Sleep related hyper motor epilepsy (SHE): a unique syndrome with heterogeneous genetic etiologies

Francesca Bisulli1,2, Laura Licchetta1,2, Paolo Tinuper1,2
1IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bellaria Hospital, Bologna, Italy
2Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy

Tóm tắt

Sleep-related hypermotor epilepsy (SHE), formerly known as Nocturnal Frontal Lobe Epilepsy is a focal epilepsy characterized by seizures with complex hyperkinetic automatisms and/or asymmetric tonic/dystonic posturing occurring mostly during sleep. SHE is a rare disease with an estimated minimum prevalence of 1.8/100,000 individuals and represent about 10% of drug-resistant surgical cases. This disorder, though uncommon, is of considerable interest to a broad spectrum of specialists, from child neurologists to neurosurgeons. Distinguishing this condition from non-epileptic paroxysmal behaviour occurring physiologically or pathologically during sleep is often difficult and sometimes impossible on clinical grounds alone, even for experienced epileptologists and sleep physicians. Recognized aetiologies of SHE are heterogeneous and include acquired injuries, genetic causes and structural anomalies such as focal cortical dysplasia. Multiple aetiologies (structural-genetic) are also possible. Non-specific clinical features distinguished different aetiologies even if SHE due to structural lesions usually manifests with early-onset drug-resistant seizures and showed a worse long-term prognosis. The causative genes for SHE are multiple and encode for proteins involved in different molecular pathways. The cholinergic system and the mTOR pathway are the most relevant. This review will provide an exhaustive overview of the genetic background of SHE.

