Variant Creutzfeldt–Jakob Disease in a Patient with Heterozygosity at <i>PRNP</i> Codon 129

Mok, Tzehow; Jaunmuktane, Zane; Joiner, Susan; Campbell, Tracy; Morgan, Catherine; Wakerley, Benjamin R; Golestani, Farhad; Rudge, Peter; Mead, Simon; Jäger, Hans Rolf; Wadsworth, Jonathan D. F.; Brandner, Sebastian; Collinge, John

doi:10.1056/nejmc1610003

Cited by 131 publications

(85 citation statements)

References 5 publications

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“…However, because the patient received treatment with hypothalamic phospholipids extracted from bovine brains for several years (12), it is conceivable that she was infected with one of the three known prion strains of bovine spongiform encepahlopathy (BSE) despite the fact that validation experiments had convincingly shown that the extraction of brain phospholipids strongly inactivated prion infectivity (25). Potential exposure to classical BSE (C-BSE) is unlikely because the neuropathological lesions and PrP TSE glycotype did not show the characteristic features observed in variant CJD, including the last reported 129 MV case (26). Moreover, studies of transmissions in TgHu mice and voles infected with CJD-MV AG were strikingly different from those observed in variant CJD-inoculated rodents (27,28).…”

Section: Discussionmentioning

confidence: 99%

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Galeno

Bari

Nonno

et al. 2017

J Virol

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In 2007, we reported a patient with an atypical form of CreutzfeldtJakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP TSE ) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP TSE MV AG ), showing that PrP TSE MV AG is composed of multiple conformers with biochemical properties distinct from those of PrP TSE type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV AG to bank voles and genetargeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP TSE deposition patterns, and PrP TSE glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV AG .IMPORTANCE Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.

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Section: Discussionmentioning

confidence: 99%

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Galeno

Bari

Nonno

et al. 2017

J Virol

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“…One concern is that all but one of the clinically apparent vCJD cases have occurred among those with the 129MM PRNP genotype and this raises the question that the 129MV or 129VV genotypes may have a much longer incubation period. As noted, the latest UK case of vCJD was in a 129MV individual , which may indicate the beginning of a second wave of the epidemic.…”

Section: Unanswered Questions and Future Directionsmentioning

confidence: 80%

“…First, the development of clinical disease in those infected through diet in the past, perhaps due to an extended incubation period in individuals of a non‐129MM PRNP genotype. The first case of vCJD in such an individual was reported from the UK in 2016 and was in a 129MV PRNP heterozygote . Does this represent the start of a second wave, or a random event?…”

Section: Tissue Studies (Tonsil/appendix)mentioning

confidence: 98%

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Creutzfeldt‐Jakob disease and blood transfusion safety

et al. 2018

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Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt-Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food-borne transmission of the prion of bovine spongiform encephalopathy (BSE, 'mad cow disease'). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27). Animal studies demonstrated highly efficient transmission of natural scrapie and experimental BSE by blood transfusion and fuelled concern that sCJD was potentially transfusion transmissible. No such case has been recorded and case-control evaluations and lookback studies indicate that, if transfusion transmission occurs at all, it is very rare. In contrast, four cases of apparent transfusion transmission of vCJD infectivity have been identified in the UK. Risk minimization strategies in response to the threat of vCJD include leucodepletion, geographically based donor deferrals and deferral of transfusion recipients. A sensitive and specific, high-throughput screening test would provide a potential path to mitigation but despite substantial effort no such test has yet appeared. The initial outbreak of vCJD appears to be over, but concern remains about subsequent waves of disease among those already infected. There is considerable uncertainty about the size of the infected population, and there will be at least a perception of some continuing risk to blood safety. Accordingly, at least some precautionary measures will remain in place and continued surveillance is necessary.

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“…Sixteen samples were found positive (presence of PK-resistant, abnormal PrP deposition) among more than 30,000 appendix samples issued from asymptomatic people [6]. All the genotypes were concerned, whereas all the reported v-CJD clinical cases are up to now Met/Met homozygous (129th amino-acid of PrP), except one recently described Met/Val case [7]. This study demonstrated that healthy carriers of v-CJD infection occur with a prevalence of 493 per million (i.e.…”

Section: The Current Apparent Situation Towards Bse and V-cjd Is Reasmentioning

confidence: 96%

Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?

Comoy

Mikol

Deslys

2018

Prion

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The recently reevaluated high prevalence of healthy carriers (1/2,000 in UK) of variant Creutzfeldt-Jakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under full control as expected. After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed (human and animal) individuals, we confirmed in these both models the transmissibility of v-CJD, but we also observed unexpected neurological syndromes transmissible by transfusion: despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the absence of detectable abnormal PrP with current techniques. It is noteworthy that macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and optical tract without affecting encephalon, which is rather evocative of spinal cord disease than prion disease in human medicine. These observations strongly suggest that the spectrum of human prion diseases may extend the current field restricted to the phenotypes associated to protease-resistant PrP, and may notably include spinal cord diseases.

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Variant Creutzfeldt–Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129

Cited by 131 publications

References 5 publications

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Creutzfeldt‐Jakob disease and blood transfusion safety

Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?

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