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Genetic Testing of Epileptic Encephalopathies of Infancy: An Approach

Published online by Cambridge University Press:  23 September 2014

Suvasini Sharma  and
Asuri N. Prasad
Suvasini Sharma
Affiliation:
Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India
Asuri N. Prasad*
Affiliation:
Department of Pediatrics, Schulich School of Medicine and Dentistry, Children's Hospital of Western Ontario, London, Ontario, Canada
*
Department of Pediatrics, Schulich School of Medicine and Dentistry, Children's Hospital of Western Ontario, London, Ontario, Canada email: narayan.prasad@lhsc.on.ca
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Abstract:

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The epileptic encephalopathies of infancy are a group of disorders characterized by intractable seizures, persistent abnormality of cortical function documented on EEG, and consequently impaired neuro-developmental outcomes. The etiologies vary and include; structural brain malformations, acquired brain insults, and inborn errors of metabolism in the majority of the affected patients. In a proportion of these cases no obvious etiology is identifiable on investigation. Recent advances in molecular diagnostics have led to the discovery of a number of gene defects that may be causal in many epileptic encephalopathies. Identification of the causative mutation is important for prognostic and genetic counseling, and may also carry treatment implications. The recently described genes include; Cyclin-Dependent Kinase-Like 5 gene (CDKL5), Protocadherin 19 (PCDH19), Sodium channel neuronal type 1a subunit gene (SCN1A), Aristaless-Related Homeobox Gene (ARX), and Syntaxin binding protein 1 gene (STXBP1), amongst others. Distinct electro-clinical syndromes are increasingly being identified amongst patients carrying the various mutations. In this review, we outline the approach to clinical evaluation and genetic testing of epileptic encephalopathies in infancy.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 40 , Issue 1 , January 2013 , pp. 10 - 16
Copyright
Copyright © The Canadian Journal of Neurological 2013

References

1. Nabbout, R, Dulac, O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol. 2003;20:393–7.Google Scholar
2. Saitsu, H, Kato, M, Mizuguchi, T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782–8.Google Scholar
3. Sartori, S, Polli, R, Bettella, E, et al. Pathogenic role of the X-linked cyclin-dependent kinase-like 5 and aristaless-related homeobox genes in epileptic encephalopathy of unknown etiology with onset in the first year of life. J Child Neurol. 2011;26:683–91.Google Scholar
4. Molinari, F, Kaminska, A, Fiermonte, G, et al. Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet. 2009;76: 188–94.Google Scholar
5. Scheffer, IE. Genetic testing in epilepsy: what should you be doing? Epilepsy Curr. 2011;11:107–11.Google Scholar
6. Berkovic, SF, Harkin, L, McMahon, JM, et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol. 2006;5: 488–92.Google Scholar
7. Donat, JF. The age-dependent epileptic encephalopathies. J Child Neurol. 1992;7:7–21.Google Scholar
8. Yamamoto, H, Okumura, A, Fukuda, M. Epilepsies and epileptic syndromes starting in the neonatal period. Brain Dev. 2011;33: 213–20.Google Scholar
9. Ohtahara, S, Yamatogi, Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol. 2003;20: 398–407.Google Scholar
10. Wang, PJ, Lee, WT, Hwu, WL, et al. The controversy regarding diagnostic criteria for early myoclonic encephalopathy. Brain Dev. 1998;20:530–5.Google Scholar
11. Yamatogi, Y, Ohtahara, S. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev. 2002;24:13–23.Google Scholar
12. Weckhuysen, S, Mandelstam, S, Suls, A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15–25.Google Scholar
13. Coppola, G. Malignant migrating partial seizures in infancy: an epilepsy syndrome of unknown etiology. Epilepsia. 2009;50 Suppl 5:49–51.Google Scholar
14. Carranza Rojo, D, Hamiwka, L, McMahon, JM, et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology. 2011;77:380–3.Google Scholar
15. Freilich, ER, Jones, JM, Gaillard, WD, et al. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch Neurol. 2011;68:665–71.Google Scholar
16. Poduri, A, Chopra, SS, Neilan, EG, et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012;53:e146–50.Google Scholar
17. Lux, AL, Osborne, JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group. Epilepsia. 2004;45:1416–28.Google Scholar
18. Archer, HL, Evans, J, Edwards, S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet. 2006;43:729–34.Google Scholar
19. Suri, M. The phenotypic spectrum of ARX mutations. Dev Med Child Neurol. 2005;47:133–7.Google Scholar
20. Otsuka, M, Oguni, H, Liang, JS, et al. STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome-result of Japanese cohort study. Epilepsia. 2010;51:2449–52.Google Scholar
21. Saitsu, H, Tohyama, J, Kumada, T, et al. Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am J Hum Genet. 2010;86:881–91.Google Scholar
22. Kurian, MA, Meyer, E, Vassallo, G, et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010;133:2964–70.Google Scholar
23. Dravet, C. The core Dravet syndrome phenotype. Epilepsia. 2011;52 Suppl 2:3–9.Google Scholar
24. Bureau, M, Dalla Bernardina, B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia. 2011;52 Suppl 2: 13–23.Google Scholar
25. Marini, C, Scheffer, IE, Nabbout, R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:24–9.Google Scholar
26. Marini, C, Mei, D, Parmeggiani, L, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology. 2010;75: 646–53.Google Scholar
27. Scheffer, IE, Turner, SJ, Dibbens, LM, et al. Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain. 2008;131:918–27.Google Scholar
28. Depienne, C, Bouteiller, D, Keren, B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5:e1000381.Google Scholar
29. Chiron, C, Dulac, O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:72–5.Google Scholar
30. Gospe, SM Jr Neonatal vitamin-responsive epileptic encephalopathies. Chang Gung Med J. 2010;33:1–12.Google Scholar
31. Liang, JS, Shimojima, K, Takayama, R, et al. CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia. 2011;52:1835–42.Google Scholar
32. Bahi-Buisson, N, Nectoux, J, Rosas-Vargas, H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008; 131:2647–61.Google Scholar
33. Guerrini, R, Moro, F, Kato, M, et al. Expansion of the first Poly A tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007;69:427–33.Google Scholar
34. Klein, KM, Yendle, SC, Harvey, AS, et al. A distinctive seizure type in patients with CDKL5 mutations: Hypermotor-tonic-spasms sequence. Neurology. 2011;76:1436–8.Google Scholar
35. Prasad, AN, Rupar, CA, Prasad, C. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev. 2011;33:758–69.Google Scholar
36. Stockler, S, Plecko, B, Gospe, SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104:48–60.Google Scholar
37. Mastrangelo, M, Leuzzi, V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012;46:24–31.Google Scholar
38. Ottman, R, Hirose, S, Jain, S, et al. Genetic testing in the epilepsies-report of the ILAE Genetics Commission. Epilepsia. 2010; 51:655–70.Google Scholar
39. Harkin, LA, McMahon, JM, Iona, X, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007;130: 843–52.Google Scholar
40. Saitsu, H, Kato, M, Okada, I, et al. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. Epilepsia. 2010;51:2397–405.Google Scholar
41. Mulley, JC, Mefford, HC. Epilepsy and the new cytogenetics. Epilepsia. 2011;52:423–32.Google Scholar
42. Miller, DT, Adam, MP, Aradhya, S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.Google Scholar
43. Mefford, HC, Yendle, SC, Hsu, C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974–85.Google Scholar
44. Paciorkowski, AR, Thio, LL, Rosenfeld, JA, et al. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. Eur J Hum Genet. 2011;19:1238–45.Google Scholar