Benign familial neonatal convulsions
From Wikipedia, the free encyclopedia
| Benign familial neonatal convulsions Classification and external resources |
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| ICD-10 | G40.3 |
|---|---|
| OMIM | 121200 121201 608217 |
| DiseasesDB | 33689 |
| eMedicine | neuro/32 |
| MeSH | D020936 |
Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant inherited form of epilepsy. 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 BFNC 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 BFNC, 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 BFNC.
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[edit] Signs and symptoms
The only sign of BFNC 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.
Patients with BFNC are more likely to develop epileptic seizures later in life. Some BFNC patients also develop myokymia (spontaneous involuntary contraction of muscle groups).
[edit] Pathophysiology
[edit] BFNC1
The most prevalent known cause of BFNC 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.[1] 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.[2] 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. [3]
| Mutation | Region | Functional Consequence | References | |
|---|---|---|---|---|
| Nucleotide | Amino acid | |||
| c.232delC | Q78fsX132 | N-Terminus | [4] | |
| c.314_316delCCT | S105CfsX872 | S1 | [4] | |
| c.387+1G→T | Splicing | S2 | [5] | |
| c.584_593del10insA | S195X | S4 | [6] | |
| c.C587T+c.T590C | A196V+L197P | S4 | [7] | |
| c.C619T | R207W | S4 | Slowed activation | [1] |
| c.G622A | M208V | S4 | Current decreased by ~50% | [5] |
| c.C641T | R214W | S4 | Slowed activation and increased deactivation | [1],[8],[9] |
| c.C674G | H228Q | S4-S5 | [5] | |
| c.T727C | L243F | S5 | [5] | |
| c.C740G | S247W | S5 | No current and dominant negative | [5] |
| c.G807A | W269X | Pore | [5] | |
| c.848_849insGT | K283fsX329 | Pore | [5],[10] | |
| c.A851G | Y284C | Pore | Current decreased by ~50% | [2],[5],[9],[10],[11] |
| c.G916A | A306T | S6 | Current decreased by ~80% | [2],[5],[10],[11] |
| c.C967T | Q323X | C-Terminus | Current reduction by ~50% | [5] |
| c.G998A | R333Q | C-Terminus | Current reduction by ~40% | [5] |
| c.T1016G | R339L | C-Terminus | [7] | |
| c.1118+1G→A | Splicing | C-Terminus | [4] | |
| c.Intron 8_3' UTR del | Deletion 382→3' UTR | C-Terminus | [5],[10] | |
| c.1217+2T→G | Splicing | C-Terminus | [12] | |
| c.C1342T | R448X | C-Terminus | Current reduction by ~40% | [5],[7] |
| c.1369_1370delAA | K457EfsX458 | C-Terminus | [13] | |
| c.1564_1576del | S522fsX524 | C-Terminus | [5],[10] | |
| c.1600_1601insGCCCT | Y534fsX538 | C-Terminus | No current due to no trafficking | [2],[11],[14] |
| c.1630-1G→A | Splicing | C-Terminus | [5],[10] | |
| c.G1658A | R553Q | C-Terminus | [7] | |
| c.G1662T* | K554N | C-Terminus | Decreased voltage sensitivity of activation | [15] |
| c.C1741T | R581X | C-Terminus | [5] | |
| c.1764-6C→A | Splicing (V589X) | C-Terminus | [16] | |
| c.1931delG | S644TfsX901(extX56) | C-Terminus | [17] | |
| c.1959del? | T653fsX929(extX56) | C-Terminus | [5] | |
| c.2127delT | P709fs929X(extX57) | C-Terminus | No current due to increased degradation | [3],[18],[19] |
| c.2597delG | G866AfsX929(extX56) | C-Terminus | Current decreased by ~95% due to increased degradation | [3],[18],[20] |
| c.2599_2600insGGGCC | W867fsX931(extX58) | C-Terminus | Current reduction by ~75% | [5] |
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* Misreported (twice in the same article) as G1662A (G1620A in the original numbering), which would not cause an amino acid change.
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| 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. | ||||
[edit] BFNC2
Shortly after the discovery of mutations in KCNQ2 related to BFNC, a novel voltage-gated potassium channel was found that is highly homologous to KCNQ2 and contains mutations also associated with BFNC. This gene, KCNQ3, contains 3 known mutations associated with BFNC, 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.[5][11][21] The reason for this change is unknown as the mutation does not lead to altered protein trafficking.[2]
A second mutation, W309G, has also been found to be associated with BFNC. This mutation was only found in one family and has not been further characterized.[22]
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.[5]
[edit] BFNC3
The rarest cause of BFNC, 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 BFNC phenotype is unknown.[23]
[edit] Treatment/Management
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).
[edit] History
BFNC was first described in 1964 by Andreas Rett[24] and named by another group four years later.[25] Andreas Rett is better known for his later characterization of Rett syndrome.[19]
[edit] References
- Mulley J, Scheffer I, Petrou S, Berkovic S (2003). "Channelopathies as a genetic cause of epilepsy.". Curr Opin Neurol 16 (2): 171–6. doi:. PMID 12644745.
- Gardiner M. "Genetics of idiopathic generalized epilepsies.". Epilepsia 46 Suppl 9: 15–20. PMID 16302872.
[edit] Footnotes
- ^ 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.". Proc Natl Acad Sci U S A 98 (21): 12272–7. doi:. PMID 11572947.
- ^ 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:. PMID 10788442.
- ^ 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:. PMID 16260777.
- ^ 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.
- ^ 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:. PMID 14534157.
- ^ 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:. PMID 16235065.
- ^ 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:. PMID 11690625.
- ^ 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.". Eur J Hum Genet 8 (12): 994–7. doi:. PMID 11175290.
- ^ 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.
- ^ 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:. PMID 9425895.
- ^ 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:. PMID 9872318.
- ^ 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:. PMID 10774989.
- ^ 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:. PMID 15030501.
- ^ 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:. PMID 9430594.
- ^ 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.
- ^ 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:. PMID 16686649.
- ^ 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:. PMID 15178210.
- ^ 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.
- ^ 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:. PMID 16966552.
- ^ 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.". Ann Neurol 46 (3): 305–12. doi:. PMID 10482260.
- ^ 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:. PMID 9425900.
- ^ 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.". Ann Neurol 47 (6): 822–6. doi:. PMID 10852552.
- ^ 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:. PMID 11897828.
- ^ Rett A, Teubel R (1964). "Neugeborenenkrämpfe im Rahmen einer epileptisch belasteten Familie.". Wien Klin Wochenschr 74: 609–13.
- ^ Bjerre I, Corelius E (1968). "Benign familial neonatal convulsions.". Acta Paediatr Scand 57 (6): 557–61. doi:. PMID 5706374.
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