ARTICLE IN BRIEF
Data collected over a period of 20 years at one British hospital identified a large family who appear to have an inherited prion disease characterized by chronic diarrhea in their 30s, followed by sensorial or autonomic peripheral polyneuropathy and slowly progressive neurocognitive symptoms years later.
Researchers at the United Kingdom's Medical Research Council (MRC) Prion Unit have reported what appears to be a new inherited prion disease in members of a family who first developed chronic diarrhea in their 30s, followed by sensorial or autonomic peripheral polyneuropathy and slowly progressive neurocognitive symptoms years later.
Data collected over a period of 20 years at one British hospital identified the large family. Investigators were able to study six of 11 affected individuals, with autopsy or biopsy samples from five of them. They were also able to use genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular, genetic, and biochemical studies. In addition, they tested whether mice injected with serum samples developed the disease.
The findings, reported in the Nov. 14 issue of the New England Journal of Medicine, suggest that prevalence of the genetic mutation and the incidence of the disease in other families may be underdiagnosed because most patients with unresponsive chronic diarrhea are typically referred to gastrointestinal experts, with later neurocognitive symptoms being attributed to other disease states, the researchers said.
Among the members who initially presented with chronic diarrhea, bloating, and fluctuating weight, most were diagnosed with irritable bowel syndrome and/or Crohn's disease.
The study was conducted by scientists at the MRC Prion Unit, as well as the University College London's departments of molecular neuroscience; department of neurodegenerative disease; Dementia Research Center; and the National Prion Clinic.
In 2010 the team first reported that the affected family members had a PRNP — gene that encodes for prion resistant protein — Y163X truncation mutation, with shared characteristics of an inherited prion disease. More than 30 mutations in the PRNP gene have been identified among individuals with inherited prion diseases, including classic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and kuru — an epidemic prion disease first identified among highland tribes in New Guinea who practice cannibalism as part of death rituals, including consumption of the brain.
Prion diseases are believed to result from misfolding of normal cellsurface prion protein that aggregate in the brain and attack the central nervous system.
The MRC researchers reported what they called a “distinct and consistent” phenotype of chronic diarrhea in the patients, with autonomic failure and a lengthdependent axonal, predominantly sensory, peripheral polyneuropathy. Onset began in early adulthood. Some patients also had postural hypotension in the early stages. Cognitive decline and seizures began when the patients were in their 40s or 50s, and the average age of death was 57 years.
Three patients underwent eight formal neuropsychological evaluations at different times of their illness. The most common finding was memory impairment and executive function difficulties when patients were in their 50s. In addition, two of the most profoundly affected individuals had phonologic language impairment.
Autopsy and biopsy data revealed deposits of amyloid throughout patients' peripheral organs, including the bowel and peripheral nerves. Moreover, neuropathological examination during endstage disease showed frequent deposits of prion protein in cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy.
Examination of brain tissue revealed a unique pattern of abnormal prion protein fragments, and cerebrospinal fluid showed elevated total tau and S100b protein, as well as elevated amounts of 1433 protein in one patient.
Duodenal biopsy samples showed extensive focal accumulation of prion protein in the muscularis mucosae, as plaques, and more diffuse deposits in the lamina propria and submucosa, in one member. Histopathological analysis of multiple internal organs obtained on autopsy from two of the six patients showed consistent, widespread, and extensive deposits of prion protein amyloid.
Histologic examination of neocortical regions of brain tissue from the first family member to be autopsied showed mild spongiosis restricted mainly to cortical layers 1 and 2, with similar findings in two additional members after they died.
Intracerebral inoculation of mice with human prion protein transgenes, however, did not result in transmission within 600 days.
CROSS-SPECIALTY AWARENESS NEEDED
Lead study author Simon Mead, PhD, who heads the National Prion Clinic based at the National Hospital for Neurology and Neurosurgery in London, said the study underscores the need for greater cross-discipline awareness among medical specialties and more genetic screening for the mutation the researchers identified in the affected family.
“I think the main impact of the study on clinical practice will be on prion protein gene testing in patients with undiagnosed diarrhea and neuropathy, or hereditary sensory and autonomic neuropathy,” he told Neurology Today.
