We present a patient with a mutation in the open reading frame of the prion protein gene (PRNP), which results in substitution of valine for alanine at codon 117. The patient is a member of a large American kindred of German descent with the telencephalic form of Gerstmann-Sträussler-Scheinker syndrome (GSS). Two other affected members of this kindred carried this mutation, as inferred from haplotypes of their offspring and spouses. The mutation was absent in one member with a protracted neurologic illness that differed from the other affected members' illnesses. The identification of a distinct PRNP mutation in the telencephalic form of GSS supports the hypothesis that allelic forms of PRNP may correspond to distinct clinical disease entities.