Journal of Pediatric Neurology 2017; 15(04): 183-186
DOI: 10.1055/s-0036-1597627
Case Report
Georg Thieme Verlag KG Stuttgart · New York

Exome Sequencing Identifying Dual Mutations in Calcium Signaling Genes GNAO1 and ATP2B3 in a Patient with Early Infantile Epileptic Encephalopathy

Keisuke Ueda
1   Division of Neurology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan, United States
2   Wayne State University School of Medicine, Detroit, Michigan, United States
,
Fatema Serajee
1   Division of Neurology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan, United States
2   Wayne State University School of Medicine, Detroit, Michigan, United States
,
Ahm M. Huq
1   Division of Neurology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan, United States
2   Wayne State University School of Medicine, Detroit, Michigan, United States
› Author Affiliations
Further Information

Publication History

13 October 2016

16 November 2016

Publication Date:
19 December 2016 (online)

Abstract

Early infantile epileptic encephalopathy (EIEE) is an age-dependent epileptic encephalopathy. It occurs early in life with various types of seizures, especially tonic spasms and its overall prognosis is poor. We report a 5-year-old boy with EIEE, severe developmental delay, intractable epilepsy, and congenital cerebellar ataxia. His infantile spasms were treated successfully with ACTH, but he later developed intractable focal seizures. Whole exome sequencing revealed a maternally inherited missense mutation in the ATP2B3 gene (c.3338C > T/p.T1113M) and a de novo missense mutation in the GNAO1 gene (c.133G > C/p.G45R). Both genes are associated with calcium signaling pathways. The ATP2B3 gene is associated with intracellular calcium clearance, resulting in abnormal calcium homeostasis and X-linked spinocerebellar ataxia-1. The GNAO1 gene is associated with G protein signaling, affecting calcium signaling, and EIEE. Both mutations are related to maintain cellular calcium homeostasis, but the phenotype was not significantly more severe than those which have been reported.

 
  • References

  • 1 Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002; 24 (01) 13-23
  • 2 Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol 2012; 46 (01) 24-31
  • 3 Nakamura K, Kodera H, Akita T. , et al. De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet 2013; 93 (03) 496-505
  • 4 Hein L. Adrenoceptors and signal transduction in neurons. Cell Tissue Res 2006; 326 (02) 541-551
  • 5 Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 1995; 268 (5208): 239-247
  • 6 Hille B. G protein-coupled mechanisms and nervous signaling. Neuron 1992; 9 (02) 187-195
  • 7 Jurgens CWD, Hammad HM, Lichter JA. , et al. Alpha2A adrenergic receptor activation inhibits epileptiform activity in the rat hippocampal CA3 region. Mol Pharmacol 2007; 71 (06) 1572-1581
  • 8 Jeong SW, Ikeda SR. Endogenous regulator of G-protein signaling proteins modify N-type calcium channel modulation in rat sympathetic neurons. J Neurosci 2000; 20 (12) 4489-4496
  • 9 Moises HC, Rusin KI, Macdonald RL. mu-Opioid receptor-mediated reduction of neuronal calcium current occurs via a G(o)-type GTP-binding protein. J Neurosci 1994; 14 (06) 3842-3851
  • 10 Valenzuela D, Han X, Mende U. , et al. G alpha(o) is necessary for muscarinic regulation of Ca2+ channels in mouse heart. Proc Natl Acad Sci U S A 1997; 94 (05) 1727-1732
  • 11 Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage 2012; 60 (01) 505-522
  • 12 Zanni G, Calì T, Kalscheuer VM. , et al. Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci U S A 2012; 109 (36) 14514-14519
  • 13 Strehler EE, Caride AJ, Filoteo AG, Xiong Y, Penniston JT, Enyedi A. Plasma membrane Ca2+ ATPases as dynamic regulators of cellular calcium handling. Ann N Y Acad Sci 2007; 1099: 226-236
  • 14 Strehler EE, Zacharias DA. Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol Rev 2001; 81 (01) 21-50
  • 15 Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 2002; 43 (01) 9-18
  • 16 Marcé-Grau A, Dalton J, López-Pisón J. , et al. GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. Orphanet J Rare Dis 2016; 11: 38 . Doi: 10.1186/s13023-016-0416-0