SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.
BACKGROUND
Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, 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 Na(V)1.2 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 Na(V)1.2 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 Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia.
Liao
Y
Y
Neurological Clinic and Institute of Applied Physiology, University of Ulm, Ulm, Germany.
Anttonen
A-K
AK
Liukkonen
E
E
Gaily
E
E
Maljevic
S
S
Schubert
S
S
Bellan-Koch
A
A
Petrou
S
S
Ahonen
V E
VE
Lerche
H
H
Lehesjoki
A-E
AE
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002648:Child; D018450:Disease Progression; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009207:Myoclonus / Q000150:complications / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000150:complications / Q000235:genetics*; D018408:Patch-Clamp Techniques / Q000379:methods; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014741:Video Recording / Q000379:methods
D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; C000654500:Scn2a protein, mouse; D015222:Sodium Channels