Từ khóa


Tài liệu tham khảo

Abdelnoura E, et al. Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature. Seizure. 2018;55:1–3. Alanis-Guevara I, et al. Sleep disturbances, socioeconomic status, and seizure control as main predictors of quality of life in epilepsy. Epilepsy Behav. 2005;7:481–5. Aridon P, et al. Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet. 2006;79:342–50. Baldassari S, et al. The landscape of epilepsy-related GATOR1 variants. Genet Med. 2019;21(2):398–408. Barcia G, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012;44(11):1255–9. Bar-Peled L, et al. A tumor suppressor complex with GAP activity for the rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340:1100–6. Baulac S, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77:675–83. Bertrand D, et al. How mutations in the nAChRs can cause ADNFLE epilepsy. Epilepsia. 2002;43(Suppl 5):112–22. Bertrand D, et al. The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. Neurobiol Dis. 2005;20(3):799–804. Bhattacharjee A, Kaczmarek LKJ. For K+ channels, Na+ is the new Ca2+. Trends Neurosci. 2005;28:422–8. Bhattacharjee A, et al. Localization of the Slack potassium channel in the rat central nervous system. J Comp Neurol. 2002;454:241–54. Bisulli F, et al. Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: a common mechanism? Epilepsia. 2010;51:1852–60. Brodtkorb E, Picard F. Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy. Epilepsy Behav. 2006;9:515–20. Brown MR, et al. Amino-termini isoforms of the slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. J Physiol Lond. 2008;586:5161–79. Chen Y, et al. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res. 2009;83(2–3):152–6. Chen ZH, et al. Exome sequencing identified a novel missense mutation c.464G>a (p.G155D) in Ca2+−binding protein 4 (CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. Oncotarget. 2017;8:78940–7. Cho YW, et al. A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. Arch Neurol. 2003;60:1625–32. Cho YW, et al. Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor. Epilepsy Behav. 2008;13:361–5. Citraro R, et al. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol Res. 2016;107:333–43. Combi R, et al. Two new putative susceptibility loci for ADNFLE. Brain Res. 2005;67:257–63. Combi R, et al. Compound heterozygosity with dominance in the Corticotropin releasing hormone (CRH) promoter in a case of nocturnal frontal lobe epilepsy. J Sleep Res. 2008;17(3):361–2. Conti V, et al. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology. 2015;84(15):1520–8. Coppola G, et al. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia. 1995;36:1017–24. De Fusco M, et al. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000;26:275–6. D'Gama AM, et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol. 2015;77(4):720–5. Díaz-Otero F, et al. Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene. Epilepsia. 2008;49(3):516–20. Dibbens LM, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546–51. Dobesberger J, et al. Successful surgical treatment of insular epilepsy with nocturnal hypermotor seizures. Epilepsia. 2008;49:159–62. Fedi M, et al. Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2008;71:795–8. Ferri L, et al. A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation. Seizure. 2017;53:51–4. Gibbs SA, et al. Sleep- related epileptic behaviors and non-REM-related parasomnias: insights from stereo-EEG. Sleep Med Rev. 2016;25:4–20. Harvey AS, et al. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia. 2008;49:146–55. Heron SE, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012;44:1188–90. Hildebrand MS, et al. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. Ann Clin Transl Neurol. 2015;2(8):821–30. Hirose S, et al. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 1999;53(8):1749–53. Hoda JC, et al. Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore. Mol Pharmacol. 2008;74(2):379–91. Ishida S, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45:552–5. Kim GE, et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep. 2014;9:1661–72. Korenke GC, et al. Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia. 2016;57(3):e60–3. Kurahashi H, Hirose S. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews®. Seattle: University of Washington Seattle; 2002. p. 1993–2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1169/ [Initial Posting: May 16, 2002; Last Update: March 15, 2018]. Lal D, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75:788–92. Leniger T, et al. A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy. Epilepsia. 2003;44(7):981–5. Licchetta L, et al. Sleep-related hypermotor epilepsy: long-term outcome in a large cohort. Neurology. 2017;88(1):70–7. Liu H, et al. The identification of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: its possible implication in non-familial nocturnal frontal lobe epilepsy. Epilepsy Res. 2011;95(1–2):94–9. Lugaresi E, Cirignotta F. Hypnogenic paroxysmal dystonia: epileptic seizure or a new syndrome? Sleep. 1981;4(2):129–38. Maccario M, Lustman LI. Paroxysmal nocturnal dystonia presenting as excessive daytime somnolence. Arch Neurol. 1990;47:291–4. Marini C, Guerrini R. The role of the nicotinic acetylcholine receptors in sleep-related epilepsy. Biochem Pharmacol. 2007;74:1308–14. Marsan E, et al. Depdc5 knockout rat: a novel model of mTORopathy. Neurobiol Dis. 2016;89:180–9. Martin C, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet. 2014;86:570–4. McLellan A, et al. Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia. 2003;44:613–7. Menghi V, et al. Sleep-related hypermotor epilepsy: prevalence, impact and management strategies. Nat Sci Sleep. 2018;10:317–26. Mikati MA, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78(6):995–9. Milligan CJ, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75:581–90. Møller RS, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia. 2015;56(9):e114–20. Montagna P. Nocturnal paroxysmal dystonia and nocturnal wandering. Neurology. 