CLINICAL AND GENETIC HETEROGENITY OF JUVENILE MYOCLONIC EPILEPSY
https://doi.org/10.17749/2077-8333.2016.8.2.020-036
Abstract
The idiopathic generalized epilepsies constitute roughly one-third of all epilepsies. Juvenile myoclonic epilepsy (Janz syndrome) is characterized by myoclonic jerks on awakening, generalized tonic-clonic seizures, and typical absences, with the latter occurring in more than one-third of the patients. However, typical absences are not the predominant seizure type, and are usually very mild and simple (with no automatisms or localized limb jerks). Juvenile myoclonic epilepsy usually appears in adolescents between 12 and 18 years old. Half of patients with this condition have relatives with epilepsy. The genetic basis of this syndrome is complex and the mechanism of transmission is unclear. It is possible that several different genes are responsible. The authors presented the review of results modern clinical and genetic studies of juvenile myoclonic epilepsy. Information obtained from this review strongly suggests a heritable condition that merits further investigation.
About the Authors
N. A. Shnayder
Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yasenetsky of the Health Ministry of Russia;
University Clinic, Neurological Center of Epileptology, Neurogenetics and Brain Research
Russian Federation
Russian Federation
MD, D. Med. Sci., Prof., head of the Department of Medical Genetics and Clinical Neurophysiology of the Postgraduate Education Institute, head of the Neurological Center of Epileptology, Neurogenetics and Brain Research,
ul. Partizana Zheleznyaka, 1, Krasnoyarsk, Krasnoyarsk region, Siberian Federal District, 660022
O. S. Shilkina
Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yasenetsky of the Health Ministry of Russia;
University Clinic, Neurological Center of Epileptology, Neurogenetics and Brain Research
Russian Federation
Russian Federation
MD, researcher of the Department of Medical Genetics and Clinical Neurophysiology of the Postgraduate Education Institute, neurologists of the Neurological Center of Epileptology, Neurogenetics and Brain Research,
ul. Partizana Zheleznyaka, 1, Krasnoyarsk, Krasnoyarsk region, Siberian Federal District, 660022
K. V. Petrov
Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yasenetsky of the Health Ministry of Russia
Russian Federation
Russian Federation
medical student of 3rd course of pediatric faculty, student`s scientific society,
ul. Partizana Zheleznyaka, 1, Krasnoyarsk, Krasnoyarsk region, Siberian Federal District, 660022
I. A. Chernykh
Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yasenetsky of the Health Ministry of Russia
Russian Federation
Russian Federation
medical student of 2d course of pediatric faculty, student`s scientific society,
ul. Partizana Zheleznyaka, 1, Krasnoyarsk, Krasnoyarsk region, Siberian Federal District, 660022
A. V. Diuzhakova
Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yasenetsky of the Health Ministry of Russia
Russian Federation
Russian Federation
medical student of 5th course of therapeutic faculty, student`s scientific society,
ul. Partizana Zheleznyaka, 1, Krasnoyarsk, Krasnoyarsk region, Siberian Federal District, 660022
References
1. Belousova E.D. Genetics of epilepsy: What for and how to examine children with epilepsy. Neurology, Neuropsychiatry, Psychosomatics. 2014; 6 (1S): 4-8. (In Russian). DOI:10.14412/2074-2711-2014-1S-4-8.
2. Karlov VA. Elilepsy in children and adults, women and men. Moscow. 2010. (In Russian).
3. Mukhin K. Yu. Idiopathic forms of epilepsy: sysmetatics, diagnosis, treatment. Moscow. 2000; (In Russian).
4. Nordli D.R. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. International Neurological J. 2008; 5: 121-135. (In Russian).
5. Fattakhova A.H., Karunas A.S., Bulatova G.R. et al. Molecular-genetic study of idiopathic generalized epilepsy in Bashkorkostan Rebublic. Medical genetics. 2005; 4 (11): 528-531. (In Russian).
6. Shnayder N.A., Pavlova O.M., Sadykova A.V., Sharavii L.K. Role of clinicalgenealogical analysis in early diagnosis of absans forms of epilepsy. Almanah of Clinical Hospital no. 51. 2008; 3 (3): 21-28 (In Russian).
