Research and analysis

Creutzfeldt-Jakob disease (CJD) biannual update (February 2014), with briefing on novel human prion disease

Updated 10 February 2017

This six-monthly report provides an update on the enhanced surveillance of potential iatrogenic (healthcare-acquired) exposures to Creutzfeldt-Jakob Disease (CJD). The data is correct as at 31 December 2013. For numbers of CJD case reports, readers should consult data provided by the National CJD Research and Surveillance Unit (NCJDRSU).

A briefing on a recently-identified human prion disease – Variably Protease-Sensitive Prionopathy – is also presented below.

1. Monitoring of patients ‘at increased risk’ of CJD

Individuals who have been identified as at increased risk of CJD as a consequence of their medical care are informed of their exposure and asked to follow public health precautions to avoid potentially transmitting the infection to others. They are also followed-up to help determine the risks of CJD transmission to patients through different routes and to ascertain whether any people who may have been exposed to increased CJD risks go on to develop CJD.

Public health follow-up activities include clinical monitoring, general practitioner (GP) updates, and post mortem investigations to determine whether asymptomatic individuals in these groups have been infected with the CJD agent. Some individuals also provide blood or tissue specimens for research purposes. A number of different organisations are involved in these activities: Public Health England (formerly the Health Protection Agency), Health Protection Scotland (HPS), UCL Institute of Child Health/Great Ormond Street Hospital (ICH), NHS Blood and Transplant (NHSBT), National CJD Research and Surveillance Unit (NCJDRSU), National Prion Clinic (NPC), and the UK Haemophilia Centre Doctors’ Organisation (UKHCDO).

The PHE CJD Section coordinates the collation of data on individuals identified as at increased risk of CJD, and who have been informed of this. These individuals are followed up through public health monitoring and research activities by different organisations (table 1).

The PHE CJD Section currently holds data on the following groups of ‘at risk’ patients:

  • recipients of blood components from donors who subsequently developed vCJD
  • blood donors to individuals who later developed vCJD
  • other recipients of blood components from these blood donors
  • recipients of certain plasma products between 1990 and 2001 (non-bleeding disorder patients)
  • certain surgical contacts of patients diagnosed with CJD
  • highly transfused recipients.

Data on the following risk groups are not held by PHE, but are held by other organisations:

  • bleeding disorder patients who received plasma products between 1990 and 2001 (UKHCDO)
  • recipients of human derived growth hormone before 1985 (ICH)
  • patients who could have received a dura mater graft before August 1992 (data not currently collected)
  • people who have been treated with gonadotrophin sourced from humans before 1973 (data not currently collected)
  • family risk of genetic prion disease (NPC).

The data from the UKHCDO are likely to be an underestimate of the true number of ‘at risk’ patients with bleeding disorders who received UK-sourced clotting factors, as there was incomplete reporting of identified ‘at risk’ patients by haemophilia centres to the UKHCDO database. Notified ‘at risk’ patients are given the option of removing their details from the UKHCDO database, and are then removed from the ‘at risk’ totals.

The data on ‘at risk’ patients who received human-derived human growth hormone held by the ICH is a slight underestimate of the total as a small number of these patients are not included in the ICH follow-up.

Table 1. Summary of all ‘at risk’ groups on which data are collected (as at 31 December 2013)

At risk Group Identified as ‘at risk’ Number notified as being ‘at risk’   Cases Asymptomatic infections [b]
    All Alive    
Recipients of blood from donors who later developed vCJD 67 27 15 3 1
Blood donors to individuals who later developed vCJD 112 107 104
Other recipients of blood components from these donors 34 32 [c] 19 [c]
Plasma product recipients (non-bleeding disorders) who received UK sourced plasma products 1980-2001 11 10 4
Certain surgical contacts of patients diagnosed with CJD 154 129 [d] 113 [e]
Highly transfused patients 11 10 6
Total for ‘at risk’ groups where PHE holds data 389 315 [f] 261 [f] 3 1
Patients with bleeding disorders who received UK-sourced plasma products 1980-2001 [a] 3,875 National information incomplete National information incomplete 1
Recipients of human-derived growth hormone [a] 1,883 1,883 1,504 75
Total for all ‘at risk’ groups [a] 6147 At least 2198 At least 1765 78 2

a. These are minimum figures. Central reporting for bleeding disorder patients is incomplete, and seven patients have opted out of the central UK Haemophilia Centre Doctors’ Organisation database. A small number of ‘at risk’ growth hormone recipients are not included in the Institute of Child Health study. Not all of ‘at risk’ growth hormone recipients have been notified. There is no central record of who has been informed.

b. An asymptomatic infection is when an individual does not exhibit any of the signs and symptoms of CJD in life but abnormal prion protein indicative of CJD infection has been found in tissue obtained from them. In these cases the abnormal prion protein was identified during post mortem after the individuals had died of other causes.

c. One patient notified by proxy.

d. Four of these notified by proxy.

e. Two of these notified by proxy.

f. Includes patients notified by proxy.

