Genotype phenotype analysis and clinical research of 95 cases of children with epilepsy_Journal of Epilepsy

Authors：

ZHANG Jun ,  GAO Li , LI Yan , YANG Liu , FAN Hongye , QI Hui , YIN Xiaojing , LI Junlong

Department of neurology, General Hospital of Henan Province, Zhengzhou 450000, China;

Corresponding author：

GAO Li, Email: 13607669006@126.com

Keywords：

Children; Epilepsy; Genotype features; Therapy effects

DOI：

10.7507/2096-0247.20170078

Video：

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ObjectiveWe have summarized the clinical features of some refractory or genetically related children with epilepsy in clinical diagnosis and treatment and carried out the two generation of high-throughput gene sequencing and generation of verification on them. To analyze the relationship between mutant genes and epilepsy, to understand the genetic pattern of children and to look for possible pathogenic or disease causing mutation.MethodsEstablish a complete pedigree database for 95 children and their parents diagnosed in pediatric neurology clinic in our hospital from septeuber 2014 to Deceln ber 2016, and carry out gene testing on them by using two generation high-throughput gene sequencing. Then we have the analysis on the basis of clinical features and gene type in children.ResultsRefractory or genetically related children had a smaller age range and had a variety of clinical features. Most of them (47/95, 49.5%)needed two or more drugs for treatment; 28.4% of them was controlled which was about 27cases; 21.1% of them was effective which was about 20 cases; 33.7% of them was marked which was about 32 cases; 12.6% of them was of no effect which was about 12 cases; 4.2% of them was missed which was about 4 cases. a small number of children (18/95, 18.9%)had poor prognosis and accompanied with exercise and mental retardation. Genotype detection results: pathogenic genes of total 16 cases (16.8%)were cleared; there were about a total of 21 cases (22.1%)of possible pathogenic gene; there were about a total of 30 cases (31.6%)of non pathogenic gene; a total of 28 cases were not detected mutated gene which was about 29.5%.ConclusionsWe have found two new virulence gene of CASK and BRAF which had few reports in China and expanded the number of genes associated with neural development and epilepsy associated genes; the clinical characteristics of SCNIA gene mutations in Dravet syndrome were more serious which include earlier onset, frequent seizures and poor treatment effect; most children with specific causative genes required the combined use of two or more Anti-epileptic drugs, which has difficulties in treatme.

Citation： ZHANG Jun, GAO Li, LI Yan, YANG Liu, FAN Hongye, QI Hui, YIN Xiaojing, LI Junlong. Genotype phenotype analysis and clinical research of 95 cases of children with epilepsy. Journal of Epilepsy, 2017, 3(6): 490-496. doi: 10.7507/2096-0247.20170078 Copy

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6.	王纪文, 葛丽娟, 孙若鹏.钠离子通道A1亚单位基因突变与癫痫关系的研究进展.中华儿科杂志, 2008, 46 (10): 797-800.
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11.	Khan S, Al Baradie R. Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. Epilepsy Res, 2012, 102(3): 403-592.
12.	Tonekaboni SH, Ebrahimi A, Bakhshandeh Bali MK, et al. Sodium channel gene mutations in children with GEFS+ and Dravet syndrome: across sectional study. Iran J Child Neurol, 2013, 7(2):31-36.
13.	Soneijen Schouwenaars FM, Veendrick MJ, van Mierlo P, et al.Carbamazepine and oxcarbazedine in adult patients with Dravet syndrome: friend or foe.Seizure, 2015, 29(3): 114-118.
14.	Chu-Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 2010, 51(7):1236-1241.
15.	Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the united states. Genet Med, 2007, 9(2): 88-100.
16.	Sancak O, Nellist M, Goedbloed M, et al.Mutational anaIysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.Eur J Ham genet, 2005, 13(6):731-741.
17.	Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.Nature Genetics, 2000, 26(1): 93-96.
18.	Najm J, Horn D, Wimplinger I, et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet, 2008. 40(4): 1065-1067.
19.	薛宁, 王纪文.婴儿痉挛的分子遗传学研究进展.实用儿科临床杂志, 2010, 25 (4): 299-301.

1. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer, 2003, 3(1): 459-465.
2. Stromme P, Mangelsdorf ME, Scheffer IE, et al. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in aristaless related homeobox gene, ARX. Brain Dev, 2002, 24(5): 266-268.
3. Olivetti PR, Maheshwari A, Noebels JL. Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome. Sci Transl Med, 2014, 6(220): 220-212.
4. Grosso S, Brogna A, Bazzotti S, et al. Seizures and electroencephalographic findings in CDKL5 mutations: case report and review. Brain Dev, 2007, 29(4): 239-242.
5. Bahi-Buisson N, Kaminska A, Boddaert N, et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia, 2008, 49(6): 1027-1037.
6. 王纪文, 葛丽娟, 孙若鹏.钠离子通道A1亚单位基因突变与癫痫关系的研究进展.中华儿科杂志, 2008, 46 (10): 797-800.
7. Heilstedt HA, Burgess DL, Anderson AE, et al. Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome. Epilepsia, 2001, 42(9): 1103-1111.
8. Liu ZL, He B, Fang F, et al. Analysis of single nucleotide polymorphisms in the melanocortin-4 receptor promoter in infantile spasms. Neuropediatrics, 2007, 38(6): 304-309.
9. Eli Ragona F, Brazzo D, Degiorgi I, et al. Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients.Brain Dev, 2010, 32(1): 71-77.
10. Morse RP. Dravet syndrome: inroads into understanding epileptic encephalopathies. J Pediatr, 2011, 158(3): 354-359.
11. Khan S, Al Baradie R. Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. Epilepsy Res, 2012, 102(3): 403-592.
12. Tonekaboni SH, Ebrahimi A, Bakhshandeh Bali MK, et al. Sodium channel gene mutations in children with GEFS+ and Dravet syndrome: across sectional study. Iran J Child Neurol, 2013, 7(2):31-36.
13. Soneijen Schouwenaars FM, Veendrick MJ, van Mierlo P, et al.Carbamazepine and oxcarbazedine in adult patients with Dravet syndrome: friend or foe.Seizure, 2015, 29(3): 114-118.
14. Chu-Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 2010, 51(7):1236-1241.
15. Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the united states. Genet Med, 2007, 9(2): 88-100.
16. Sancak O, Nellist M, Goedbloed M, et al.Mutational anaIysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.Eur J Ham genet, 2005, 13(6):731-741.
17. Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.Nature Genetics, 2000, 26(1): 93-96.
18. Najm J, Horn D, Wimplinger I, et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet, 2008. 40(4): 1065-1067.
19. 薛宁, 王纪文.婴儿痉挛的分子遗传学研究进展.实用儿科临床杂志, 2010, 25 (4): 299-301.

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