepsy syndrome. Nearly 300 mutations of SCN1A gene coding for the Nav1.1 channel protein have been identified that contribute to the pathology of epilepsy. Besides Na, potassium and calcium channels are also implicated in epileptic encephalopathies. Therapeutic management of epileptic encephalopathies has been challenging as the majority of the medications are not efficient and often have many undesirable side effects. A better understanding of the molecular nature of epilepsy in an individual is important to design a personalized medication, considering the number of possible genetic mutations that can contribute to epileptic encephalopathies.

View Figures

View References

1	Pal DK, Pong AW and Chung WK: Genetic evaluation and counseling for epilepsy. Nat Rev Neurol. 6:445–453. 2010. View Article : Google Scholar : PubMed/NCBI
2	Elia M, Musumeci SA, Ferri R and Ayala GF: Chromosome abnormalities and epilepsy. Epilepsia. 42:(Suppl 1). 24–27; discussion 28. 2001. View Article : Google Scholar : PubMed/NCBI
3	Peljto AL, Barker-Cummings C, Vasoli VM, Leibson CL, Hauser WA, Buchhalter JR and Ottman R: Familial risk of epilepsy: A population-based study. Brain. 137:795–805. 2014. View Article : Google Scholar : PubMed/NCBI
4	Guerrini R and Noebels J: How can advances in epilepsy genetics lead to better treatments and cures? Adv Exp Med Biol. 813:309–317. 2014. View Article : Google Scholar : PubMed/NCBI
5	Nieh SE and Sherr EH: Epileptic encephalopathies: New genes and new pathways. Neurotherapeutics. 11:796–806. 2014. View Article : Google Scholar : PubMed/NCBI
6	Helbig I: New technologies in molecular genetics: The impact on epilepsy research. Prog Brain Res. 213:253–278. 2014. View Article : Google Scholar : PubMed/NCBI
7	Scheffer IE: Epilepsy genetics revolutionizes clinical practice. Neuropediatrics. 45:70–74. 2014. View Article : Google Scholar : PubMed/NCBI
8	Tripathi M and Jain S: Genetics in epilepsy: Transcultural perspectives. Epilepsia. 44:(Suppl 1). 12–16. 2003. View Article : Google Scholar : PubMed/NCBI
9	Thomas RH and Berkovic SF: The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 10:283–292. 2014. View Article : Google Scholar : PubMed/NCBI
10	Novarino G, Baek ST and Gleeson JG: The sacred disease: The puzzling genetics of epileptic disorders. Neuron. 80:9–11. 2013. View Article : Google Scholar : PubMed/NCBI
11	Reid CA, Berkovic SF and Petrou S: Mechanisms of human inherited epilepsies. Prog Neurobiol. 87:41–57. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nabbout R and Dulac O: Epileptic syndromes in infancy and childhood. Curr Opin Neurol. 21:161–166. 2008. View Article : Google Scholar : PubMed/NCBI
13	Verrotti A, Carelli A, di Genova L and Striano P: Epilepsy and chromosome 18 abnormalities: A review. Seizure. 32:78–83. 2015. View Article : Google Scholar : PubMed/NCBI
14	Heron SE, Cox K, Grinton BE, Zuberi SM, Kivity S, Afawi Z, Straussberg R, Berkovic SF, Scheffer IE and Mulley JC: Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures. J Med Genet. 44:791–796. 2007. View Article : Google Scholar : PubMed/NCBI
15	Helbig I, Scheffer IE, Mulley JC and Berkovic SF: Navigating the channels and beyond: Unravelling the genetics of the epilepsies. Lancet Neurol. 7:231–245. 2008. View Article : Google Scholar : PubMed/NCBI
16	Steinlein OK: Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci. 5:400–408. 2004. View Article : Google Scholar : PubMed/NCBI
17	Waxman SG: Channel, neuronal and clinical function in sodium channelopathies: From genotype to phenotype. Nat Neurosci. 10:405–409. 2007. View Article : Google Scholar : PubMed/NCBI
18	Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson VE, Sanguinetti MC, Leppert MF and Consortium BP: BFNC Physician Consortium: KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain. 126:2726–2737. 2003. View Article : Google Scholar : PubMed/NCBI
