Creutzfeldt-Jakob disease

Genetic Creutzfeldt-Jakob disease typically manifests in the sixth decade, with onset between 50 and 60 years. A nonspecific prodromal phase with dizziness, fatigue, blurred vision, depressive mood, and weight loss is followed within weeks by progressive cognitive decline, ataxia, and myoclonus. Within a few months, affected individuals become bedridden and akinetic or mute; the
advanced stage is dominated by myoclonus, rigidity or spasticity, ataxia, and cortical visual disturbances, with a median survival of approximately six months from disease onset. Genetic Creutzfeldt-Jakob disease forms part of a wider clinical spectrum of genetic prion disease that also encompasses fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome, with substantial inter- and intra-familial variability in presenting features and in the predominance of cognitive, cerebellar, or sleep-related involvement.

Epidemiologic studies utilising reports of prion disease from centers around the world are frequently consistent with respect to the prevalence of genetic prion disease, as 15% of all individuals with newly diagnosed prion disease have genetic prion disease (GeneReviews, 2021).

Genetic Creutzfeldt-Jakob disease is caused by germline pathogenic variants in PRNP on chromosome 20p13, which encodes the major cellular prion protein (PrPC). A pathogenic PRNP variant destabilises PrPC and enhances its propensity to convert into the misfolded, scrapie-type isoform PrPSc; PrPSc then acts as a conformational template, recruiting further PrPC and propagating misfolding through central nervous system tissue. The mechanism by which PrPSc accumulation
becomes neurotoxic is currently not understood. Although some PRNP pathogenic variants are associated with specific neuropathologic phenotypes, evidence also suggests that heterozygotes for the same variant in the same family may develop distinct clinicopathologic phenotypes.

Genetic Creutzfeldt-Jakob disease is inherited in an autosomal dominant manner. Each child of an individual with a pathogenic PRNP variant has a 50% chance of inheriting the variant.

Genetic Creutzfeldt-Jakob disease is diagnosed primarily by molecular genetic testing for pathogenic variants in PRNP. Cerebrospinal fluid analysis may demonstrate elevated 14-3-3 protein and protein tau, and the real-time quaking-induced conversion (RT-QuIC) assay is typically positive; brain MRI may show high signal intensities in the caudate nucleus and cortical regions on diffusion-weighted and T2/FLAIR sequences.

Main differential diagnoses include:

• Sporadic Creutzfeldt-Jakob disease: clinically near-identical to gCJD but without a pathogenic PRNP variant and without a positive family history; sporadic, no causal gene.
• : autosomal dominant progressive dementia with onset before 65, predominantly amnestic and psychiatric rather than ataxic; APP, PSEN1, PSEN2.
• Frontotemporal dementia: behavioural- or language-variant dementia with frontotemporal atrophy, typically lacking the CSF 14-3-3/RT-QuIC profile of CJD; C9orf72, GRN, MAPT.

• Establishing the diagnosis confirms the clinical suspicion at the molecular level and provides the basis for individualised counselling of affected individuals and their relatives.
• Identification of the underlying pathogenic variant is a prerequisite for targeted medical care; further clinical management decisions remain with the treating physicians in consultation with the affected individual.
• Once a pathogenic variant has been identified in an affected family member, predictive testing of asymptomatic at-risk relatives becomes possible within a framework of pre- and post-test genetic counselling.

• Zerr I, Schmitz M. Genetic prion disease. 2003 Mar 27 [Updated 2021 Jan 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301407.
• Tejedor-Romero L, López-Cuadrado T, Almazán-Isla J, Calero M, García López FJ, de Pedro-Cuesta J. Survival patterns of human prion diseases in Spain, 1998-2018: clinical phenotypes and etiological clues. Front Neurosci. 2021;15:773727. doi:10.3389/fnins.2021.773727. PMID:; PMCID: PMC8811314. 
• Watson N, Brandel JP, Green A, Hermann P, Ladogana A, Lindsay T, et al. The importance of ongoing international surveillance for Creutzfeldt-Jakob disease. Nat Rev Neurol. 2021;17(6):362-79. doi:10.1038/s41582-021-00488-7. PMID:; PMCID: PMC8109225. 
• Ladogana A, Kovacs GG. Genetic Creutzfeldt-Jakob disease. Handb Clin Neurol. 2018;153:219-42. doi:10.1016/B978-0-444-63945-5.00013-1. PMID:.