We report a family with an autosomal dominant inherited prion disease caused by a novel PrP truncating mutation Y157X, characterized by features of a systemic amyloidosis (peripheral sensory and autonomic neuropathy, gastrointestinal symptoms), slowly progressive cognitive decline and neuropathology demonstrating PrP-CAA and hyperphosphorylated-tau pathology. The gene discussed is PRNP; the disease is primary systemic amyloidosis.