FAMILIAL PRION DISEASE WITH A NOVEL 144-BP INSERTION IN THE PRION PROTEIN GENE IN A BASQUE FAMILY

Three members of a Basque family carrying a novel six R-2 octapeptide repeat 144-bp insertion in the prion protein gene (PRNP) showed a slow ly progressive dementia associated with cerebellar signs, myoclonic je rks, and seizures. Although postmortem examination revealed only focal and minimal spongiform degeneration in one subject with a 4-year cour se, significant astrogliosis and neuronal-loss were associated with pr onounced spongiform degeneration in the patient with a duration of sym ptoms of 10 years. Prion protein (PrP)-immunoreactive patches with a u nique morphology were present in the molecular layer of the cerebellum in both subjects. Western blot analysis demonstrated the presence of protease-resistant prion protein (prp(res)) with the same characterist ics (size and ratio of the three differently glycosylated isoforms) of that found in typical sporadic Creutzfeldt-Jakob disease (CJD129M/M, PrPres type 1). The amount of PrPres correlated with presence and seve rity of spongiform degeneration in the cerebral cortex. The findings s uggest that a relatively low rate of PrPres deposition is the cause of the lack of spongiform degeneration in subjects carrying a 144-bp ins ertion in PRNP. The presence of PrP-immunoreactive patches with unique morphology in the molecular layer of the cerebellum is a hallmark of certain prion encephalopathies with insertional mutations and is usefu l in the diagnosis of this subtype of human prion disease.