Juvenile Myoclonic Epilepsy
Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a fairly common form of generalized epilepsy of presumed genetic origin (previously known an idiopathic generalized epilepsy), representing 5-10% of all epilepsy cases. This disorder typically first manifests itself between the ages of 12 and 18 with sudden brief involuntary single or multiple episodes of muscle(s) contractions caused by an abnormal excessive or synchronous neuronal activity in the brain. These events typically occur either early in the morning or upon sleep deprivation.
Additional clinical presentations include seizures with either a motor (tonic-clonic seizure) or nonmotor (absence seizure) generalized onset. Genetic studies have demonstrated several loci for JME and identified mutations in 4 genes.
Signs and symptoms
The characteristic signs of JME are brief episodes of involuntary muscle twitching. These are brief episodes of involuntary muscle contractions occurring early in the morning or shortly before falling asleep. They are more common in the arms than in the legs and may result in dropping objects. Myoclonic jerks may as well appear in clusters. Other seizure types include those with either motor or non motor generalized onset. 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. Sleep deprivation is a major factor in triggering seizures in JME patients.
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. The majority of JME cases have an onset in early childhood to puberty.
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. In mice, a naturally occurring null mutation leads to the "lethargic" phenotype. This is characterized by ataxia and lethargic behaviour at early stages of development followed within days by the onset of both focal motor seizures as well as episodes of behavioural immobility which correlates with patterns of cortical spike and wave discharges at the EEG A premature-termination mutation R482X was identified in a patient with JME while an additional missense mutation C104F was identified in a German family with generalized epilepsy and praxis – induced seizures.
The R482X mutation results in increased current amplitudes and an accelerated fast time constant of inactivation. Whether these modest functional differences may be in charge of JME remains to be established. Calcium channel β4 subunit (CACNB4) is not strictly considered a putative JME gene because its mutation did not segregate in affected family members, and it was found in only one member of a JME family from Germany, and it has not been replicated.
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/sub>. This missense mutation results in channels with reduced peak GABA-evoked currents. Furthermore, the presence of such mutation alter the composition and reduce the expression of wild type GABAA receptors.
GABRD encodes the δ subunit of the GABA receptor, which is an important constituent of the GABAA receptor mediating tonic inhibition in neurons (extrasynaptic GABA receptors, i.e. receptors that are localized outside of the synapse). Among the mutations that have been reported in this in this gene, one (R220H) has been identified in a small family with JME. This mutation affects GABAergic transmission by altering the surface expression of the receptor as well as reducing the channel – opening duration.
The final known associated gene is EFHC1. Myoclonin1/EFHC1 encodes for a protein that has been known to play a wide range of roles from cell division, neuroblast migration and synapse/dendrite formation. 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 four JME-causing mutations discovered (D210N, R221H, F229L and D253Y). The mutations do not seem to alter the ability of the protein to colocalize with centrosomes and mitotic spindles but induce mitotic spindle defects. Moreover, the mutations impact radial and tangential migration during brain development. As such a theory has been put forward that JME may be the result of a brain developmental disorder.
Three SNP alleles in BRD2, Cx-36 and ME2 and microdeletions in 15q13.3, 15q11.2 and 16p.13.11 also contribute risk to JME.
Diagnosis is typically made based on patient history. The physical examination is usually 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 characteristic pattern of waves and spikes associated with the syndrome such as generalized 4–6 Hz polyspike and slow wave discharges. These discharges may be evoked by photic stimulation (blinking lights) and/or hyperventilation.
Both a magnetic resonance imaging scan (MRI) and computed tomography scan (CT scan) generally appear normal in JME patients. However a number of quantitative MRI studies have reported focal or regional abnormalities of the subcortical and cortical grey matter, particularly the thalamus and frontal cortex, in JME patients.
The most effective anti-epileptic medication for JME is valproic acid (Depakote). Due to valproic acid's high incidence of fetal malformations, women of child-bearing age are started on alternative medications such as Lamotrigine, levetiracetam. Carbamazepine may aggravate genetic generalized epilepsies and as such its use should be avoided in 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.
Stand-up comedian Maisie Adam has JME and her award-winning show "Vague" (2018) discussed it.
The 2018 documentary film Separating The Strains dealt with the use of CBD oil to treat symptoms of JME. Currently, no scientific evidence exist to support the use of CBD oil to treat symptoms of JME.
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