Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity

Background Familial Creutzfeldt-Jakob disease (fCJD) (genetic human prion disease) is caused by mutations in the prion protein gene (PRNP), which is located on chromosome 20p13. The etiology of the sporadic form of CJD (sCJD) is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), for example, is often seen in conjunction with sCJD. Method In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis , prion disease, and Parkinson’s disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau (MAPT) haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between apolipoprotein E gene (APOE) and PRNP in sCJD patients. Results We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G variant of uncertain significance (VUS) in PSEN1 in three patients. The importance of this variant is currently still a matter of debate. In PRNP, we also found a previously described nonpathogenic insertion (p.P84_Q91Q). Conclusion Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.