Jeff Lowe, age 64, was a world-renowned mountain climber who was on the cover of Sports Illustrated in 1978. Around 1998, he began having odd episodes where he would lose his balance and even fall unexpectedly—the onset of a progressive neurologic disorder that has gradually robbed him of his climbing life and landed him in a wheelchair. He got a power wheelchair in 2009, and today continues to live fully, mentor young climbers and enjoy the outdoors from the chair. Last summer he got a feeding tube and he uses supplemental oxygen at night. He spent nearly two and a half years on hospice but recently came off. Jeff has difficulty speaking, but is an excellent writer and communicates through a speaking device or his partner Connie interprets for him.
Amyotrophic lateral sclerosis (ALS) and multiple sclerosis have been ruled out. Initially, Jeff was diagnosed with multiple sclerosis and then olivopontocerebellar atrophy (OPCA), a rare condition involving the degeneration of neurons in specific areas of the brain, but in 2009, this diagnosis was withdrawn. Broadly, he is considered to have a motor neuron disease of unknown origin, but a new feeding formulation called Liquid Hope has allowed him to regain some strength.
"Everybody kind of makes up their own diagnosis—they need to write treatment orders," says Connie Self, his partner and caregiver. "Without a diagnosis, you fall through the cracks and can't get prescriptions and treatment approved."
Jeff and Connie are glad to be part of CLARITY Undiagnosed. "We thought it was a tremendous opportunity we could never get otherwise," says Connie. "We're hoping to learn something that would be helpful in terms of making Jeff more comfortable, and if there's something disease-altering, we'd be thrilled."
A documentary about Jeff's life and climbs, Jeff Lowe's Metanoia (narrated by Jon Krakauer) is currently making the rounds of film festivals all over the world.
What CLARITY Undiagnosed found
The CLARITY teams identified several different genetic variants, two of which were thought worth highlighting. One variant, reported by four teams, and considered by some to be "possibly pathogenic," was in a gene called CSF1R. Mutations of CSF1R are known to cause progressive loss of motor function and cognitive and behavioral changes. Although Jeff's mental functions are completely normal, this variant was considered a potential cause for his progressive weakness; however, it was ultimately ruled out because the particular change in Jeff's CSF1R gene is also found in about 1 in 1,000 healthy people.
Another variant, in a gene called AARS, was reported by a single team that had looked at DNA regions that can help control gene expression. Mutations in this gene have been reported to cause disorders ranging from problems with peripheral nerves, which Jeff does not have good evidence for, to defects in the brain. The CLARITY teams reported a unique type of AARS mutation in Jeff that is predicted to create a protein that is larger than normal. This does not appear to have been seen before, so the implications are unknown. However, this variant can now be looked for in Jeff's healthy brother and sister, and in additional unaffected individuals, to determine whether it correlates with disease.
For now, the family is submitting a new blood samples from Jeff to study his cells and see if they contain proteins with altered function. In addition, Jeff's physician has a collaborator who studies a gene associated with SCA36. Through a research collaboration with the Manton Center, that gene will be tested in Jeff.
The Challenge again ruled out a diagnosis of ALS.
"There also appears to be no smoking gun for Jeff's family, and that's good news," says Connie. "We're feeling positive about what they learned, and it makes sense what they learned."
Jeff notes that his interest in CLARITY Undiagnosed goes far beyond his own disease process. Connie agrees.
"We know this has to be of value to medicine, we're so excited to have been a part of this," she says. "We're grateful for any and all information and excited for the future of medicine. We feel this collaborative effort is so important. Usually medicine is competitive, but we need to get over that! The more people collaborate, the more information can move quickly. Now that NIH has a database and this information is going to be collected, maybe we will have more knowledge that can help a lot of undiagnosed people."