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Gerstmann-Sträussler-Scheinker disease (GSS) is a hereditary transmissible spongiform encephalopathy associated with prion protein gene mutation P102L. The age of onset is roughly restricted to around the sixth decade; however, it is unclear whether the disease-specific pathology of GSS is already evident in the pre-clinical stage. We had a chance to examine an autopsy case with PRNP P102L mutation. The patient had died at 50 years of age before the clinical symptoms of GSS had appeared; neither neuronal loss, gliosis nor spongiform change was found anywhere in the brain. Immunohistochemistry failed to detect any deposition of prion protein. It is thus considered that amyloid plaque formation in GSS probably develops in a relatively rapid fashion compared with Alzheimer's disease. Although the patient suffered from schizophrenia, no significant pathological changes were detected except for astrocytic inclusion bodies in the cerebral cortex. The nature and significance of the inclusion bodies, which are not observed in patients with GSS, remain unclear.

We report a 74-year-old man with late onset Gerstmann-Sträussler-Scheinker syndrome (GSS). In this family, 3 out of 6 siblings and his father developed cerebellar ataxia and mental deterioration in their fifth decades. He complained of unsteady walking and tingling pain in the legs at the age of 70. Neurological examination revealed moderate truncal ataxia, mild limb ataxia, ataxic speech, sensory impairment, paresthesia and areflexia in the lower extremities. CSF examination showed elevated CSF and 14-3-3 proteins with a normal cell count. EEG and brain MRI demonstrated no abnormality. Somatosensory evoked potential (SEP) study showed delayed N13-N20 interpeak latencies in the upper extremities and delayed N20 at 12th thoracic spinous process, indicating dysfunction of the posterior roots or columns of the spinal cord including the dorsal horns and proximal peripheral nerve. Analysis of the prion protein gene demonstrated a Pro102Leu amino acid substitution, which is compatible with classical GSS. Haplotype analysis of the PrP gene identified a Glu219Lys polymorphism on another allele. Recently, it was confirmed that protein X, which accelerates the conversion of the normal type of PrP (PrPC) into a pathological type of PrP (PrPSc), binds to the 219th amino acid residue of PrP. Therefore, the 219Lys polymorphism theoretically inhibited formation of PrPSc and may thus have delayed the onset of the disease in this patient.

Proteinase K (PK)-resistant prion protein (PrPres) isoforms were examined in three patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) carrying proline-to-leucine mutation at codon 102 in prion protein gene (PRNP), and in nine patients with sporadic Creutzfeldt-Jakob disease (CJD). PrPres isoform termed 'type A', which showed a more prominent band of highly glycosylated form than both a lower glycosylated band and an unglycosylated band in immunoblotting, was exclusively found in the GSS patients examined. In eight of nine CJD patients, electrophoretic mobilities of three PrPres glycoforms were similar to type A, but the ratio of these glycoforms termed 'type B' was distinct from that of type A. On the other hand, one sporadic CJD case with wild-type PRNP had a different PrPres isoform termed type C, which showed higher molecular shift of each of the PrPres glycoforms. There was no significant relationships among genotypes, clinical features and PrPres isoforms in sporadic CJD cases. Our finding suggests that type A PrPres isoform is specifically found in the patients with GSS carrying codon 102 mutation, and there are at least two different PrPres isoforms in the patients with sporadic CJD.

We found 3 novel missense variants in the open reading frame of the prion protein (PrP) gene. The codon 105 point mutation (proline to leucine) was found on a codon 129 (Valine) PrP allele in 4 patients from 3 different Japanese families with Gerstmann-Sträussler syndrome. The codon 180 variant PrP (valine to isoleucine) was found in Creutzfeldt-Jakob disease (CJD) patients with a similar clinical course to that of codon 178 mutation. The codon 232 variant PrP (methionine to arginine) was documented in the CJD patients with typical clinical and pathological findings. These variant PrP molecules were not detected in 200 normal Japanese PrP alleles. PrP has a large repertoire of variant forms, and each primary structure of PrP corresponds to the distinct phenotype of prion diseases.

The clinical progression of Gerstmann-Sträussler-Scheinker disease in a family of Alsatian origin is reported. The age of onset and the duration of evolution were variable. The clinical picture became more complex over the generations: in the first generations, isolated dementia and in later generations a triad of pyramidal, pseudobulbar syndromes and dementia associated with spinal cord and cerebellar features. Prion gene analysis showed that four surviving patients carry double missense changes at codons 117 and 129, identical to those found in one case at necropsy and 10 other healthy members of the family. The missense changes were not found in 100 controls. No member of the family had modification of condons 102, 178, or 200. The lod score suggests linkage between the missense change at codon 117 and Gerstmann-Sträussler-Scheinker disease in this family.

The authors examined 10 patients with Gerstmann-Sträussler syndrome or Creutzfeldt-Jakob disease and 10 with Alzheimer's disease (AD). Immunohistochemistry using anti-prion protein (PrP) and anti-beta/A4 protein (beta/A4) coupled with formic acid pretreatment could detect Congophilic and non-Congophilic deposits. Prion protein deposits were classified into five types and compared with types of beta/A4 deposits. Kuru plaques with multicentric cores and fine granular deposits were a characteristic feature of PrP deposits. Some types of PrP or beta/A4 deposits depend on the anatomic sites. To clarify the relationship of microglia and astrocytes to PrP or beta/A4 deposits, double-immunostaining method was performed. In both kuru and senile plaques, microglia were closely linked to the Congophilic plaques. Astrocytes, however, extended their processes toward the plaques even in the non-Congophilic plaques. These observations strongly suggest that similar glial association with plaque formation may be involved in both kuru and senile plaques, although the amyloid core proteins differ.

Kuru plaques are the pathologic hallmark in Gerstmann-Sträussler syndrome (GSS). To demonstrate that prion protein (PrP) is a component of kuru plaque cores, we fractionated and sequenced kuru plaque core derived peptides, following digestion with Achromobacter lyticus protease I. We identified 3 PrP-derived peptides by reverse-phase high-performance liquid chromatography and found a fragment of digests derived from a missense variant of PrP. The variant PrP was also present in the prion rod fraction in patients with GSS. This substitution may play a major role in cerebral amyloidogenesis.

We report the clinical progression of the Gerstmann-Sträussler-Scheinker disease (GSS) in a family of Alsatian origin. The age of onset and duration of evolution were variable. The clinical picture became more complex over the generations: isolated dementia in the first generations, then, more recently, a triad of pyramidal, pseudobulbar syndrome and dementia associated with symptoms indicating spread of damage to the spinal cord and cerebellum. Study of the prion gene showed that in all patients analyzed and in 10 healthy family members, there is a double mutation of codon 117 leading to loss of the restriction site PvuII and to the replacement of an alanine by a valine. We did not find the mutation of codon 102 reported in 5 GSS families. The role of these mutations in the pathogenesis of the disease is unclear: marker for a particular susceptibility to the encephalopathies due to the prion, or direct role in the disease? Further study of the family, particularly the healthy carriers, could suggest the answer. GSS seems to be an especially useful model for the study of the role of a foreign abnormal protein in the synthesis and regulation of host proteins.

Using immunostaining with anti-prion protein (PrP) antiserum, we detected numerous kuru plaques in the brain of a 24-year-old man with Gerstmann-Sträussler-Scheinker syndrome. Immunoreactivity on Western blotting of the protease-resistant PrP fraction from the frozen brain was weak. PrP gene analysis showed substitution of alanine to valine in codon 117 but no substitution in codon 102. As the experimental transmission of the disease to mice was negative, a pathogen of a relatively low infectivity may cause the disease in predisposed family members.