CODON P102L

GSS with mutation at codon 102 of the prion protein gene (PRNP) was the first target of the molecular-genetic approach in 1989. Both alleles of case J.J. from an American GSS family were sequenced; they were readily discriminated because the restriction site for PvuII was present on only one of the pair. At codon 102, a mutation leading to a substitution of Pro (CCG) by Leu (CTG) was found. This mutation was subsequently found in several families from Japan including Japanese family “I”, in Germany in the well characterized “Sch” family, in Israel, Hungary, Poland, the UK and Italy and in the original Viennese family “H”. The Japanese cases are interesting, as before the era of molecular biology they were regarded as CJD cases with abundant plaques. It is now evident that GSS was merely over-represented in those studies. Support for the linkage of GSS to PRNP was published by Speer et al. The original family from which four cases were de-scribed by Seitelberger then numbered 81 members; currently the genealogical tree has been expanded to 221 members including 20 definitive GSS cases. As in other GSS families linked to the 102 codon mutation, the disease manifests itself as slowly progressive cerebellar ataxia with dementia appearing late in the course of disease. The last case of GSS from this family (the children of this female were tested for a mutation and proved negative for the codon 102 mutation) exhibited, however, features of otherwise typical CJD, namely early symptoms of dementia and a characteristic periodic EEG. For some GSS families harboring the 102-codon mutation a typical feature is heterogeneity of neurological signs and symptoms. The classical ataxic type starts between the second and the sixth decade and the duration of the disease ranges from a few months to several years. Ataxia, dysarthria and alterations in saccadic eye movements, pyramidal and extrapyramidal signs and symptoms and cognitive changes leading to frank dementia have been listed among typical features. These leads, in the terminal phase of the illness, to a state of akinetic mutism. Visual symptoms caused by optic atrophy have been reported, as have sympathetic hyperactivity and parasympathetic hypoactivity not unlike those encountered in FFI. Hyperthermia, tachycardia and hyperhidrosis have, as a result, also been observed. In a proportion of cases, a CJDlike disease is observed with myoclonic jerks and a periodic EEG pattern. In these cases, an accelerated course is seen leading, as is also typical for s-CJD, to death within 5–9 months. Proton magnetic resonance spectroscopy revealed a reduction in the N-acetylaspartate/creatine ratio in the frontal lobe, the cerebellum and the putamen. MRI demonstrated mild atrophy of the cerebellum and the brain. Reduced perfusion was shown by 99mHMPAO SPECT. In another case hyperintensity in T2-weighed MRI images were seen in the bilateral caudate nuclei, the putamen, the frontal lobes and the white matter. The status of codon 129 in a coupling with a mutated codon 102 is a separate issue. In almost all GSS cases with this mutation, it is coupled with 129Met. Cases coupled with 129Val are rare. A case described by Young et al. was a 33--year-old male, clinically significantly different from those of 129Met, with seizures as a first sign, lower limb paraesthesias and bilateral deafness. Dementia was not observed. This male died at the age of 45, some 12 years after the first signs and symptoms were noticed. Neuro-pathological examination revealed numerous PrP-immunoreactive plaques in the cerebral cortex, nucleus caudatus, putamen, globus pallidus and cerebellar cortex and in the substantia gelatinosa. Another four cases of GSS with 102 mutation were described by Furukawa et al. and then by Tanaka et al.; these cases additionally harbored a poly-morphism at 219Lys, the latter replacing 219Gln (GAG to AAG). Two patients demonstrated signs of a cerebellar syndrome but not dementia, while two others had progressive dementia and no cerebellar syndrome. GSS with a mutation of codon 102 is transmissible to nonhuman primates as well as to rodents. It seems that only GSS cases with 102 mutations transmitted thus far. Antibodies raised against different segments of the prion protein (PrP) sequence help to elucidate the composition of the peptides forming plaques. Plaques were labelled with Abs raised against PrP 90–102 and, in a much smaller proportion, with Abs raised against peptide PrP 58–71. Plaque cores were also strongly stained with Abs raised against residues 95–108, 127– –147 and 151–165. Abs raised against PrP residues 23–40 (N-terminus) and 220–231 (C-terminus) stained the peripheries of plaques as ring-shaped structures. Some plaque cores are labelled, however, entirely with Abs, irrespective of whether raised against the mid-portion of the PrP or its N and Ctermini. The latter findings indicate that both truncated peptides and full-length PrP may form amyloid fibrils but the truncated fibrils predominate.