Juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a common form of genetic generalized epilepsy (previously known as idiopathic generalized epilepsy),[1] representing 5-10% of all epilepsy cases.[2][3][4] This disorder typically first presents between the ages of 12 and 18 with myoclonic seizure manifesting as sudden brief involuntary single or multiple episodes of muscle(s) contractions caused by an abnormal excessive or synchronous neuronal activity in the brain.[5] These events typically occur after awakening from sleep, during the evening or upon sleep deprivation. JME is also characterized by generalized tonic-clonic seizures and a minority also have absence seizures.[6] The genetics of JME are complex and rapidly evolving as over 20 chromosomal loci and multiple genes have been identified thus far.[7] Given the genetic and clinical heterogeneity of JME some authors have suggested that it should be thought of as a spectrum disorder.

Juvenile myoclonic epilepsy
Other namesJanz syndrome
SpecialtyNeurology

Epidemiology

The prevalence of JME is approximately 0.1-0.2 per 100,000 and constitutes approximately 5-10% of all epilepsies.[8] Some studies suggest that JME is slightly more common in females than males.[9] The onset of symptoms ranges between the ages of 8 and 36 years and has a peak between the ages of 12 and 18 years.[3] Approximately 15% of children with childhood absence epilepsy and juvenile absence epilepsy subsequently develop JME.[10] In most cases, myoclonic jerks precede the first generalized tonic-clonic seizure by a mean of 3.3 years.[11] A long-term population-based study suggested that at 25 years from seizure onset all seizure types in JME resolved in 17% and in 13% only myoclonus remained despite discontinuing medication. Thus, disabling seizures resolve in around one-third of patients.[9]

Signs and symptoms

There are three principle seizures types which may occur in JME: myoclonus, generalized tonic-clonic seizures and absence seizures. Approximately one-third of patients have all three seizure types.[12] The majority of patients (58.2%) have frequent myoclonic jerks and uncommon generalized tonic-clonic seizures.[12] Absence seizures are believed to be the least common with studies estimating a prevalence of 10% to as high as 38%.[12][13] Myoclonic status epilepticus may occur as a complication but it is uncommon.

Patient’s typically initially present to medical providers following their first generalized tonic-clonic seizure. It is often subsequently reported that the patient was having myoclonus for several years prior. The first generalized tonic-clonic seizure usually occurs in the context of a particular provoking factor such as sleep deprivation, stress or alcohol consumption.[14] There are other potential provoking factors such as praxis induction which refers to the precipitation of seizures or epileptiform discharges in the context of a complex cognitive tasks.[15] Patients with JME tend to perform worse on neuropsychological assessments in multiple cognitive domains and are also more likely to have psychiatric comorbidities such as depression and anxiety when compared to control populations.[16][17][18] The majority of patients with JME report satisfaction with their health, work, friendships and social life.[9]

Cause

JME is believed to be most often caused by a heterogeneous and complex interaction of multiple genes rather than an unidentified single genetic cause.[19] Thus far seven genes and over 20 chromosomal loci have been implicated in the pathogenesis of JME.[20] A minority of cases are caused by single genes and are inherited in an autosomal dominant fashion.[21] The majority of the genes which have been associated with JME encode for ion channel subunits.[22] More recently, variants in intestinal cell kinase which is encoded by a gene on chromosome 6p12 was found to be associated with JME. This gene is involved in mitosis, cell-cycle exit and radial neuroblast migration as well as apoptosis.[23] Another gene that is associated with JME called EFHC1 has similar functions.[24] These findings may explain subtle structural and functional brain abnormalities that are seen in patients with JME.[25]

JME is distinct from other forms of genetic generalized epilepsies due to the prominence of myoclonus. There is evidence that patients with JME have hyperexcitable motor cortexes that is most pronounced in the morning and after sleep deprivation.[26][27] In addition, there is evidence that patients with JME have hyperexcitable and hyperconnected cortical networks that are involved in ictogenesis.[28]

Genetics

CACNB4

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.[29] In mice, a naturally occurring null mutation leads to the "lethargic" phenotype. This is characterized by ataxia and lethargic behavior at early stages of development followed within days by the onset of both focal motor seizures as well as episodes of behavioral immobility which correlates with patterns of cortical spike and wave discharges at the EEG[30] 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.[31]

The R482X mutation results in increased current amplitudes and an accelerated fast time constant of inactivation.[32] Whether these modest functional differences may be in charge of JME remains to be established.[32] 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.[33]

GABRA1

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.[34] This missense mutation results in channels with reduced peak GABA-evoked currents.[35] Furthermore, the presence of such mutation alters the composition and reduces the expression of wild-type GABAA receptors.[35]

GABRD

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).[36] 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.

Myoclonin1/EFHC1

The final known associated gene is EFHC1. Myoclonin1/EFHC1 encodes for a protein that has been known to play a wide range of wild-type 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.[24]

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.[24] As such a theory has been put forward that JME may be the result of a brain developmental disorder.[24]

Other loci

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.[37]

Diagnosis

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.[38] 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.[39] Positron emission tomography reports in some patients may indicate local deviations in many transmitter systems.[40]

Management

The most effective anti-epileptic medication for JME is valproic acid (Depakote).[41][11]

Due to valproic acid's high incidence of fetal malformations,[42][41] 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. However, recent follow-up researches on a subgroup of patients showed them becoming seizure-free and off anti-epileptic drugs in due course of time.[43][44][45] This makes this dogma questionable. Patients should be warned to avoid sleep deprivation.

History

The first citation of JME was made in 1857 when Théodore Herpin described a 13-year-old boy with myoclonic jerks, which progressed to tonic-clonic seizures three months later.[46] In 1957, Janz and Christian published a journal article describing several patients with JME.[47] The name Juvenile Myoclonic Epilepsy was proposed in 1975 and adopted by the International League Against Epilepsy.[46]

Culture

Stand-up comedian Maisie Adam has JME and her award-winning show "Vague" (2018) discussed it.[48]

The 2018 documentary film Separating The Strains dealt with the use of CBD oil to treat symptoms of JME.[49] Currently, no scientific evidence exist to support the use of CBD oil to treat symptoms of JME.

See also

References
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  48. "Comedian Maisie Adam shares her experiences growing up with epilepsy in her new show Vague Epilepsy Action". www.epilepsy.org.uk.
  49. "Cannabis documentary about epilepsy to foster more understanding". 2018-06-13.
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