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 and symptoms
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
β subunit. β subunits
are important regulators of calcium channel current amplitude, voltage dependence, and also regulate channel trafficking. The β4
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 β4
subunit associated with JME, C104F and R482X. When wild-type α1A
subunits are expressed in oocytes
they produce large Ba2+
currents that inactivate slowly. Incorporation of either of the mutant β4
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.
GABRA1 encodes an α 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 α1
combination of subunits in HEK 293
cells produces 6-fold greater current than similar subunits compositions containing mutant α1
subunits. The mutation also results in greatly decreased sensitivity in the receptor for activation by GABA
. 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 α1
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.
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.
GABRD encodes the δ subunit of the GABA receptor
, which is a subunit yielding receptors which do not desensitize
and are localized outside of the synapse
. There are three mutations in this gene associated with JME, E177A, R220C, and R220H, all located in the N-terminus of the protein. The last of these mutations is also present in normal controls. Receptors containing the E177A mutation have greatly decreased current compared to wild-type. This is not the case for the R220C mutation but is similar to the R220H mutation, though to a lesser extent than the E177A mutation. More recent study has found that the E177A mutant also has greatly decreased desensitization
compared to wild-type receptors. Receptors containing only E177A or R220H mutants, versus heterozygotes, had significantly decreased surface expression compared to wild-type or heterozygotic receptors. These mutants also have decreased single-channel open times compared to wild-type. It should be noted, however, that these mutations are very rare as causes of JME.
The final known associated gene is EFHC1, which is poorly understood. EFHC1 has three DM10 domains (themselves of unknown function) and an EF hand motif, which is known to bind intracellular calcium
. EFHC1 is expressed in many tissues, including the brain, where it is localized to the soma
of neurons, particularly the hippocampal CA1
region, pyramidal neurons in the cerebral cortex
, and Purkinje cells
in the cerebellum
. There are 5 mutations in EFHC1 associated with JME; D210N, F229L, D253Y, P77T and R221H. The last two mutations were originally detected as a pair in the same individual. EFHC1 seems to be involved in programmed cell death
as EFHC1 transfected cells have a higher rate of apoptosis
. This rate is decreased by the double mutations P77T + R221H. Wild-type EFHC1 increased the R-type calcium channel
currents in transfected cells. This stimulation is decreased by JME associated mutations. Because of this, programmed cell death is decreased and the pruning of unwanted neurons may be hampered. As with some other loci, mutations in EFHC1 is not a common loci for JME. More recently, R221H has been found without P77T in one JME kindred.
There is also evidence linking a gene or genes on chromosome 15 (15q14) and chromosome 6 (6p21) to JME. Causative genes in this region, however, have not been shown.
Relation to other rare disorders: genetic ciliopathy
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely-varying set of medical symptoms that are clinically visible in the disorders. This emerging class of diseases are called cilopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration.. It has been suggested that juvenile myoclonic epilepsy may be a ciliopathy.
Diagnosis is typically made based on patient history. EEG
recordings are also sometimes used as confirmation.
See the equivalent section in the main epilepsy article.
Before giving Carbamazepine do ask for history of early morning fits especially in a young person. Carbamazepine aggravates these.