Dura mater graft‐associated Creutzfeldt‐Jakob disease in Japan: Clinicopathological and molecular characterization of the two distinct subtypes

Abstract

Up to February 2008, a total of 132 patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been identified in Japan, accounting for a majority of the world's patients with dCJD. The patients received dura mater grafts from 1978 to 1993. Lyodura (B. Braun, Melsungen, Germany) was used for all the patients in whom the brand name of the dura mater could be identified. After the incubation period of 1 to 25 years (mean, 11.8 years), CJD appeared from 1985 through to 2006. We analyzed clinical, pathological, and molecular features in 74 patients with dCJD who had been prospectively registered by the CJD Surveillance Committee. The cases of dCJD could be classified into two distinct clinicopathological phenotypes: a non-plaque type, showing typical features identical with those of classic CJD, and a plaque type, characterized by atypical features, including slow progression, lack of or late occurrence of periodic sharp wave complexes on EEG, and plaque formation in the brain. The plaque type accounted for one-third of the pathologically confirmed or clinically diagnosed cases of dCJD. The non-plaque type was associated with methionine homozygosity at codon 129 (129M/M) of the PrP gene in all patients, except for in one patient with the 129M/valine (V) genotype and type 1 protease-resistant PrP (PrP(res)), whereas the plaque type was always associated with the 129M/M genotype and the intermediate type between types 1 and 2 of PrP(res) in all cases. Thus, the clinicopathological and molecular features of the plaque type are distinct from those of the non-plaque type, suggesting contamination of the dura mater grafts with different prion strains.

Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

“…Since widespread kuru plaques have also been reported in pituitary hormone-associated iatrogenic CJD cases with the 129M/M genotype (28,29), the type of PrP Sc in these cases needs to be examined in the future. In addition to these neuropathological and biochemical clues, clinical features of acquired CJD-MMiK, such as slow progression of disease and absence or late occurrence of periodic sharp-wave complexes on electroencephalogram, may also be distinctive as revealed by a comprehensive analysis of plaque-type dCJD (6,7). Moreover, the experimental trans- (A) Transmissibility to the PrP-humanized knock-in mice in the secondary passage of case 2.…”

“…While animals carrying codon 129 valine homozygosity show plaque-type PrP deposition and type 2 PrP Sc accumu-lation resembling those of human sCJD-VV2 cases, the animals carrying codon 129 methionine homozygosity develop numerous amyloid plaques (kuru plaques) and a unique PrP Sc with electrophoretic mobility of about 20 kDa, which is intermediate in size between types 1 and 2 PrP Sc and thus designated an intermediate type (type i) (5). It is noteworthy that the equivalent to the mouse phenotype with kuru plaques and type i PrP Sc , reflecting transmission of the V2 sCJD strain to codon 129 methionine homozygotes, has been observed only in acquired prion diseases, especially in a subgroup of dura mater graft-associated iatrogenic CJD (plaque-type dCJD) cases in Japan, but not in sCJD cases (5)(6)(7)(8)(9). Thus, in addition to phenotypic expression, the codon 129 genotype may also influence prion strain susceptibility depending on the disease etiology, e.g., acquired versus sporadic.…”

Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt–Jakob disease in cell-protein misfolding cyclic amplification

“…[9][10][11] Interestingly, type i PrP Sc and kuru plaques in patients homozygous for methionine at codon 129 have only been observed in acquired prion diseases, especially in p-dCJD. 9,[12][13][14][15] A correct diagnosis and classification of cases is of critical importance for CJD surveillance centers worldwide aiming to identify potentially new disease forms or risk factors.…”

Sporadic and Infectious Human Prion Diseases

“…9) . Small numbers of florid plaques have also been identified in occasional cases of iCJD associated with dura mater grafts in Japan, but these cases do not exhibit any of the other neuropathological features of vCJD as described above (Yamada et al 2009). Variant CJD is unique among human prion diseases in that the accumulation of PrP res in lymphoid tissues outside the CNS is readily detected by immunohistochemistry, paraffin-em- …”

“…In human dura mater graft recipients in Japan, a group of cases contained florid plaques in the brain, without any other evidence of variant CJD-like pathology (Yamada et al 2009). In the United Kingdom, most cases of iCJD in human dura mater graft recipients have type 1 PrP res in the brain, but in hGH recipients, there is a predominance of type 2 PrP res ).…”