Variant CJD in an individual heterozygous for PRNP codon 129

A 30-year-old man was admitted to hospital in June, 2008, with a 13-month history of personality change, progres sive unsteadiness, and intellectual decline. He complained of severe leg pain and poor memory. 2 months later he developed 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 refl ex. There was mild ataxia in the arms. His legs were severely ataxic with brisk tendon refl exes and a left extensor plantar response. He needed two crutches to walk. Medical history included tonsil lectomy and removal of a cervical lymph node 15 years previously but he had never had a blood transfusion 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 (fi gure A). Although not all neuroradiologists consulted considered the pulvinar sign positive, quantitative assessment showed symmetrical higher signal in the pulvinar nuclei than the caudate nuclei (fi gure 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 diagnosis of variant Creutzfeldt-Jakob disease (vCJD) was made on the basis of a characteristic clinical onset and progression, exclusion of other diagnoses, and MRI fi ndings. Sporadic CJD was judged unlikely given the com bination of young age, clinical features, MRI fi ndings, and absence of pseudoperiodic complexes on EEG. His carers did not want further investigation. His condition deteri orated 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. Since 1994, about 200 cases of vCJD, causally related to exposure to bovine spongiform encephal opathy (BSE) prions, have been identifi ed worldwide. vCJD is generally seen in young adults, has characteristic neuropathological features and tissue distribution of infectivity, and a distinctive type 4 (London classifi cation) molecular strain type. 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 diff erent mean incubation periods, which can span decades; PRNP codon 129 heterozygotes gen er ally 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 hetero zygous. Animal studies have suggested that diff erent clinicopathological phenotypes could occur in people with various PRNP codon 129 genotypes. 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 geno types 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 aff ected by other genetic loci, and the possibility remains that cases of vCJD to date may have unusual combinations of geno types at these loci, yet to be fully characterised.