Benign familial neonatal seizures

From Wikipedia, the free encyclopedia
  (Redirected from Benign familial neonatal epilepsy)
Jump to: navigation, search
Benign familial neonatal epilepsy[1]
Classification and external resources
OMIM 121200 121201 608217
DiseasesDB 33689
eMedicine neuro/32
MeSH D020936

Benign familial neonatal seizures (BFNS), formerly called benign familial neonatal convulsions (BFNC), is a rare autosomal dominant inherited form of seizures. It manifests in newborns, normally within the first 7 days of life, as tonic-clonic seizures. Infants are otherwise normal between attacks and develop without incident. Attacks normally spontaneously cease within the first 15 weeks of life. Lifetime susceptibility to seizures is increased, as 16% of those diagnosed with BFNE earlier in life will go on to have seizures versus a 2% lifetime risk for the general population. There are three known genetic causes of BFNE, two being the voltage-gated potassium channels KCNQ2 (BFNC1) and KCNQ3 (BFNC2) and the third being a chromosomal inversion (BFNC3). There is no obvious correlation between most of the known mutations and clinical variability seen in BFNE.

Signs and symptoms[edit]

The only sign of BFNE are seizures, generally tonic-clonic, which occur within the first week of life. Seizures often begin as apnea, cyanosis, and hypertonia and last less than 1 minute.

People with BFNE are not more likely to develop epileptic seizures later in life.[2]

Pathophysiology[edit]

BFNC1[edit]

The most prevalent known cause of BFNE is mutation of KCNQ2, a gene encoding a voltage-gated potassium channel (KV7.2). There are at least 35 such mutations, see Table 1, primarily located in the voltage sensitive S4 segment through the C-terminus. Of these mutations, 5 are nonsense mutations, 13 are missense mutations and 11 cause a frameshift in the coding sequence. There are also 5 splice variants, one of which has been characterized at the protein level and leads to a nonsense mutation. Finally, there is one large deletion that removes much of the carboxy-terminus of the channel.

While most BFNC1 mutations have not been further characterized, 14 have and all seem to lead to functional defects. Two of the mutations in the voltage-sensitive S4 segment, R207W and R214W, do not lead to a decrease in the whole-cell current produced by KCNQ2 channels but to a change in channel kinetics. The R207W mutation takes fourfold longer and the R214W mutation takes twofold longer to reach maximal current compared to wild-type channels.[3] Since the time-course of an action potential is shorter than the time required for mutant KCNQ2 channels to reach proper levels of inactivation these mutants are expected to lead to neuronal hyperexcitability.

Though many of the other characterized mutations lead to decreased whole-cell current that has not been further delineated, three mutations have. Y534fsX538, for example, leads to a truncation that removes much of the carboxy-terminus of the channel. This mutant has been studied and shown to not traffic properly to the membrane.[4] Two other mutations, P709fs929X and W867fsX931, lead to altered carboxy-termini, though they actually lengthen rather than truncate the protein. These abnormal extended proteins have been shown to be more rapidly degraded within cells and, thus, produce little current.[5]

