When Debbie and Andrea’s sister shut down and stopped talking, after she publically obsessed over the beauty of her own feet, after the length of her sentences fractured into one word, after her blood was sent off for scrutiny, the pieces of a sad family puzzle finally fell into place. Their sister has a newly identified genetic mutation called chromosome 9 open reading frame 72 (C9ORF72) that can cause either frontotemporal dementia or motor neuron disease.
She has FTD. This generation of three sisters and one brother lost their father and grandfather to amyotrophic lateral sclerosis. At the time, doctors said it was a mere coincidence that the father and son died of the same thing.
The diagnosis of a genetic mutation arrived on Election Day 2017. One day of shock and tears was enough for Debbie, now 57, who called her sister Andrea and announced that she wanted to be tested. She has no symptoms whatsoever but a lifetime history of anxiety was enough to push her into overdrive. “I just have to know,” she told her 71-year old sister, who wasn’t quite so sure that she wanted to bet with 50-50 odds on the table. But she also didn’t want her sister to go after this answer alone.
“I’ll go with you,” Andrea said.
Four months after the C9ORF72 was outed in this family, the sister duo showed up at the Memory and Aging Center for a battery of tests, including genetics. Neither sister thought they had the gene mutation. There was nothing wrong with them. By contrast, they always thought their other sister, now mute, was a bit odd.
Three weeks later, their lives would change forever. The genetic tests showed that one sister has the gene mutation and the other doesn’t. These two sisters set in motion a discussion in their families: Do people want to know whether they are C9ORF72 positive or not?
In 2011, two teams of scientists from the Mayo Clinic and the National Institute on Aging (NIA) independently identified a hexanucleotide expansion of C9ORF72 as a cause of both FTD and ALS. The finding at the same genetic address changed the way scientists think about these two seemingly disparate conditions. These C9ORF72 mutations account for 34 percent of the familial ALS cases, almost six percent of the sporadic ALS cases, and one-quarter of familial FTD cases, and five percent of sporadic FTD cases.
It is a major scientific discovery. It is a story of science at its best: a hint of some strange connection in families with both FTD and ALS, the accumulation of DNA to search for genes that would explain this odd disease pair, years of coming up empty, an invitation to colleagues the world over to send more DNA from their pedigrees to help solve the puzzle, to the final discovery from Rosa Rademakers at the Mayo Clinic and Bryan Traynor at the NIA that the two conditions share a repeat of a snippet of DNA that has copied itself hundreds to thousands of times to trigger FTD or ALS, and often both together.
Rademakers was drawn into the puzzle of FTD. Her mentor, Christine Van Broeckhoven, PhD, a professor of molecular biology and genetics at the University of Antwerp, had already published groundbreaking research on the amyloid precursor protein (APP) gene and Alzheimer’s and was searching for genes for FTD. Rademakers signed on to help with a study during her senior year. She would continue on in the laboratory until she finished her PhD. She continued mining chromosomes at the Mayo Clinic, and she and her colleagues there identified the progranulin gene on chromosome 17 as a cause of FTD. Progranulin wasn’t even known as a brain protein. (Her former colleagues in Antwerp also discovered that the progranulin gene linked to FTD. Both papers appeared in the same issue of Nature in 2006. Rademakers was an author on both papers.
A year later, Rademakers got a grant to study families who were popping up around the world with both ALS and FTD. They ran patients’ DNA through just about every genetic test to identify the culprit. Nothing turned up. Finally, they were down to five genes in a particular region on chromosome 9. They scrutinized every one. There was nothing remarkable. There were no coding changes. They finally figured out that it was a repeat expansion, a 6-base pair DNA segment in a non-coding region that isn’t supposed to make protein. In healthy people, there are usually no more than 20 copies of this small piece of DNA. But they used other techniques to discover a long string of this genetic alphabet that was being repeated hundreds and even thousands of times.
The finding was published in 2011 in Neuron. In the same issue, NIA’s Bryan Traynor published findings from an independent study showing that C9ORF72 was linked to FTD. Traynor and his federal colleagues went after DNA from a highly conserved population in Finland. For some unexplained reason, the country had the highest rates of ALS in the world. The data and the latest genetic techniques allowed them to narrow the search to the middle of the C9 chromosome. They had gone from seven million base pairs to 250,000. And this neighborhood had only three genes of interest. Then, the federal researchers identified their culprit: C9ORF72.
