Juvenile Myoclonic Epilepsy

Updated: Jun 24, 2016
  • Author: James Selph, MD; Chief Editor: Selim R Benbadis, MD  more...
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Overview

Background

Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epileptic syndrome characterized by myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and sometimes absence seizures. JME is relatively common and responds well to treatment with appropriate anticonvulsants.

Other features suggestive of the diagnosis include normal intelligence, onset around adolescence, and a family history of the condition. GTCSs occur shortly after awakening or after precipitating factors such as sleep deprivation, alcohol use, or psychological stress. Patients usually require lifelong anticonvulsant therapy, but their overall prognosis is generally good.

Definition of juvenile myoclonic epilepsy

Since the first description of a probable case of JME in 1867, [1] various names have been applied to this condition. [2, 3, 4, 5] The term “juvenile myoclonic epilepsy” was proposed in 1975 [6] and has been adopted by the International League Against Epilepsy (ILAE). Under the proposal for revised classification of epilepsies and epileptic syndromes, in 1989 the ILAE Commission on Classification and Terminology defined JME (impulsive petit mal) as follows. [7]

“Impulsive petit mal appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. Often, there are GTCS and, less often infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation."

“Interictal and ictal EEG have rapid, generalized, often irregular spike-waves (SW) and polyspike-waves (PSW); there is no close phase correlation between EEG [electroencephalographic] spikes and jerks. Frequently the patients are photosensitive. The disorder may be inherited and sex distribution is equal. Response to appropriate drugs is good.”

For more information, see the following:

  • Epilepsy and Seizures
  • Generalized Tonic-Clonic Seizures
  • Absence Seizures
  • Antiepileptic Drugs
  • Pediatric Status Epilepticus
  • Benign Childhood Epilepsy
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Pathophysiology

JME is an idiopathic primary generalized epilepsy syndrome. It is not secondary to other conditions such as head trauma, brain tumor, encephalitis, or other cerebral abnormalities that can lead to focal onset seizures.

Results from routine pathologic analyses of brain specimens from patients with JME are typically normal. However, histology occasionally reveals increased numbers of partially dystropic neurons in the stratum moleculare, white matter, hippocampus, and cerebellar cortex; an indistinct boundary between the cortex and the subcortical white matter and between lamina 1 and 2 can also be found. These findings are termed microdysgenesia and have been interpreted as a manifestation of minimal developmental disturbances.

Some families have specific mutations that yield the clinical phenotype of JME. (See Etiology.) Known mutations include ion channel proteins, such as the beta-4 subunit of calcium channels and the chloride channel 2 protein.

One study of a large Canadian family with JME demonstrated increased gamma-aminobutyric acid (GABA)-A receptor subunit degradation from a mutation of the alpha1-subunit (A322D) of the GABA-A receptor. [8] This results in a decreased functional lifespan of the GABA-A receptor and consequent CNS hyperexcitability. A review article by MacDonald and Kang describes additional mechanisms that might result in hyperexcitability. [9]

In another study, there was a reduction in the regional binding potential to the dopamine transporter (DAT) in the substantia nigra and midbrain (but not in caudate or putamen) in a positron emission tomography (PET) study of patients with JME as compared with healthy controls. [10]

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Etiology

The exact cause of JME remains unknown, though genetic factors are suspected. Specific mutations in various genes have been identified with a complex mode of inheritance. [11] Most likely, multiple genes result in a similar electroclinical syndrome.

Mutations in genes encoding ion channels have been associated with JME, inclusive of the beta-4 calcium channel subunit (CACNB4), the GABA receptor subunit (GABRA1), and the chloride channel (CLCN2). Each of these channelopathies has been described in a single family, and all are rare causes of JME. [12]

Discussion by Suzuki et al [13] and Delgado-Escueta’s group [14] describe missense mutations of the myoclonin gene (EFHC1) in the EJM1 site at 6p12–p11. Calcium dysregulation versus abnormalities during cortical development may be the underlying reason for dysfunction in affected patients with JME and mutation in the EFHC1 gene. Gene dysfunction at other loci (EJM2, EJM3) are also being studied.

