Use of Tonsillar Biopsy to Identify the Variant Prion of Creutzfeldt-Jakob Disease

abstract & commentary

Source: Hill AF, et al. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999;353:183-189.

The devastating, fatal encephalopathy of Creutzfeldt-Jakob disease (CJD), otherwise identified as prion disease, derives from the development of one of four pathologic isoforms of the body’s normal cellular prion protein (PRPc). Each of the abnormal variables, inclusively designated as PRPsc, has been clinically and molecularly distinctly identified as: inherited, sporadic, acquired (e.g., iatrogenically or kuru) and, most recently, a variant form. (The four abnormal varieties differ in protein conformation and immunomolecular staining.) The variant form links to the British (and a single French case) epidemic of bovine spongiform encephalopathy (BSE). More important is that variant type 4 PrPsc can be selectively identified by western blotting and replicated by specimens drawn from a carrier’s bodily lymphoreticular system. This tissue is apparently not consistent for harboring the other three variants. (Sheep scrapie prions also can be identified in lymphoreticular tissue.) Taking advantage of this singularity, Hill and colleagues examined tonsillar biopsy tissue in three autopsy brains and six presumed variant CJD cases. By random occurrence, they found variant prions in the intestinal appendiceal lymphoreticular system of one patient presenting with possible CJD. All patients were younger than 36 years of age and suspected of possible variant form of CJD. In the still alive group, behavioral and mood disorders were frequent, as were dysesthesias and signs of motor dysfunction. Dementia, however, marked all patients by the time that variant CJD was suspected. CSF protein 14-3-3, a relatively dependable diagnostic finding in the other forms of CJD, was positive in only five variant patients, while three other variant patients showed only traces.

Tonsillar biopsies in all nine variant patients were positive by western blotting for PrPsc, immunohistochemistry, or both. In five patients clinically suspected of variant CJD, tonsillar biopsy provided selectively accurate diagnosis of PrP on an average of 8.5 months preceding death. During the period of investigation, two out of five autopsies of CJD performed elsewhere in England revealed variant CJD prions. The remaining had sporadic or iatrogenic CJD and showed neither western blot nor immunochemical identification of variant CJD.

COMMENTARY

This is a most important report. "Mad Cow" disease is due presumably to cattle innocently consuming remnants of contaminated offal from scrapie-affected sheep. The variant prion of CJD was discovered in humans in 1996, by which time most English and much Continental cattle had been sacrificed. Thus far, Hill et al indicate that 34 cases of variant prion disease have slowly become identified. That lymphoreticular tissue, easily obtained by tonsillar biopsy, has been found to contain the variant prion as early as 16 months before death is an important tool for early diagnosis. Hopefully, it also will catalyze greater and successful efforts to halt the progress of the clinical disease.