Present and previous data together suggest that not all patients with familial prion disease have infectious prions. Possibly certain PrP mutations do not form a conformation capable of generating an infectious moiety. Alternatively, there might be a low titer of infectivity in the tissues which have not shown transmission. So far there has been no side by side comparison of transmission of familial prion disease brain infectivity using the sensitive bank vole animal model  or various human PrP expressing mice presently available. Regardless of which system is used, negative transmission results can always be interpreted as being due to an inefficient recipient animal system. However, in the present experiments using tg66 mice, if infectivity is present in Q227X patient brain, the titer must be below the level in the Y226X patient.