Genetic risk factors

Although JME is known to be an inherited disorder, the exact mode of inheritance is not clear. About a third of patients with JME have a positive family history of epilepsy. About 17-49% of patients with JME have relatives who have epileptic seizures, including parents (about 4%) and children (about 7%). The risk of expressing clinical JME is higher in relatives of people with JME.

Although investigators in most studies have presumed that JME is an autosomal dominant condition (ie, 50% risk of inheritance), it has incomplete penetrance, which means that some individuals who inherit the JME gene or genes do not express clinical JME. However, their children may inherit the JME genes and express clinically obvious disease. To an untrained observer, the disease seems to skip generations. For relatives of a patient with JME, the risk of having clinically obvious JME is small: 3.4% in parents, 7% in siblings, and 6.6% in children.

Despite similar genetic burden, the phenotype of JME might vary among relatives, as in a case of identical twins in which the proband had JME (myoclonus and GTCSs) but the identical twin only had childhood absence epilepsy. A French-Canadian study of probands with JME demonstrated only an absence syndrome in 27% of relatives with seizures. [15]  Certainly, disease burden does vary across the spectrum of individuals with JME.

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Epidemiology

The incidence of JME in the general population is estimated to be 1 case per 1000-2000 people internationally. JME represents approximately 5-10% of all epilepsies; however, the exact figures may be higher, as the condition is often misdiagnosed.

Age-related differences in incidence

JME typically begins in adolescence. Although the reported age of onset varies from 6 years up to 36 years, symptoms typically begin in adolescents, with a peak age most commonly of 12-18 years. Why the onset of this genetic disorder is delayed until adolescence is unclear.

Myoclonic jerks, GTCSs, and absence seizures all have an age-related onset in JME. If absence seizures are a feature, they usually begin between the ages of 5 years and 16 years. Myoclonic jerks may follow 1-9 years later, usually around the age of 15 years. GTCSs typically appear a few years later than myoclonic jerks.

Sexual differences in incidence

Findings from some studies suggest that JME is slightly more prevalent among females than males. The reason is unknown. However, data from other studies indicate similar prevalences in both sexes.

Racial differences in incidence

No systematic racial differences have been observed. However, it is likely that some specific genetic mutations among the different types described in families with JME might be more prevalent among different racial groups. For example, the myoclonin (EFHC1) mutation has been found in 9-20% of Mexican-American families with JME but in only 3% of Japanese families with this disorder. [11]

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Prognosis

In general, excellent seizure control can be achieved in JME patients with relatively low doses of appropriate anticonvulsants (eg, valproic acid). The risk of recurrence is higher than 80% if anticonvulsants are withdrawn; hence, lifelong treatment is usually necessary.

While for many patients this is a lifelong disorder, the burden of JME seizures appears to decrease in adulthood and senescence. Whether patients outgrow JME, as compared with other primary generalized epilepsies, at a late age (ie, >60 y) is unknown. An epidemiologic study is needed to settle this issue. Rare cases of late-onset JME have been reported as late as the eighth decade of life. [16]

Camfield and Camfield conducted a long-term population-based study of patients with JME. Between 1977 and 1985, the 24 patients in Nova Scotia who developed JME by age 16 years were contacted 25 years later. In 17%, all seizure types in JME had resolved; in 13%, only myoclonus persisted. Nevertheless, many patients’ lives were complicated by depression, social isolation, unemployment, and social impulsiveness. [17]

Sudden unexpected death in epilepsy (SUDEP) and accidental morbidity and mortality have been observed in JME, as in other epileptic syndromes involving GTCSs.

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Patient Education

The Epilepsy Foundation has a large selection of brochures and informational booklets for patients and their families. The American Epilepsy Society is the professional organization for people treating patients with epilepsy or for those doing research in this field.

For patient education resources, see the Brain and Nervous System Center, as well as Epilepsy.

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