The genotype and phenotype of <i>CACNA1A</i> variants related developmental and epileptic encephalopathy_Journal of Epilepsy

Authors：

NIU Xueyang , CHENG Miaomiao , CHEN Yi , YANG Ying , YANG Xiaoling , YANG Zhixian , JIANG Yuwu ,  ZHANG Yuehua

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

Corresponding author：

ZHANG Yuehua, Email: zhangyhdr@126.com

Keywords：

CACNA1A Gene; Epilepsy; Developmental delay; Cerebral atrophy

DOI：

10.7507/2096-0247.202204012

Video：

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Objective To analyze the genotype and clinical features of children with epilepsy associated with CACNA1A variants. Methods The genotype, phenotype and neuroimaging features of 27 patients with CACNA1A variants in the pediatrics department of Peking University First Hospital from September 2013 to February 2022 were analyzed. Results There were 9 males and 18 females, whose age ranged from 6 months to 19 years old (medium: 4 years old and 3 months). There were 22 missense variants, three nonsense variants and two frameshift variants. 25 variants were de novo. Age at seizure onset ranged from 1 day to 8 years old and 6 months (medium: 14 months). Multiple seizure types were observed, including focal seizures in 20 patients, generalized tonic–clonic seizures (GTCS) in 7 patients, absence seizures in 5 patients, myoclonic seizures in 3 patients, epileptic spasms and tonic seizures in 1 patient respectively. 16 patients had status epilepticus, including focal motor status epilepticus in 14 patients and generalized motor status epilepticus occurred in two patients. Two patients had acute encephalopathy. All 27 patients showed developmental delay. Interictal electroencephalogram showed generalized discharges in 8 patients, multi-focal discharges in 4 patients and focal discharges in 11 patients. Unilateral cortical atrophy occurred in 5 patients after focal motor status epilepticus. Two patients had bilateral cerebral atrophy after acute encephalopathy. Cerebellar atrophy in 2 patients. The age of last follow-up ranged from one year old to 17 years old and 3 months. Six patients were seizure-free , whereas 21 still had seizures. Conclusion The seizure onset age of patients with CACNA1A variants usually began in infancy. The common seizure types include focal seizures, GTCS and absence seizures. Seizures are prone to status epilepticus, mainly focal motor status epilepticus. Patients usually had developmental delay. Unilateral cortical atrophy may occur after focal motor status epilepticus. Epilepsy associated with CACNA1A variants is usually refractory.

Citation： NIU Xueyang, CHENG Miaomiao, CHEN Yi, YANG Ying, YANG Xiaoling, YANG Zhixian, JIANG Yuwu, ZHANG Yuehua. The genotype and phenotype of CACNA1A variants related developmental and epileptic encephalopathy. Journal of Epilepsy, 2022, 8(5): 407-415. doi: 10.7507/2096-0247.202204012 Copy

1.	Du X, Wei C, Hejazi Pastor DP, et al. α1ACT is essential for survival and early cerebellar programming in a critical neonatal window. Neuron, 2019, 102(4): 770-785.
2.	Pan R, Qi X, Wang F, et al. Correlations of calcium voltage-gated channel subunit alpha1 a (cacna1a) gene polymorphisms with benign paroxysmal positional vertigo. Med Sci Monit, 2019, 25(2): 946-951.
3.	Hommersom MP, van Prooije TH, Pennings M, et al. The complexities of CACNA1A in clinical neurogenetics. Journal of Neurology, 2021, 269(6): 3094-3108.
4.	Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia, 2018, 59(6): 1177-1187.
5.	Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca²⁺ channel gene CACNL1A4. Cell, 1996, 87(3): 543-552.
6.	Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet, 2001, 358(9284): 801-807.
7.	Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501: 217-221.
8.	Alehabib E, Esmaeilizadeh Z, Ranji-Burachaloo S, et al. Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients. Orphanet Journal of Rare Diseases, 2021, 16(1): 461.
9.	Niu X, Yang Y, Chen Y, et al. Genotype-phenotype correlation of CACNA1A variants in children with epilepsy. Developmental Medicine and Child Neurology, 2022, 64(1): 105-111.
10.	Angelini C, van Gils J, Bigourdan A, et al. Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. European Journal of Medical Genetics, 2018, 62(6): 103530.
11.	Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet, 2016, 99(2): 287-298.
12.	Gauquelin L, Hawkins C, Tam EWY, et al. Pearls & Oy-sters: fatal brain edema is a rare complication of severe CACNA1A-related disorder. Neurology, 2020, 94(14): 631-634.
13.	Indelicato E, Nachbauer W, Karner E, et al. The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature. European Journal of Neurology, 2019, 26(1): e66-e67.
14.	Rajakulendran S, Graves TD, Labrum RW, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. The Journal of Physiology, 2009, 588: 1905-1913.
15.	Pietrobon D. Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. J Physiol, 2010, 588(11): 1871-1878.
16.	Jiang X, Raju PK, D'Avanzo N, et al. Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia, 2019, 60(9): 1881-1894.
17.	Cianfoni A, Caulo M, Cerase A, et al. Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities. Eur J Radiol, 2013, 82(11): 1964-1972.
18.	Tian X, Ye J, Zeng Q, et al. The clinical outcome and neuroimaging of acute encephalopathy after status epilepticus in Dravet syndrome. Dev Med Child Neurol, 2018, 60(6): 566-573.
19.	Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet, 2017, 101(5): 664-685.
20.	Travaglini L, Nardella M, Bellacchio E, et al. Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Eur J Paediatr. Neurol, 2017, 21(3): 450-456.
21.	Balck A, Tunc S, Schmitz J, et al. A novel frameshift CACNA1A mutation causing episodic ataxia type 2. Cerebellum, 2018, 17(4): 504-506.
22.	Reinson K, Õiglane-Shlik E, Talvik I, et al. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. American Journal of Medical Genetics, 2016, 170(8): 2173-2176.
23.	Gudenkauf FJ, Azamian MS, Hunter JV, et al. A novel CACNA1A variant in a child with early stroke and intractable epilepsy. Mol Genet Genomic Med, 2020, 8(10): e1383.
24.	Le Roux M, Barth M, Gueden S, et al. CACNA1A-associated epilepsy: electroclinical findings and treatment response on seizures in 18 patients. European Journal of Paediatric Neurology, 2021, 33: 75-85.

1. Du X, Wei C, Hejazi Pastor DP, et al. α1ACT is essential for survival and early cerebellar programming in a critical neonatal window. Neuron, 2019, 102(4): 770-785.
2. Pan R, Qi X, Wang F, et al. Correlations of calcium voltage-gated channel subunit alpha1 a (cacna1a) gene polymorphisms with benign paroxysmal positional vertigo. Med Sci Monit, 2019, 25(2): 946-951.
3. Hommersom MP, van Prooije TH, Pennings M, et al. The complexities of CACNA1A in clinical neurogenetics. Journal of Neurology, 2021, 269(6): 3094-3108.
4. Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia, 2018, 59(6): 1177-1187.
5. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca²⁺ channel gene CACNL1A4. Cell, 1996, 87(3): 543-552.
6. Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet, 2001, 358(9284): 801-807.
7. Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501: 217-221.
8. Alehabib E, Esmaeilizadeh Z, Ranji-Burachaloo S, et al. Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients. Orphanet Journal of Rare Diseases, 2021, 16(1): 461.
9. Niu X, Yang Y, Chen Y, et al. Genotype-phenotype correlation of CACNA1A variants in children with epilepsy. Developmental Medicine and Child Neurology, 2022, 64(1): 105-111.
10. Angelini C, van Gils J, Bigourdan A, et al. Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. European Journal of Medical Genetics, 2018, 62(6): 103530.
11. Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet, 2016, 99(2): 287-298.
12. Gauquelin L, Hawkins C, Tam EWY, et al. Pearls & Oy-sters: fatal brain edema is a rare complication of severe CACNA1A-related disorder. Neurology, 2020, 94(14): 631-634.
13. Indelicato E, Nachbauer W, Karner E, et al. The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature. European Journal of Neurology, 2019, 26(1): e66-e67.
14. Rajakulendran S, Graves TD, Labrum RW, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. The Journal of Physiology, 2009, 588: 1905-1913.
15. Pietrobon D. Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. J Physiol, 2010, 588(11): 1871-1878.
16. Jiang X, Raju PK, D'Avanzo N, et al. Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia, 2019, 60(9): 1881-1894.
17. Cianfoni A, Caulo M, Cerase A, et al. Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities. Eur J Radiol, 2013, 82(11): 1964-1972.
18. Tian X, Ye J, Zeng Q, et al. The clinical outcome and neuroimaging of acute encephalopathy after status epilepticus in Dravet syndrome. Dev Med Child Neurol, 2018, 60(6): 566-573.
19. Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet, 2017, 101(5): 664-685.
20. Travaglini L, Nardella M, Bellacchio E, et al. Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Eur J Paediatr. Neurol, 2017, 21(3): 450-456.
21. Balck A, Tunc S, Schmitz J, et al. A novel frameshift CACNA1A mutation causing episodic ataxia type 2. Cerebellum, 2018, 17(4): 504-506.
22. Reinson K, Õiglane-Shlik E, Talvik I, et al. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. American Journal of Medical Genetics, 2016, 170(8): 2173-2176.
23. Gudenkauf FJ, Azamian MS, Hunter JV, et al. A novel CACNA1A variant in a child with early stroke and intractable epilepsy. Mol Genet Genomic Med, 2020, 8(10): e1383.
24. Le Roux M, Barth M, Gueden S, et al. CACNA1A-associated epilepsy: electroclinical findings and treatment response on seizures in 18 patients. European Journal of Paediatric Neurology, 2021, 33: 75-85.

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