2. Variably Protease-Sensitive Prionopathy

Professor James W Ironside and Dr Mark W Head, The National CJD Research and Surveillance Unit, University of Edinburgh.

Variably protease-sensitive prionopathy (VPSPr) is the most recently identified human prion disease, first described in the USA by Gambetti et al. in 2008 as “a novel human disease with abnormal prion protein sensitive to protease” [1]. Since then, similar cases have been identified in other countries; the National CJD Research and Surveillance Unit has identified nine cases in the UK, three of which have been identified retrospectively and the others prospectively from samples and data collected since 1991 [2-6]. Other candidate cases are currently under investigation.

Patients with VPSPr have no identified risk factors for acquired human prion disease and no associated mutations in the prion protein gene (PRNP) coding sequence have been found. In the original description a proportion of the patients had family histories of ill-defined dementia, but this has not been a feature in more recently identified cases [1,2,6]. VPSPr affects patients in the same age range as sporadic Creutzfeldt-Jakob disease (sCJD), occurring mostly in patients over the age of 60. The clinical features are more varied than in sCJD and include movement abnormalities, cognitive decline and unsteadiness while walking. The clinical illness is longer than for sCJD; most patients survive for over a year before succumbing to the illness. Diagnostic clinical criteria are therefore difficult to establish, and further work is required on this topic since this disease is likely to be under-ascertained [2,6].

Like sCJD, VPSPr occurs in all genetic groups defined by the polymorphism at codon 129 in the PRNP gene, ie MM, MV and MV. Unlike sCJD, there is a preponderance of the codon 129-V haplotype. VPSPr has distinctive neuropathological features, the most typical of which are microplaques that occur in a target-like arrangement and are particularly common in the cerebellum. These microplaques show differential staining with a panel of different anti-PrP antibodies, allowing a distinction from both the common sCJD VV2 and the rare sCJD VV1 subtypes [1,2,5,6]. The most distinctive and defining feature of VPSPr is the biochemistry of the abnormal prion protein in the brain, which is only poorly resistant to proteolytic digestion, yielding a low abundance, truncated 8kDa (approx) band in Western blot assays [1]. This fragment is often accompanied by a faint ladder of bands extending into the 18-30kDa range [1,2]. Some cases of VPSPr also show a sCJD-like pattern on Western blot analysis for abnormal prion protein, often in the cerebellum, suggesting molecular overlaps between VPSPr and sCJD [6,7].

Further work is required to fully establish the epidemiology, clinical and pathological diagnostic criteria and transmission characteristics of VPSPr. The Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy (ACDP TSE) Subgroup concluded that until further research can demonstrate how transmissible VPSPr may be, it would be advisable to add this novel form of human prion disease to the infection control guidance for CJD and other related disorders.

2.1 References

  1. Gambetti P, Dong, Yuan J, et al. A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 2008; 63: 697-708.
  2. Zou WQ, Puoti G, Xiao X, et al. Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein. Ann Neurol 2010; 68: 162-72.
  3. Head MW, Knight R, Zeidler M, et al. A case of protease sensitive prionopathy in a patient in the United Kingdom. Neuropathol Appl Neurobiol 2009; 35: 628-32.
  4. Jansen C, Head MW, van Gool WA, et al. The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype. J Neurol Neurosurg Psychiatry 2010; 81: 1052-5.
  5. Head MW, Lowrie S, Chohan G, et al. Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, a synclein and Aß pathology. Acta Neuropathol 2010: 120: 821-3.
  6. Head MW, Yull HM, Ritchie DL, et al. Variably protease-sensitive prionopathy in the UK: a retrospective review 1991-2008. Brain 2013; 136: 1102-15.
  7. Rodriguez-Martinez AB, de Munain AL, Ferrer I, et al. Coexistence of protease sensitive and resistant prion protein in 129 VV homozygous sporadic Creutzfeldt-Jakob disease. J Med Case Rep 2012; 6: 348.

This report was published in Health Protection Report volume 8 issue 6.