The phenotype study of KCNQ2 gene related epilepsy_Journal of Epilepsy

Authors：

ZENG Qi ,  ZHANG Yuehua , YANG Xiaoling , CHEN Jiaoyang , ZHANG Jing , YANG Ying , JIANG Yuwu , WU Xiru

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China;

Corresponding author：

ZHANG Yuehua, Email: zhangyhdr@126.com

Keywords：

Epilepsy; KCNQ2 gene; Phenotype; Variant; Newborn

DOI：

10.7507/2096-0247.20190042

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Objective To study the phenotype of children with KCNQ2 gene related epilepsy.Methods Forty epilepsy children who were detected with KCNQ2 gene variants were enrolled. Their genotype and phenotype were analyzed.Results Thirty-six KCNQ2 variants were identified. Twenty variants were novel. Twelve patients had inherited variants, and 28 patients had de novo variants. The age of seizure onset was from one day to 9 months. 80.0% patients had their seizure onset in neonates (32/40). Multiple seizure types were observed. Focal seizure was observed in 38 patients (95.0%). Epileptic spasm was observed in 10 patients (25.0%). Myoclonic seizure was observed in 4 patients. Tonic spasm seizure was observed in 3 patients. In all patients, seizures manifested in clusters. In 28 patients with de novo KCNQ2 variants, 24 had development delay (85.7%), the other 4 patients had normal development. In 12 patients with inherited KCNQ2 variants, one had development delay, the other 11 patients had normal development (91.7%). The most common interictal EEG changes were local epilepsy discharges (31/40). The MRI of brain was abnormal in 14 patients with de novo KCNQ2 variants and developmental delay. The agenesis of corpus callosum was identified in 10 patient (25.0%). Enlargement of subarachnoid spaces in the frontal and temporal region was identified in 11 patients (27.5%). Cortial dysplasia in the bilateral frontal and temporal region was identified in 2 patients. Sulus deepening was identified in 4 patients. Enlargement of bilateral lateral ventricle was identified in 3 patients. In 40 patients with KCNQ2 variants, 3 were diagnosed as benign familial neonatal epilepsy (BFNE), 2 were diagnosed as benign familial neonatal-infantile epilepsy (BFNIE), 3 were benign familial infantile epilepsy (BFIE), 3 were benign infantile epilepsy (BIE), 5 were benign neonatal epilepsy (BNE), 3 wer Ohtahara syndrome (OS), 9 were West syndrome (WS), 12 were unclassified early infantile epileptic encephalopathy (EIEE), one was epilepsy with autism. Sodium channel blockers oxcarbazepine was the most effective among antiepileptic drugs, with a effective rate of 90.9%.Conclusions Most KCNQ2 variants are missense variants. De novo variants are more common in patients with KCNQ2 variants. The clinical features of patients with KCNQ2 variants including that mainly with seizure onset in neonate, the main seizure type is focal seizures, seizures occur in clusters. Patients with de novo KCNQ2 variants often had developmental delay, and about half of them had frontal and temporal lobe dysplasia and agenesis of corpus callosum. Sodium channel blockers are effective agents for epilepsy patients with KCNQ2 variants.

Citation： ZENG Qi, ZHANG Yuehua, YANG Xiaoling, CHEN Jiaoyang, ZHANG Jing, YANG Ying, JIANG Yuwu, WU Xiru. The phenotype study of KCNQ2 gene related epilepsy. Journal of Epilepsy, 2019, 5(4): 244-256. doi: 10.7507/2096-0247.20190042 Copy

