Genetics and differenzial developmental expression of the Na+ channel gene SCN2A reveal molecular correlates for early-onset (neonatal-infantile) seizures and late-onset episodic ataxia, myoclonus and pain

Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism which can explain that epileptic spells in benign familial neonatal-infantile seizures (BFNIS) occur almost exclusively during the first days to months of life. BFNIS is caused by mutations in the gene SCN2A encoding the voltage-gated Na+ channel NaV1.2. We describe three novel SCN2A mutations causing BFNIS in three independent families, two of them occurring de novo, and their functional consequences in a neonatal and an adult splice variant of the Na+ channel NaV1.2. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na+ current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation and inactivation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced or the same for the adult form for the other two, suggesting that a differenzial developmental splicing does not provide a general explanation for seizure remission. We therefore analyzed the developmental expression of NaV1.2, and of another voltage-gated Na+ channel, NaV1.6, using immunohistochemistry in mouse brain slices. We found that NaV1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by NaV1.6 during maturation. This finding provides a plausible explanation for the transient expression of neonatal-infantile seizures that occur due to a gain-of-function of mutant NaV1.2 channels. One of the de novo cases suffered from additional variable episodes of ataxia, myoclonia, headache and back pain after 18 months of age. The detected mutation leads to the most severe electrophysiological consequences, in particular a 3-fold increased persistent Na+ current. Additional immunohistochemical studies of the cerebellum suggest a developmentally increasing expression of NaV1.2 in unmyelinated granule cell axons projecting to Purkinje neurons, which may be responsible for the later onset of episodic ataxia. Our results suggest that gain-of-function mutations in SCN2A are associated with characteristic age-dependent symptoms caused by a differenzial developmental expression of NaV1.2 channels in distinct myelinated and unmyelinated axons of the brain.