7. Shnayder N.A., Shapovalova E.A., Dmitrenko D.V. et al. Epidemiology of childhood epilepsy. Siberian Medical Rewev. 2012; 74 (2): 44-50. (In Russian).
8. Annesi F., Gambardella A., Michelucci R. et al. Mutational analysis of EFHC1 gene in Italian families with juvenile myoclonic epilepsy. Epilepsia. 2007; 48 (9): 1686-1690.
9. Arain F.M., Boyd K. L., Gallagher M. J. Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor α1 subunit. Epilepsia. 2012; 53 (8): 161-165.
10. Born J.P., Santos B.P., Secolin R. et al. Lack of association between the prothrombin rs1799963 polymorphism and juvenile myoclonic epilepsy. Arq Neuropsiquiatr. 2015; 73 (4): 289-292.
11. Bosco D., Haefliger J.-A., Meda P. Connexins: Key Mediators of Endocrine Function. Physiological Reviews. 2011; 91 (4): 1393-1445.
12. Burgess D. L., Jones J.M., Meisler M.H., Noebels J. L. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell. 1997; 88: 385-392.
13. Chachua T., Goletiani C., Maglakelidze G. et al. Sex-specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy. Genes Brain Behav. 2014; 13 (7): 702-712.
14. Chioza B., Goodwin H., Blower J. et al. Failure to replicate association between the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and IGE. Am J Med Genet. 2000; 96: 814-816.
15. Cossette P., Liu L., Brisebois K. et al. Mutation of GABRA1 in an autosomal dominantform of juvenile myoclonic epilepsy. Nat Genet. 2002; 31: 184-189.
16. Cossette P., Lortie A., Vanasse M. et al. Autosomal dominant juvenile myoclonic epilepsy and GABRa1 In: Advances in Neurology Vol. 95, Myoclonic Epilepsies. Philadelphia. 2005; 255-264.
17. D’Agostino D., Bertelli M., Gallo S. et al. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology. 2004; 63: 1500-1502.
18. Dani J.A., Balfour D. J.K. Historical and current perspective on tobacco use and nicotine addiction. Trends in Neuroscince. 2011; 34 (7): 383-392.
19. de Kovel C.G., Pinto D., de Haan G. J. et al. Association analysis of BRD2 (RING3) and epilepsy in a Dutch population. Epilepsia. 2007; 48 (11): 2191-2192.
20. Delgado-Escueta A.V., Greenberg D.A. et al. Mapping the gene for juvenile myoclonic epilepsy. Epilepsia. 1989; 30: 8-18.
21. Delgado-Escueta A.V., Koeleman B.P., Bailey J.N. et al. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 2013; 28 (1): 52-57.
22. Delgado-Escueta A.V. Advances in genetics of juvenile myoclonic epilepsies. Epilepsy Curr. 2007; 7 (3): 61-67.
23. Dibbens L.M., Feng H. J., Richards M.C. et al. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004; 13: 1315-1319.
24. Ding L., Feng H. J., Macdonald R. L. et al. GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem. 2010; 285 (34): 26390-405.
25. Escayg A., DeWaard M., Lee D.D. et al. Coding and noncoding variation of the human calcium-channelB4-subunit geneCACNB4in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000; 66: 1531-1539.
26. Etemad S., Campiglio M., Obermair G. J., Flucher B. E. The juvenile myoclonic epilepsy mutant of the calcium channel β(4) subunit displays normal nuclear targeting in nerve and muscle cells. Channels (Austin). 2014; 8 (4): 334-343.
27. Fletcher C. F., Lutz C.M., O’Sullivan T.N. et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell. 1996; 87: 607-617
28. GABRA1 gamma-aminobutyric acid type A receptor alpha1 subunit (Homo sapiens (human). URL: http://www.ncbi.nlm.nih.gov/gene/2554 (accessed: 28.09.2015).
29. Gallagher M. J., Song L., Arain F., Macdonald R. L. 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. 2004; 24 (24): 5570-5578.