Table 1. Mutations in KCNQ2 associated with BFNE
Mutation Region Functional Consequence References
Nucleotide Amino acid
c.232delC Q78fsX132 N-Terminus [6]
c.314_316delCCT S105CfsX872 S1 [6]
c.387+1G→T Splicing S2 [7]
c.584_593del10insA S195X S4 [8]
c.C587T+c.T590C A196V+L197P S4 [9]
c.C619T R207W S4 Slowed activation [3]
c.G622A M208V S4 Current decreased by ~50% [7]
c.C641T R214W S4 Slowed activation and increased deactivation [3],[10],[11]
c.C674G H228Q S4-S5 [7]
c.T727C L243F S5 [7]
c.C740G S247W S5 No current and dominant negative [7]
c.G807A W269X Pore [7]
c.848_849insGT K283fsX329 Pore [7],[12]
c.A851G Y284C Pore Current decreased by ~50% [4],[7],[11],[12],[13]
c.G916A A306T S6 Current decreased by ~80% [4],[7],[12],[13]
c.C967T Q323X C-Terminus Current reduction by ~50% [7]
c.G998A R333Q C-Terminus Current reduction by ~40% [7]
c.T1016G R339L C-Terminus [9]
c.1118+1G→A Splicing C-Terminus [6]
c.Intron 8_3' UTR del Deletion 382→3' UTR C-Terminus [7],[12]
c.1217+2T→G Splicing C-Terminus [14]
c.C1342T R448X C-Terminus Current reduction by ~40% [7],[9]
c.1369_1370delAA K457EfsX458 C-Terminus [15]
c.1564_1576del S522fsX524 C-Terminus [7],[12]
c.1600_1601insGCCCT Y534fsX538 C-Terminus No current due to no trafficking [4],[13],[16]
c.1630-1G→A Splicing C-Terminus [7],[12]
c.G1658A R553Q C-Terminus [9]
c.G1662T* K554N C-Terminus Decreased voltage sensitivity of activation [17]
c.C1741T R581X C-Terminus [7]
c.1764-6C→A Splicing (V589X) C-Terminus [18]
c.1931delG S644TfsX901(extX56) C-Terminus [19]
c.1959del? T653fsX929(extX56) C-Terminus [7]
c.2127delT P709fs929X(extX57) C-Terminus No current due to increased degradation [5],[20],[21]
c.2597delG G866AfsX929(extX56) C-Terminus Current decreased by ~95% due to increased degradation [5],[20],[22]
c.2599_2600insGGGCC W867fsX931(extX58) C-Terminus Current reduction by ~75% [7]
* Misreported (twice in the same article) as G1662A (G1620A in the original numbering), which would not cause an amino acid change.
N.B. Mutations nucleotide/amino acid positions in terms of transcript variant 1 (NM_172107) available from Pubmed. Consequently, some mutation positions differ from those reported in the original literature.

BFNC2[edit]

Shortly after the discovery of mutations in KCNQ2 related to BFNE, a novel voltage-gated potassium channel was found that is highly homologous to KCNQ2 and contains mutations also associated with BFNE. This gene, KCNQ3, contains 3 known mutations associated with BFNE, all within the pore region of the channel. The first of these mutations, G310V, leads to a 50% reduction in whole-cell current compared to cells expressing wild-type channels.[7][13][23] The reason for this change is unknown as the mutation does not lead to altered protein trafficking.[4]

A second mutation, W309G, has also been found to be associated with BFNE. This mutation was only found in one family and has not been further characterized.[24]

The final known BFNC2 mutation, D305G is also in the pore region of the channel. This mutation leads to an approximately 40% reduction in whole-cell current compared to wild-type expressing cells. The underlying mechanism for this current decrease has not been further delineated.[7]

BFNC3[edit]

The rarest cause of BFNE, occurring in only one known family, is a chromosomal inversion. This occurs on chromosome 5 and the inversion is of the p15 through q11 area. Affected individuals, thus, have the karyotype 46,XY,inv(5)(p15q11). Why this inversion leads to the BFNE phenotype is unknown.[25]

Management[edit]

Neonatal seizures are often controlled with phenobarbital administration. Recurrent seizures later in life are treated in the standard ways (covered in the main epilepsy article). Depending on the severity, some infants are sent home with heart and oxygen monitors that are hooked to the child with stick on electrodes to signal any seizure activity. Once a month the monitor readings are downloaded into a central location for the doctor to be able to read at a future date. This monitor is only kept as a safeguard as usually the medication wards off any seizures. Once the child is weaned off the phenobarbital, the monitor is no longer necessary.

