Patients with iatrogenic
Creutzfeldt-Jakob disease due to administration of cadaver-sourced
growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic
Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic
codon 129 of the
prion protein gene (PRNP) from predominantly
valine homozygous to a mixed picture of
methionine homozygous and
methionine-
valine heterozygous over time. The incubation period of iatrogenic
Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different
growth hormone batches with different strains of human
prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic
Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years.
Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had
myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in
methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid
14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic
prion deposition with numerous
kuru type plaques in the basal ganglia, anterior frontal and parietal cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest clinical duration had an atypical synaptic deposition of abnormal
prion protein and no
kuru plaques. Taken together, these data provide a remarkable example of the interplay between the strain of the pathogen and host
prion protein genotype. Based on extensive modelling of human
prion transmission barriers in transgenic mice expressing human
prion protein on a mouse
prion protein null background, the temporal distribution of
codon 129 genotypes within the cohort of patients with iatrogenic
Creutzfeldt-Jakob disease in the UK suggests that there was a point source of infecting
prion contamination of
growth hormone derived from a patient with
Creutzfeldt-Jakob disease expressing
prion protein valine 129.