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A novel neurodegenerative disease with multi-system features

Inherited prion diseases (IPD) are caused by mutations in the prion protein gene (PRNP) leading to accu- mulation of misfolded prion protein (PrP). Here we describe three novel PRNP mutations. A patient with gradually progressive cognitive decline, peripheral neuropathy, diarrhoea and autonomic dysfunction, starting in the 6th decade, whose father suffered a similar illness with neuropathology showing PrP-cerebral amyloid angiopathy, PrP-amyloid plaques and abundant tau disease with co-localising TDP-43, had a truncation mutation at codon 157. A missense mutation at codon 107 of PRNP causing an amino acid change from threonine to isoleucine was observed in a patient with a 9-year illness starting with cognitive decline followed by gait disturbance. Neuropathology shows multi-centric PrP-amyloid plaques. Substitution of proline to serine at codon 105 has previously been reported in one patient, however our case exhibited a different phenotype: dysphasia in the absence of neurological signs, with subsequent rapid cognitive then motor decline with myoclonus. Neuropathology showed predominantly synaptic deposition of PrP and sparse cerebellar plaques. These cases highlight the remarkable heterogeneity which can be seen within IPD, and the importance of genetic screening of PRNP in cases where there is an unexplained phenotype, particularly when there is a family history.