Prion mutation yields disease marked by diarrhea

Rare ailment starts in adulthood, attacking gut before brain

FAMILY PEDIGREE  This diagram shows five generations of an extended family beset by a novel genetic mutation that results in misfolded prion proteins and disease. On this chart, black denotes a person who inherited the mutation. White is someone who didn't. Women are circles and men are squares. A deceased person is lined out, and age at the time of death is noted.

Mead et al/NEJM 2013

A newly discovered prion disease damages parts of the body far from the brain. The finding unveils a curious new version of these misfolded proteins infamous for causing brain-wasting diseases such as mad cow disease. Researchers report that 11 of 27 people spanning five generations in one family have inherited a prion mutation, which causes the slow-developing but lethal disease.

The report, in the Nov. 14 New England Journal of Medicine, describes the first prion disease known to primarily attack the peripheral nervous system, causing chronic diarrhea and other problems beginning in adulthood. People with the genetic defect did develop cognitive and memory problems but not until their 40s or 50s. Average age at death was 57 for the family members with the disease.

The research stands as a solid addition to the prion literature, says Jan Stöhr, a biochemist at the University of California, San Francisco. “They really did their homework, with all the tests they ran,” he says.

Prions are normally uneventful proteins in the body, but nobody knows what they do. Problems arise when these proteins become misfolded and prove damaging to tissues.

In the new study, the researchers identified the mutation responsible for this abnormal prion. They also examined six of the 11 affected family members and described the unique way the disease unfolds. The onset is gradual, brought about by inexorable accumulations of amyloid deposits: clumps of fibrous, insoluble protein. Unlike amyloid in Alzheimer’s or other diseases, the clumps in the new disease show up throughout the body and ultimately compromise various organs’ functions.

The aberrant prion encoded by the newfound mutation also differs from some other rogue prions at the cell level because it isn’t tethered to cell membranes. “It’s free floating in the blood,” says study coauthor Simon Mead, a neurologist at University College London. He suspects that this characteristic might contribute to the protein’s tendency to aggregate widely, forming amyloids and damaging a variety of tissues.

The chronic diarrhea that patients endure may arise from damage to the autonomic nervous system, a part of the peripheral nervous system that extends away from the brain and spinal column. The autonomic network runs processes such as moving food through the gut. Just why the disease hits the intestines years before the brain is a mystery. “Maybe it’s easier to compromise certain gastrointestinal circuits,” Stöhr surmises.

Although this prion disease lacks a cure and is probably rare, Mead says, knowing about it might help to diagnose other people whose diarrhea or other gastrointestinal ailments defy a clear explanation.  

While other prion diseases are contagious, this one didn’t seem transmissible in tests involving mice.

Editor’s Note: This story was updated on November 18, 2013, to correct the number of affected family members studied.

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