Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene.
OBJECTIVE
To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease.


BACKGROUND
Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques.


METHODS
The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998.


RESULTS
Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety.


CONCLUSIONS
Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.
Hauw
J J
JJ
Raymond Escourolle Neuropathology Laboratory, Pitié-Salpêtrière Hospital, Paris, France. jean-jazques.hauw@psl.ap-hop-paris.fr
Sazdovitch
V
V
Laplanche
J L
JL
Peoc'h
K
K
Kopp
N
N
Kemeny
J
J
Privat
N
N
Delasnerie-Lauprêtre
N
N
Brandel
J P
JP
Deslys
J P
JP
Dormont
D
D
Alpérovitch
A
A
D017677:Age Distribution; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003062:Codon / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005602:France / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011328:Prions / Q000235:genetics* / Q000378:metabolism
D003062:Codon; D011328:Prions