CODON A117V

This mutation was discovered in families characterized by dementia but not by the cerebellar ataxia otherwise typical for GSS. Hence the term the “telencephalic type” of GSS was coined but in reality, the clinical picture is also highly heterogeneous. The proband described by Mastrianni et al. is particularly interesting because in other affected members of the same family the cerebellar syndrome was readily noticed. In an Alsatian family, a generation effect was observed; in earlier generations only “pure” dementia was observed, while in later generations a more complex pattern of signs and symptoms were noticed, including dementia. How comprehensive the earlier descriptions are, however, is opened to debate. The neuropathological picture is typical and consists of numerous multi-centric plaques in cerebral and cerebellar cortices, basal ganglia and white matter. Amyloid plaques were reactive with Abs raised against the central region of PrP while Abs to the C and N-termini of the molecule stained the peripheries of plaques. The amount of PrPd on west-ern blot was reported to be negligible. However, in the following publications, a 7 kDa peptide of PrPd was found by western blot but the presence of PrPd varies; in some samples no PrPd was found at all. In the brain of an asymptomatic carrier, no PrPd was seen. Because codon 117 is confined within the sequence STE that controls the formation of both the transmembrane (PrPCtm) and secretory (PrPSec) forms of PrP, this mutation became an ideal target to test the hypothesis that an abundance of PrPCtm may exert a pathological effect. Indeed, in GSS brains harboring this mutation over-representation of the PrPCtm form was demonstrated. This phenomenon suggests that the orientation of PrPSc with regard to the cellular mem-brane and not merely the presence of this molecule may be important.