CODON F198S

This mutation was discovered in a family from Indiana, known as the “Indiana kindred” (IK), probably the most thoroughly studied GSS family apart from the original Austrian GSS family. The same mutation was found in another unrelated family. Patients harboring a mutation of codon 198 are homozygous or heterozygous with respect to Val at codon 129. The ex-act role of this mutation is unclear as it lies outside the sequence that encodes for the 11 kDa PrP peptide, which deposits in affected brains. The IK is characterized by a mixture of pyramidal and cerebellar signs, dementia, dysarthria and progressive clumsiness and difficulty in walking. In contrast to other GSS families, the IK displays prominent parkinsonian features, namely “masked face”, bradykinesia and cogwheel rigidity but tremors are not readily detected. Characteristic alterations in saccadic eye movements may be detected before other signs and symptoms appear and optokinetic nystagmus has also been noticed. Sleep disturbances have been seen. The disease starts between 40 and 70 years of age and in patients homozygous for 129Val Val the onset is approximately 10 years earlier than in heterozygous 129Val Met patients. The disease lasts on average 5 years (from 2 to 12 years) but an accelerated course of 1–2 years is also possible. Neuropathological examination has revealed changes otherwise typical for GSS. PrP-amyloid plaques were seen in the grey matter of the neocortex, cerebellum, midbrain, pontine tegmen-tum and medulla. Plaques were also visible in the stria-tum, claustrum, amygdale, hypothalamus and thalamus; all nuclei except the anterior were involved. Some plaques were neuritic. In IK neurites around plaques contained NFT composed, not unlike those of Alzheimer’s disease, of hyperphosphorylated MAP-t. Those neurites were also immunoreactive for τ, synaptophys in and βAPP. Spongiform changes were occasion-ally visible around plaques. Ghetti et al. provided morphometric data on the number of plaques in the IK: 15.9 plaques/mm2 for the entire thickness of the cerebral cortex in the Para hippocampal gyrus, 11.5/mm2 for the insular cortex and 10.6/mm2 for the superior frontal gyrus. It is of note that PrP plaques were also immunoreactive for Ab. Both PrP and Ab were either mixed or Ab surrounded PrP cores. Antibodies raised against different segments of PrP peptides helped to resolve the question of plaque com-position. Tagliavini et al. showed that plaques are composed of two species of PrP, 7 and 11 kDa, spanning PrP residues 81–150 and 58–150 respectively. In contrast, nonfibrillar (pre-amyloid) PrP is immunolabelled with antibodies raised against residues 23–40 and 220–231. Abs raised against peptide PrP 58–71 stained more plaques than in GSS 102Leu. Whereas in GSS 102Leu Abs raised against PrP residues 95–108 stained plaque cores, in IK these Abs stained the peripheries of plaques but the cores were infrequently stained. Abs raised against PrP residues 23–40 (N-terminus) and 220–231 (C-terminus) stained the peripheries of plaques as ringshaped structures. Astrocytic gliosis was seen, including hypertrophy of the Bergmann glia in the cerebellum. As in other PrP plaques, astrocytes penetrated the perimeter of plaques.