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A new prion disease: relationship with central and peripheral amyloidoses

Nature Reviews Neurology volume 11, pages 90–97 (2015)Cite this article

Subjects

Key Points

  • The misfolding of proteins and their subsequent deposition as amyloid in peripheral nerves lead to sensory and autonomic neuropathy

  • A new hereditary form of neuropathy, prion protein (PrP) systemic amyloidosis, is caused by truncation mutations of the prion protein gene PRNP

  • Some acquired prion diseases are known to have a peripheral phase in their pathogenesis, but were not previously thought to cause peripheral disease

  • The new prion disease is unlikely to pose any risk of iatrogenic transmission, but precautionary measures are recommended

  • Peripheral manifestations are increasingly recognized in common neurodegenerative diseases associated with protein misfolding

  • Regional variability in protein deposition and toxicity associated with protein-misfolding disorders is only partly explained by known factors, and is a key area for future research

Abstract

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.

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Figure 1: Tissue distribution of abnormal PrP in three prion diseases, with affected areas shown in colour.
Figure 2: Overlap in the phenotypes of prion diseases HSAN, FAP and CAA.
Figure 3: Suggested diagnostic flow chart for undiagnosed sensory and autonomic neuropathy.

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Acknowledgements

S.M. is funded by core support for the UK Medical Research Council (MRC) Prion Unit. M.M.R. is grateful to the MRC for an MRC Centre Grant (G0601943), and the US National Institutes of Neurological Diseases and Stroke and the Office of Rare Diseases (U54NS065712) for their support. This work was undertaken at University College London Hospitals and University College London, which received a proportion of funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

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Authors and Affiliations

  1. Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Simon Mead

  2. Department of Molecular Neurosciences, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Mary M. Reilly

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The authors contributed equally to researching data for the article, discussion of content, writing the article, and review and editing of the manuscript before submission.

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Correspondence to Simon Mead.

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Mead, S., Reilly, M. A new prion disease: relationship with central and peripheral amyloidoses. Nat Rev Neurol 11, 90–97 (2015). https://doi.org/10.1038/nrneurol.2014.263

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