1.	Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet, 1998, 18(1): 25-29.
2.	Grinton BE, Heron SE, Pelekanos JT, et al. Familial neonatal seizures in 36 families: clinical and genetic features correlate with outcome. Epilepsia, 2015, 56(7): 1071-1080.
3.	Zara F, Specchio N, Striano P, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia, 2013, 54(3): 425-436.
4.	Dedek K, Fusco L, Teloy N, et al. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res, 2003, 54(1): 21-27.
5.	Schmitt B, Wohlrab G, Sander T, et al. Neonatal seizures with tonic clonic sequences and poor developmental outcome. Epilepsy Res, 2005, 65(3): 161-168.
6.	Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol, 2012, 71(1): 15-25.
7.	Millichap JJ, Miceli F, De Maria M, et al. Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia, 2017, 58(1): e10-e15.
8.	Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.
9.	Zhou X, Ma A, Liu X, et al. Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2. Eur J Pediatr, 2006, 165(10): 691-695.
10.	Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology, 2013, 81(19): 1697-1703.
11.	Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia, 2016, 57(12): 2019-2030.
12.	Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain, 2003, 126(Pt 12): 2726-2737.
13.	Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet, 2016, 2(5): e96.
14.	Saitsu H, Kato M, Koide A, et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol, 2012, 72(2): 298-300.
15.	Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia, 2015, 56(5): 685-691.
16.	Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
17.	Epi KC, Epilepsy Phenome/Genome P, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(7466): 217-221.
18.	Jiang YH, Yuen RK, Jin X, et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet, 2013, 93(2): 249-263.
19.	Dedek K, Kunath B, Kananura C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci USA, 2001, 98(21): 12272-12277.
20.	Blumkin L, Suls A, Deconinck T, et al. Neonatal seizures associated with a severe neonatal myoclonus like dyskinesia due to a familial KCNQ2 gene mutation. Eur J Paediatr Neurol, 2012, 16(4): 356-360.
21.	Wuttke TV, Jurkat-Rott K, Paulus W, et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology, 2007, 69(22): 2045-2053.
22.	Hortiguela M, Fernandez-Marmiesse A, Cantarin V, et al. Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. J Hum Genet, 2017, 62(2): 185-189.
23.	Alfonso I, Hahn JS, Papazian O, et al. Bilateral tonic-clonic epileptic seizures in non-benign familial neonatal convulsions. Pediatr Neurol, 1997, 16(3): 249-251.
24.	Borgatti R, Zucca C, Cavallini A, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology, 2004, 63(1): 57-65.
25.	Soldovieri MV, Miceli F, Bellini G, et al. Correlating the clinical and genetic features of benign familial neonatal seizures (BFNS) with the functional consequences of underlying mutations. Channels (Austin), 2007, 1(4): 228-233.
26.	Milh M, Lacoste C, Cacciagli P, et al. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet A, 2015, 167A(10): 2314-2318.
27.	Kato M, Yamagata T, Kubota M, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia, 2013, 54(7): 1282-1287.
28.	Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology, 2014, 82(4): 368-370.
29.	Miceli F, Soldovieri MV, Ambrosino P, et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci USA, 2013, 110(11): 4386-4391.
30.	Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol, 2014, 75(3): 382-394.

1. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet, 1998, 18(1): 25-29.
2. Grinton BE, Heron SE, Pelekanos JT, et al. Familial neonatal seizures in 36 families: clinical and genetic features correlate with outcome. Epilepsia, 2015, 56(7): 1071-1080.
3. Zara F, Specchio N, Striano P, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia, 2013, 54(3): 425-436.
4. Dedek K, Fusco L, Teloy N, et al. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res, 2003, 54(1): 21-27.
5. Schmitt B, Wohlrab G, Sander T, et al. Neonatal seizures with tonic clonic sequences and poor developmental outcome. Epilepsy Res, 2005, 65(3): 161-168.
6. Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol, 2012, 71(1): 15-25.
7. Millichap JJ, Miceli F, De Maria M, et al. Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia, 2017, 58(1): e10-e15.
8. Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.
9. Zhou X, Ma A, Liu X, et al. Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2. Eur J Pediatr, 2006, 165(10): 691-695.
10. Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology, 2013, 81(19): 1697-1703.
11. Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia, 2016, 57(12): 2019-2030.
12. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain, 2003, 126(Pt 12): 2726-2737.
13. Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet, 2016, 2(5): e96.
14. Saitsu H, Kato M, Koide A, et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol, 2012, 72(2): 298-300.
15. Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia, 2015, 56(5): 685-691.
16. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
17. Epi KC, Epilepsy Phenome/Genome P, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(7466): 217-221.
18. Jiang YH, Yuen RK, Jin X, et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet, 2013, 93(2): 249-263.
19. Dedek K, Kunath B, Kananura C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci USA, 2001, 98(21): 12272-12277.
20. Blumkin L, Suls A, Deconinck T, et al. Neonatal seizures associated with a severe neonatal myoclonus like dyskinesia due to a familial KCNQ2 gene mutation. Eur J Paediatr Neurol, 2012, 16(4): 356-360.
21. Wuttke TV, Jurkat-Rott K, Paulus W, et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology, 2007, 69(22): 2045-2053.
22. Hortiguela M, Fernandez-Marmiesse A, Cantarin V, et al. Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. J Hum Genet, 2017, 62(2): 185-189.
23. Alfonso I, Hahn JS, Papazian O, et al. Bilateral tonic-clonic epileptic seizures in non-benign familial neonatal convulsions. Pediatr Neurol, 1997, 16(3): 249-251.
24. Borgatti R, Zucca C, Cavallini A, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology, 2004, 63(1): 57-65.
25. Soldovieri MV, Miceli F, Bellini G, et al. Correlating the clinical and genetic features of benign familial neonatal seizures (BFNS) with the functional consequences of underlying mutations. Channels (Austin), 2007, 1(4): 228-233.
26. Milh M, Lacoste C, Cacciagli P, et al. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet A, 2015, 167A(10): 2314-2318.
27. Kato M, Yamagata T, Kubota M, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia, 2013, 54(7): 1282-1287.
28. Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology, 2014, 82(4): 368-370.
29. Miceli F, Soldovieri MV, Ambrosino P, et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci USA, 2013, 110(11): 4386-4391.
30. Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol, 2014, 75(3): 382-394.

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