1992;42:61–7. Montagna P, et al. Nocturnal epileptic seizures versus the arousal parasomnias. Somnologie. 2008;12:25–37. Montavont A, et al. Hypermotor seizures in lateral and mesial parietal epilepsy. Epilepsy Behav. 2013;28:408–12. Nakashima M, et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol. 2015;78:375–86. Naldi I, et al. Tobacco habits in nocturnal frontal lobe epilepsy. Epilepsy Behav. 2013;26:114–7. Nguyen DK, et al. Revisiting the role of the insula in refractory partial epilepsy. Epilepsia. 2009;50:2599–604. Nobili L, et al. Nocturnal frontal lobe epilepsy: intracerebral recordings of paroxysmal motor attacks with increasing complexity. Sleep. 2003;26:883–6. Nobili L, et al. Sleep-related hyperkinetic seizures of temporal lobe origin. Neurology. 2004;62:482–5. Nobili L, et al. Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy. Brain. 2007;130:561–73. Nobili L, et al. Taylor’s focal cortical dysplasia increases the risk of sleep-related epilepsy. Epilepsia. 2009;50:2599–604. Ohba C, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia. 2015;56(9):e121–8. Oldani A, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain. 1998;121:205–23. Peled R, Lavie P. Paroxysmal awakenings from sleep associated with excessive daytime somnolence: a form of nocturnal epilepsy. Neurology. 1986;36:95–8. Phillips HA, et al. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nat Genet. 1995;10:117–8. Phillips HA, et al. A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann Neurol. 2000;48(2):264–7. Phillips HA, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2001;68(1):225–31. Picard F, et al. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain. 2006;129:2047–60. Picard F, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82:2101–6. Proserpio P, et al. Insular-opercular seizures manifesting with sleep-related paroxysmal motor behaviors: a stereo-EEG study. Epilepsia. 2011;52:1781–91. Provini F, et al. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain. 1999;122:1017–31. Puligheddu M, et al. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia. 2017;58:1762–70. Rheims S, et al. Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures. Epilepsia. 2008;49:2030–40. Ricos MG, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79:120–31. Rizzo F, et al. Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci. 2016;72:54–63. Rozycka A, et al. Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia. 2003;44(8):1113–7. Rubboli G, et al. Mild malformations of cortical development insleep-related hypermotor epilepsy due to KCNT1 mutations. Ann Clin Transl Neurol. 2018;6(2):386–91. Ryvlin P, Minotti L, Demarquay G, et al. Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can originate in the insula. Epilepsia. 2006;47:755–65. Sáenz A, et al. Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. Arch Neurol. 1999;56(8):1004–9. Sansoni V, et al. A de novo mutation in an Italian sporadic patient affected by nocturnal frontal lobe epilepsy. J Sleep Res. 2012;21:352–3. Sansoni V, et al. Functional characterization of a CRH missense mutation identified in an ADNFLE family. PLoS One. 2013;8(4):e61306. Scerri T, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol. 2015;2(5):575–80. Scheffer IE, et al. Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder. Lancet. 1994;343:515–7. Scheffer IE, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782–7. Schwalen S, Jorg J. Day-time fatigue in frontal lobe epilepsy with primarily sleep-related seizures. A case report. Nervenarzt. 1998;69:166–70. Shimada S, et al. A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures. Hum Genome Var. 2014;1:14027. Steinlein OK. Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res. 2014;213:1–15. Steinlein OK, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11:201–3. Steinlein OK, et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet. 1997;6(6):943–7. Steinlein OK, et al. Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia. 2000;41(5):529–35. Steinlein OK, et al. Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. Seizure. 2012;21:118–23. Terzaghi M, et al. Coupling of minor motor events and epileptiform discharges with arousal fluctuations in NFLE. Epilepsia. 2008;49:670–6. Tinuper P, Bisulli F. From nocturnal frontal lobe epilepsy to sleep-related Hypermotor epilepsy: a 35-year diagnostic challenge. Seizure. 2017;44:87–92. Tinuper P, et al. Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures. Epilepsia. 1990;31(5):549–56. Tinuper P, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016;86:1834–42. van Kranenburg M, et al. Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. Hum Mutat. 2015;36(2):200–9. Vaugier L, et al. Neural networks underlying hyperkinetic seizures of “temporal lobe” origin. Epilepsy Res. 2009;86:200–8. Vignatelli L, et al. Excessive daytime sleepiness and subjective sleep quality in patients with nocturnal frontal lobe epilepsy: a case-control study. Epilepsia. 2006;47(suppl 5):73–7. Vignatelli L, et al. Prevalence of nocturnal frontal lobe epilepsy in the adult population of Bologna and Modena, Emilia-Romagna region, Italy. Sleep. 2015;38:479–85. Vignatelli L, et al. Prevalence of nocturnal frontal lobe epilepsy in the adult population of Bologna and Modena, Emilia-Romagna region. Italy Sleep. 2017;1(2):40. Wang MY, et al. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in a Chinese patient with non-familial nocturnal frontal lobe epilepsy. Epilepsy Res. 2014;108(10):1927–31. Waterman K, et al. An epileptic syndrome caused by mesial frontal lobe seizure foci. Neurology. 1987;37(4):577–82. Wiebe S, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311–8. Williamson PD, et al. Complex partial seizures of frontal lobe origin. Ann Neurol. 1985;18(4):497–504. Willoughby JO, et al. Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study. Epilepsia. 2003;44(9):1238–40. Zucconi M, et al. The macrostructure and microstructure of sleep in patients with autosomal dominant nocturnal frontal lobe epilepsy. J Clin Neurophysiol. 2000;17:77–86.