The Original Gerstmann‐Sträussler‐Scheinker Family of Austria: Divergent Clinicopathological Phenotypes but Constant PrP Genotype

Abstract

We present new data on the original Austrian kindred with Gerstmann-Sträussler-Scheinker disease (GSS) which encompasses currently 221 members in 9 generations. The mode of inheritance is autosomal dominant. Predominant clinical features are slowly progressive ataxia and late impairment of higher cerebral functions. In contrast, a recent case with proven P102L mutation of the PRNP gene had rapidly developing dementia and severe cortical damage indistinguishable from the clinicopathological phenotype of Creutzfeldt-Jakob disease (CJD). PRNP codon 129 was homozygous for methionine in both the historic and recent cases. Neuropathology confirms spongiosis of variable degree and numerous protease resistant/prion protein (PrP) amyloid plaques scattered throughout most of the brain as constant features in this family. Some amyloid deposits are surrounded by dystrophic neurites with accumulation of phosphorylated neurofilaments and abnormal organelles, reminiscent of Alzheimer-type plaques. Severe telencephalic damage and a synaptic-type fine granular immunoreactivity in laminar distribution in the cortex with anti-PrP after hydrated autoclaving of sections were seen only in the recent patient. In conclusion, factors in addition to the PRNP genotype at codons 102 and 129 must play a role in determining clinicopathological characteristics of this inherited brain amyloidosis.

Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann–Sträussler–Scheinker disease

“…To contribute to the definition of the full spectrum of PrP-res types that forms in human prion diseases, we examined the physicochemical properties of the PrP-res fragments extracted from the affected brain of subjects carrying the P102L mutation, the most common mutation linked to GSS. The study of the PrP-res and its correlation with the phenotype of the disease is particularly appropriate in the P102L GSS subtype because this disease shows an heterogeneous phenotype that is not fully explained by variation in the PRNP genotype (8,9). We show that, in subjects carrying the P102L mutation who were syngenic at PRNP codon 129 and 219, distinct pathological features of the disease correlate with different patterns of PrP-res fragments.…”

“…The seven subjects analyzed were from seven unrelated kindreds. Pedigree, clinical features, and histopathological data for five subjects were reported in detail (8)(9)(10)(11)(12)(13). These data, and those obtained from the two previously unreported patients, are summarized in Table 1.…”

Prion Protein-Deficient Neurons Reveal Lower Glutathione Reductase Activity and Increased Susceptibility to Hydrogen Peroxide Toxicity

“…4 The disease process is characterized neuropathologically by vacuolar neuronal degeneration and accumulation of altered forms of prion protein (PrP) in the brain. 5,6 Normal cellular PrP (PrP c ) can be expressed in neurons as either a glycosylphosphotidylinositol-anchored sialoglycoprotein or as a transmembrane molecule. 7,8 The molecular and cellular events leading to PrP accumulation appear to involve transformation of the soluble low ␤-sheet-containing PrP c to the infectious, relatively protease-resistant form with a high ␤-sheet content (PrP res ).…”

Molecular Genetics of Gerstmann-Straussler-Scheinker Disease and Creutzfeld-Jakob Disease

“…In 1990, Professor Herbert Budka consulted on a female case suspected of CJD whose father died with a diagnosis of "Friedreich ataxia". The maiden name of this case "H" was the name of the GSS family [58,59]. This discovery enabled modern studies of those fascinating kindred.…”

“…The original family from which 4 cases were described by Seitelberger [55] numbered then 81 members; currently the genealogical tree was expanded to 221 member including 20 definitive GSS cases [58]; no update exists, Hainfellner -personal communication]. As in other GSS families linked to the 102 codon mutation, the disease manifests as slowly progressive cerebellar ataxia with dementia appearing late in the course of disease.…”