At variance with the series of 11 cases of PSPr described in 2008 and 2 cases subsequently published by others—all 13 of which were 129VV homozygous at the PrP gene—the 15 cases reported here also include affected subjects who are 129MV and 129MM, in addition to new 129VV subjects.3–5
Comparative analyses indicated that all these cases are affected by the same disease process, and that most of the heterogeneity that we observed results from distinct 129 genotypes.
These cases are likely to be affected by the same disease because of the overall similarity in major phenotypical characteristics, including the clinical features, which prominently exhibit aphasia, ataxia, and parkinsonian signs; SD, displaying vacuoles comparable in size in the 3 genotypes but otherwise different from the vacuoles of other common prion diseases; and finally PrP immunostaining patterns, which also display comparable general features in all these cases. However, the 2 most striking similarities reside in the ladderlike electrophoretic pattern of the PK-resistant fragments and in the unique immunoreactivity of PrPDis with mAb 1E4. Cumulatively, these findings suggest that all these cases share a similar molecular mechanism of PrPDis formation.
Significant clinical differences among the 129VV and 129MV groups (only 2 129MM symptomatic subjects were available) occurred in the mean age at onset and in disease duration (see ). PrP immunostaining patterns were also distinguishable in the 3 groups. An additional difference might lay in disease prevalence, which appeared to be highest in 129VV subjects (65% of the cases), followed by the 129MV (23%) and 129MM subjects (12%) (see ). However, 2 distinctive features were evident among the 3 groups; these were: (1) the apparent resistance to PK digestion, which was generally much lower in the 129VV cases than in the 129MM and 129MV cases; and (2) the immunoreactivity of the PK-resistant PrPDis with mAb 3F4, which was strong in the 129MM cases, weak in the 129MV cases, and lacking in the 129VV cases. Cumulatively, these findings argue that, although PrPDis may be formed by a similar mechanism in the 3 genotypes, the conformation or aggregation is likely different, and this difference results in variable resistance to PK, variable accessibility by 3F4, or both.
These findings also indicate that, in the present series of cases, it is the 129 genotype that modifies the phenotypic characteristics, including PK resistance and antibody immunoreactivity of PrPDis. However, the possibility that phenotypic heterogeneity is caused by other variations in PrPDis among the 3 groups or by a combination of different 129 genotypes and PrPDis characteristics, as is the case with sCJD, cannot be excluded.
The variations in prevalence are likely to be associated with the 129 genotype as well. This also is a feature of sCJD, in which 129MM cases account for about 70% of the total, 129MV for 11%, and 129VV for 17%.1,12
It is remarkable that the effect of the 129 genotype on disease prevalence in our series of cases appears to be the opposite of that in sCJD. The high percentage of 129VV subjects described to date (20 of 28 known subjects, including the 2 cases reported elsewhere) and the apparent rarity of 129MM subjects (only 3 of 28 subjects) suggest that the prevalence of VPSPr is directly related to the presence of the 129V allele.3–5
Indeed, at least 1 129V allele is present in 25 of the 28 known cases of VPSPr. The prevalence of the 3 129 genotypes in VPSPr is quite different from that in normal Caucasian populations, in which the 129MM genotype accounts for 43% of subjects, the 129MV for 49%, and the 129VV for 8%.21
The present findings raise a number of questions concerning the nature of VPSPr and its place within the group of known prion diseases.
In our series of 26 VPSPr cases collected to date, 8 subjects apparently had familial dementia; they were all 129VV except for 1 129MM. One of the 2 VPSPr-129VV cases reported by others also had a definitive family history of neurodegenerative disease.4
This raises the possibility that VPSPr is a familial disease with a locus other than the ORF of the PrP gene (which is free of mutations), a condition analogous to that of familial Alzheimer disease. 3,22
Whether the VPSPr subjects reported to date also include inherited cases belonging solely to the 129VV and 129MM genotype remains to be determined.
Well-recognized prion diseases, which are associated with the classic PrPDis
commonly identified as PrP27–30, such as all sCJD subtypes and several subtypes of familial CJD and sporadic and familial fatal insomnia, are transmissible with relative ease to receptive animals. Inoculated animals develop a full-blown disease with clinical signs, SD, and presence of a PrP27–30 that generally reproduces the characteristics of the PrP27–30 present in the inoculum.1,23,24
In contrast, other prion diseases, especially GSS, a rare phenotype that to date has been reported as exclusively associated with PrP gene mutations, have been more difficult to transmit or have been reported not to be transmissible at all.25–28
For example, inoculation of brain homogenate from a subtype of GSS linked to the P102L mutation and characterized by the immunoblot presence of only a PK-resistant fragment of 7kDa similar to that present in VPSPr did not cause a symptomatic disease in recipient transgenic mice, but elicited the formation of PrP amyloid deposits in the absence of abnormal PrP.26
Similarly, inoculation of PK-sensitive recombinant PrP polymerized into amyloid fibers generated a prion disease in PrP overexpressing transgenic mice that was apparently asymptomatic but caused SD and deposition of PK-sensitive abnormal PrP, 2 features shared by the 129VV genotype of VPSPr, only late in the life of the inoculated animals, consistent with very long incubation times.29
Furthermore, similar transmission patterns on inoculation of brain homogenates from affected animals or humans have been observed in other neurodegenerative diseases, such as Alzheimer disease and diseases of the tau protein or tauopathies.30,31
Experiments on the transmissibility of VPSPr are ongoing. Preliminary data indicate that VPSPr transmissibility, if it occurs at all, is not efficient, and it could be more like that of GSS-P102L associated with PrPDis
7kDa or of PK-sensitive PrP amyloid fibers, which require long incubation times and do not shorten the life span of the affected animals.26,29
It is intriguing that GSS also shows characteristics of the phenotype and of the PrPDis
associated with some of the mutations that resemble those of VPSPr.25
They include long disease duration, multiple PK-resistant fragments, and variable PK resistance of PrPDis
. Our comparative analysis of the electrophoretic profiles in VPSPr and GSS-A117V reveals provocative similarities. This finding raise the issue of whether VPSPr might be viewed as the sporadic form of GSS.
Regardless of its relationship with GSS, the finding that VPSPr affects all 3 129 genotypes, resulting in distinct disease phenotypes and PrPDis characteristics, establishes VPSPr as the second “sporadic” prion protein disease, after sCJD.