Background/Aims: Since detection of the prion protein gene (PRNP) more than 30 mutations have been discovered. Some have only been found in single case reports without known intrafamilial accumulation or neuropathological proof so that the causal connection between mutation and disease could not be proved. Those patients often present atypical clinical phenotypes, and it is not unusual that they are classified as diseases other than Creutzfeldt-Jakob disease (CJD). Methods: Cases of suspected CJD have been reported to the national reference center for prion diseases. Clinical and diagnostic data were collected, and a classification of definite, possible or probable prion disease was made. Molecular analysis of PRNP was performed by capillary sequencing. Results: We have described 4 cases with atypical clinical and diagnostic findings and unknown mutations in PRNP so far. Conclusion: Three patients fulfilled the criteria of probable CJD, and 1 patient fulfilled the criteria of possible CJD but the clinical picture in none of the patients was typical CJD; hence, it remained questionable whether the mutations were causal of the disease.

Mitrova E, Brown P, Hroncova D, Tatara M, Zilák J: Focal accumulation of CJD in Slovakia: retrospective investigation of a new rural familial cluster. Eur J Epidemiol 1991;7:487-489.
Kovacs GG, Puopolo M, Ladogana A, Pocchiari M, Budka H, van Duijn C, Collins SJ, Boyd A, Giulivi A, Coulthart M, Delasnerie-Laupretre N, Brandel JP, Zerr I, Kretzschmar HA, de Pedro-Cuesta J, Calero-Lara M, Glatzel M, Aguzzi A, Bishop M, Knight R, Belay G, Will R, Mitrova E, EUROCJD: Genetic prion disease: the EUROCJD experience. Hum Genet 2005;118:166-174.
Ladogana A, Puopolo M, Poleggi, Almonti S, Mellina V, Equestre M, Pocchiari M: High incidence of genetic human transmissible spongiform encephalopathies in Italy. Neurology 2005;64:1592-1597.
Meiner Z, Gabizon R, Prusiner SB: Familial Creutzfeldt-Jakob disease. Codon 200 prion disease in Libyan Jews. Medicine (Baltimore) 1997;76:227-237.
Schelzke G, Eigenbrod S, Romero C, Varges D, Breithaupt M, Taratuto AL, Kretzschmar HA, Zerr I: Genetic prion disease with codon 196 PRNP mutation: clinical and pathological findings. Neurobiol Aging 2011;32:756, e1-9.
Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E: Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol 1995;5:43-51.
Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, Westaway D, Ott J, Prusiner SB: Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 1989;338:342-345.
Kitamoto T, Ohta M, Doh-ura K, Hitoshi S, Terao Y, Tateishi J: Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome. Biochem Biophys Res Commun 1993;191:709-714.
Doh-ura K, Tateishi J, Sasaki H, Kitamoto T, Sakaki Y: Pro-Leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Straussler syndrome. Biochem Biophys Res Commun 1989;163:974-979.
Hsiao KK, Cass C, Schellenberg G, Bird T, Devine-Gage E, Wisniewski H, Prusiner SB: A prion protein variant in a family with the telencephalic form of Gerstmann-Straussler-Scheinker syndrome. Neurology 1991;41:681-684.
Hsiao K, Dlouhy SR, Farlow MR, Cass C, Da Costa M, Conneally PM, Hodes ME, Ghetti B, Prusiner SB: Mutant prion proteins in Gerstmann-Straussler-Scheinker disease with neurofibrillary tangles. Nat Genet 1992;1:68-71.
Ghetti B, Tagliavini F, Giaccone G, Bugiani O, Frangione B, Farlow MR, Dlouhy SR: Familial Gerstmann-Straussler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol 1994;8:41-48.
Piccardo P, Dlouhy SR, Lievens PM, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV, Zimmerman TR, Mackenzie IR, Kish SJ, Ang LC, De Carli C, Pocchiari M, Brown P, Gibbs CJ, Gajdusek DC, Bugiani O, Ironside J, Tagliavini F, Ghetti B: Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 1998;57:979-988.
Sanchez-Juan P, Green A, Ladogana A, Cuadrado-Corrales N, Sáanchez-Valle R, Mitrová E, Stoeck K, Sklaviadis T, Kulczycki J, Hess K, Bodemer M, Slivarichová D, Saiz A, Calero M, Ingrosso L, Knight R, Janssens AC, van Duijn CM, Zerr I: CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease Neurology 2006;67:637-643.
Zerr I, Pocchiari M, Collins S, Brandel JP, de Pedro Cuesta J, Knight RS, Bernheimer H, Cardone F, Delasnerie-Lauprêtre N, Cuadrado Corrales N, Ladogana A, Bodemer M, Fletcher A, Awan T, Ruiz Bremón A, Budka H, Laplanche JL, Will RG, Poser S: Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000;55:811-815.
Steinhoff BJ, Zerr I, Glatting M, Schulz-Schaeffer W, Poser S, Kretzschmar HA: Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease. Ann Neurol 2004;56:702-708.
Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, Breithaupt M, Varges D, Meissner B, Ladogana A, Schuur M, Haik S, Collins SJ, Jansen GH, Stokin GB, Pimentel J, Hewer E, Collie D, Smith P, Roberts H, Brandel JP, van Duijn C, Pocchiari M, Begue C, Cras P, Will RG, Sanchez-Juan P: Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain 2009;132:2659-2668.
Grasbon-Frodl E, Schmalzbauer R, Weber P, Krebs B, Windl O, Zerr I, Kretzschmar HA: A novel three extra-repeat insertion in the prion protein gene (PRNP) in a patient with Creutzfeldt-Jakob disease. Neurogenetics 2004;5:249-250.
Windl O, Giese A, Schulz-Schaeffer W, Zerr I, Skworc K, Arendt S, Oberdieck C, Bodemer M, Poser S, Kretzschmar HA: Molecular genetics of human prion diseases in Germany. Hum Genet 1999;105:244-252.
Peoc'h K, Guerin C, Brandel JP, Launay JM, Laplanche JL: First report of polymorphisms in the prion-like protein gene (PRND): implications for human prion diseases. Neurosci Lett 2000;286:144-148.
Jeong BH, Jeon YC, Lee YJ, Cho HJ, Park SJ, Chung DI, Kim J, Kim SH, Kim HT, Choi EK, Choi KC, Carp RI, Kim YS: Creutzfeldt-Jakob disease with the V203I mutation and M129V polymorphism of the prion protein gene (PRNP) and a 17 kDa prion protein fragment. Neuropathol Appl Neurobiol 2010;36:558-563.
Peoc'h K, Manivet P, Beaudry P, Attane F, Besson G, Hannequin D, Delasnerie-Lauprêtre N, Laplanche JL: Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype. Hum Mutat 2000;15:482.
Pocchiari M, Salvatore M, Cutruzzola F, Genuardi M, Allocatelli CT, Masullo C, Macchi G, Alemá G, Galgani S, Xi YG: A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease. Ann Neurol 1993;34:802-807.
Beck JA, Poulter M, Campbell TA, Adamson G, Uphill JB, Guerreiro R, Jackson GS, Stevens JC, Manji H, Collinge J, Mead S: PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit. Hum Mutat 2010;31:E1551-1563.
Samaia HB, Mari JJ, Vallada HP, Moura RP, Simpson AJ, Brentani RR: A prion-linked psychiatric disorder. Nature 1997;390:241.
Tsai MT, Su YC, Chen YH, Chen CH: Lack of evidence to support the association of the human prion gene with schizophrenia. Mol Psychiatry 2001;6:74-78.
Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J: Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 2003;300:640-643.
Appleby BS, Appleby KK, Hall RC, Wallin MT: D178N, 129Val and N171S, 129Val genotype in a family with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 2010;30:424-431.
Gambetti P: Fatal familial insomnia and familial Creutzfeldt-Jakob disease: a tale of two diseases with the same genetic mutation. Curr Top Microbiol Immunol 1996;207:19-25.
Heinemann U, Krasnianski A, Meissner B, Grasbon-Frodl EM, Kretzschmar HA, Zerr I: Novel PRNP mutation in a patient with a slow progressive dementia syndrome. Med Sci Monit 2008;14:CS41-43.
Hilton DA, Head MW, Singh VK, Bishop M, Ironside JW: Familial prion disease with a novel serine to isoleucine mutation at codon 132 of prion protein gene (PRNP). Neuropathol Appl Neurobiol 2009;35:111-115.
Panegyres PK, Toufexis K, Kakulas BA, Cernevakova L, Brown P, Ghetti B, Piccardo P, Dlouhy SR: A new PRNP mutation (G131V) associated with Gerstmann-Straussler-Scheinker disease. Arch Neurol 2001;58:1899-1902.
Rowe DB, Lewis V, Needham M, Rodriguez M, Boyd A, McLean C, Roberts H, Masters CL, Collins SJ: Novel prion protein gene mutation presenting with subacute PSP-like syndrome. Neurology 2007;68:868-870.
Tunnell E, Wollman R, Mallik S, Cortes CJ, Dearmond SJ, Mastrianni JA: A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrPSc conformation. Neurology 2008;71:1431-1438.
Basset-Leobon C, Uro-Coste E, Peoc'h K, Haik S, Sazdovitch V, Rigal M, Andreoletti O, Hauw JJ, Delisle MB: Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques. Arch Neurol 2006;63:449-452.
Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A: High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 2000;66:110-117.
Roeber S, Grasbon-Frodl EM, Windl O, Krebs B, Xiang W, Vollmert C, Illig T, Schröter A, Arzberger T, Weber P, Zerr I, Kretzschmar HA: Evidence for a pathogenic role of different mutations at codon 188 of PRNP. PLoS One 2005;14;3:e2147.
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