Lev G. Goldfarb

A group of 43 patients from seven families affected by Creutzfeldt-Jakob disease (CJD) with the codon 178Asn mutation of the PRNP amyloid precursor gene is compared to a group of 211 patients with the sporadic form of the disease. As a group, the patients with the codon 178Asn mutation had an earlier age at onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic electroencephalographic activity. Transmission of disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings are interpreted and discussed in terms of possible differences in the temporospatial evolution of damage to the brain, and of accelerated induction of polymerized amyloid protein by its mutationally altered template precursor.

There is currently much interest in the role of apolipoprotein E (apoE) genotype in late-onset Alzheimer's disease, and examination of this question involves the genotyping of large groups of cases. 1,2 Many of the studies have used the method of apoE genotyping described by Hixson and Vernier 3, which has the advantage of using a single restriction enzyme to identify two polymorphic sites. However, this method involves the separation of relatively small fragments (72, 83, and 91 bp) of DNA, necessitating the use of large polyacrylamide gels that need more expensive equipment and are more technically demanding than agarose gels. This is especially relevant when there is need to screen hundreds of dementia patients for apoE genotype. Furthermore, even when the assays are done by well-equipped laboratories, the results are sometimes ambiguous 4, and although the use of radioactive reagents may improve the quality of …

Genetic studies of over 200 cases of Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru have brought a reliable body of evidence that the familial forms of CJD and all known cases of GSS and FFI are linked to germline mutations in the coding region of the PRNP gene on chromosome 20, either point substitutions or expansion of the number of 24-nucleotide repeat units. Phenotypic expression of FFI and familial CJD, clinically and pathologically distinct syndromes linked to the 178Asp-->Asn substitution, is dependent on a polymorphism at codon 129. Synthetic peptides homologous to several regions of PrP spontaneously form insoluble amyloid fibrils with unique morphological characteristics and polymerization tendencies. Peptides homologous to mutated regions of PrP exhibit enhanced fibrillogenic properties and, if mixed with the wild-type peptide, produce even more abundant and larger fibrous aggregates. A similar process in vivo may be the primary event leading to amyloid accumulation and disease.