Role of PRRT2 in common paroxysmal neurological disorders: A gene with remarkable pleiotrop

Journal of Medical Genetics

Volumn 50, Issue 3, 2013, Pages 133-139

  Heron, Sarah E ^a   Dibbens, Leanne M ^a  

^a UNIVERSITY OF SOUTH AUSTRALIA   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

PROLINE RICH TRANSMEMBRANE PROTEIN 2; PROTEIN; SYNAPTOSOMAL ASSOCIATED PROTEIN 25; UNCLASSIFIED DRUG;

ARTICLE; BENIGN FAMILIAL INFANTILE EPILEPSY; BRAIN; CHROMOSOME 16; GENE EXPRESSION; GENE FUNCTION; GENE LOCUS; GENE MUTATION; GENETIC LINKAGE; INFANTILE CONVULSION WITH CHOREOATHETOSIS SYNDROME; NEUROLOGIC DISEASE; PAROXYSMAL KINESIGENIC DYSKINESIA; PHENOTYPE; PLEIOTROPY; PRESYNAPTIC MEMBRANE; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; SYNAPTIC TRANSMISSION;

ANIMALS; BASE SEQUENCE; CHOREA; DYSKINESIAS; EPILEPSY, BENIGN NEONATAL; HUMANS; MEMBRANE PROTEINS; MOLECULAR SEQUENCE DATA; MUTATION; NERVE TISSUE PROTEINS; SEIZURES;

EID: 84874766771     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmedgenet-2012-101406     Document Type: Article

References (67)

