RESUMEN
BACKGROUND: Human prion diseases have sporadic, acquired and inherited etiologies and show considerable phenotypic heterogeneity. An individual inherited prion disease offers an opportunity to study the determinants of this clinicopathologic heterogeneity among individuals with the same causal mutation. METHODS: We report clinical and pathologic data from three families with different 5-octapeptide repeat insertion (5-OPRI) mutations of the prion protein gene (PRNP), extending the reported phenotypic range of this mutation. RESULTS: The proband of a South African family presented with a rapidly progressive dementia and atypical pathology associated with kuru-like prion protein plaques. The original mutation in this family probably occurred on a PRNP allele encoding a 1-octapeptide repeat deletion polymorphism. This has not been previously reported as a precursor allele in over 30 other OPRI mutation kindreds. An English family with a genetically distinct mutation but identical protein product showed clinical onsets that varied 30 years between father and daughter, an effect that may be explained by their genotypes at PRNP codon 129. A patient from Northern Ireland with a phenotype of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance was unexpectedly found to have a 5-OPRI. CONCLUSIONS: When these cases were combined with the existing world literature, the mean age at onset for patients with 5-octapeptide repeat insertion (5-OPRI) was significantly later than that for patients with 6-OPRI, but both mutations exhibit a similar powerful disease modifying effect of PRNP codon 129.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación/genética , Enfermedades por Prión/genética , Priones/genética , Secuencias Repetitivas de Aminoácido/genética , Adulto , Codón/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Pruebas Genéticas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Irlanda del Norte , Linaje , Fenotipo , Polimorfismo Genético/genética , Enfermedades por Prión/etnología , Enfermedades por Prión/metabolismo , SudáfricaRESUMEN
Two carcinomas of the breast containing large areas of sarcomatous tissue were studied by light and electron microscopy. In one of these, the sarcomatous element was frankly cartilaginous and in the other, predominantly myxoid but with small cartilaginous-looking foci. By light microscopy, a highly suggestive metaplastic transition could be traced from cells within the epithelial nests to those within the sarcomatous lobules. Ultrastructurally, cells in the former region showed epithelial characteristics and those in the latter region, mesenchymal and/or cartilaginous features. The carcinomatous cells contained desmosomes and formed intercellular spaces lined by microvilli; a few cells showed prominent profiles of rough endoplasmic reticulum. In the first case, the cells in the immediate vicinity of the epithelial nests and those in the fully developed cartilaginous regions showed a progressive dilatation of their endoplasmic reticulum to form large sac-like structures filled with a finely granular and floccular material. The intercellular matrix was electron lucent and contained scattered dense particles, fibrillo-granular material and collagen fibres. Condensation of this material at some distance from the cell resulted in the formation of lacunae. In the second case, the cells in the myxoid areas also showed prominent dilatation of endoplasmic reticulum.