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Clinical characteristics: Genetic prion diseases generally manifest 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. Familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) represent the core phenotypes of genetic prion disease. Note: A fourth clinical phenotype, known as Huntington disease like-1 (HDL-1), has been proposed, but this is based on a single report, and the underlying pathologic features would categorize it as GSS. Although it is clear that these four subtypes 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 ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically 5-7 years; in rare instances, >10 years).
Diagnosis/testing: PRNP is the only gene in which pathogenic variants are known to cause genetic prion disease. The presence of a PRNP pathogenic variant is necessary to establish the diagnosis of genetic prion disease in a symptomatic individual. Sequence analysis of PRNP may not detect all pathogenic variants; thus, the absence of a PRNP pathogenic variant does not rule out the diagnosis of genetic human prion disease.
Management: Treatment of manifestations: Antiepileptic drugs (AEDs) including diphenylhydantoin or carbamazepine for seizures; clonazepam for myoclonus; use of a permanent feeding tube for dysphagia on a case-by-case basis; involvement of a social worker to assist the family in management planning. Prevention of secondary complications: Caution is advised for any affected individual undergoing a surgical procedure, including endoscopy, brain biopsy, etc., as the surgical instruments used must be properly decontaminated or discarded, to reduce the possibility of transmission of prion disease to other persons. Surveillance: Examination at regular intervals for complications (related to, e.g., swallowing difficulties, intercurrent infections, and other disease manifestations). Agents/circumstances to avoid: There are no known substances that are reported to specifically worsen prion diseases, but as with any dementia, anticholinergics and antihistamines with high anticholinergic potential should be avoided. Therapies under investigation: Clinical trials of quinacrine were unsuccessful in proving benefit for CJD. Several experimental therapies (antibodies against PrP, gene silencing with RNA inhibitors, and anti-amyloids) are being tested in animal models.
Genetic counseling: Genetic prion disease is inherited in an autosomal dominant manner. Most individuals diagnosed with genetic prion disease have an affected parent. However, a proband with genetic prion disease may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with a pathogenic PRNP variant has a 50% chance of inheriting the variant. Prenatal testing for pregnancies at increased risk of having a PRNP pathogenic variant is possible if the family-specific variant has been identified.
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