Clinical Pearls & Morning Reports
Published October 16, 2019
Sporadic Creutzfeldt–Jakob disease is the most common human prion disease and has a broad and heterogeneous spectrum of manifestations. Read the latest Case Records of the Massachusetts General Hospital here.
Q: What causes Creutzfeldt–Jakob disease?
A: The pathogenesis of Creutzfeldt–Jakob disease centers around cellular prion protein (PrPC), a cell-surface glycoprotein of unknown function that is abnormally folded into the scrapie form (PrPSc). PrPSc replicates itself by misfolding PrPC into PrPSc by means of post-translational modification.
Q: What is the most common form of Creutzfeldt–Jakob disease?
A: Creutzfeldt–Jakob disease may be classified as sporadic, familial, or acquired, with the sporadic form accounting for approximately 85 to 90% of cases. The cerebellar form of Creutzfeldt–Jakob disease (Brownell–Oppenheimer variant) is characterized by a cerebellar syndrome with no evidence of cognitive impairment in the first month of illness, and it accounts for approximately 20% of cases of sporadic Creutzfeldt–Jakob disease.
A: The mean age at onset is 63 years, and the first symptoms that occur are most commonly gait dysfunction, dizziness, and incoordination. Cognitive impairment occurs a mean of 3 months after the onset of other symptoms. Other neurologic features, such as pyramidal signs, myoclonus, or vision impairment, become evident with progression. Abnormal MRI findings usually occur at some point in the disease course, but they may initially be subtle or misread. EEG has low sensitivity for the cerebellar form of Creutzfeldt–Jakob disease.
A: Both tau and 14-3-3 are released into the CSF during the development of rapid neuronal damage, but their presence in the CSF is not specific to neuronal damage induced by PrPSc. Both tests can detect Creutzfeldt–Jakob disease with a sensitivity of greater than 90%; however, specificity is near 80%. The CSF RT-QuIC assay has emerged as the reference standard for the diagnosis of Creutzfeldt–Jakob disease. The RT-QuIC assay directly tests the inherent infectivity of PrPSc by reproducing the misfolding process in vitro. With the use of recombinant, conformationally normal prion protein as a substrate, PrPSc that is present in the sample of CSF replicates itself during cycles of vigorous shaking. The accumulated misfolded prion protein is detected with the use of thioflavin T. The RT-QuIC assay detects Creutzfeldt–Jakob disease with a sensitivity of 92% and a specificity of 99 to 100%.