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 R2 octapeptide repeat 144-bp insertion in the prion protein gene (PRNP) showed a slowly progressive dementia associated with cerebellar signs, myoclonic jerks, and seizures. Although postmortem examination revealed only focal and minimal spongiform degeneration in one subject with a 4-year course, significant astrogliosis and neuronal loss were associated with pronounced spongiform degeneration in the patient with a duration of symptoms of 10 years. Prion protein (PrP)-immunoreactive patches with a unique morphology were present in the molecular layer of the cerebellum in both subjects. Western blot analysis demonstrated the presence of protease-resistant prion protein (PrPres) with the same characteristics (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 severity of spongiform degeneration in the cerebral cortex. The findings suggest that a relatively low rate of PrPres deposition is the cause of the lack of spongiform degeneration in subjects carrying a 144-bp insertion 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 useful in the diagnosis of this subtype of human prion disease.
Capellari
S
S
Division of Neuropathology, Case Western Reserve University, Cleveland, OH.
Vital
C
C
Parchi
P
P
Petersen
R B
RB
Ferrer
X
X
Jarnier
D
D
Pegoraro
E
E
Gambetti
P
P
Julien
J
J
D000328:Adult; D015153:Blotting, Western; D002531:Cerebellum / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D011328:Prions / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D013030:Spain
D011328:Prions