History[edit]

BFNE was first described in 1964 by Andreas Rett[26] and named by another group four years later.[27] Andreas Rett is better known for his later characterization of Rett syndrome.[21]

References[edit]

  1. ^ Berg AT, Berkovic SF, Brodie MJ, et al. (April 2010). "Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009". Epilepsia 51 (4): 676–85. doi:10.1111/j.1528-1167.2010.02522.x. PMID 20196795. 
  2. ^ National Institute for Health and Clinical Excellence (January 2012). "9". The Epilepsies: The diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Clinical Guideline Centre. pp. 119–129. 
  3. ^ a b c Dedek K, Kunath B, Kananura C, Reuner U, Jentsch T, Steinlein O (2001). "Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.". Proceedings of the National Academy of Sciences of the United States of America 98 (21): 12272–7. doi:10.1073/pnas.211431298. PMC 59804. PMID 11572947. 
  4. ^ a b c d e Schwake M, Pusch M, Kharkovets T, Jentsch T (2000). "Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy.". J Biol Chem 275 (18): 13343–8. doi:10.1074/jbc.275.18.13343. PMID 10788442. 
  5. ^ a b c Soldovieri M, Castaldo P, Iodice L, Miceli F, Barrese V, Bellini G, Miraglia del Giudice E, Pascotto A, Bonatti S, Annunziato L, Taglialatela M (2006). "Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C terminus mutation causing benign familial neonatal convulsions.". J Biol Chem 281 (1): 418–28. doi:10.1074/jbc.M510980200. PMID 16260777. 
  6. ^ a b c Claes L, Ceulemans B, Audenaert D, Deprez L, Jansen A, Hasaerts D, Weckx S, Claeys K, Del-Favero J, Van Broeckhoven C, De Jonghe P (2004). "De novo KCNQ2 mutations in patients with benign neonatal seizures.". Neurology 63 (11): 2155–8. PMID 15596769. 
  7. ^ a b c d e f g h i j k l m n o p q r s t Singh N, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson V, Sanguinetti M, Leppert M (2003). "KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum.". Brain 126 (Pt 12): 2726–37. doi:10.1093/brain/awg286. PMID 14534157. 
  8. ^ Bassi M, Balottin U, Panzeri C, Piccinelli P, Castaldo P, Barrese V, Soldovieri M, Miceli F, Colombo M, Bresolin N, Borgatti R, Taglialatela M (2005). "Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC).". Neurogenetics 6 (4): 185–93. doi:10.1007/s10048-005-0012-2. PMID 16235065. 
  9. ^ a b c d Moulard B, Picard F, le Hellard S, Agulhon C, Weiland S, Favre I, Bertrand S, Malafosse A, Bertrand D (2001). "Ion channel variation causes epilepsies.". Brain Res Brain Res Rev 36 (2–3): 275–84. doi:10.1016/S0165-0173(01)00104-7. PMID 11690625. 
  10. ^ Miraglia del Giudice E, Coppola G, Scuccimarra G, Cirillo G, Bellini G, Pascotto A (2000). "Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor". European Journal of Human Genetics 8 (12): 994–7. doi:10.1038/sj.ejhg.5200570. PMID 11175290. 
  11. ^ a b Castaldo P, del Giudice E, Coppola G, Pascotto A, Annunziato L, Taglialatela M (2002). "Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels". J Neurosci 22 (2): RC199. PMID 11784811. 
  12. ^ a b c d e f Singh N, Charlier C, Stauffer D, DuPont B, Leach R, Melis R, Ronen G, Bjerre I, Quattlebaum T, Murphy J, McHarg M, Gagnon D, Rosales T, Peiffer A, Anderson V, Leppert M (1998). "A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns". Nat Genet 18 (1): 25–9. doi:10.1038/ng0198-25. PMID 9425895. 
  13. ^ a b c d Schroeder B, Kubisch C, Stein V, Jentsch T (1998). "Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy". Nature 396 (6712): 687–90. doi:10.1038/25367. PMID 9872318. 
