Juvenile myoclonic epilepsy
|Juvenile myoclonic epilepsy|
|Classification and external resources|
|OMIM||606904 254770 604827 608816|
Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy, representing 5-10% of all epilepsy cases. This disorder typically first manifests itself between the ages of 12 and 18 with brief episodes of involuntary muscle twitching occurring early in the morning. Most patients also have generalized seizures that affect the entire brain and many also have absence seizures. Genetic 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.[not verified in body]
Signs and symptoms
Signs of JME are brief episodes of involuntary muscle twitching occurring early in the morning or shortly before falling asleep. This does not usually result in the person falling, but rather dropping objects. These muscle twitching episodes are more common in the arms than in the legs. Other seizure types such as generalized tonic-clonic and absence seizures can also occur. Patients often report quick jerking movements in the morning that results in knocking over objects such as their morning orange juice. Clusters of myoclonic seizures can lead to absence seizures, and clusters of absence seizures can lead to generalized tonic-clonic seizures. The onset of symptoms is generally around age 10-16 although some patients can present in their 20s or even early 30s. The myoclonic jerks generally precede the generalized tonic-clonic seizures by several months. Some people with the disorder never get generalized tonic-clonic seizures (GTCs). Sleep deprivation is a major factor in triggering GTCs. College students often present with a GTC after "pulling an all-nighter." Patients with JME generally do not have other neurological problems.
Juvenile myoclonic epilepsy is an inherited genetic syndrome, but the way in which this disorder is inherited is unclear. Frequently (17-49%) those with JME have relatives with a history of epileptic seizures. There is also a higher rate of females showing JME symptoms than males. Almost all cases of JME, however, have an onset in early childhood to puberty.
Diagnosis is typically made based on patient history. The physical examination should be normal. The primary diagnosis for JME is a good knowledge of patient history and the neurologist's familiarity with the myoclonic jerks, which are the hallmark of the syndrome. Additionally, an electroencephalogram (EEG), will indicate a pattern of waves and spikes associated with the syndrome. The EEG generally shows a very characteristic pattern with generalized 4–6 Hz polyspike and slow wave discharges. These discharges are often provoked by photic stimulation (blinking lights) and sometimes hyperventilation. Both a magnetic resonance imaging scan (MRI) and computed tomography scan (CT scan) should appear normal in JME patients.
CACNB4 is a gene that encodes the calcium channel β subunit protein. 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 and β4 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 is a gene that encodes for an α subunit of the GABA A receptor protein, 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 α1β2γ2 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 protein 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 and dendrites 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.
Relation to other rare disorders
Until recently, the medical literature did not indicate a connection among many genetic disorders; however, genetic syndromes and genetic diseases 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 ciliopathies. 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.
The most effective anti-epileptic medication for JME is valproic acid (Depakote). Women are often started on alternative medications due to valproic acid's high incidence of fetal malformations. Lamotrigine, levetiracetam, topiramate, and zonisamide are alternative anti-epileptic medications with less frequent incidence of pregnancy related complications, and they are often used first in females of childbearing age. Carbamazepine may aggravate primary generalized seizure disorders such as JME. Treatment is lifelong. Patients should be warned to avoid sleep deprivation.
The first citation of JME was made in 1857 when Théodore Herpin described a 13-year-old boy suffering from myoclonic jerks, which progressed to tonic-clonic seizures three months later. In 1957, Janz and Christian published a journal article describing several patients with JME. The name Juvenile Myoclonic Epilepsy was proposed in 1975 and adopted by the International League Against Epilepsy.
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