1. Watanabe K, Yamamoto N, Negoro T, Takaesu E, Aso K, Furune S, Takahashi I. Benign complex partial epilepsies in infancy. Pediatr Neurol 1987;3:208-11.
2. Vigevano F, Fusco L, DiCapua M, Ricci S, Sebastianelli R, Lucchini P. Benign infantile familial convulsions. Eur J Pediatr 1992;151:608-12.
3. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 2010;51:676-85.
4. Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252-5.
5. Bruno MK, Hallett M, Gwinn-Hardy K, Sorenson B, Considine E, Tucker S, Lynch DR, Mathews KD, Swoboda KJ, Harris J, Soong B-W, Ashizawa T, Jankovic J, Renner D, Fu Y-H, Ptacek LJ. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia. Neurology 2004;63:2280-7.
6. Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology 1967;17:680-90.
7. Goodenough DJ, Fariello RG, Annis BL, Chun RW. Familial and acquired paroxysmal dyskinesias. A proposed classification with delineation of clinical features. Arch Neurol 1978;35:827-31.
8. Szepetowski P, Rochette J, Berquin P, Piussan C, Lathrop GM, Monaco AP. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet 1997;61:889-98.
9. Lee WL, Tay A, Ong HT, Goh LM, Monaco AP, Szepetowski P. Association of infantile convulsions with paroxysmal dyskinesias (ICCA syndrome): confirmation of linkage to human chromosome 16p12-q12 in a Chinese family. Hum Genet 1998;103:608-12.
10. Swoboda KJ, Soong B, McKenna C, Brunt ER, Litt M, Bale JF Jr, Ashizawa T, Bennett LB, Bowcock AM, Roach ES, Gerson D, Matsuura T, Heydemann PT, Nespeca MP, Jankovic J, Leppert M, Ptácek LJ. Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies. Neurology 2000;55:224-30.
11. Caraballo R, Pavek S, Lemainque A, Gastaldi M, Echenne B, Motte J, Genton P, Cersósimo R, Humbertclaude V, Fejerman N, Monaco AP, Lathrop MG, Rochette J, Szepetowski P. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet 2001;68:788-94.
12. Weber YG, Berger A, Bebek N, Maier S, Karafyllakes S, Meyer N, Fukuyama Y, Halbach A, Hikel C, Kurlemann G, Neubauer B, Osawa M, Püst B, Rating D, Saito K, Stephani U, Tauer U, Lehmann-Horn F, Jurkat-Rott K, Lerche H. Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families. Epilepsia 2004;45:601-9.
13. Callenbach PMC, van den Boogerd EH, de Coo RFM, ten Houten R, Oosterwijk JC, Hageman G, Frants RR, Brouwer OF, van den Maagdenberg AMJM. Refinement of the chromosome 16 locus for benign familial infantile convulsions. Clin Genet 2005;67:517-25.
14. Striano P, Lispi ML, Gennaro E, Madia F, Traverso M, Bordo L, Aridon P, Boneschi F Martinelli, Barone B, dalla Bernardina B, Bianchi A, Capovilla G, De Marco P, Dulac O, Gaggero R, Gambardella A, Nabbout R, Prud'homme JF, Day R, Vanadia F, Vecchi M, Veggiotti P, Vigevano F, Viri M, Minetti C, Zara F. Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families. Epilepsia 2006;47:1029-34.
15. Weber YG, Jacob M, Weber G, Lerche H. A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1. Epilepsia 2008;49:1959-64.
16. Tomita H, Nagamitsu S, Wakui K, Fukushima Y, Yamada K, Sadamatsu M, Masui A, Konishi T, Matsuishi T, Aihara M, Shimizu K, Hashimoto K, Mineta M, Matsushima M, Tsujita T, Saito M, Tanaka H, Tsuji S, Takagi T, Nakamura Y, Nanko S, Kato N, Nakane Y, Niikawa N. Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1. Am J Hum Genet 1999;65:1688-97.
17. Bennett LB, Roach ES, Bowcock AM. A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology 2000;54:125-30.
18. Cuenca-Leon E, Cormand B, Thomson T, Macaya A. Paroxysmal kinesigenic dyskinesia and generalized seizures: clinical and genetic analysis in a Spanish pedigree. Neuropediatrics 2002;33:288-93.
19. Kikuchi T, Nomura M, Tomita H, Harada N, Kanai K, Konishi T, Yasuda A, Matsuura M, Kato N, Yoshiura K, Niikawa N. Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families. J Hum Genet 2007;52:334-41.
20. Valente EM, Spacey SD, Wali GM, Bhatia KP, Dixon PH, Wood NW, Davis MB. A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16. Brain 2000;123:2040-5.
21. Roll P, Sanlaville D, Cillario J, Labalme A, Bruneau N, Massacrier A, Délepine M, Dessen P, Lazar V, Robaglia-Schlupp A, Lesca G, Jouve E, Rudolf G, Rochette J, Lathrop GM, Szepetowski P. Infantile convulsions with paroxysmal dyskinesia (ICCA syndrome) and copy number variation at human chromosome 16p11. PLoS One 2010;5:e13750.
22. Wang JL, Cao L, Li XH, Hu ZM, Li JD, Zhang JG, Liang Y, San -A, Li N, Chen SQ, Guo JF, Jiang H, Shen L, Zheng L, Mao X, Yan WQ, Zhou Y, Shi YT, Ai SX, Dai MZ, Zhang P, Xia K, Chen SD, Tang BS. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 2011;134:3493-501.
23. Li J, Zhu X, Wang X, Sun W, Feng B, Du T, Sun B, Niu F, Wei H, Wu X, Dong L, Li L, Cai X, Wang Y, Liu Y. Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis. J Med Genet 2012;49:76-8.
