Human
prion diseases may be acquired as
infectious diseases, they may be inherited in an autosomal dominant fashion or occur sporadically. Mutations and polymorphisms in the sequence of the coding region of the
prion protein gene (PRNP) have been established as an important factor in all of these three types of
prion diseases. Therefore, a total of 578 patients with suspect
prion diseases referred to the German
Creutzfeldt-Jakob disease (CJD) surveillance unit over a period of 4.5 years have been examined for mutations and polymorphisms in the coding region of PRNP. We found 40 cases with a missense mutation previously reported as pathogenic. Amongst these, the
aspartate to
asparagine change at
codon 178 (D178N) was the most common mutation. All of these cases carried the D178N mutation in coupling with
methionine at
codon 129, resulting in the typical
fatal familial insomnia (FFI) genotype. Most cases with pathogenic mutations were not found in the group of clinically "probable" cases according to established clinical criteria, supporting the notion that inherited
prion diseases often exhibit atypical features. Two novel missense mutations (T188R and P238S) and several silent polymorphisms were found, demonstrating the quality of our screening procedure based on a modified version of the single-stranded conformational polymorphism technique. In "definite" CJD cases with no pathogenic mutation, the patients clinically classified as "probable" were mostly homozygous for
methionine at the common polymorphism at
codon 129, whereas there was a marked over-representation of patients homozygous for
valine amongst those clinically classified as "possible". This large study on suspect cases of human
prion diseases in Germany clearly shows that PRNP genetics is essential for a comprehensive analysis of
prion diseases.