Inherited human prion disease

Inherited human prion disease (also known as genetic or familial prion disease) is a group of rare, fatal neurodegenerative disorders caused by pathogenic variants in the PRNP gene located on chromosome 20. This gene encodes the prion protein (PrP), and mutations lead to misfolding of this protein into an abnormal, disease-causing form (PrPSc) that accumulates in the brain, causing progressive neuronal damage and spongiform (sponge-like) changes in brain tissue. The three major clinical subtypes of inherited prion disease are familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI), each associated with specific PRNP mutations and distinct clinical presentations. The central nervous system is the primary system affected. Common clinical features across subtypes include rapidly progressive dementia, cerebellar ataxia (difficulty with coordination and balance), myoclonus (sudden involuntary muscle jerks), visual disturbances, psychiatric symptoms (depression, anxiety, personality changes), and sleep disturbances. In FFI, intractable insomnia and dysautonomia (dysfunction of the autonomic nervous system) are hallmark features. In GSS, progressive cerebellar ataxia tends to predominate early in the disease course. Familial CJD most closely resembles sporadic CJD with rapid cognitive decline and myoclonus. Disease duration varies by subtype, ranging from months in fCJD to several years in GSS. There are currently no curative or disease-modifying treatments for inherited prion diseases. Management is entirely supportive and palliative, focusing on symptom control, comfort care, and psychosocial support for patients and families. Genetic counseling is essential for affected families, as the disease follows an autosomal dominant inheritance pattern with variable penetrance depending on the specific mutation and the polymorphism at codon 129 of the PRNP gene. Research into potential therapies, including antisense oligonucleotides targeting PRNP expression, is ongoing but remains in early stages.

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