Article

Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity.

Institute of Neurology, Medical University of Vienna, Austria.
Acta Neuropathologica (impact factor: 9.32). 12/2005; 110(5):513-9. DOI:10.1007/s00401-005-1073-x
Source: PubMed

ABSTRACT Sporadic, acquired, and genetic human prion diseases are characterized neuropathologically by distinct deposition patterns of the abnormal, disease-associated form of the prion protein (PrP(sc)). In addition to mutations in the prion protein gene (PRNP), PrP(sc) immunostaining patterns correlate with molecular phenotypes of prion diseases defined by the PRNP polymorphism at codon 129 and with protease-resistant PrP classified by Western blotting. Some point or insertional PRNP mutations share similar clinical and neuropathological phenotypes, whereas others show great variability even within the same family. Here we report a patient who presented clinically as sporadic Creutzfeldt-Jakob disease (CJD). Histologically moderate spongiform change was seen in cerebral and cerebellar cortical areas. Neuronal loss was restricted mainly to the occipital cortex and the basal ganglia. Surprisingly, numerous eosinophilic globular structures were noted in the molecular layer and the parahippocampal gyrus. These globules showed intense PrP immunopositivity using anti-PrP antibodies against different epitopes. They were stained with PAS but lacked congophilia and birefringence in polarized light. Ultrastructurally, globules were composed of 21-nm-thick intermingled filaments without dense core. Genetic analysis revealed a PRNP 144 base pair insertion. Our case reinforces the importance of molecular genetic diagnosis, especially in those patients who lack a family history of prion disease and show unusual neuropathological changes. It also widens the phenotypic spectrum of prion diseases. The phenotypic variability within the same mutation suggests further, yet uncharacterized, genetic or epigenetic influence on phenotype in these diseases.

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    Article: Early onset prion disease from octarepeat expansion correlates with copper binding properties.
    Daniel J Stevens, Eric D Walter, Abel Rodríguez, David Draper, Paul Davies, David R Brown, Glenn L Millhauser
    [show abstract] [hide abstract]
    ABSTRACT: Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu(2+)) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu(2+) to protein. At low Cu(2+) levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease.
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    A Vital, J-L Laplanche, J-R Bastard, X Xiao, W-Q Zou, C Vital
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Keywords

cerebellar cortical areas
 
disease-associated form
 
distinct deposition patterns
 
epigenetic influence
 
family history
 
genetic human prion diseases
 
great variability
 
Histologically moderate spongiform change
 
insertional PRNP mutations share similar clinical
 
molecular genetic diagnosis
 
molecular phenotypes
 
neuropathological phenotypes
 
parahippocampal gyrus
 
phenotypic spectrum
 
phenotypic variability
 
prion disease
 
prion protein
 
prion protein gene
 
sporadic Creutzfeldt-Jakob disease
 
unusual neuropathological changes