The author: Professor Yasser Metwally
http://yassermetwally.com
INTRODUCTION
February 6, 2010 — Benign familial neonatal convulsions (BFNC) is an autosomal dominant condition characterized by neonatal seizures in otherwise healthy newborns. Seizures usually begin between the first and fourteenth days of life and typically remit spontaneously by 6 weeks of age. The risk of subsequent epilepsy is about 15%. The seizures are clinically heterogeneous and include eye deviation, tonic posturing, focal clonic activity and apnea with evolution to generalized convulsions. [1-3]
Early studies demonstrated BFNC to be genetically heterogeneous. The two genes on chromosomes 20q and 8q encode highly homologous potassium channel subunits, KCNQ2 and KCNQ3. [2–3] Expression of either subunit alone in Xenopus oocytes results in small currents, but co-expression of the two genes yields a channel with currents 10–50 times larger, [4] and with the gating properties of the neuronal M-channel. [24] In-situ hybridization has demonstrated overlapping patterns of expression of KCNQ2 and KCNQ3. [4,5] These data cohere to suggest that KCNQ2 and KCNQ3 coassemble in vivo to form the M-channel. This molecular mechanism would explain why patients with BFNC linked to the loci on chromosomes 20q and 8q are clinically indistinguishable.
Functional expression of the disease causing missense mutations in these subunits are associated with a variable reduction (20–95%) in current magnitude. [3,6] Coexpression of mutant and wild-type subunits yielded potassium currents of similar amplitude, essentially excluding a dominant negative effect. [6,7] Rather, these results are consistent with neuronal excitability being critically dependent on the absolute magnitude of KCNQ2/KCNQ3 potassium channel current.
Reduced activity of the M-channel would be expected to cause neurons to become slightly depolarized and to fire multiple action potentials rhythmically after receiving excitatory inputs. The known functional effects of the KCNQ2 and KCNQ3 mutations are thus consistent with the clinical phenotype of seizures. It is unclear, however, why these mutations preferentially lead to seizures in the neonatal period. Possibilities include that the neonatal brain simply has a lower seizure threshold, or that potassium channel subunit expression is developmentally regulated, with neuronal excitability more dependent on the M-channel than on other voltage-sensitive potassium channels in the neonatal period.
References
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