19	Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Scheffer IE and Berkovic SF: A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 11:201–203. 1995. View Article : Google Scholar : PubMed/NCBI
20	Ragsdale DS: How do mutant Nav1.1 sodium channels cause epilepsy? Brain Res Brain Res Rev. 58:149–159. 2008. View Article : Google Scholar
21	George AL Jr: Inherited disorders of voltage-gated sodium channels. J Clin Invest. 115:1990–1999. 2005. View Article : Google Scholar : PubMed/NCBI
22	Catterall WA, Dib-Hajj S, Meisler MH and Pietrobon D: Inherited neuronal ion channelopathies: New windows on complex neurological diseases. J Neurosci. 28:11768–11777. 2008. View Article : Google Scholar : PubMed/NCBI
23	Palmer LM and Stuart GJ: Site of action potential initiation in layer 5 pyramidal neurons. J Neurosci. 26:1854–1863. 2006. View Article : Google Scholar : PubMed/NCBI
24	Scheffer IE and Berkovic SF: Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain. 120:479–490. 1997. View Article : Google Scholar : PubMed/NCBI
25	Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, Saar K, Reis A, Johnson EW, Sutherland GR, et al: Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet. 19:366–370. 1998. View Article : Google Scholar : PubMed/NCBI
26	Stafstrom CE: Severe epilepsy syndromes of early childhood: The link between genetics and pathophysiology with a focus on SCN1A mutations. J Child Neurol. 24:15S–23S. 2009. View Article : Google Scholar : PubMed/NCBI
27	Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, et al: A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci USA. 98:6384–6389. 2001. View Article : Google Scholar : PubMed/NCBI
28	Fujiwara T, Sugawara T, Mazaki-Miyazaki E, Takahashi Y, Fukushima K, Watanabe M, Hara K, Morikawa T, Yagi K, Yamakawa K, et al: Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures. Brain. 126:531–546. 2003. View Article : Google Scholar : PubMed/NCBI
29	Lossin C: A catalog of SCN1A variants. Brain Dev. 31:114–130. 2009. View Article : Google Scholar : PubMed/NCBI
30	Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, et al: De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 90:502–510. 2012. View Article : Google Scholar : PubMed/NCBI
31	Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, Depienne C, Brilstra E, Mang Y, Nielsen JE, et al: EuroEPINOMICS RES Consortium CRP: The phenotypic spectrum of SCN8A encephalopathy. Neurology. 84:480–489. 2015. View Article : Google Scholar : PubMed/NCBI
32	Guerrini R, Marini C and Mantegazza M: Genetic epilepsy syndromes without structural brain abnormalities: Clinical features and experimental models. Neurotherapeutics. 11:269–285. 2014. View Article : Google Scholar : PubMed/NCBI
33	Maljevic S, Wuttke TV, Seebohm G and Lerche H: KV7 channelopathies. Pflugers Arch. 460:277–288. 2010. View Article : Google Scholar : PubMed/NCBI
34	Weber YG and Lerche H: Genetic mechanisms in idiopathic epilepsies. Dev Med Child Neurol. 50:648–654. 2008. View Article : Google Scholar : PubMed/NCBI
35	Srivastava S, Cohen JS, Vernon H, Barañano K, McClellan R, Jamal L, Naidu S and Fatemi A: Clinical whole exome sequencing in child neurology practice. Ann Neurol. 76:473–483. 2014. View Article : Google Scholar : PubMed/NCBI
36	Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, et al: De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 44:1255–1259. 2012. View Article : Google Scholar : PubMed/NCBI
37	Edvardson S, Oz S, Abulhijaa FA, Taher FB, Shaag A, Zenvirt S, Dascal N and Elpeleg O: Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. J Med Genet. 50:118–123. 2013. View Article : Google Scholar : PubMed/NCBI
38	Nava C, Dalle C, Rastetter A, Striano P, de Kovel CG, Nabbout R, Cancès C, Ville D, Brilstra EH, Gobbi G, et al: EuroEPINOMICS RES Consortium: De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 46:640–645. 2014. View Article : Google Scholar : PubMed/NCBI
39	Vigevano F: Benign familial infantile seizures. Brain Dev. 27:172–177. 2005. View Article : Google Scholar : PubMed/NCBI
