Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

Fabio Moda; Pierluigi Gambetti; Silvio Notari; Luis Concha-Marambio; Marcella Catania; Kyung-Won Park; Emanuela Maderna; Silvia Suardi; Stéphane Haïk; Jean-Philippe Brandel; James Ironside; Richard Knight; Fabrizio Tagliavini; Claudio Soto

doi:10.1056/NEJMoa1404401

Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

Fabio Moda, Pierluigi Gambetti, Silvio Notari, Luis Concha-Marambio, Marcella Catania, Kyung-Won Park, Emanuela Maderna, Silvia Suardi, Stéphane Haïk, Jean-Philippe Brandel, James Ironside, Richard Knight, Fabrizio Tagliavini, Claudio Soto^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrP^Sc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.

METHODS: To investigate whether PrP^Sc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrP_Sc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons.

RESULTS: PrP^Sc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrP^Sc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrP^Sc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10⁻¹⁶ g per milliliter, or 3×10⁻²¹ mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrP^Sc per milliliter of urine.

CONCLUSIONS: Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrP^Sc. (Funded by the National Institutes of Health and others.)

Original language	English
Pages (from-to)	530-539
Number of pages	10
Journal	New England Journal of Medicine
Volume	371
Issue number	6
DOIs	https://doi.org/10.1056/NEJMoa1404401
Publication status	Published - 7 Aug 2014

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@article{63fa560ec0b84746a51d92fbff13113b,

title = "Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease",

abstract = "BACKGROUND: Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.METHODS: To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS: PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9\% (95\% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0\% (95\% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS: Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrPSc. (Funded by the National Institutes of Health and others.)",

author = "Fabio Moda and Pierluigi Gambetti and Silvio Notari and Luis Concha-Marambio and Marcella Catania and Kyung-Won Park and Emanuela Maderna and Silvia Suardi and St{\'e}phane Ha{\"i}k and Jean-Philippe Brandel and James Ironside and Richard Knight and Fabrizio Tagliavini and Claudio Soto",

year = "2014",

month = aug,

day = "7",

doi = "10.1056/NEJMoa1404401",

language = "English",

volume = "371",

pages = "530--539",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "6",

}

TY - JOUR

T1 - Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

AU - Moda, Fabio

AU - Gambetti, Pierluigi

AU - Notari, Silvio

AU - Concha-Marambio, Luis

AU - Catania, Marcella

AU - Park, Kyung-Won

AU - Maderna, Emanuela

AU - Suardi, Silvia

AU - Haïk, Stéphane

AU - Brandel, Jean-Philippe

AU - Ironside, James

AU - Knight, Richard

AU - Tagliavini, Fabrizio

AU - Soto, Claudio

PY - 2014/8/7

Y1 - 2014/8/7

N2 - BACKGROUND: Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.METHODS: To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS: PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS: Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrPSc. (Funded by the National Institutes of Health and others.)

AB - BACKGROUND: Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.METHODS: To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS: PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS: Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrPSc. (Funded by the National Institutes of Health and others.)

UR - https://www.scopus.com/pages/publications/84905836913

U2 - 10.1056/NEJMoa1404401

DO - 10.1056/NEJMoa1404401

M3 - Article

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SN - 0028-4793

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

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ER -

Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

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