Molecular Characterization of the Danish Prion Diseases Cohort With Special Emphasis on Rare and Unique Cases

Abstract The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.

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The neuroepidemiology of human prion disease

Oxford Textbook of Neurologic and Neuropsychiatric Epidemiology ◽

10.1093/med/9780198749493.003.0035 ◽

2020 ◽

pp. 367-378

Author(s):

Patrick JM Urwin ◽

Anna M Molesworth

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Protein Misfolding ◽

Prion Diseases ◽

Prion Protein Gene ◽

Human Prion Disease ◽

Disease States ◽

Jakob Disease ◽

The Central Nervous System ◽

Sporadic Disease

Human prion diseases comprise a number of rare and fatal neurodegenerative conditions that result from the accumulation in the central nervous system of an abnormal form of a naturally occurring protein, called the prion protein. The diseases occur in genetic, sporadic, and acquired forms: genetic disease is associated with mutations in the prion protein gene (PRNP); sporadic disease is thought to result from a spontaneous protein misfolding event; acquired disease results from transmission of infection from an animal or another human. The potential transmissibility of the prion in any of these forms, either in disease states or during the incubation period, has implications for public health. Here we focus on Creutzfeldt-Jakob Disease (CJD), including variant Creutzfeldt-Jakob Disease (vCJD), although we will also discuss other forms of human prion disease.

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Creutzfeldt–Jakob disease surveillance in Australia: update to December 2017

Communicable Diseases Intelligence ◽

10.33321/cdi.2019.43.32 ◽

2019 ◽

Vol 43 ◽

Cited By ~ 1

Author(s):

Christiane Stehmann ◽

Shannon Sarros ◽

Matteo Senesi ◽

Victoria Lewis ◽

Marion Simpson ◽

...

Keyword(s):

Prion Disease ◽

Disease Surveillance ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Annual Number ◽

Prospective Surveillance ◽

Surveillance Period ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

Neuropathological Examination

Nationwide surveillance of human prion diseases (also known as transmissible spongiform encephalopathies), the most common being Creutzfeldt–Jakob disease (CJD), is performed by the Australian National Creutzfeldt–Jakob Disease Registry (ANCJDR), based at the University of Melbourne. National surveillance encompasses the period since 1970, with prospective surveillance occurring from 1993 onwards. Over this prospective surveillance period considerable developments have occurred, especially in relation to pre-mortem diagnostics, the delineation of new disease subtypes and a heightened awareness of prion diseases in the health care setting. The surveillance practices of the ANCJDR have evolved and adapted accordingly. Since the ANCJDR began offering cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased to a maximum of 508 in 2017. The number of CSF test referrals in 2017 represents a 20% increase compared to that of 2016. In 2017, there was an overall stabilisation of the annual incidence rate of confirmed prion disease in Australia at expected levels; 72 persons with suspected human prion disease were added to the national register, with 72% of all suspected CJD cases undergoing neuropathological examination. The majority of the 72 suspected cases added to the register are as of 31 December 2017 still classified as “incomplete” (47 cases), while four cases were excluded by either detailed clinical follow-up (1 case) or neuropathological examination (3 cases); 19 cases were classified as definite and two as probable prion disease. No cases of variant CJD (vCJD) were confirmed.

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Genetic Influences on Disease Subtypes

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-120319-095026 ◽

2020 ◽

Vol 21 (1) ◽

pp. 413-435

Author(s):

Andy Dahl ◽

Noah Zaitlen

Keyword(s):

Gold Standard ◽

Genetic Data ◽

Disease Classification ◽

Careful Examination ◽

Primary Interest ◽

The Past ◽

Disease Biology ◽

Fundamental Process ◽

Medical Benefits ◽

Disease Subtypes

Disease classification, or nosology, was historically driven by careful examination of clinical features of patients. As technologies to measure and understand human phenotypes advanced, so too did classifications of disease, and the advent of genetic data has led to a surge in genetic subtyping in the past decades. Although the fundamental process of refining disease definitions and subtypes is shared across diverse fields, each field is driven by its own goals and technological expertise, leading to inconsistent and conflicting definitions of disease subtypes. Here, we review several classical and recent subtypes and subtyping approaches and provide concrete definitions to delineate subtypes. In particular, we focus on subtypes with distinct causal disease biology, which are of primary interest to scientists, and subtypes with pragmatic medical benefits, which are of primary interest to physicians. We propose genetic heterogeneity as a gold standard for establishing biologically distinct subtypes of complex polygenic disease. We focus especially on methods to find and validate genetic subtypes, emphasizing common pitfalls and how to avoid them.