40	Marini C, Conti V, Mei D, Battaglia D, Lettori D, Losito E, Bruccini G, Tortorella G and Guerrini R: PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology. 79:2109–2114. 2012. View Article : Google Scholar : PubMed/NCBI
41	Guerrini R and Mink JW: Paroxysmal disorders associated with PRRT2 mutations shake up expectations on ion channel genes. Neurology. 79:2086–2088. 2012. View Article : Google Scholar : PubMed/NCBI
42	Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, et al: X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 40:776–781. 2008. View Article : Google Scholar : PubMed/NCBI
43	Gécz J, Cloosterman D and Partington M: ARX: A gene for all seasons. Curr Opin Genet Dev. 16:308–316. 2006. View Article : Google Scholar : PubMed/NCBI
44	Buoni S, Zannolli R, Colamaria V, Macucci F, di Bartolo RM, Corbini L, Orsi A, Zappella M and Hayek J: Myoclonic encephalopathy in the CDKL5 gene mutation. Clin Neurophysiol. 117:223–227. 2006. View Article : Google Scholar : PubMed/NCBI
45	Ohtahara S and Yamatogi Y: Ohtahara syndrome: With special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 70:(Suppl 1). S58–S67. 2006. View Article : Google Scholar : PubMed/NCBI
46	Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, et al: Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 45:825–830. 2013. View Article : Google Scholar : PubMed/NCBI
47	Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A, Djémié T, Afrikanova T, Gormley P, et al: EuroEPINOMICS RES Consortium: De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 93:967–975. 2013. View Article : Google Scholar : PubMed/NCBI
48	McTague A and Cross JH: Treatment of epileptic encephalopathies. CNS Drugs. 27:175–184. 2013. View Article : Google Scholar : PubMed/NCBI
49	Maguire MJ, Hemming K, Wild JM, Hutton JL and Marson AG: Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review. Epilepsia. 51:2423–2431. 2010. View Article : Google Scholar : PubMed/NCBI
50	Lemmon ME and Kossoff EH: New treatment options for lennox-gastaut syndrome. Curr Treat Options Neurol. 15:519–528. 2013. View Article : Google Scholar : PubMed/NCBI
51	Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C and Arroyo S: Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 70:1950–1958. 2008. View Article : Google Scholar : PubMed/NCBI
52	Fejerman N, Caraballo R, Cersósimo R, Ferraro SM, Galicchio S and Amartino H: Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES). Epilepsia. 53:1156–1161. 2012. View Article : Google Scholar : PubMed/NCBI
53	Goldsmith IL, Zupanc ML and Buchhalter JR: Long-term seizure outcome in 74 patients with Lennox-Gastaut syndrome: Effects of incorporating MRI head imaging in defining the cryptogenic subgroup. Epilepsia. 41:395–399. 2000. View Article : Google Scholar : PubMed/NCBI
54	Nunes VD, Sawyer L, Neilson J, Sarri G and Cross JH: Diagnosis and management of the epilepsies in adults and children: Summary of updated NICE guidance. BMJ. 344:e2812012. View Article : Google Scholar : PubMed/NCBI
55	Li B, Tong L, Jia G and Sun R: Effects of ketogenic diet on the clinical and electroencephalographic features of children with drug therapy-resistant epilepsy. Exp Ther Med. 5:611–615. 2013.PubMed/NCBI
56	Thammongkol S, Vears DF, Bicknell-Royle J, Nation J, Draffin K, Stewart KG, Scheffer IE and Mackay MT: Efficacy of the ketogenic diet: Which epilepsies respond? Epilepsia. 53:e55–e59. 2012. View Article : Google Scholar : PubMed/NCBI
57	Cross JH and Neville BG: The surgical treatment of Landau-Kleffner syndrome. Epilepsia. 50:(Suppl 7). 63–67. 2009. View Article : Google Scholar : PubMed/NCBI
58	Peltola ME, Liukkonen E, Granström ML, Paetau R, Kantola-Sorsa E, Valanne L, Falck B, Blomstedt G and Gaily E: The effect of surgery in encephalopathy with electrical status epilepticus during sleep. Epilepsia. 52:602–609. 2011. View Article : Google Scholar : PubMed/NCBI