Determinants of Creutzfeldt-Jakob disease : a genetic epidemiologic study

Creutzfeldt-Jakob disease (CJD) is the most common form of the human transmissible spongiform encephalopathies.1 The disease is characterised by rapid neurodegeneration leading to death within weeks to months. CJD is a rare disorder with an intriguing etiology, involving genetic and iatrogenic transmission. Ten to fifteen percent of patients with CJD are determined by mutations in the prion protein gene.2 The clinical expression of these familial forms is highly variable and may range from a ‘typical’ CJD phenotype with rapid deterioration to a slowly progressive dementia mimicking Alzheimer’s disease. Apart from the causative mutations, a common polymorphism within the prion protein gene determines susceptibility to CJD.3 Subjects who are homozygous for either allele of this polymorphism are at increased risk of CJD. There is growing evidence that this polymorphism further may influence clinical expression of CJD. Finally, the effect of the prion protein may extend to other forms of neurodegenerative disorders. Besides a role in rare diseases such as Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia, the gene may also have an effect on cognitive decline and dementia in the general population. Up to date, findings in this field have been inconsistent. The challenge for genetic epidemiology is to unravel the role of this gene in common neurodegenerative disorders. In about 5% of patients with CJD, the disease has been caused by iatrogenic transmission. Unintended transmission of CJD occurred in various ways and has led in some instances to epidemics of the disease.4 The most notorious epidemic started in the mid eighties and was due to human growth hormone administration. A second epidemic was related to dura mater transplantation. The clinical phenotype of patients with the iatrogenic form of CJD may depend on the mode of transmission as well as on the prion protein genotype. As a consequence, for each new epidemic parameters like the minimum effective dosage and the range of the incubation time are to be assessed. Case studies of individual patients may help in establishing the phenotype of the disease, which may facilitate an early identification of cases and ultimately may prevent further transmission of disease from human to human.

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