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Abstract
Background: Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel NaV1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy.
Methods: We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of NaV1.2 in cerebellum by immunohistochemical analysis.
Results: The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na+ current. Immunohistochemical studies suggest a developmentally increasing expression of NaV1.2 in granule cell axons projecting to Purkinje neurons.
Conclusions: These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of NaV1.2 in cerebellum may be responsible for the later onset of episodic ataxia.
Footnotes
Study funding: Supported by the Folkhälsan Research Foundation, the University of Helsinki, the Academy of Finland (Center of Excellence Programme 2006–2011), the German Research Foundation (DFG Le1030/10-1, /8-2), the National Genome Network of the Federal Ministry for Education and Research (BMBF: NGFNplus/01GS08123), the European Union (EPICURE: LSH 037315), and the University of Ulm.
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- BFNIS
- benign familial neonatal-infantile seizure
Supplemental data at www.neurology.org
- Received December 23, 2009.
- Accepted June 30, 2010.
- Copyright © 2010 by AAN Enterprises, Inc.
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