A Case Report published in this week’s The Lancet, written by Professor John Collinge, MRC Prion Unit and National Prion Clinic, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, reports the particular genetic make-up of a 30-year old man who has died of variant Creutzfeldt–Jakob disease (vCJD). The case report suggests that there could be other people with the condition who at the moment have no symptoms.
vCJD is caused by infectious agents called prions, which are made primarily of protein. The prions which cause vCJD are the same as those that cause bovine spongiform encephalopathy (BSE, also known as mad cow disease) in cows. Prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and eventually fatal. Disease-causing prions are thought to consist of abnormally folded proteins that spread by encouraging the normal healthy prion protein found on the surface of most cells in the body to change shape. Prion diseases share similar disease mechanisms with Alzheimer’s, Parkinson’s, and other neurodegenerative brain diseases.
The 30-year-old man was admitted to hospital in June, 2008, with a 13-month history of personality change, progressive unsteadiness, and intellectual decline. He complained of severe leg pain and poor memory. Two months later he developed visual hallucinations. His symptoms worsened over the next three months. An MRI scan and other tests led to a diagnosis of vCJD. The man died in January 2009.
The case is unusual because tests showed the man had a particular genotype at his human prion protein gene (PRNP 129 codon), which can code for the amino acids valine (V) or methionine (M). People can be VV (homozygous), MM (again homozygous), or MV (heterozygous). Since 1994, around 200 cases of vCJD have been identified worldwide, and all those tested have been MM homozygous. However, the man in this Case Report was heterozygous.
Other prion diseases such as kuru or CJD associated with the use of pituitary hormones tend to have longer incubation periods in people who are PRNP heterozygous than those who are MM homozygous. The authors have recently reported some heterozygous patients with kuru had been incubating the disease over 50 years. Thus the authors believe there could be other cases like this one in which people are infected with vCJD but experiencing a long incubation period.
The authors say “The majority of the UK population have potentially been exposed to BSE prions but the extent of clinically silent infection remains unclear. About a third of the UK population are PRNP codon 129 methionine homozygous. If individuals with other genotypes are similarly susceptible to developing prion disease after BSE prion exposure, but with longer incubation periods, further cases, which may or may not meet diagnostic criteria for vCJD, would be expected in these PRNP codon 129 genotypes.”
They conclude “However, prion disease susceptibility and incubation periods are also affected by other genetic loci, and the possibility remains that cases of vCJD to date may have unusual combinations of genotypes at these loci, yet to be fully characterised.”
Variant CJD in an individual heterozygous for PRNP codon 129
Diego Kaski, Simon Mead, Harpreet Hyare, Sarah Cooper, Ravi Jampana, James Overell, Richard Knight, John Collinge, Peter Rudge
A 30-year-old man was admitted to hospital in June, 2008, with a 13-month history of personality change, progressive unsteadiness, and intellectual decline. He complained of severe leg pain and poor memory. 2 months later he de-veloped visual hallucinations and falsely believed he had an abdominal tumour. Symptoms worsened over the next 3 months. In October, 2008, his score on the mini mental state examination was 26/30. Pursuit eye movements were saccadic. He had a pout reflex. There was mild ataxia in the arms. His legs were severely ataxic with brisk tendon reflexes and a left extensor plantar response. He needed two crutches to walk. Medical history included tonsillectomy and removal of a cervical lymph node 15 years previously but he had never had a blood trans-fusion or received implantation of other human tissues.
EEG showed slow wave activity. CSF protein, glucose, and cell count were normal but the 14-3-3 protein was positive. MRI of the brain was consistent with the pulvinar sign (figure A). Although not all neuroradiologists con-sulted considered the pulvinar sign positive, quantitative assessment showed symmetrical higher signal in the pul-vinar nuclei than the caudate nuclei (figure B). Extensive screens for genetic, metabolic, and autoimmune diseases, including those induced by neoplasia, were negative. PRNP analysis did not show any known disease-associated mutations; codon 129 was heterozygous. A clinical diag-nosis of variant Creutzfeldt-Jakob disease (vCJD) was made on the basis of a characteristic clinical onset and progres-sion, exclusion of other diagnoses, and MRI findings. Sporadic CJD was judged unlikely given the combination of young age, clinical features, MRI findings, and absence of pseudoperiodic complexes on EEG. His carers did not want further investigation. His condition deteriorated and he died in January, 2009. Autopsy was not done.
Human prion diseases have acquired, sporadic, and inherited aetiologies, show wide phenotypic heterogeneity, and are associated with propagation of infectious prions of many distinct strain types.1 Since 1994, about 200 cases of vCJD, causally related to exposure to bovine spongiform encephalopathy (BSE) prions, have been identified world-wide. vCJD is generally seen in young adults, has charac-teristic neuropathological features and tissue distribution of infectivity, and a distinctive type 4 (London classifica-tion) molecular strain type.1 A polymorphism at codon 129 (encoding methionine or valine) of the human prion protein gene (PRNP), constitutes a powerful susceptibility factor in all types of prion disease. In vCJD, every case genotyped to date has been methionine homozygous. In the other acquired prion diseases, cases have occurred in all genotypes but with different mean incubation periods,1 which can span decades;2 PRNP codon 129 heterozygotes generally have the longest incubation periods. There is a report of a recipient of a blood transfusion from a donor incubating vCJD who died of unrelated causes but showed signs of prion infection at autopsy and was PRNP codon 129 heterozygous.3 Animal studies have suggested that different clinicopathological phenotypes could occur in people with various PRNP codon 129 genotypes.4,5 The majority of the UK population have potentially been exposed to BSE prions but the extent of clinically silent infection remains unclear. About a third of the UK population are PRNP codon 129 methionine homozygous. If individuals with other genotypes are similarly susceptible to developing prion disease after BSE prion exposure, but with longer incubation periods, further cases, which may or may not meet diagnostic criteria for vCJD, would be expected in these PRNP codon 129 genotypes. However, prion disease susceptibility and incubation periods are also affected by other genetic loci, and the possibility remains that cases of vCJD to date may have unusual combinations of genotypes at these loci, yet to be fully characterised.
Figure: MRI (A) Increased signal intensity in the pulvinar nucleus bilaterally (arrow). (B) MR signal intensity in the pulvinar (Pu) is higher than in the head of the caudate nuclei (C), putamen (P), and right frontal white matter (FWM).
All authors were involved in discussion about diagnosis, care of the patient, and preparation of the report. Written consent to publish was obtained.
Conflicts of interest
JC is a director and shareholder of D-Gen Ltd, an academic spin-out company in the field of prion disease diagnosis, decontamination, and therapy. The other authors declare that they have no conflicts of interest.
1 Collinge J. Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 2001; 24: 519–50.
2 Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century–an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–74.
3 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527–29.
4 Asante E, Linehan J, Gowland I, et al. Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice. Proc Natl Acad Sci USA 2006; 103: 10759–64.
5 Wadsworth JD, Asante E, Desbruslais M, et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 2004; 306: 1793–96.