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Enzymatic detergent treatment protocol that reduces protease-resistant prion protein load and infectivity from surgical-steel monofilaments contaminated with a human-derived prion strain

Journal of General Virology ◽

10.1099/vir.0.82961-0 ◽

2007 ◽

Vol 88 (10) ◽

pp. 2905-2914 ◽

Cited By ~ 30

Author(s):

Victoria A. Lawson ◽

James D. Stewart ◽

Colin L. Masters

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Disease Transmission ◽

Prion Diseases ◽

Medical Instrument ◽

Treatment Protocol ◽

Infectious Agent ◽

Surgical Instruments ◽

Prion Strain ◽

Jakob Disease

The unconventional nature of the infectious agent of prion diseases poses a challenge to conventional infection control methodologies. The extraneural tissue distribution of variant and sporadic Creutzfeldt–Jakob disease has increased concern regarding the risk of prion disease transmission via general surgical procedures and highlighted the need for decontamination procedures that can be incorporated into routine processing. In this study, the ability of preparations of enzymatic medical instrument cleaners to reduce the infectivity associated with a rodent-adapted strain of human prion disease, previously reported to be resistant to decontamination, was tested. Efficient degradation of the disease-associated prion protein by enzymatic cleaning preparations required high treatment temperatures (50–60 °C). Standard decontamination methods (1 M NaOH for 1 h or autoclaving at 134 °C for 18 min) reduced infectivity associated with the human-derived prion strain by less than 3 log10 LD50. In contrast, a 30 min treatment with the optimized enzymatic cleaning preparation protocols reduced infectivity by more than 3 log10 LD50 and when used in conjunction with autoclave cycles eliminated detectable levels of infectivity. The development of prion decontamination procedures that are compatible with routine cleaning and sterilization of medical and surgical instruments may reduce the risk of the transmission of prion disease in general surgery.

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Human Prion Diseases

Escourolle and Poirier's Manual of Basic Neuropathology ◽

10.1093/med/9780199929054.003.0006 ◽

2013 ◽

pp. 149-160

Author(s):

James W. Ironside ◽

Matthew P. Frosch ◽

Bernardino Ghetti

Keyword(s):

Prion Diseases ◽

Neuronal Loss ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Pituitary Hormone ◽

Human Pituitary ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

Prnp Codon ◽

Codon 129

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.

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Case report of homozygous E200D mutation of PRNP in apparently sporadic Creutzfeldt-Jakob disease

BMC Neurology ◽

10.1186/s12883-021-02274-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ahamad Hassan ◽

Tracy Campbell ◽

Lee Darwent ◽

Hans Odd ◽

Alison Green ◽

...

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Chinese Patient ◽

Motor Disorder ◽

Homozygous Mutation ◽

Case Presentation ◽

Asian Populations ◽

Clinical Presentations ◽

History Of ◽

Jakob Disease

Abstract Background Inherited prion diseases are rare autosomal dominant disorders associated with diverse clinical presentations. All are associated with mutation of the gene that encodes prion protein (PRNP). Homozygous mutations with atypical clinical phenotypes have been described but are extremely rare. Case presentation A Chinese patient presented with a rapidly progressive cognitive and motor disorder in the clinical spectrum of sCJD. Investigations strongly suggested a diagnosis of CJD. He was found to carry a homozygous mutation at PRNP codon 200 (E200D), but there was no known family history of the disorder. The estimated allele frequency of E200D in East Asian populations is incompatible with it being a highly penetrant mutation in the heterozygous state. Conclusion In our view the homozygous PRNP E200D genotype is likely to be causal of CJD in this patient. Homotypic PrP interactions are well known to favour the development of prion disease. The case is compatible with recessively inherited prion disease.

