The clinical and pathologic features in this kindred contrast with other reported CJD cases with BPI. All three affected members of this kindred had cognitive and behavioral changes more consistent with FTD 26
than AD 27
or CJD 28
. Dementia is usually present in CJD with BPI, but most reports have not included the specific cognitive and behavioral features that permit comparisons to the “modern” syndromic terminology of FTD, PNFA, corticobasal syndrome, etc. The speech and language features in the proband were not entirely consistent with the PNFA syndrome, but were abnormal nonetheless. Gait ataxia is not typical of FTD, and this clinical feature in all three cases represented a clue to a disorder not usually considered within the FTD spectrum.
Elevations in 14-3-3 and NSE levels are common in sporadic CJD, but there is minimal data on values in familial prion disorders, and increases in CSF 14-3-3 or NSE are not specific to prion disorders. Despite the long duration of symptoms in the proband (six years from onset of symptoms to the time her CSF was examined), the mildly elevated NSE did suggest a prion disorder. The low CSF Aβ42 and high total tau observed in the proband is typical of AD - a false-positive result that reinforces the observation that such findings must be interpreted with caution when the clinical syndrome is not typical of AD. How common very high total CSF tau results are in familial CJD cases is not known.
The MRI findings in CJD cases with BPI have not been well-characterized. Symmetric bifrontal atrophy was present on MRI in the proband. There were no abnormal signal changes on fluid attenuation inversion recovery (FLAIR) or diffusion-weighted images. Clinical or electrophysiologic evidence of epileptiform activity was present in all affected members of this kindred. Seizures have been reported in the P301S MAPT
but rarely if ever in the other MAPT
mutations. Furthermore, seizures and particularly the spike and wave pattern on EEG are uncommon in the familial prion disorders. While we cannot exclude the possibility of another etiology for the seizures and EEG findings, we suspect the EEG pattern and seizures are related to the underlying prion disorder. This constellation of antemortem findings is therefore unique to this kindred.
The pathologic findings in both cases are more in keeping with the few other familial prion disorders with BPI of eight octapeptide repeats or more, in which the pathologic phenotype shares many similarities with GSS 30, 31
. We suspect that the topographic involvement of pathology in the bifrontal regions explains the FTD-like clinical and radiologic features, and involvement in the cerebellum explains the gait ataxia. If one can surmise the topographic evolution of pathology in cases like these based on their evolution of symptoms and findings, it appears that significant frontal pathology occurs prior to the development of significant cerebellar pathology. This sequence of evolution can also occur in GSS due to point mutations in PRNP
, potentially leading to diagnostic confusion with the disorders more typically associated with FTD.
The cases in this kindred therefore exemplify that a familial prion disorder should be considered in the setting of an autosomal dominant FTD-like syndrome, particularly if gait ataxia or generalized tonic-clonic seizures are present and if no mutations are present on PSEN1 and MAPT testing.