A newly discovered mutation in the human prion protein gene produces a clinical syndrome marked by chronic diarrhea, autonomic abnormalities, and peripheral neuropathy, researchers said.
Eleven members of an extended family in Britain were found to share the syndrome, according to John Collinge, MD, of the U.K. Medical Research Council in London, and colleagues, who identified a specific, inherited Y163X mutation in the PRNP gene in six of these individuals with DNA samples available.
The resulting aberrant prion protein did not appear to be transmissible, unlike those responsible for Creutzfeldt-Jakob disease (CJD), Collinge and colleagues reported in the New England Journal of Medicine. No evidence of illness was seen in mice for up to 600 days after they were injected with prion proteins isolated from the patients.
Also unlike CJD, substantial deposits of the rogue protein accumulated in organs outside the central nervous system in these patients, including in the gastrointestinal tract, liver, kidneys, lungs, and cardiovascular system.
Symptoms were slow to progress in the patients included in the current study, generally not appearing until they were in their 30s, with age at death ranging up to 70.
"PRNP analysis should be considered in the investigation of unexplained chronic diarrhea associated with a neuropathy or an unexplained syndrome similar to familial amyloid polyneuropathy," the researchers wrote.
"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."
About 15% of prion disease cases involve inherited mutations, the researchers indicated. Manifestations of those previously described mostly involved the brain and central nervous system.
Collinge and colleagues reviewed medical history data and, for those still living or who had provided consent prior to death, performed tissue analyses on five generations of the British family. They started with a woman who had died at age 66 with the syndrome and who had donated her brain for research.
The woman's father, one of her two children, and two of her three siblings (one male, one female) also had a similar phenotype. The researchers ultimately found that a great-uncle appeared to be the first in the family to develop the syndrome. Five members of another branch of the family showed the phenotype as well. All were descended from the woman's great-grandparents.
The inheritance pattern indicated a dominant transmission pattern. DNA analysis revealed the Y163X mutation in the prion protein gene in the index patient and in the others for whom samples were available.
The syndrome's most salient feature was chronic, watery diarrhea beginning when affected individuals were in their 30s. Most of these individuals were diagnosed with either Crohn's disease or irritable bowel syndrome.
Also common was neuropathy mainly affecting the legs and feet, with abnormal heat sensitivity and, later in life, motor involvement. Seizures and cognitive impairments began to occur when patients reached their 40s and 50s.
Laboratory analyses showed elevated tau and S100b protein levels in cerebrospinal fluid, both of which were more than three times the upper limit of normal.
Autopsy findings in some of the patients showed extensive deposits of the abnormal prion protein in numerous locations throughout the body. These included the brain, with prion plaques as well as neurofibrillary tau-based threads and tangles.
The researchers' tissue analyses pointed to a length-dependent, peripheral axonal neuropathy as the main basis for the clinical symptoms. They suggested that the diarrhea, for example, probably resulted from bowel denervation. Likewise, the sensory and motor abnormalities in the lower extremities were likely to due to denervation in those areas.
Collinge and colleagues noted that the lack of transmissibility to mice, although reassuring, is not a guarantee that the rogue prions could not be pathogenic in humans.
The work was funded by the Medical Research Council and other government and private foundation grants.
Study authors reported relationships with D-Gen, Takeda, Warner-Chilcott, B. Braun, Shire, Dr. Falk, Orion, Merck Serono, and Novartis.
- Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
New England Journal of MedicineSource Reference: Mead S, et al "A novel prion disease associated with diarrhea and autonomic neuropathy" N Engl J Med 2013; 369:1904-1914.