30. Gitaí L. L., de Almeida D.H., Born J.P., et al. Lack of association between rs211037 of the GABRG2 gene and juvenile myoclonic epilepsy in Brazilian population. Neurol India. 2012; 60 (6): 585-588.
31. Greenberg D.A., Cayanis E., Strug L. et al. Malic enzyme 2 may underliesusceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet. 2005; 76: 139-146
32. Greenberg D.A., Delgado-Escueta A.V., Maldonado H.M., Widelitz H. Segregation analysis of juvenile myoclonic epilepsy. Genet Epidemiol. 1988; 5: 81-94.
33. Greenberg D.A., Shang E., Luo J. et al. Knockout mouse data support BRD2 as a gene for Juvenile Myoclonic Epilepsy. Epilepsia. 2007;
34. Grisar T., Lakaye B., de Nijs L. et al. Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy Jasper’s Basic Mechanisms of the Epilepsies. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
35. Haug K., Warnstedt M., Alekov A.K. et al. Mutations in CLCN2 encoding a voltagegated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003; 33: 527-532.
36. Hempelmann A., Heils A., Sander T. Confirmatory evidence for an association of the connexin-36 gene with juvenile myoclonic epilepsy. Epilepsy Res. 2006; 71: 223-228.
37. Herpin T.H. Des asces incomplets de l’epilepsie. J Balliere et Fils. 1867.
38. Hirose S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res. 2014; 213: 55-85.
39. Janz D., Christian W. Impulsive petit mal. Deutsche Leitschrift f Nervenheilkunde. 1957. 176: 346-386.
40. Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand. 1985; 52: 449-459.
41. Janz D. Juvenile myoclonic epilepsy. Cleve Clin J Med. 1989; 56: 23-33.
42. Jingami N., Matsumoto R., Ito H. et al. A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures. Epileptic Disord. 2014; 16 (2): 227-231.
43. Kapoor A., Vijai J., Ravishankar H.M. et al. Absence of GABRA1 Ala322Asp mutation in juvenile myoclonic epilepsy families from India. J Genet. 2003; 82 (1-2): 17-21.
44. Kapoor A., Ratnapriya R., Kuruttukulam G., Anand A. A novel genetic locus for juvenile myoclonic epilepsy at chromosome 5q12-q14. Hum. Genet. 2007; 121: 655-662.
45. Kapoor A., Satishchandra P., Ratnapriya R. et al. An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann. Neurol. 2008; 64: 158-167.
46. Kinirons P., Rabinowitz D., Gravel M. et al. Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy. Epilepsy Res. 2008; 82 (1): 21-28.
47. Koepp M.J., Hamandi K. Systems and Networks in Myoclonic Seizures and Epilepsies in Generalized Seisures: From Clinical Phenomenology to Underlying Systems and Networks. Montrouge. 2006; 163-182.
48. Lenzen K.P., Heils A., Lorenz S. et al. Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res. 2005; 65: 53-57.
49. Lorenz S., Taylor K.P., Gehrmann A. et al. Association of BRD2 polymorphisms with photoparoxysmal response. Neurosci Lett. 2006; 400: 135-139.
50. Ma S., Blair M.A., Abou-Khalil B. et al. Mutations in the GABRa1 and EFHC1 genes are rarein familial juvenile myoclonic epilepsy. Epilepsy Res. 2006; 71: 129-134.
51. Macdonald R. L., Kang J.Q., Gallagher M. J. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol. 2010; 588 (11): 1861-1869.
52. Martínez-Juárez I. E., Alonso M. E., Medina M. T. et al. Juvenile myoclonic epilepsy subsyndromes: family studies and long-term follow-up. Brain. 2006; 129 (5): 1269-1280.
53. Mas C., Taske N., Deutsch S. et al. Association of theconnexin 36 gene with juvenile myoclonic epilepsy. Am J Med Genet. 2004; 41. doi:10.1136/jmg.2003.017954.
54. Medina M.T., Suzuki T., Alonso M.E. et al. Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy Neurology. 2008; 70 (22 Pt 2): 2137-2144.
