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Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus occurring early in the morning. Most patients also have tonic-clonic seizures and many also have absence seizures. Linkage studies have demonstrated at least 6 loci for JME, 4 with known causative genes. Most of these genes are ion channels with the one non-ion channel gene having been shown to affect ion channel currents.
Signs of JME are myoclonus occurring early in the morning. This rarely results in patients falling, but rather dropping objects. Attacks of myoclonia are more common in the arms than the legs. Other seizure types such as generalized tonic-clonic and absence seizures can also occur.
CACNB4 encodes a calcium channel ß subunit. ß subunits are important regulators of calcium channel current amplitude, voltage dependence, and also regulate channel trafficking. The ß4 isoform encoded by CACNB4 is most prevalent in the cerebellum. In mice, a naturally occurring null mutation leads to the “lethargic” phenotype, which is similar to JME. There are at least two mutations in the ß4 subunit associated with JME, C104F and R482X. When wild-type a1A and ß4 subunits are expressed in oocytes they produce large Ba2+ currents that inactivate slowly. Incorporation of either of the mutant ß4 subunit into channels instead of wild-type subunits produces currents that are larger by 30-40%. The R482X mutation also increases the rate of fast inactivation of the channel. Since these effects are subtle, it is believed that they are contributory rather than completely causative for JME.[1]
GABRA1 encodes an a subunit of the GABA A receptor, which encodes one of the major inhibitory neurotransmitter receptors. There is one known mutation in this gene that is associated with JME, A322D, which is located in the third segment of the protein. Expression of the a1ß2?2 combination of subunits in HEK 293 cells produces 6-fold greater current than similar subunits compositions containing mutant a1 subunits. The mutation also results in greatly decreased sensitivity in the receptor for activation by GABA.[2] This combination of mutant containing receptors also activates far more slowly than wild-type containing receptors. Although originally not reported to result in altered protein trafficking, more recent study has indicated that the A322D mutation reduced a1 subunit trafficking to the membrane by >90%. Heterozygous expression of wild-type and mutant subunits produces current approximately 50% the size of wild-type due to this altered trafficking.[3][4]
The CLCN2 gene encodes a chloride channel that is heavily expressed in brain regions inhibited by GABA. It is believed to be important in maintaining a proper chloride reversal potential needed in inhibitory neurotransmission by GABA. There are three known mutations in CLCN2 associated with JME, M200fsX231, 74_117del, and G715E. Neither the M200fsX231 nor the 74_117del mutation yield current when expressed in cells. Since these channels are responsible for the removal of intracellular chloride, these mutations are expected to lead to increased chloride concentrations and, thus, altered chloride reversal potential (ECl). As chloride is conducted through the normally inhibitory GABA receptors, this alteration in ECl may lead to either decreased GABAergic currents or GABAergic currents that are actually excitatory. The G715E mutation, on the other hand, produces normal sized currents but has altered voltage dependent activation. For this mutant, activation occurs at more positive potentials compared to wild-type channels. This may cause increased neuronal excitability.[5]
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