Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 6204001; ORPHA: 307; DO: 4890;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p12.2 | {Myoclonic epilepsy, juvenile, susceptibility to, 1} | 254770 | Autosomal dominant | 3 | EFHC1 | 608815 |
A number sign (#) is used with this entry because of evidence that susceptibility to juvenile myoclonic epilepsy-1 (EJM1) is conferred by variation in the EFHC1 gene (608815) on chromosome 6p12.
Susceptibility to juvenile absence epilepsy (EAJ1; 607631) is also conferred by variation in the EFHC1 gene.
Juvenile myoclonic epilepsy (EJM, JME) is a subtype of idiopathic generalized epilepsy (EIG; see 600669), affecting up to 26% of all individuals with EIG. Individuals with EJM have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks usually occur in the morning (Janz and Durner, 1997).
Genetic Heterogeneity of Juvenile Myoclonic Seizures
Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12.
In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Dreifuss (1989) gave a clinical review of EJM. He reported the case of a young college woman who sought medical treatment after experiencing her first generalized convulsive seizure, which occurred after a period of sleep deprivation and alcohol consumption. She had recalled occasional myoclonic jerks when she awoke in the morning. The ictal EEG shows a typical 4- to 6-Hz multispike and wave complex; the interictal EEG may be normal. Valproate controls seizures in most JME patients. JME is said to account for between 5.4 and 10.2% of epilepsy, but despite clinical and EEG features that should enable its easy identification, the rate of misdiagnosis remains high (Grunewald et al., 1992).
Liu et al. (1995) stated that juvenile myoclonic epilepsy is the most frequent form of hereditary grand mal epilepsy. In the EEG, 15- to 30-Hz multispikes are associated with myoclonic and tonic-clonic convulsions beginning at 8 to 20 years of age. Moreover, EEG 3.5- to 6-Hz multispike wave complexes appear in clinically asymptomatic family members.
Medina et al. (2008) reported a 4-generation family from Honduras in which 4 individuals had clinical features of juvenile myoclonic epilepsy. The proband had childhood absence epilepsy (see, e.g., ECA1; 600131) evolving to JME, and his sister had JME. Two affected relatives had febrile seizures and grand mal seizures, respectively. Seven additional family members with the mutation were clinically asymptomatic but had epileptiform-EEG patterns consisting of spontaneous and frequent 3 to 6-Hz diffuse and bilateral multispike wave complexes or bifrontal 5 to 7-Hz spikes.
Camfield and Camfield (2009) performed a questionnaire-based review of 23 patients with JME after a mean disease duration of 25.8 years. The mean age at onset of first seizure was 10.4 years. All patients had myoclonic and generalized tonic-clonic seizures, and 14 (60%) had a history of absence seizures. At the time of follow-up, 11 (48%) had discontinued antiepileptic medication: 6 were seizure-free, 3 had myoclonic seizures only, and 2 continued to have rare seizures. Status epilepticus occurred in 8 (36%) and intractable epilepsy in 3. About 65 to 77% reported they were 'very satisfied' with work, health, friendships, and social life, but 17 (74%) of 23 had at least 1 major unfavorable social outcome, such as unemployment, living alone, or unplanned pregnancy.
Murray et al. (1994) investigated the incidence of psychiatric disorders among first-degree relatives of 23 patients with juvenile myoclonic epilepsy and 26 patients with acquired epilepsy. Psychiatric diagnoses were established in 7 probands with juvenile myoclonic epilepsy and 8 with acquired epilepsy. For juvenile myoclonic epilepsy patients without a psychiatric diagnosis, 18% of first-degree relatives had a psychiatric diagnosis, compared with 5% for the acquired epilepsy group. Depression was the most common psychiatric diagnosis in probands as well as family members. Murray et al. (1994) suggested that depressive illness may be a pleiotropic effect of a juvenile myoclonic epilepsy gene.
Using PET and a serotonin-1A receptor (HTR1A; 109760) antagonist, carbonyl-(11)C-WAY-100635, Meschaks et al. (2005) found that 11 patients with JME showed decreased serotonin-1A receptor binding in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus compared to controls. The authors suggested that the serotonin system is affected in JME and that the data provided evidence for regional brain differences in the disorder.
Using PET scans, Ciumas et al. (2008) found that 12 patients with JME had decreased binding to the dopamine transporter (SLC6A3; 126455) in the substantia nigra and midbrain compared to 12 controls. The patients also exhibited impaired psychomotor speed and motor function, which in some tests correlated with SLC6A3 binding potential in the midbrain. The findings implicated defects in dopamine signaling in JME and suggested a role for dopamine abnormalities in the neuropsychologic defects that are often observed in patients with JME.
Panayiotopoulos and Obeid (1989) concluded that JME is an autosomal recessive disorder. They found parental consanguinity in 9 of 17 sibships, and in 8 of the sibships more than 1 member was affected. Through an extensive study of families of JME probands, Durner et al. (1991) concluded that the gene may be responsible for other types of idiopathic generalized epilepsy including epilepsy with absences and epilepsy with generalized tonic-clonic seizures.
Cossette et al. (2002) noted that the mode of inheritance remained debated. The family they studied exhibited clear autosomal dominant transmission.
Winawer et al. (2003) studied 84 persons from 31 families with myoclonic or absence seizures and found that 65% (20 families) were concordant for seizure type (myoclonic, absence, or both). In 2 families, all affected members had myoclonic seizures; in 12 families, all affected members had absence seizures; in 2 families, all affected members had myoclonic and absence seizures. The number of families concordant for JME was greater when compared to juvenile absence epilepsy (JAE; 607631) and childhood absence epilepsy (CAE; 600131), but not when JAE was compared to CAE. Winawer et al. (2003) concluded that there are distinct genetic effects on absence and myoclonic seizures, and suggested that examining seizure types as opposed to syndromes may be more useful in linkage studies.
Liu et al. (1995) reported a 4-generation Los Angeles-Belize family in which 5 living members had juvenile myoclonic epilepsy and 4 clinically asymptomatic members had EEG multispike wave complexes consistent with JME. Linkage analysis in this family and 7 other multiplex pedigrees with JME suggested a disease locus at chromosome 6p21.2-p11 (lod score greater than 7 for D6S294 and D6S257 at theta = 0.0). By multipoint analyses and findings of recombinants in 3 new families with JME, Liu et al. (1996) narrowed the disease locus to a 7-cM interval flanked by D6S272 and D6S257. Multiple families were found to be unlinked to 6p, indicating locus heterogeneity.
To narrow the JME region on chromosome 6p, Bai et al. (2002) ascertained and genotyped 31 new JME families from Mexico, using a later generation of Genethon microsatellite markers at 6p12-p11. Significant lod scores were obtained in the region, and haplotype and recombination analysis refined the JME locus to a 3.53-cM interval flanked by D6S272 and D6S1573, approximately 30 cM centromeric to the HLA region. The model assumed autosomal dominant inheritance with 70% penetrance.
Genetic Heterogeneity
Whitehouse et al. (1993) reported linkage analysis in a set of 25 families that included a patient with JME and at least one first-degree relative with idiopathic generalized epilepsy. Family members were typed for 8 polymorphic loci on chromosome 6p. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data, i.e., lod score less than -2.0, at HLA (142800) on chromosome 6p21 and for a region 10 to 30 cM telomeric to HLA, the extent of the region varying with the level of penetrance assumed. These observations indicated that genetic heterogeneity exists within the phenotype of JME.
Elmslie et al. (1996) performed a linkage study of a group of 19 families in which 2 or more individuals were affected with clinical JME, as stringently defined, using 7 marker loci that encompass HLA and the entire region between HLA and the centromere. The region formally excluded (i.e., lod score less than -2 using multipoint analysis) varied depending on the assumption made concerning inheritance parameters and the proportion of linked families (i.e., the degree of locus heterogeneity), but the authors concluded there was no linkage to chromosome 6p in their families.
In affected members of 6 unrelated families with juvenile myoclonic epilepsy, Suzuki et al. (2004) identified several heterozygous mutations in the EFHC1 gene (608815.0001-608815.0005). Several unaffected family members carried mutations, indicating reduced penetrance. The affected families included the Belize kindred reported by Liu et al. (1995) and several of the Mexican families reported by Bai et al. (2002).
Medina et al. (2008) identified 5 novel mutations in transcripts A and B of the EFHC1 gene (see, e.g., 608815.0008) in 4 (9%) of 44 Hispanic patients from Mexico and Honduras and in 2 (3%) of 67 Japanese patients with juvenile myoclonic epilepsy. Clinically unaffected mutation carriers had abnormal EEG patterns.
Bai et al. (2002) stated that juvenile myoclonic epilepsy accounts for 4 to 11% of all epilepsies.
A locus for juvenile myoclonic epilepsy linked to HLA on chromosome 6p21.3 was originally termed 'EJM1' (Sander et al., 1995). Since then, EJM1 has been used to refer to a different JME phenotype caused by mutation in the EFHC1 gene (608815) on chromosome 6p12-p11 (Suzuki et al., 2004).
Bai, D., Alonso, M. E., Medina, M. T., Bailey, J. N., Morita, R., Cordova, S., Rasmussen, A., Ramos-Peek, J., Ochoa, A., Jara, A., Donnadieu, F. R., Cadena, G., Yamakawa, K., Delgado-Escueta, A. V. Juvenile myoclonic epilepsy: linkage to chromosome 6p12 in Mexico families. Am. J. Med. Genet. 113: 268-274, 2002. [PubMed: 12439895] [Full Text: https://doi.org/10.1002/ajmg.10724]
Camfield, C. S., Camfield, P. R. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 73: 1041-1045, 2009. Note: Erratum: Neurology 100: 545 only, 2023. [PubMed: 19786695] [Full Text: https://doi.org/10.1212/WNL.0b013e3181b9c86f]
Ciumas, C., Wahlin, T.-B. R., Jucaite, A., Lindstrom, P., Halldin, C., Savic, I. Reduced dopamine transporter binding in patients with juvenile myoclonic epilepsy. Neurology 71: 788-794, 2008. [PubMed: 18463366] [Full Text: https://doi.org/10.1212/01.wnl.0000316120.70504.d5]
Cossette, P., Liu, L., Brisebois, K., Dong, H., Lortie, A., Vanasse, M., Saint-Hilaire, J.-M., Carmant, L., Verner, A., Lu, W.-Y., Wang, Y. T., Rouleau, G. A. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 31: 184-189, 2002. [PubMed: 11992121] [Full Text: https://doi.org/10.1038/ng885]
Dreifuss, F. E. Juvenile myoclonic epilepsy: characteristics of a primary generalized epilepsy. Epilepsia 30 (suppl. 4): S1-S7, 1989. [PubMed: 2506006] [Full Text: https://doi.org/10.1111/j.1528-1157.1989.tb05832.x]
Durner, M., Sander, T., Greenberg, D. A., Johnson, K., Beck-Mannagetta, G., Janz, D. Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 41: 1651-1655, 1991. [PubMed: 1922810] [Full Text: https://doi.org/10.1212/wnl.41.10.1651]
Elmslie, F. V., Williamson, M. P., Rees, M., Kerr, M., Kjeldsen, M. J., Pang, K. A., Sundqvist, A., Friis, M. L., Richens, A., Chadwick, D., Whitehouse, W. P., Gardiner, R. M. Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region. Am. J. Hum. Genet. 59: 653-663, 1996. [PubMed: 8751867]
Grunewald, R. A., Chroni, E., Panayiotopoulos, C. P. Delayed diagnosis of juvenile myoclonic epilepsy. J. Neurol. Neurosurg. Psychiat. 55: 497-499, 1992. [PubMed: 1619419] [Full Text: https://doi.org/10.1136/jnnp.55.6.497]
Janz, D., Durner, M. Juvenile myoclonic epilepsy. In: Engel, J., Jr.; Pedley, T. A. (eds.): Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven 1997. Pp. 2389-2400.
Liu, A. W., Delgado-Escueta, A. V., Gee, M. N., Serratosa, J. M., Zhang, Q. W., Alonso, M. E., Medina, M. T., Cordova, S., Zhao, H. Z., Spellman, J. M., Rubio Donnadieu, F., Ramos Peek, J., Treiman, L. J., Sparkes, R. S. Juvenile myoclonic epilepsy in chromosome 6p12-p11: locus heterogeneity and recombinations. Am. J. Med. Genet. 63: 438-446, 1996. [PubMed: 8737649] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960614)63:3<438::AID-AJMG5>3.0.CO;2-N]
Liu, A. W., Delgado-Escueta, A. V., Serratosa, J. M., Alonso, M. E., Medina, M. T., Gee, M. N., Cordova, S., Zhao, H. Z., Spellman, J. M., Ramos Peek, J. R., Rubio Donnadieu, F., Sparkes, R. S. Juvenile myoclonic epilepsy locus in chromosome 6p21.2-p11: linkage to convulsions and electroencephalography trait. Am. J. Hum. Genet. 57: 368-381, 1995. [PubMed: 7668263]
Medina, M. T., Suzuki, T., Alonso, M. E., Duron, R. M., Martinez-Juarez, I. E., Bailey, J. N., Bai, D., Inoue, Y., Yoshimura, I., Kaneko, S., Montoya, N. C., Ochoa, A., and 13 others. Novel mutations in myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy. Neurology 70: 2137-2144, 2008. [PubMed: 18505993] [Full Text: https://doi.org/10.1212/01.wnl.0000313149.73035.99]
Meschaks, A., Lindstrom, P., Halldin, C., Farde, L., Savic, I. Regional reductions in serotonin 1A receptor binding in juvenile myoclonic epilepsy. Arch. Neurol. 62: 946-950, 2005. [PubMed: 15956165] [Full Text: https://doi.org/10.1001/archneur.62.6.946]
Murray, R. E., Abou-Khalil, B., Griner, L. Evidence for familial association of psychiatric disorders and epilepsy. Biol. Psychiat. 36: 428-429, 1994. [PubMed: 7803604] [Full Text: https://doi.org/10.1016/0006-3223(94)91218-1]
Panayiotopoulos, C., Obeid, T. Juvenile myoclonic epilepsy: an autosomal recessive disease. Ann. Neurol. 25: 440-443, 1989. [PubMed: 2505665] [Full Text: https://doi.org/10.1002/ana.410250504]
Sander, T., Hildmann, T., Janz, D., Wienker, T. F., Neitzel, H., Bianchi, A., Bauer, G., Sailer, U., Berek, K., Schmitz, B., Beck-Mannagetta, G. The phenotypic spectrum related to the human epilepsy susceptibility gene 'EJM1'. Ann. Neurol. 38: 210-217, 1995. [PubMed: 7654068] [Full Text: https://doi.org/10.1002/ana.410380213]
Suzuki, T., Delgado-Escueta, A. V., Aguan, K., Alonso, M. E., Shi, J., Hara, Y., Nishida, M., Numata, T., Medina, M. T., Takeuchi, T., Morita, R., Bai, D., and 16 others. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature Genet. 36: 842-849, 2004. [PubMed: 15258581] [Full Text: https://doi.org/10.1038/ng1393]
Whitehouse, W. P., Rees, M., Curtis, D., Sundqvist, A., Parker, K., Chung, E., Baralle, D., Gardiner, R. M. Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. Am. J. Hum. Genet. 53: 652-662, 1993. [PubMed: 8352275]
Winawer, M. R., Rabinowitz, D., Pedley, T. A., Hauser, W. A., Ottman, R. Genetic influences on myoclonic and absence seizures. Neurology 61: 1576-1581, 2003. [PubMed: 14663045] [Full Text: https://doi.org/10.1212/wnl.61.11.1576]