24. Liu Q, Qi Z, Wan XH, Li JY, Shi L, Lu Q, Zhou XQ, Qiao L, Wu LW, Liu XQ, Yang W, Liu Y, Cui LY, Zhang X. Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. J Med Genet 2012;49:79-82.
25. Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gécz J, Thomas PQ, Mulley JC, Berkovic SF, Scheffer IE, Dibbens LM. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 2012;90:152-60.
26. Cao L, Huang XJ, Zheng L, Xiao Q, Wang XJ, Chen SD. Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot. Parkinsonism Relat Disord 2012;18:704-6.
27. Ono S, Yoshiura K, Kinoshita A, Kikuchi T, Nakane Y, Kato N, Sadamatsu M, Konishi T, Nagamitsu S, Matsuura M, Yasuda A, Komine M, Kanai K, Inoue T, Osamura T, Saito K, Hirose S, Koide H, Tomita H, Ozawa H, Niikawa N, Kurotaki N. Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions. J Hum Genet 2012;57:338-41.
28. Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohamed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock A, Szepetowski P, Fu YH, Ptácek LJ. Mutations in the novel protein PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 2012;1:2-12.
29. Schubert J, Paravidino R, Becker F, Berger A, Bebek N, Bianchi A, Brockmann K, Capovilla G, Dalla Bernardina B, Fukuyama Y, Hoffmann GF, Jurkat-Rott K, Anttonen AK, Kurlemann G, Lehesjoki AE, Lehmann-Horn F, Mastrangelo M, Mause U, Müller S, Neubauer B, Püst B, Rating D, Robbiano A, Ruf S, Schroeder C, Seidel A, Specchio N, Stephani U, Striano P, Teichler J, Turkdogan D, Vigevano F, Viri M, Bauer P, Zara F, Lerche H, Weber YG. PRRT2 Mutations are the major cause of benign familial infantile seizures. Hum Mutat 2012;33:1439-43.
30. Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, Lagroua I, Bouteiller D, Mignot C, Doummar D, Anheim M, Tranchant C, Burbaud P, Jedynak CP, Gras D, Steschenko D, Devos D, Billette de Villemeur T, Vidailhet M, Brice A, Roze E. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012;79:170-4.
31. Groffen AJ, Klapwijk T, van Rootselaar AF, Groen JL, Tijssen MA. Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia. J Neurol 2013;260:93-9.
32. Schmidt A, Kumar KR, Redyk K, Grünewald A, Leben M, Münchau A, Sue CM, Hagenah J, Hartmann H, Lohmann K, Christen HJ, Klein C. Two Faces of the Same Coin: Benign Familial Infantile Seizures and Paroxysmal Kinesigenic Dyskinesia Caused by PRRT2 Mutations. Arch Neurol 2012;69:668-70.
33. Dale RC, Gardiner A, Antony J, Houlden H. Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Dev Med Child Neurol 2012;54:958-60.
34. Lee YC, Lee MJ, Yu HY, Chen C, Hsu CH, Lin KP, Liao KK, Chang MH, Liao YC, Soong BW. PRRT2 Mutations in Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions in a Taiwanese Cohort. PLoS One 2012;7:e38543.
35. van Vliet R, Breedveld G, de Rijk-van Andel J, Brilstra E, Verbeek N, Verschuuren-Bemelmans C, Boon M, Samijn J, Diderich K, van de Laar I, Oostra B, Bonifati V, Maat-Kievit A. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 2012;79:777-84.
36. Steinlein OK, Villain M, Korenke C. The PRRT2 mutation c.649dupC is the so far most frequent cause of benign familial infantile convulsions. Seizure 2012;21:740-2.
37. Friedman J, Olvera J, Silhavy JL, Gabriel SB, Gleeson JG. Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance. Neurology 2012;79:946-8.
38. Wang K, Zhao X, Du Y, He F, Peng G, Luo B. Phenotypic overlap among paroxysmal dyskinesia subtypes: lesson from a family with PRRT2 gene mutation. Brain Dev 2012 http://dx.doi.org/10.1016/j.braindev.2012.07.018 [Epub ahead of print].
39. Specchio N, Terracciano A, Trivisano M, Cappelletti S, Claps D, Travaglini L, Cusmai R, Marras CE, Zara F, Fusco L, Bertini E, Vigevano F. PRRT2 is mutated in familial and non-familial benign infantile seizures. Eur J Paediatr Neurol 2012 http://dx.doi.org/10.1016/j.ejpn.2012.07.006 [Epub ahead of print].
40. van Strien TW, van Rootselaar AF, Hilgevoord AAJ, Linssen WHJP, Groffen AJA, Tijssen MAJ. Paroxysmal kinesigenic dyskinesia: cortical or non-cortical origin. Parkinsonism Rel Dis 2012;18:645-8.
41. Hedera P, Xiao J, Puschmann A, Momcilovic D, Wu SW, LeDoux MS. Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia. BMC Neurol 2012;12:93.
42. Cai C, Shi O, Li WD. Missense mutations of the proline-rich transmembrane protein 2 gene cosegregate with mild paroxysmal kinesigenic dyskinesia and infantile convulsions in a Chinese pedigree. Parkinsonism Relat Disord 2012 http://dx.doi. org/10.1016/j.parkreldis.2012.08.014 [Epub ahead of print].
43. Ishii A, Yasumoto S, Ihara Y, Inoue T, Fujita T, Nakamura N, Ohfu M, Yamashita Y, Takatsuka H, Taga T, Miyata R, Ito M, Tsuchiya H, Matsuoka T, Kitao T, Murakami K, Lee WT, Kaneko S, Hirose S. Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis. Brain Dev http://dx.doi.org/10.1016/j.braindev. 2012.09.006. [Epub ahead of print].