55. Meencke H.J, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia. 1984; 25: 8-21.
56. Meencke H. J., Veith G. The relevance of slight migrational disturbances (microdysgenesis) to the etiology of the epilepsies. In: Delgado-Escueta AV, Wilson WA, Olsen RW, Porter RJ, editors. Jasper’s Basic Mechanisms of the Epilepsies. Advances in Neurology. 3. Vol. 79. Philadelphia: Lippincott Williams and Wilkins; 1999. pp. 123-131.
57. Mumoli L., Tarantino P., Michelucci R. et al. Genetic Commission, Italian League against Epilepsy. No evidence of a role for cystatin B gene in juvenile myoclonic epilepsy. Epilepsia. 2015; 56 (4): 40-43.
58. Online Mendelian Inheritance in Man. URL: http://www.omim.org/ (accessed: 28.09.2015).
59. Pal D.K., Durner M., Klotz I. et al. Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. Brain Dev. 2006; 28: 92-98.
60. Pal D.K., Evgrafov O.V., Tabares P. et al. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003; 73: 261-270.
61. Pal D.K., Greenberg D.A. Major susceptibility genes for common idiopathic epilepsies: ELP4 in rolandic epilepsy and BRD2 in juvenile myoclonic epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, DelgadoEscueta AV, editors. Source. Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
62. Parihar R., Mishra R., Singh S.K. et al. Association of the GRM4 gene variants with juvenile myoclonic epilepsy in an Indian population. J Genet. 2014; 93 (1): 193-197.
63. Ratnapriya R., Vijai J., Kadandale J.S. et al. A locus for juvenile myoclonic epilepsy maps to 2q33-q36. Hum. Genet. 2010; 128: 123-130.
64. Roebling R., Scheerer N., Uttner I. et al. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia. 2009; 50: 2456-2465.
65. Rozycka A., Steinborn B., Trzeciak W.H. The 1674+11C>T polymorphism of CHRNA4 is associated with juvenile myoclonic epilepsy. Seizure. 2009; 18 (8): 601-603.
66. Santos B., Marques T., Malta M. et al. PER2 rs2304672, CLOCK rs1801260, and PER3
67. rs57875989 polymorphisms are not associated with juvenile myoclonic epilepsy. Epilepsy Behav. 2014; 36: 82-85.
68. Sapio M.R., Vessaz M., Thomas P. et al. Novel carboxypeptidase A6 (CPA6) mutations identified in patients with juvenile myoclonic and generalized epilepsy. PLoS One. 2015; 10 (4): e0123180.
69. Shang E., Wang X., Wen D. et al. Double bromodomain-containing gene Brd2 is essential for embryonic development in mouse. Dev Dyn. 2009; 238: 908-917.
70. Steinlein O., Sander T., Stoodt J. et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha4 with common idiopathic generalized epilepsies. Am J Med Genet. 1997; 74: 445-449.
71. Stogman E., Lichtner P., Baumgartner C. et al. Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology. 2006; 67 (11): 2029-2031.
72. Tadmouri A., Kiyonaka S., Barbado M. et al. Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J. 2012; 31: 3730-3744.
73. Tan N.C., Mulley J.C., Berkovic S. F. Genetic association studies in epilepsy: The truth is out there. Epilepsia. 2004; 45: 1429-1442.
74. Woermann F.G., Free S. L., Koepp M. J. et al. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain. 1999; 122: 2101-2109.
75. Wolf P., Yacubian E.M., Avanzini G. et al. Juvenile myoclonic epilepsy of the brain. Epilepsy Res. 2015; 114: 2-12.
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For citations:
Shnayder N.A., Shilkina O.S., Petrov K.V., Chernykh I.A., Diuzhakova A.V. CLINICAL AND GENETIC HETEROGENITY OF JUVENILE MYOCLONIC EPILEPSY. Epilepsy and paroxysmal conditions. 2016;8(2):20-36. (In Russ.) https://doi.org/10.17749/2077-8333.2016.8.2.020-036
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