A novel prion disease associated with diarrhea and autonomic neuropathy.
BACKGROUND
Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.


METHODS
We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.


RESULTS
We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.


CONCLUSIONS
Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Simon
S
Mead
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Sonia
S
Gandhi
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Jon
J
Beck
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Diana
D
Caine
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Dillip
D
Gallujipali
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Christopher
C
Carswell
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Harpreet
H
Hyare
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Susan
S
Joiner
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Hilary
H
Ayling
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Tammaryn
T
Lashley
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Jacqueline M
JM
Linehan
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Huda
H
Al-Doujaily
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Bernadette
B
Sharps
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Tamas
T
Revesz
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Malin K
MK
Sandberg
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Mary M
MM
Reilly
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Martin
M
Koltzenburg
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Alastair
A
Forbes
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Peter
P
Rudge
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Sebastian
S
Brandner
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Jason D
JD
Warren
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Jonathan D F
JDF
Wadsworth
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Nicholas W
NW
Wood
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
Janice L
JL
Holton
Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
John
J
Collinge
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000209:etiology* / Q000473:pathology; D001921:Brain / Q000473:pathology*; D003967:Diarrhea / Q000209:etiology*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D017096:Prion Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000635:transmission; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*
C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions