Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature
myoclonus and
cerebellar ataxia. Several families have now been described with a late-onset hereditary sensory and autonomic neuropathy caused by truncation of
prion protein (PrP), and associated with systemic
amyloidosis, which was a profoundly unexpected phenotype. The chronic symptoms of this disorder, termed PrP systemic
amyloidosis, can be very disabling, and are comparable to
familial amyloid polyneuropathy (FAP) caused by
transthyretin mutations. Patients require symptomatic
therapies directed towards control of
nausea, diarrhoea, incontinence,
neuropathic pain and
postural hypotension. Although the potential transmissibility of this new
prion disease is probably extremely low, we advocate PrP gene analysis before biopsy in the investigation of peripheral and autonomic neuropathies, or for patients with unexplained diarrhoea and neuropathy.
Prion diseases and the FAPs both display prominent effects of mutation type on clinical presentation and patterns of pathology-a fascinating but unexplained observation. Several
neurodegenerative diseases associated with central
protein misfolding, such as Huntington and Parkinson diseases, also have under-recognized peripheral components. Most of the
familial amyloidoses can be explained by known gene mutations, but
amino acid variants in
proteins involved in other central
neurodegenerative diseases might direct the initial pathology to the periphery.