44. Cloarec R, Bruneau N, Rudolf G, Massacrier A, Salmi M, Bataillard M, Bolay C, Caraballo R, Fejerman N, Genton P, Hirsch E, Hunter A, Lesca G, Motte J, Roubertie A, Sanlaville D, Wong SW, Fu YH, Rochette J, Ptácek LJ, Szepetowski P. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology 2012;79:2097-103.
45. Gardiner A, Bhatia KP, Stamelou M, Dale RC, Kurian MA, Schneider SA, Wali GM, Counihan T, Schapira AH, Spacay SD, Valente EM, Silviera-Moriyama L, Tieve HAG, Raskin S, Sander JW, Lees A, Warner T, Kullmann D, Wood NW, Hanna M, Houlden H. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012;79:2115-21.
46. Marini C, Conti V, Mai D, Battaglia D, Lettori D, Losito E, Bruccini G, Tortorella G, Guerrini R. PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology 2012;79:2109-14.
47. Riant F, Roze E, Barbance C, Méneret A, Guyant-Maréchal L, Lucas C, Sabourand P, Trébuchon A, Depienne C, Tournier-Lasserve E. PRRT2 mutations cause hemiplegic migraine. Neurology 2012;79:2122-4.
48. Scheffer IE, Grinton BE, Heron SE, Kivity S, Afawi Z, Iona X, Goldberg-Stern H, Kinali M, Andrews I, Guerrini R, Marini C, Sadleir LG, Berkovic SF, Dibbens LM. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 2012;79:2104-8.
49. de Vries B, Callenbach PMC, Kamphorst JT, Weller CM, Koelwijn SC, ten Houten R, de Coo IFM, Brouwer OF, van den Maagdenberg AMJM. PRRT2 mutation causes benign familial infantile convulsions. Neurology 2012;79:2154-5.Review Downloaded from jmg.bmj.com on February 25, 2013 - Published by group.bmj.com
50. Okumura A, Shimojima K, Kubota T, Abe S, Yamashita S, Imai K, Okanishi T, Enoki H, Fukasawa T, Tanabe T, Dibbens LM, Shimizu T, Yamamoto T. PRRT2 mutation in Japanese children with benign infantile epilepsy. Brain Dev 2012. http:// dx.doi.org/10.1016/j.braindev.2012.09.015 [Epub ahead of print].
51. Li HF, Ni w, Xiong ZQ, Xu J, Wu ZY. PRRT2 c.649dupC mutation derived from De Novo in paroxysmal kinesigenic dyskinesia. CNS Neurosci Ther 2012; http://dx.doi. org/10.1111/cns.12034 [Epub ahead of print].
52. Sheerin U-M, Stamelou M, Charlesworth G, Shiner T, Spacey S, Valente EM, Wood MW, Bhatia KP. Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation. J Neurol 2012 http://dx.doi.org/10.1007/ s00415-012-6747-4 [Epub ahead of print].
53. Castiglioni C, López I, Riant F, Bertini E, Terracciano A. PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins. Eur J Paediatr Neurol 2012 http://dx.doi.org/10.1016/j.ejpn.2012.10.010 [Epub ahead of print].
54. Liu XR, Wu M, He N, Meng H, Wen L, Wang JL, Zhang MP, Li WB, Mao X, Qin JM, Li BM, Tang B, Deng YH, Shi YW, Su T, Yi YH, Tang BS, Liao WP. Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes. Genes Brain Behav 2012; http://dx.doi.org/10.1111/gbb.12008 [Epub ahead of print].
55. Lipton J, Rivkin MJ. 16p11.2-related paroxysmal kinesigenic dyskinesia and dopa-responsive parkinsonism in a child. Neurology 2009;73:479-80.
56. Dale RC, Grattan-Smith P, Fung VS, Peters GB. Infantile convulsions and paroxysmal kinesigenic dyskinesia with 16p11.2 microdeletion. Neurology 2011;77:1401-2.
57. Dale RC, Grattan-Smith P, Nicholson M, Peters GB. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol 2012;54:618-23.
58. Vanmolkot KRJ, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WAJ, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AMJM. Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003;54:360-6.
59. Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AMJM, Pusch M, Strom TM. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371-7.
60. Castro MJ, Stam AH, Lemos C, de Vries B, Vanmolkot KRJ, Barros J, Terwindt GM, Frants RR, Sequeiros J, Ferrari MD, Pereira-Monteiro JM, van den Maagdenberg AMJM. First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy. Cephalalgia 2009;29:308-13.
61. Bellini G, Miceli F, Soldovieri MV, Miraglia del Giudice E, Pascotto A, Taglialatela M. Benign familial neonatal seizures. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. Gene reviews (internet). Seattle, WA: University of Washington, Seattle, 1993-2010 [updated 2011 Aug 04].
62. Specchio N, Vigevano F. The spectrum of benign infantile seizures. Epilepsy Res 2006;70S:S156-67.
63. Mardis ER. Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet 2008;9:387-402.
64. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE. A human protein-protein interaction network: a resource for annotating the proteome. Cell 2005;122:957-68.
65. Pang ZP, Südhof TC. Cell biology of Ca2+-triggered exocytosis. Curr Opin Cell Biol 2010;22:496-505.
66. Evergren E, Benfanati F, Shupliakov O. The synapsin cycle: a view from the synaptic endocytic zone. J Neurosci Res 2007;85:2648-56.
67. Fornasiero EF, Bonanomi D, Benfenati F, Valtorta F. The role of synapsins in neuronal development. Cell Mol Life Sci 2010;67:1383-96.