Genetic Prion Disease Caused by PRNP Q160X Mutation Presenting with an Orbitofrontal Syndrome, Cyclic Diarrhea, and Peripheral Neuropathy

Abstract

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.

Keywords: Amyloidosis; DNA sequencing; dysautonomia; exome; mutation; peripheral neuropathy; prion dementia.

Fig. 1

Pedigree of family affected with PRNP Q160X. An autosomal dominant inheritance pattern was noted. The proband's asymptomatic father was a confirmed heterozygous Q160X carrier. The proband's paternal grandfather had severe dysautonomia, peripheral neuropathy, and cognitive decline. The arrow denotes the proband. The asterisks correspond to genetically confirmed PRNP Q160X cases. MM, codon 129 methionine homozygosity; MV, codon 129 heterozygosity; d., death age.

Fig. 2

Brain magnetic resonance imaging of the proband at age 31. Axial (a), coronal (b), and sagittal (c) T1-weighted images show severe symmetric temporal, perisylvian, parietal, and thalamic atrophy with associated ex-vacuo hydrocephalus.