  14. ^ Lee W, Biervert C, Hallmann K, Tay A, Dean J, Steinlein O (2000). "A KCNQ2 splice site mutation causing benign neonatal convulsions in a Scottish family". Neuropediatrics 31 (1): 9–12. doi:10.1055/s-2000-15290. PMID 10774989. 
  15. ^ Pereira S, Roll P, Krizova J, Genton P, Brazdil M, Kuba R, Cau P, Rektor I, Szepetowski P (2004). "Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium channel: a novel mutation in a large Czech pedigree with benign neonatal convulsions or other epileptic phenotypes". Epilepsia 45 (4): 384–90. doi:10.1111/j.0013-9580.2004.47703.x. PMID 15030501. 
  16. ^ Biervert C, Schroeder B, Kubisch C, Berkovic S, Propping P, Jentsch T, Steinlein O (1998). "A potassium channel mutation in neonatal human epilepsy". Science 279 (5349): 403–6. doi:10.1126/science.279.5349.403. PMID 9430594. 
  17. ^ Borgatti R, Zucca C, Cavallini A, Ferrario M, Panzeri C, Castaldo P, Soldovieri M, Baschirotto C, Bresolin N, Dalla Bernardina B, Taglialatela M, Bassi M (2004). "A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation". Neurology 63 (1): 57–65. PMID 15249611. 
  18. ^ de Haan G, Pinto D, Carton D, Bader A, Witte J, Peters E, van Erp G, Vandereyken W, Boezeman E, Wapenaar M, Boon P, Halley D, Koeleman B, Lindhout D (2006). "A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years". Epilepsia 47 (5): 851–9. doi:10.1111/j.1528-1167.2006.00552.x. PMID 16686649. 
  19. ^ Tang B, Li H, Xia K, Jiang H, Pan Q, Shen L, Long Z, Zhao G, Cai F (2004). "A novel mutation in KCNQ2 gene causes benign familial neonatal convulsions in a Chinese family". J Neurol Sci 221 (1–2): 31–4. doi:10.1016/j.jns.2004.03.001. PMID 15178210. 
  20. ^ a b Coppola G, Castaldo P, Miraglia del Giudice E, Bellini G, Galasso F, Soldovieri M, Anzalone L, Sferro C, Annunziato L, Pascotto A, Taglialatela M (2003). "A novel KCNQ2 K+ channel mutation in benign neonatal convulsions and centrotemporal spikes". Neurology 61 (1): 131–4. PMID 12847176. 
  21. ^ a b Zimprich F, Ronen G, Stögmann W, Baumgartner C, Stögmann E, Rett B, Pappas C, Leppert M, Singh N, Anderson V (2006). "Andreas Rett and benign familial neonatal convulsions revisited". Neurology 67 (5): 864–6. doi:10.1212/01.wnl.0000234066.46806.90. PMID 16966552. 
  22. ^ Lerche H, Biervert C, Alekov A, Schleithoff L, Lindner M, Klinger W, Bretschneider F, Mitrovic N, Jurkat-Rott K, Bode H, Lehmann-Horn F, Steinlein O (1999). "A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions". Annals of Neurology 46 (3): 305–12. doi:10.1002/1531-8249(199909)46:3<305::AID-ANA5>3.0.CO;2-5. PMID 10482260. 
  23. ^ Charlier C, Singh N, Ryan S, Lewis T, Reus B, Leach R, Leppert M (1998). "A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family". Nat Genet 18 (1): 53–5. doi:10.1038/ng0198-53. PMID 9425900. 
  24. ^ Hirose S, Zenri F, Akiyoshi H, Fukuma G, Iwata H, Inoue T, Yonetani M, Tsutsumi M, Muranaka H, Kurokawa T, Hanai T, Wada K, Kaneko S, Mitsudome A (2000). "A novel mutation of KCNQ3 (c.925T-->C) in a Japanese family with benign familial neonatal convulsions". Annals of Neurology 47 (6): 822–6. doi:10.1002/1531-8249(200006)47:6<822::AID-ANA19>3.0.CO;2-X. PMID 10852552. 
  25. ^ Concolino D, Iembo M, Rossi E, Giglio S, Coppola G, Miraglia Del Giudice E, Strisciuglio P (2002). "Familial pericentric inversion of chromosome 5 in a family with benign neonatal convulsions". J Med Genet 39 (3): 214–6. doi:10.1136/jmg.39.3.214. PMC 1735071. PMID 11897828. 
  26. ^ Rett A, Teubel R (1964). "Neugeborenenkrämpfe im Rahmen einer epileptisch belasteten Familie". Wien Klin Wochenschr 74: 609–13. 
  27. ^ Bjerre I, Corelius E (1968). "Benign familial neonatal convulsions". Acta Paediatr Scand 57 (6): 557–61. doi:10.1111/j.1651-2227.1968.tb06980.x. PMID 5706374.