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  • In a missense mutation at codon

    2024-04-24

    In 1989, a missense mutation at codon 102 of the PRNP gene was first reported to be associated with GSS and, in 1991, the same mutation was also found in affected members of the “H” family (Hsiao et al., 1989; Kretzschmar et al., 1991). By 1995, the pedigree of the “H” family included 221 family members, with 20 having been affected by the disease (Hainfellner et al., 1995). In 1991, an insert of eight extra copies of a repeating octapeptide coding sequence was identified in the PRNP region between codons 51 and 91, in individuals affected by a GSS-like hereditary syndrome (Goldfarb et al., 1991). This was the first instance of an insertion mutation, rather than a point mutation, being associated with clinical and neuropathologic changes seen in a GSS-like disorder. A primate, inoculated with a tissue homogenate obtained postmortem from NHS-12-Biotin of one of the affected individuals, developed a spongiform encephalopathy (Goldfarb et al., 1991). In 1992, the disease-causing gene in individuals of the Indiana kindred was mapped and a missense mutation at codon 198 of PRNP was found in all affected individuals (Dlouhy et al., 1992; Hsiao et al., 1992). In 1996, the first case of a unique, previously unrecognized, novel and peculiar PrP amyloidosis was reported (Ghetti et al., 1996b). The patient, who carried a nonsense mutation at codon 145 of PRNP, presented with an Alzheimer disease-like symptomatology. Neuropathologically, a PrP cerebral amyloid angiopathy (PrP-CAA) coexisted with numerous tau-immunopositive NHS-12-Biotin neurofibrillary tangles. Thus, PrP amyloidosis appears to be a central unifying pathologic event in a clinically heterogeneous group of dominantly inherited prion diseases that, from the neuropsychiatric and neuropathologic points of view, differs substantially from the group of prion diseases, that are characterized predominantly by the presence of a spongiform encephalopathy. For this reason, we choose to group under the broader term of dominantly inherited PrP cerebral amyloidoses those syndromes that have the following characteristics: (1) one of the following types of PRNP mutations: missense, insertion, nonsense, and deletion; (2) PrP parenchymal or vascular amyloid in the central nervous system; (3) variable clinical phenotype, that may be characterized by one of the following: (1) ataxia and personality disorder, similar to that described by Gerstmann et al. in the “H”. family, often accompanied by pyramidal and parkinsonian signs; (2) psychosis followed by neurologic and cognitive decline; (3) Alzheimer disease-like dementia; (4) frontotemporal dementia. In the GSS phenotype, associated with missense mutations, the neurologic symptoms start, in most cases, between the third and the sixth decades of life; they may be preceded by apathy and depression. The disease duration ranges from a few months to 15 years (Ghetti et al., 2011). In the cases with six or more octapeptide repeat insertions, the neurologic phenotype is predominantly characterized by cognitive and behavioral changes consistent with frontotemporal dementia, language dysfunction, and gait ataxia as well as clinical or electrophysiologic evidence of epileptiform activity. Symptoms start, in most cases, between the third and fifth decades of life. The disease duration ranges from 1 to 7 years (Schmitz et al., 2017). The clinical phenotype associated with nonsense (stop codon) mutations is predominantly characterized by cognitive and behavioral changes, consistent with those seen in Alzheimer disease (Ghetti et al., 1996b; Jayadev et al., 2011; Mead et al., 2013). Onset of chronic diarrhea and autonomic failure may precede the Alzheimer-like syndrome. The disease may last as long as 7 years. The signs and symptoms of dominantly inherited PrP cerebral amyloidoses may vary in onset and combination. The pathologic features may vary according to PRNP mutation and variability occurs in the neuropathology that accompanies PrP amyloid deposits. The neuropathologic phenotype is characterized by parenchymal or vascular amyloidosis, which may be accompanied by tau neurofibrillary tangles or, less frequently, by spongiform changes. The dominantly inherited PrP cerebral amyloidoses may be subdivided into the following four neuropathologic subgroups, characterized by: (1) parenchymal PrP amyloid and prominent spongiform changes; (2) parenchymal PrP amyloid and minimal or no spongiform changes; (3) parenchymal PrP amyloid coexisting with severe tau neurofibrillary pathology, and absent or minimal spongiform changes; and (4) vascular PrP-CAA coexisting with severe neurofibrillary pathology. The lesions of these dominantly inherited PrP cerebral amyloidoses are most numerous in the cerebral cortex, basal ganglia, and cerebellar cortex.