Juvenile myoclonic epilepsy

Jump to navigation Jump to search
Juvenile myoclonic epilepsy
ICD-10 G40.3
ICD-9 345.1
OMIM 606904 254770 604827 608816
DiseasesDB 32202
eMedicine neuro/416 
MeSH D020190

WikiDoc Resources for Juvenile myoclonic epilepsy


Most recent articles on Juvenile myoclonic epilepsy

Most cited articles on Juvenile myoclonic epilepsy

Review articles on Juvenile myoclonic epilepsy

Articles on Juvenile myoclonic epilepsy in N Eng J Med, Lancet, BMJ


Powerpoint slides on Juvenile myoclonic epilepsy

Images of Juvenile myoclonic epilepsy

Photos of Juvenile myoclonic epilepsy

Podcasts & MP3s on Juvenile myoclonic epilepsy

Videos on Juvenile myoclonic epilepsy

Evidence Based Medicine

Cochrane Collaboration on Juvenile myoclonic epilepsy

Bandolier on Juvenile myoclonic epilepsy

TRIP on Juvenile myoclonic epilepsy

Clinical Trials

Ongoing Trials on Juvenile myoclonic epilepsy at Clinical Trials.gov

Trial results on Juvenile myoclonic epilepsy

Clinical Trials on Juvenile myoclonic epilepsy at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Juvenile myoclonic epilepsy

NICE Guidance on Juvenile myoclonic epilepsy


FDA on Juvenile myoclonic epilepsy

CDC on Juvenile myoclonic epilepsy


Books on Juvenile myoclonic epilepsy


Juvenile myoclonic epilepsy in the news

Be alerted to news on Juvenile myoclonic epilepsy

News trends on Juvenile myoclonic epilepsy


Blogs on Juvenile myoclonic epilepsy


Definitions of Juvenile myoclonic epilepsy

Patient Resources / Community

Patient resources on Juvenile myoclonic epilepsy

Discussion groups on Juvenile myoclonic epilepsy

Patient Handouts on Juvenile myoclonic epilepsy

Directions to Hospitals Treating Juvenile myoclonic epilepsy

Risk calculators and risk factors for Juvenile myoclonic epilepsy

Healthcare Provider Resources

Symptoms of Juvenile myoclonic epilepsy

Causes & Risk Factors for Juvenile myoclonic epilepsy

Diagnostic studies for Juvenile myoclonic epilepsy

Treatment of Juvenile myoclonic epilepsy

Continuing Medical Education (CME)

CME Programs on Juvenile myoclonic epilepsy


Juvenile myoclonic epilepsy en Espanol

Juvenile myoclonic epilepsy en Francais


Juvenile myoclonic epilepsy in the Marketplace

Patents on Juvenile myoclonic epilepsy

Experimental / Informatics

List of terms related to Juvenile myoclonic epilepsy

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 is 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 and β4 subunits are expressed in oocytes they produce large Ba2+ currents that inactivate slowly. Interestingly, 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.[1]


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 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.[2] 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.[3][4]


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.[5]


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.[6] 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.[7] It should be noted, however, that these mutations are very rare as causes of JME.[8]


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. Interestingly, 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.[9][10] 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.[11]

Other loci

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.


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.


  1. Escayg A, De Waard M, Lee D, Bichet D, Wolf P, Mayer T, Johnston J, Baloh R, Sander T, Meisler M (2000). "Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia". Am J Hum Genet. 66 (5): 1531–9. PMID 10762541.
  2. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire J, Carmant L, Verner A, Lu W, Wang Y, Rouleau G (2002). "Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy". Nat Genet. 31 (2): 184–9. PMID 11992121.
  3. Gallagher M, Song L, Arain F, Macdonald R (2004). "The juvenile myoclonic epilepsy GABA(A) receptor alpha1 subunit mutation A322D produces asymmetrical, subunit position-dependent reduction of heterozygous receptor currents and alpha1 subunit protein expression". J Neurosci. 24 (24): 5570–8. PMID 15201329.
  4. Krampfl K, Maljevic S, Cossette P, Ziegler E, Rouleau G, Lerche H, Bufler J (2005). "Molecular analysis of the A322D mutation in the GABA receptor alpha-subunit causing juvenile myoclonic epilepsy". Eur J Neurosci. 22 (1): 10–20. PMID 16029191.
  5. Haug K, Warnstedt M, Alekov A, Sander T, Ramírez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger J, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Müller-Newen G, Propping P, Elger C, Fahlke C, Lerche H, Heils A (2003). "Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies". Nat Genet. 33 (4): 527–32. PMID 12612585.
  6. Dibbens L, Feng H, Richards M, Harkin L, Hodgson B, Scott D, Jenkins M, Petrou S, Sutherland G, Scheffer I, Berkovic S, Macdonald R, Mulley J (2004). "GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies". Hum Mol Genet. 13 (13): 1315–9. PMID 15115768.
  7. Feng H, Kang J, Song L, Dibbens L, Mulley J, Macdonald R (2006). "Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors". J Neurosci. 26 (5): 1499–506. PMID 16452673.
  8. Lenzen K, Heils A, Lorenz S, Hempelmann A, Sander T (2005). "Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy". Epilepsy Res. 65 (1–2): 53–7. PMID 16023832.
  9. Suzuki T, Delgado-Escueta A, Aguan K, Alonso M, Shi J, Hara Y, Nishida M, Numata T, Medina M, Takeuchi T, Morita R, Bai D, Ganesh S, Sugimoto Y, Inazawa J, Bailey J, Ochoa A, Jara-Prado A, Rasmussen A, Ramos-Peek J, Cordova S, Rubio-Donnadieu F, Inoue Y, Osawa M, Kaneko S, Oguni H, Mori Y, Yamakawa K (2004). "Mutations in EFHC1 cause juvenile myoclonic epilepsy". Nat Genet. 36 (8): 842–9. PMID 15258581.
  10. Suzuki T, Delgado-Escueta A, Alonso M, Morita R, Okamura N, Sugimoto Y, Bai D, Medina M, Bailey J, Rasmussen A, Ramos-Peek J, Cordova S, Rubio-Donnadieu F, Ochoa A, Jara-Prado A, Inazawa J, Yamakawa K (2006). "Mutation analyses of genes on 6p12-p11 in patients with juvenile myoclonic epilepsy". Neurosci Lett. 405 (1–2): 126–31. PMID 16876319.
  11. "Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy". Epilepsy Res. PMID 16839746.

Template:WH Template:WikiDoc Sources