“More generally, physicians should be more alert to protein misfolding conditions of the central nervous system accompanied by peripheral deposits and symptoms.”
He added that the researchers hope to develop a transgenic animal model of the disease for further study.
The findings suggest that peripheral abnormalities in other brain diseases may too be associated with protein misfolding, and because patients with peripheral symptoms, including diarrhea, are usually referred initially to a gastroenterologist and undergo gastrointestinal endoscopy and biopsy before a neurologic consultation, the condition may be challenging to diagnose, the researchers noted.
They recommend that PRNP analysis be considered whenever a patient presents with unexplained chronic diarrhea associated with a neuropathy, or an unexplained syndrome similar to familial amyloid polyneuropathy.
“The prevalence of systemic amyloidosis associated with prion protein is probably low, but might be better characterized with more widespread testing of PRNP and histologic examination for prion protein in biopsy samples.”
ORGAN DISTRIBUTION ‘BAFFLING’
Herbert Budka, MD, professor at the Institute of Neurology at the Medical University of Vienna and Austrian Reference Center for Human Prion Diseases in Austria, told Neurology Today that the findings “significantly expand the phenotypic spectrum of prion diseases to the peripheral and vegetative nervous system.”
Dr. Budka, who is a team leader for the NeuroPrion program, a worldwide network of prion researchers at 52 research institutes in 20 different countries, said: “For the clinical neurologist, this report means that such a disorder should be included among the differential diagnoses of hereditary sensory and autonomic neuropathy and familial amyloidotic polyneuropathy. For neuropathologists, the multi-organ distribution of prion protein amyloid is baffling. For the prion scientist, what is perplexing is the unique pattern of prion protein fragments on Western blots after protease digestion.”
The common distribution of prion protein amyloid deposits in tissues and organs among the family members might be a reason for concern, and even though transmission was not seen in inoculated mice, “it seems too early to close the door on potential transmission risks for humans,” Dr. Budka noted.
“Finally, and probably most importantly, this new disease demonstrates that protein misfolding diseases — usually considered mainly as CNS diseases like Alzheimer's and Parkinson's — could, in principle, affect almost all human organs, although the precise molecular pathogenesis of the disorder reported in the study still needs clarification.”
HISTOLOGIC AND IMMUNOHISTOCHEMICAL ANALYSES of spinal cord and peripheral tissue obtained from family members were performed to clarify the distribution of deposits of prion protein and to determine whether this finding might shed light on the clinical findings. The findings were very similar for Patient IV-1 (Panels A, B, and C) and Patient IV-6 (Panels D through J). In the spinal cord, myelinated axonal loss in the dorsal columns was shown by a marked reduction in staining of myelin (Panel A, arrow). Immunohistochemical analysis showed deposition of prion protein in the gray matter of the spinal cord, which was largely confined to vessel walls (Panel B, arrow) and the immediately adjacent neuropil (arrowhead). In the dorsal roots, there was abundant deposition of prion protein between nerve fibers (Panel C,arrow) and in the walls of blood vessels (arrowhead). Widespread deposition of prion protein was found in the peripheral nervous system and in systemic organs in Patient IV-6. Punctate deposits were found in the lamina propria and muscularis mucosae of the duodenum in a biopsy specimen (Panel D, arrows). In postmortem samples, the colon showed similar punctate staining of the lamina propria and muscularis mucosae (Panel E, arrows) in addition to staining at the periphery of lymphoid aggregates (arrowhead). In the spleen (Panel F) and a mesenteric lymph node (Panel G), similar staining was seen at the margins of follicles (arrows), but follicular dendritic cells were unstained, a finding that contrasts with findings in samples obtained from patients with variant Creutzfeldt–Jakob disease. There was pronounced deposition of prion protein around ganglion cells in a dorsal-root ganglion (Panel H, arrow) and around nerve fibers in peripheral nerves (Panel I, median nerve, arrow). In the lung, punctate deposition of prion protein was observed in the alveolar walls (Panel J, arrow).