Variant in CACNA1G as a Possible Genetic Modifier of Neonatal Epilepsy in an Infant with a De Novo SCN2A Mutation

Abstract

Mutations in SCN2A genes have been described in patients with epilepsy, finding a large phenotypic variability, from benign familial epilepsy to epileptic encephalopathy. To explain this variability, it was proposed the existence of dominant modifier alleles at one or more loci that contribute to determine the severity of the epilepsy phenotype. One example of modifier factor may be the CACNA1G gene, as proved in animal models. We present a 6-day-old male newborn with recurrent seizures in which a mutation in the SCN2A gene is observed, in addition to a variant in CACNA1G gene. Our patient suffered in the first days of life myoclonic seizures, with pathologic intercritical electroencephalogram pattern, requiring multiple drugs to achieve adequate control of them. During the next weeks, the patient progressively improved until complete remission at the second month of life, being possible to withdraw the antiepileptic treatment. We propose that the variant in CACNA1G gene could have acted as a modifier of the epilepsy syndrome produced by the mutation in SCN2A gene in our patient.

Keywords

neonatal epilepsy - SCN2A - CACNA1G - genetic modifier

Publikationsverlauf

Eingereicht: 15. Juni 2020

Angenommen: 04. Januar 2021

Artikel online veröffentlicht:
19. Februar 2021

• References

• 1 Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013; 18 (04) 185-191
• 2 Shellhaas RA, Wusthoff CJ, Tsuchida TN. et al; Neonatal Seizure Registry. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 2017; 89 (09) 893-899
• 3 Sanders SJ, Campbell AJ, Cottrell JR. et al. Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci 2018; 41 (07) 442-456
• 4 Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 2010; 9 (04) 413-424
• 5 Ogiwara I, Ito K, Sawaishi Y. et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology 2009; 73 (13) 1046-1053
• 6 Howell KB, McMahon JM, Carvill GL. et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015; 85 (11) 958-966
• 7 Leppert M, Novel K. Novel K+ channel genes in benign familial neonatal convulsions. Epilepsia 2000; 41 (08) 1066-1067
• 8 Oliva M, Berkovic SF, Petrou S. Sodium channels and the neurobiology of epilepsy. Epilepsia 2012; 53 (11) 1849-1859
• 9 Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL. eds. The Comprehensive Evaluation and Treatment of Epilepsy. San Diego, CA: Academic Press; 1997: 1-36
• 10 Perez-Reyes E, Cribbs LL, Daud A. et al. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 1998; 391 (6670): 896-900
• 11 Morino H, Matsuda Y, Muguruma K. et al. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Mol Brain 2015; 8 (01) 89
• 12 Bergren SK, Chen S, Galecki A, Kearney JA. Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. Mamm Genome 2005; 16 (09) 683-690
• 13 Kim D, Song I, Keum S. et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking α(1G) T-type Ca(2+) channels. Neuron 2001; 31 (01) 35-45
• 14 Ernst WL, Zhang Y, Yoo JW, Ernst SJ, Noebels JL. Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence epilepsy. J Neurosci 2009; 29 (06) 1615-1625
• 15 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 16 Calhoun JD, Hawkins NA, Zachwieja NJ, Kearney JA. Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Epilepsia 2016; 57 (06) e103-e107
• 17 Chemin J, Siquier-Pernet K, Nicouleau M. et al. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain 2018; 141 (07) 1998-2013
• 18 Wolff M, Johannesen KM, Hedrich UBS. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017; 140 (05) 1316-1336