Quantifying the Risk for Prion Disease

Megan Brooks

February 03, 2016

Eric Minikel and his wife Sonia Vallabh didn't start their careers in prion disease research — Minikel is a lawyer and Vallabh an engineer — but they're now engaged in a very personal battle against prion disease.

In late 2011, Vallabh learned that she carries the genetic mutation in the prion protein that caused her mother to abruptly develop fatal familial insomnia (FFI), a rare autosomal dominant inherited prion disease of the brain, and die in her 50s. At present, FFI and other prion diseases are untreatable and typically fatal within the first year that symptoms develop, which was the case with Sonia's mother.

Rather than viewing it as an unambiguous early death sentence, Vallabh and Minikel took action. They left their respective careers and entered PhD programs at Harvard, focusing their research efforts on prion diseases.

Now as PhD students and researchers at the Broad Institute of MIT and Harvard, they have used large patient data cohorts to identify four variants of the prion protein (PRNP) gene that are "clearly pathogenic with approximately 100% penetrance, whereas another three, previously thought to be pathogenic with high penetrance, were likely benign," Robert C. Green, MD, MPH, from the Division of Genetics at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues note in an accompanying Focus article published online January 20 in Science Translational Medicine.

Three additional variants were identified as neither benign nor fully penetrant, but the researchers were able to develop more quantitative estimates of their penetrance, ranging from 0.1% to 10%, Dr Green and colleagues note.

"The clinical implications of this paper are profound at two levels: an individual level for persons at risk for some prion diseases and for all persons suffering or at risk for prion diseases," Dr Green, who was not involved in the research, told Medscape Medical News.

"For at least some individuals who are living under the specter of parental mutations that have been represented as pathogenic and fully penetrant, this paper will dramatically alter their lives, relieving them of the fear that accompanies the questions of whether to be tested or not, or relieving them of their expectation that if they have the mutation previously thought to be pathogenic, they will inevitably get the disease," he explained.

"At another level, these findings have suggested that one copy of the PRNP gene could be knocked out without harming a patient, suggesting a path to the development of a treatment or a preventive strategy of genetic editing in the not too distant future," Dr Green said.

Challenging Genetic Destiny

In a research article in the journal, Minikel and Vallabh and an international team of collaborators confirm that four variants in the PRNP gene, including the one Vallabh carries, are clearly pathogenic with roughly 100% penetrance, whereas another three, previously thought to be pathogenic with high penetrance, are likely benign.

To do this, they assessed the effect of PRNP variants on the risk for prion diseases by analyzing 16,025 prion disease cases, as well as 60,706 population control exomes from the Exome Aggregation Consortium (ExAC) data set and 531,575 individuals genotyped through 23andMe Inc.

"We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence," the authors write. "Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%."

They also found that truncating variants in PRNP "have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression."

The results unfortunately provided "cruel confirmation" that the variant Vallabh carries is nearly 100% penetrant, Dr Green et al write.

But for at least one family, the burden of carrying a pathogenic variant has been "radically altered in a positive way by the new findings," Dr Green and colleagues report in their commentary. They have been following an individual in their genetics clinic whose mother died of prion disease attributed to the p.E196A variant, which was previously thought to be pathogenic but, through this new work, has now been shown likely to be benign, they explain.

"Upon acceptance of the Minikel et al paper by Science Translational Medicine, we placed one of the most exhilarating phone calls a clinician can make—reassuring an untested adult that her mother's mutation was likely benign. Although the tragic demise of our patient's mother remains raw and, even in some sense, less explicable than before, the specter of inheriting a fatal mutation has been mitigated for her, for her children, and for their children to come," Dr Green and colleagues say.

Animal studies have shown that it's possible to delay onset of prion disease by reducing the amount of normal prion protein, explained Vallabh in a journal podcast. "However, we have never seen previously people with less than normal levels of prion protein so we didn't actually know from human data whether it's safe to reduce amounts of prion protein. We don't know its native function and so there have been skeptics as to whether that would be a viable and safe therapeutic strategy," she said.

In their large data set, the researchers identified three individuals who have a portion of the gene inactivated, "meaning that they have, we assume, 50% of normal prion protein levels, and these individuals were older and they were healthy. This gives us the first human validation that therapeutics that could reduce the levels of prion protein might not only be hopefully effective but also safe," Vallabh said.

"Actionability" and Patient Empowerment

Dr Green and colleagues say this research also "stands as a testament to the generosity of unrequited data sharing from thousands of individuals and scientists around the globe and the unflinching devotion of a young couple to altering their seemingly unalterable genetic destiny."

The work of Minikel and Vallabh also speaks to the "confusing concept" of actionability in genomic testing and the debate about disclosure of genetic test results, they note.

"In the strictest sense, Sonia's test results would never have been considered medically actionable, as prion disease is rapidly progressive, universally fatal, and completely untreatable at this time," the authors write. "By many published standards and expert perspectives, Sonia should have been heavily counseled, if not dissuaded, about the potential psychological damage of learning whether or not she carried this mutation, with the underlying assumption that no medical good could result from such knowledge. But the notion of actionability has proven to be far less parochial than current conventions would suggest."

Taken together, we have seen over the past few years that there is less harm and more unanticipated benefit than was previously expected in disclosing genetic information. Robert C. Green et al.

"We should never be cavalier about the potential for risk information of any sort (whether genetic or not) to distress people and lead to confusion, misperception and mismanagement," Dr Green said. "However, our research over the past 15 years has consistently shown that when people are well informed about genetic risk information and elect to receive it, they cope well, even when there are no medical interventions.

"These data, along with unusual stories such as that of Eric and Sonia, suggest that our current construct of 'actionability' for genetic information may be far too narrow. Taken together, we have seen over the past few years that there is less harm and more unanticipated benefit than was previously expected in disclosing genetic information," he concluded.

Asked to comment on these new findings, James O'Leary, chair, Social Issues Committee, American Society of Human Genetics, told Medscape Medical News that in terms of genetic information, "it boils down to whether people are going to be empowered by this information or whether it's going to have lasting harm," and that's hard to predict.

"Especially around genetics, people think of actionable results as only those that are medically actionable, but there are a lot more actions you can take besides medical treatment," said O'Leary, chief innovation officer with Genetics Alliance, a nonprofit health advocacy organization based in Washington, DC.

Receiving genetic information fuels "connections," he said. "In learning you have a certain condition, you can share information about symptoms, receive and give social support, connect with other people with the same condition, all the way up to participating in international research and driving towards a treatment for the condition," he said. These positive actions sometimes get lost in media coverage, "which sometimes goes for scare tactics," O'Leary said.  

This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the National Institutes of Health, by Broad Institute NextGen funds, and by Prion Alliance sundry funds. The authors have disclosed no relevant financial relationships. Dr Green receives compensation for consulting to Invitae, Helix, AIA, and Prudential.

Sci Transl Med. Published online January 20, 2016. Abstract Commentary


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