KU-55933 br Epidemiology br Genetics The dominantly inherite

Epidemiology
Genetics The dominantly inherited PrP cerebral amyloidoses are genetically transmitted with a penetrance of almost 100%. Early linkage analysis studies helped to established the relationship between GSS and mutations in the PRNP gene. PRNP is located on the short arm of chromosome 20 and encodes for PrP (Hsiao et al., 1989; Dlouhy et al., 1992; Prusiner, 1999; Collinge, 2001). Currently, at least 24 missense and nonsense mutations in the PRNP gene are known to be associated with hereditary cerebral PrP amyloidoses, including 19 missense mutations associated with a GSS-like phenotype and five nonsense (stop codon) mutations, mostly associated with a PrP-CAA. A two-basepair deletion at KU-55933 178 results in a premature stop codon mutation at codon 203 (Honda et al., 2016). Furthermore, hereditary PrP cerebral amyloidosis is also seen in association with insertional mutations of 144, 168, 192, 216, and 288 additional basepair repeats in the octapeptide repeat region or a 24-basepair repeat insertional mutation between codon 129 and 130 (Hinnell et al., 2011) (Fig. 14.1 and Table 14.1, Table 14.2). Commonly, in prion diseases the haplotype is defined by a PRNP mutation in combination with the genotype at codon 129; the latter codes for methionine or valine. Genetic mutation in PRNP and polymorphisms at codon 129; in the PRNP may be a modifier of the clinical and pathologic characteristics (Dlouhy et al., 1992; Prusiner, 1999; Collinge, 2001). Polymorphism at codon 219 may also modify the phenotype (Furukawa et al., 1995).
The dominantly inherited prion protein cerebral amyloidoses The initial phases of the psychiatric and neurologic manifestations of the dominantly inherited PrP cerebral amyloidoses will require future detailed studies. An early molecular diagnosis of PRNP mutations along with the knowledge of biomarker alterations and structural modifications as seen by imaging will allow researchers to carefully identify the psychiatric symptoms that precede neurologic manifestations. Psychiatric symptoms in early stages of disease have been described in dominantly inherited PrP cerebral amyloidoses that are associated with insertional mutations and missense mutations. Furthermore, it remais to be determined if specific PRNP mutations can also affect any central nervous system developmental stages. Due to the wide spectrum of clinical and neuropathologic characteristics, it is useful to describe individually the phenotypic characteristics associated with each of the PRNP mutations. In dominantly inherited PrP cerebral amyloidoses, the most common neuropathologic features are PrP amyloid plaques and diffuse deposits, moderate to severe neuronal loss and glial proliferation in the cerebral cortex, deep gray nuclei, and cerebellar cortex. Parenchymal PrP amyloid deposits are birefringent after Congo red stain and strongly fluorescent in thioflavin S preparations. On electron microscopy, the amyloid is composed of bundles of fibrils radiating out from a central core, each fibril measuring 8–10nm in diameter. The core of the amyloid plaque is immunoreactive to antibodies raised against the midregion of PrP, but nonreactive or weakly reactive to antibodies raised against the amino- and carboxy-terminal regions of PrP. In contrast, there is immunopositivity to antibodies raised against the amino and carboxy-terminal regions of PrP in the area surrounding the amyloid core. Nonfibrillar PrP deposits appear as diffusely immunolabeled areas in the neuropil (Ghetti et al., 1995, Ghetti et al., 1996a). The biochemical features of pathologic PrP in dominantly inherited PrP cerebral amyloidoses are unique and distinctive from other human prion disorders. These consist in the detection of pathognomonic C- and N-terminally truncated PrP fragments, also named PrP internal fragments (PrPIF), resistant to protease treatment and absent in large series of CJD (Tagliavini et al., 1991; Ghetti et al., 1996a; Piccardo et al., 1996, Piccardo et al., 1998; Zanusso et al., 2014) (Fig. 14.2).