Clinical Guidance

Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Strussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from ages 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome. provides information on the frequency of neurologic features in the most frequent genetic prion disease phenotypes that emerge during the disease course. While some PRNP pathogenic variants are associated with specific neuropathologic phenotypes, individuals in the same family who are heterozygous for the same PRNP variant may develop distinct clinicopathologic phenotypes . Table 2. Select Features of Genetic Prion Disease by Phenotype and PRNP Pathogenic Variant Feature | % of Persons w/Feature by Phenotype PRNP Variant

Source: GeneReviews — "Genetic Prion Disease"

Penetrance

The penetrance for genetic prion disease in general is assumed to be 100%; however, only a limited number of studies have been performed to address this issue. The penetrance for the E200K variant (which has been studied more extensively than for other variants) was 60%-70% in Italian and Slovak families and 100% in Libyan Jewish families .

Source: GeneReviews — "Genetic Prion Disease"

Differential Diagnosis

Because of the progressive neurologic decline, the range of neurologic signs, and the heterogeneous presentation of genetic prion disease, the differential diagnosis is broad and needs to include other hereditary neurodegenerative disorders as well as a variety of acquired disorders. Because potential treatment options depend on identification of the underlying cause, autoimmune and paraneoplastic disorders need to be considered .

Table 3.

Disorders Potentially Associated with Rapid Progression of Interest in the Differential Diagnosis of Genetic Prior Disease

Etiology | Disorder/Comment | Gene(s)

Hereditary

neurodegenerative

disorders | CSF1R-related adult-onset leukoencephalopathy w/axonal spheroids pigmented glia | CSF1R

Dementia w/Lewy bodies (OMIM 127750) | GBA1 (GBA)SNCASNCB

Source: GeneReviews — "Genetic Prion Disease"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Genetic Prion Disease"