Molecular basis of phenotypic variability in sporadc creudeldt‐jakob disease

Abstract

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease

“…These differences have major implications for the patient as rapid action needs to be taken by both the treating physicians and the families in order to ensure an appropriate medical and nursing care. One prognostic marker for disease progression and patient survival is the patient's molecular subtype (MM1, MM2, MV1, MV2, VV1, VV2) which is compound of two different kinds of information: 1) codon 129 genotype (MM, MV or VV) and 2) prion protein type (PrP type 1 or 2) (Parchi, et al, 1996,Puoti, et al, 2012. While codon 129 genotype is easily available by genetic testing during life-time, information on PrP type can only be obtained by neuropathological evaluation which is mostly limited to post-mortems.…”

Diagnostic profiles of patients with late-onset Creutzfeldt–Jakob disease differ from those of younger Creutzfeldt–Jakob patients: a historical cohort study using data from the German National Reference Center

“…Whereas a definite diagnosis is restricted to neuropathological examination, in vivo diagnosis of sCJD is based on clinical symptoms, cerebrospinal fluid (CSF) markers, MRI and EEG profiles [15,17]. Six molecular subtypes (MM1, MM2, MV1, MV2, VV1, VV2) of sCJD have been identified [11]. Classification is based on the methionine-valine polymorphism at codon 129 of the Prion Protein gene (PRNP) and on two distinct types of prion protein (PrP Sc type 1 and 2).…”

“…Classification is based on the methionine-valine polymorphism at codon 129 of the Prion Protein gene (PRNP) and on two distinct types of prion protein (PrP Sc type 1 and 2). Subtypes differ from each other with respect to disease course, survival time, CSF and MRI profiles [11,13].…”

Risikofaktoren der sporadischen Creutzfeldt-Jakob-Krankheit

“…Es liegen zwei Typen des pathologischen Prion-Proteins (Typ I und II) vor, die sich nach ihren Wanderungseigenschaften in der Gelelektrophorese unterscheiden lassen (je nach Molekulargewicht und Glykosylierungsmuster) (Parchi et al 1996).…”

“…Für die PRNP-Codon-129-Genotypen MV und VV sind atypische Verläufe der sCJK beschrieben (Parchi et al 1996(Parchi et al , 1999). …”