Familial progressive subcortical gliosis: presence of prions and linkage to chromosome 17.
ABSTRACT Progressive subcortical gliosis (PSG) is a sporadic and familial dementing disease characterized pathologically by astrogliosis at the cortex-white matter junction, a feature present in some prion diseases. With immunocytochemical and Western blot analyses, we investigated the presence of deposits of the prion protein (PrP) and of the protease-resistant PrP isoform, the hallmarks of prion diseases, in six affected members of two large kindreds with PSG. The coding region of the PrP gene was sequenced and chromosomal linkage determined. We demonstrated "diffuse" PrP plaques in the cerebral cortex of two subjects from one kindred and protease-resistant PrP fragments in four of the five subjects examined. We found no mutation in the coding region of the PrP gene. Moreover, the disease was linked to chromosome 17 and not to chromosome 20, where the PrP gene resides. The familial form of PSG is the first human genetic disease characterized by the presence of protease-resistant PrP that lacks a mutation in the coding region of the PrP gene. The linkage to chromosome 17 suggests that other genes are involved in the PrP metabolism. Whether the protease-resistant PrP plays a primary or secondary role in the pathogenesis of this form of PSG remains to be determined.
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ABSTRACT: At the turn of the nineteenth century into the 20th century many leading neurologists were active to devise new pathological or clinical classifications of the large group of dementing illnesses in later life, the 'dementia senilis' . Until then that eponym included every psychiatrie, behavioral and cognitive disturbance, occurring after middle age and leading to complete deterioration of the mental functions. In 1892, Arnold Piek (1851-1924), professor in neurology and psychiatry at the German University of Prague, reported a patient with a two-year history of progressive 'feeble-mindedness' , behavioral disturbances and eventually aphasia. Focal temporal atrophy of the brain was found at autopsy. Piek subsequently described a few more cases with frontal and temporal atrophy and considered this focal pathology as a localized type of 'seniIe dementia' and not a distinct disease-entity. However he suggested a possible clinical-pathological relation without being specific. Alois Alzheimer (1911) described the microscopical findings to become associated with 'Piek's disease": neuronalloss, spongiosis and gliosis in the frontal and temporal cortex, argentophilic granules in the neuronal cytoplasm pushing the nucleus towards the cell body (Pick bodies), and swollen neurons (Piek cells) in the absence of neurofibrillary tangles and plaques. Van Mansvelt (1953), in a review, classified Pick's disease according to the localization of atrophy into three types: frontal, temporal and mixed' Piek bodies were reported in only one third of the cases. For a diagnosis of Piek' s disease at that time, Piek bodies were not essential. Constantinidis (1974) classified frontotemporal atrophy into three types based on the presence of Piek bodies and Piek cells: (1) cases with: Piek bodies and swollen neurons, (2) cases with only swollen neurons, and cases without Pick bodies and Piek cells.' Fronto-temporal dementia in the absence of Piek bodies became also described by Brun as 'frontal lobe degeneration of non-Alzheimer type'.
European Journal of Neurology 01/2011; 3(6):487 - 499. DOI:10.1111/j.1468-1331.1996.tb00263.x · 3.85 Impact Factor
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ABSTRACT: Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition. Ann Neurol 1999;45:704–715Annals of Neurology 05/2001; 45(6):704 - 715. DOI:10.1002/1531-8249(199906)45:6<704::AID-ANA4>3.0.CO;2-X · 11.91 Impact Factor