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Medial Temporal Lobe Involvement in Human Prion Diseases: Implications for the Study of Focal Non Prion Neurodegenerative Pathology

Biomolecules ◽

10.3390/biom11030413 ◽

2021 ◽

Vol 11 (3) ◽

pp. 413

Author(s):

Alberto Rábano ◽

Carmen Guerrero Márquez ◽

Ramón A. Juste ◽

María V. Geijo ◽

Miguel Calero

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Prion Diseases ◽

Current Evidence ◽

Neuron Populations ◽

Jakob Disease ◽

Protein Isoform ◽

Prnp Codon ◽

Lesion Profile ◽

Codon 129

Human prion and non-prion neurodegenerative diseases share pathogenic mechanisms and neuropathological features. The lesion profile of a particular entity results from specific involvement of vulnerable neuron populations and connectivity circuits by a pathogenic protein isoform with strain-like properties. The lesion profile of the medial temporal lobe (MTL) was studied in postmortem tissue of 143 patients with human prion disease (HPD) including sporadic, genetic, and acquired forms. Most cases (90%) were classified according to PrPres type and/or PRNP codon 129 status, in addition to a full neuropathological profile. Mixed histotypes represented 29.4% of total sporadic Creutzfeldt-Jakob disease (sCJD) cases. An intensity score of involvement including spongiosis and astrogliosis was determined for the amygdala, presubiculum, subiculum, entorhinal cortex, CA1 to CA4 sectors of the hippocampal cortex, and dentate gyrus. Connectivity hubs within the MTL presented the highest scores. Diverse lesion profiles were obtained for different types and subtypes of HPD. Impact of mixed PrPres types on the MTL lesion profile was higher for sCJDMV2K cases than in other histotypes. Differences between MTL profiles was globally consistent with current evidence on specific strains in HPD. These results may be relevant for the analysis of possible strain effects in focal non-prion neurodegenerative conditions limited to the MTL.

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Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019

Communicable Diseases Intelligence ◽

10.33321/cdi.2020.44.56 ◽

2020 ◽

Vol 44 ◽

Author(s):

Christiane Stehmann ◽

Matteo Senesi ◽

Shannon Sarros ◽

Amelia McGlade ◽

Marion Simpson ◽

...

Keyword(s):

Prion Disease ◽

Disease Surveillance ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathy ◽

Annual Number ◽

Spongiform Encephalopathy ◽

Human Prion Disease ◽

Prospective Surveillance ◽

Jakob Disease ◽

Neuropathological Examination

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as ‘incomplete’; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as ‘definite’ and seven as ‘probable’ prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified. Keywords: Creutzfeldt-Jakob disease, prion disease, transmissible spongiform encephalopathy, disease surveillance

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Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2018

Communicable Diseases Intelligence ◽

10.33321/cdi.2019.43.35 ◽

2019 ◽

Vol 43 ◽

Cited By ~ 2

Author(s):

Christine Stehmann ◽

Matteo Senesi ◽

Victoria Lewis ◽

Mairin Ummi ◽

Marion Simpson ◽

...

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Annual Number ◽

Human Prion Disease ◽

Prospective Surveillance ◽

Surveillance Period ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

Neuropathological Examination

Nationwide surveillance of human prion diseases (also known as transmissible spongiform encephalopathies), the most common being Creutzfeldt-Jakob disease (CJD), is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR), based at the University of Melbourne. National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period considerable developments have occurred in relation to pre-mortem diagnostics, the delineation of new disease subtypes and a heightened awareness of prion diseases in health care settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR from 1 January to 31 December 2018. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2018, 465 domestic CSF specimens were referred for 14-3-3 protein testing and 78 persons with suspected human prion disease were formally added to the national register. The majority of the 78 suspect case notifications remain as of 31 December 2018 classified as “incomplete” (42 cases), while eleven cases were excluded by either detailed clinical follow-up (one case) or neuropathological examination (ten cases); 15 cases were classified as “definite” and ten as “probable” prion disease. Sixty-two percent of all suspected human prion disease related deaths underwent neuropathological examination. No cases of variant CJD were confirmed.

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Prion Diseases

10.1093/med/9780199937837.003.0166 ◽

2017 ◽

Author(s):

James A. Mastrianni ◽

Joshuae G. Gallardo

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Neurodegenerative Disorders ◽

Protein Gene ◽

Prion Diseases ◽

Prion Protein Gene ◽

Secondary Transmission ◽

Jakob Disease

Prion diseases are transmissible fatal neurodegenerative disorders resulting from the accumulation of misfolded prion protein. Although primarily sporadic diseases, 5% to 10% result from a mutation of the prion protein gene (PRNP), and less than 1% occur from exposure to prions. The current family of prion diseases includes Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal insomnia (FI), variant CJD (vCJD), and variably protease-sensitive prionopathy (VPSPr). Kuru is a disease of historical interest that was transmitted through cannibalistic rituals. Iatrogenic CJD (iCJD) is the result of secondary transmission of prion disease from contaminated biologicals.

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