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Commentary for “Genetic Creutzfeldt–Jakob disease with R208H mutation presenting as progressive supranuclear palsy”

Matěj and colleagues described a case of genetic Creutzfeld–Jakob disease (gCJD) that was initially diagnosed as progressive supranuclear gaze palsy (PSP). The patient exhibited the clinical features of supranuclear gaze palsy and unexplained falls, which are the best features for predicting the diagnosis of PSP and are also consistent with the Richardson’s syndrome subtype. Additional features of Richardson’s syndrome were present in this case including axial greater than limb rigidity and early cognitive impairment. It is important to note that the combination of clinical features that include eye movement abnormalities, postural instability, and parkinsonism are not exclusive to PSP and that a diverse range of etiologies are associated with a PSP phenotype. Examples include other tauopathies such as frontotemporal dementia with parkinsonism-17, caused by mutations in the MAPT gene. In addition, parkinsonism and abnormal vertical gaze can be manifestations of Whipple’s disease. Furthermore, a PSP-like syndrome due to hypoxic-ischemic injury can occur after surgical repair of ascending aorta dissection or aneurysm. As illustrated by the vignette reported by Matěj and colleagues, CJD should also be considered in the differential diagnosis of PSP-like syndromes. The patient eventually demonstrated all elements of the CJD ‘‘clinical triad’’ of dementia, myoclonus, and periodic or pseudoperiodic discharges on electroencephalogram. Additional features of CJD were present, such as corticospinal tract and cerebellar signs and signs of an akinetic-rigid syndrome. The initial MRI was normal, but a subsequent scan showed typical changes of CJD, underscoring the utility of serial MRIs in obtaining a diagnosis. The cerebrospinal fluid findings further supported the diagnosis of CJD. Moreover, the course of the illness was more rapid than expected for PSP, with PSP patients having a median survival of 8 years, compared with 12 months for CJD patients. Genetic forms of transmissible spongiform encephalopathy account for approximately 10% of cases and are linked to specific mutations in the PRNP gene. The patient described in the clinical vignette was found to have a p.R208H mutation in the PRNP gene and a VV2 molecular subtype. Previous reports have described the phenotype of other CJD patients with the p.R208H mutation; however, eye movement abnormalities were documented in only 1 of these case studies, and clear-cut genotypephenotype correlations were overall absent in carriers of pathogenic PRNP mutations. Conversely, there appears to be a correlation between the 6 molecular subtypes (MM1 or -2, MV1 or -2, VV1 or -2) and the phenotype in both the sporadic and genetic forms of CJD. Interestingly, compared with other subtypes, VV2 cases had the highest percentage of ‘‘oculomotor’’ impairment at disease onset (32%), suggesting a predilection for eye movement abnormalities among carriers of this variant. This clinical vignette further highlights the heterogeneity of clinical presentations in CJD, which should be considered in the differential diagnosis of any adult reaching middle age with otherwise unexplained neurological deficits, especially those with dementia and myoclonus. Although CJD is an incurable disorder, it is beneficial to obtain an early diagnosis in order to provide an accurate prognosis and to avoid unnecessary investigations and treatments.