2. Academic Validation
  3. Mutations in SCN3A cause early infantile epileptic encephalopathy

Mutations in SCN3A cause early infantile epileptic encephalopathy

  • Ann Neurol. 2018 Apr;83(4):703-717. doi: 10.1002/ana.25188.
Tariq Zaman 1,  Ingo Helbig 1 2 3,  Ivana Babić Božović 4,  Suzanne D DeBrosse 5,  A Christina Bergqvist 1,  Kimberly Wallis 5,  Livija Medne 6,  Aleš Maver 7,  Borut Peterlin 7,  Katherine L Helbig 1 8,  Xiaohong Zhang 1,  Ethan M Goldberg 1 3 9
Affiliations

Affiliations

  • 1 Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 2 Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrecht University, Kiel, Germany.
  • 3 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 4 Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Rijeka, Croatia.
  • 5 Departments of Genetics and Genome Sciences, Pediatrics, and Neurology, and Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland, OH.
  • 6 Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 7 Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
  • 8 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
  • 9 Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
PMID: 29466837 DOI: 10.1002/ana.25188
Abstract

Objective: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala).

Methods: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria.

Results: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels.

Interpretation: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.

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