Prion disease gets personal

Sonia Vallabh knows what will probably kill her.

In 2011, the Boston-area law school graduate learned she carries the same genetic mutation that caused her mother’s death from a rare brain-wasting prion disease. Prions are twisted forms of normal brain proteins that clump together and destroy nerves. About 10 to 15 percent of prion diseases are caused by a mutation in the PRNP gene, leading to such deadly diseases as Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia, the disease that killed Vallabh’s mother.

Grief, shared with family and friends, came first. Eventually, Vallabh realized, “We can’t get around this prognosis.… We’ve got to go through it.” So began her and husband Eric Minikel’s odyssey to learn about the disease that had turned their lives upside down.

A scientist friend came by with a flash drive loaded with research papers about prion diseases. “We didn’t have the vocabulary” to understand the information, Vallabh says. So she took a sabbatical from her job to take biology and chemistry classes. Minikel kept writing transportation software, but attended night classes with his wife.

Vallabh’s first foray into brain research was as a technician in a lab studying Huntington’s disease. During “science nights” at the couple’s home, scientist pals team-taught biology and biochemistry. The couple took the biggest step when Minikel left his consulting job and both enrolled in graduate school to study prion diseases.

First, they had to learn whether Vallabh’s mutation was really likely to cause disease. The couple worked with Harvard University geneticist Daniel MacArthur to examine genetic data from 16,025 people with prion diseases and 60,706 others who had the protein-coding parts of their genomes sequenced as part of the ExAC project, an effort to find disease-causing genetic variants (SN: 12/12/15, p. 8). If mutations appear more often in people with the diseases than in the general population, the mutation is thought to be associated with the disease.

Several variants in the PRNP gene carry small risk, the couple and colleagues reported in the Jan. 20 Science Translational Medicine. Many people who carry those variants never develop prion diseases. Doctors could tell those patients that they have little to worry about. Four other variants, including the one Vallabh has, virtually guarantee the disease will develop.

After presenting preliminary results at a scientific conference, Minikel started losing sleep. What if they were wrong? So the two approached scientists at the genetic testing company 23andMe for help. The company provided anonymous genetic data from 531,575 customers. This larger analysis showed the results held.

Unfortunately, the findings don’t change Vallabh’s prognosis. But the couple is now working with chemical biologist Stuart Schreiber of the Broad Institute in Cambridge, Mass., to design drugs to treat prion diseases.

At age 31, Vallabh knows she doesn’t have much time. Her disease strikes, on average, at age 49. When the pressure of an accelerated timeline gets hard, Vallabh reminds herself, “your clock was always ticking.” At least now, she and Minikel may be able to find a way to buy time for her and others.