No one knows why some people with the mutation develop ALS and others go on to be diagnosed with FTD, or why other patients develop both conditions.
“This gene has become important on many levels,” says Traynor. “It unifies two diseases. It also gives scientists a new way to develop gene therapies to silence the expanded segment on the chromosome.”
The one sister who is no longer talking was the family historian. She made intricate family trees and found one outlier from generations ago, an ancestor from Finland.
Their grandfather was a physician. At 62, he diagnosed himself with ALS and died three years later. His son, diagnosed with ALS on his 59th birthday, also lived with the disease for three years. Debbie said that she is sure that her father, who had lost a lot of speech to the disease, did not have cognitive problems. The night before he died, he called his daughter to his side and settled an age-old debate the two of them had about Hiroshima. Was America right about dropping the bomb? In healthier times, he thought it should not have been done.
“I think you are right, after all,” he told his daughter. He died the next day.
The family mourned for their father and grandfather. They never thought of ALS as a family legacy.
Six years ago, Susan and Andrea’s middle sister began acting strange. It began with the feet. Not just preening over her feet but telling her sisters that their own pads were, well, ugly. She no longer lowered the volume when she was at the movies. She would cry when someone told her to pipe down. Even the slightest criticism would be met with tears. Once, she took razor blades into the bathroom. Everyone was on guard.
At first, they thought she was depressed. She grew quieter. It was as if she were blocking out the world. They suggested she get her hearing checked. Then, she seemed to forget she had a granddaughter. In 2015, she was hospitalized on a behavioral unit at a local hospital. She could not even fit the pieces of a child’s puzzle together. Ten days and a few brain scans later, she was sent home. In 2016, a neurologist at Stanford took a detailed family history and raised the possibility that she had FTD. Blood was drawn and sent out for genetic testing.
The 66-year old woman was no longer talking by the time the tests came back positive. She has no signs of a movement disorder.
Susan couldn’t sleep. She couldn’t stop thinking about knowing whether she inherited the gene. She signed on to a research study, and she and her sister would go all out for this disease – spinal taps and brain scans, cognitive testing, neurological exams. “We were completely exhausted after the three days of testing, but we felt that at least we will know,” said Susan.
The results were ready in three weeks. They were told that they should be in the presence of their family doctor. Susan decided she would take the call from home, with her husband and friend there. Andrea went with her husband to their doctor’s office. The sisters decided they would send an emoji—either a happy face or a sad one—once Andrea got home.
Susan took the call at 9 a.m. Her sister’s call came thirty minutes later. Susan’s test was positive. Andrea did not have the disease gene. Andrea decided not to wait until she got home. From her doctor’s waiting room she texted a happy face.
A minute later, her baby sister texted a sad face.
No, no, no, no, no no, she kept typing. She could not stop crying. Susan did not pick up the ringing phone. She just wanted to get under her bed covers and cry for two days.
It is now three months later, and the sisters are consumed by the news. Susan didn’t last long under the covers; about an hour. She immediately went online to find a clinical trial that might offer a chance at a therapy to stall this gene from taking hold. She is around the same age as her father, grandfather, and sister when they got sick.
She and her husband both worked for the government and retired two years ago. “I do regret knowing,” she now says. “I felt like my life was over when I heard I was positive.” She has a grown son, and she does not want him to be tested.
“Right now, there is nothing wrong with me,” she says. “I feel great, and I want to stay this way.”
During the three days of testing, her older sister said: “I am preoccupied with this illness. Every time I walk into a room and forget why I am there. Every time my tongue gets twisted with words I can’t remember. I have a chance of not worrying. That would bring peace to my life. If I find out I don’t have it, I would do a jig. If I have it, I would cry for two days.”
She did not dance, and she still cries.
The sisters remain close. “This did not come between us,” said her older sister. “It’s made us even closer.”
Jamie Talan is an Atlantic Fellow in the Global Brain Health Institute, a collaborative program between UCSF and Trinity College in Dublin. She has spent six months at UCSF writing about the inner workings of the brain and giving voice to patients and the doctors, nurses, psychologists, geneticists and researchers involved in building the foundation for a whole body of non-Alzheimer dementias that are often missed, lost or ignored.