PHILADELPHIA — Not long after Rickie Samuel learned that she had ALS, a heartbreakingly disabling and fatal neurological disease, she and several members of her family met with her treatment team to hear more horrible news.
Two years ago at Temple University Hospital, Terry Heiman-Patterson told them that Samuel’s illness was caused by an abnormality of the C9orf72 gene. The mistake, which was identified just 10 years ago, causes ALS and a form of dementia that first affects judgment and language skills rather than memory. Scientists believe that almost everyone who carries the mutation will get one of the diseases if they live long enough. Some, like Samuel, get both.
Samuel’s son, Daniel Gerson and his wife, Mollie Elkman, along with Samuel’s sister and others, learned at the meeting that Samuel’s siblings and her children each had a 50-50 chance of having the errant gene. Grandchildren could also be at risk. Elkman felt time stop as those words sunk in. She and Gerson have two children.
The doctor then asked a momentous question: Did the other family members want to be tested, too?
The results could bring immense relief or terror or both. But even bad news offered a level of hope not available to the majority of ALS patients, who have no known disease cause to target with treatment.
Medicines that combat specific ALS mutations, including C9, are already being tested. ALS specialists like Heiman-Patterson, who is a neurologist, believe people with inherited forms of ALS have the best shot at true treatment breakthroughs.
Gerson and two other family members instantly asked to be tested.
Almost as quickly, Gerson, now 44, had second thoughts, but his wife insisted she had to know.
Elkman describes the five weeks they waited for results as a “black hole.” She filled it with researching the disease she feared would take her husband and children. She cried and slept, exhausted by the cacophony of emotion. In her gut, she was sure that Gerson, who had had a serious-but-undiagnosed illness years earlier, had the gene.
Long before he knew of his genetic predisposition, Gerson had what he called an “irrational fear” of ALS. He was worried about twitching leg muscles his doctors hadn’t been able to explain. He and a friend went to the Havasupai Indian Reservation near Grand Canyon. Surely that would calm him down. Instead, he found himself ”flipping out inside” while surrounded by breathtaking scenery.
As he hiked through the spectacular landscape, Gerson silently repeated a mantra thousands of times: “I am not a carrier of ALS genes. I will not get ALS.”
‘A lot of hope for genetic patients’
ALS, or amyotrophic lateral sclerosis, is an exceptionally cruel disease, perhaps most infamous for killing baseball great Lou Gehrig. Only about 15,000 people in the United States have it at any given time. They typically die within three to five years. Most commonly they are diagnosed in their mid-50s, but cases can occur among adults of any age.
It affects nerve cells that trigger muscles to move. In many cases it starts in hands or feet. Rickie Samuel’s first symptom, though, was slurred speech. While she had cognitive and psychological symptoms, many patients remain clear-headed as the disease progresses. Eventually, patients become unable to chew, swallow, speak or breathe. They must make difficult choices about whether to accept tube feeding or a breathing machine.
About 10% of ALS cases are considered familial. The rest are labeled sporadic — no one knows why they have the disease. “Different people have different mechanisms propelling their disease, and that’s why we haven’t made a lot of progress,” Heiman-Patterson said.
Mutations in the SOD1 gene were identified as a cause of ALS in 1993. It‘s the culprit in 20% of familial ALS and 2% of all ALS. One type of SOD1 mutation is so aggressive it kills within months while others lead to slow progression. It is not associated with dementia.
The C9 gene was identified in 2011. It’s responsible for just over a third of familial cases and 12% of all cases. It is found in up to 10% of people thought to have sporadic ALS, Heiman-Patterson said. Sometimes families are surprised they have an ALS gene, but then realize, as Samuel’s family did, that there is dementia in their family tree. Forebears who died young — too early for symptoms to emerge — might have been carriers.
Lauren Elman, a neurologist who directs the Penn Comprehensive ALS Center, said more than 40 genes that either cause or increase risk have now been identified. Penn found one — mutations to the ATXN2 gene — that about 2% of ALS patients have.
Clinical trials are currently underway for ALS patients with mutations to the SOD1, C9 and ATXN2 genes. The SOD1 trial is in phase 3. The other two are in the earliest stage. All are testing antisense oligonucleotide therapies from Biogen. Elman calls this approach, which targets genetic material, a “cousin” of gene therapy. Penn is involved in the SOD1 and ATXN2 trials and hopes to later join testing for the C9 treatment. Johns Hopkins University is participating in all three.
In the early-phase trial, those who received the highest dose of the SOD1 treatment, known as tofersen, had a 33 percentage-point reduction in SOD1 protein levels in spinal fluid, a possible marker of disease. While the primary goal was to study safety, there also was evidence that the drug slowed functional decline.
The 12-week study was small, but Elman said the results took her breath away. Among people with fast-progressing ALS, the treatment group that received the highest dose actually improved slightly — 0.84 points — on a functional rating scale. The placebo group’s score worsened by 16.3 points.
“We never see those kinds of numbers in an ALS drug,” said Elman, who has been in practice since 2003. “I personally have never felt more energized about the clinical research that’s happening.”
Biogen has agreed to make tofersen available on a compassionate-use basis to patients with the gene as early as this month. The company, which is embroiled in controversy about its new Alzheimer’s drug, declined to offer a specific date.
Piera Pasinelli, a neuroscientist who heads the Weinberg ALS Center at Jefferson Health, sees trials that could benefit patients with sporadic ALS as well, but she is especially optimistic about antisense treatments. “There is a lot of hope for genetic patients,” she said, “because this is a technology I am convinced is going to work.”
A ‘sea change’ in testing
Deciding whether to be tested for these ALS genes is hard. Some people want to know what’s coming and why. Others would rather wait until they have no choice. All have to consider that the information could affect not just them but their children and grandchildren, siblings and spouses.
Legally, medical insurers can’t discriminate against those with risky genes, but life and long-term care insurance companies can. Before patients are tested, Elman tells them, “You must, must, must buy all the life insurance you ever need to have.”
Gerson was so worried about discrimination that he used a fake name for his test. He was afraid to put it on his credit card, so his aunt paid.
Nonetheless, ALS specialists said genetic testing has become routine.
“That’s been really a sea change,” said Elman, who discusses genetic testing with about 80% of her patients. Two-thirds choose to get it. Heiman-Patterson said Biogen has now offered to pay for testing for 24 genes that cause ALS. She now offers all patients the test. About 90% accept.
Jennifer Roggenbach, an Ohio State University genetic counselor, said people often get tested because they want to participate in clinical trials. “People who have a clear family history, they sort of already know that it’s genetic in the family,” she said. “Those people in many cases feel validated.” They know that joining a trial may not save them, but hope it could help their children or grandchildren.
Even though their genes are out of their control, some feel responsible for their descendants’ risks. Roggenbach points out that some people with abnormal SOD1 and C9 genes live well into late life without getting ALS or dementia. The risk is high, but it is not 100%. Plus, she said, “we all pass traits and qualities to our children, good and bad.”
Getting the news
A couple days after Gerson returned from his Arizona trip, in July 2019, the family again gathered at Temple — Gerson’s aunt was on the telephone in Ohio — for the test results. They insisted on hearing the results together, an idea the Temple team strongly discouraged because the news is so personal.
Gerson desperately wanted the suspense to end. When the introductory chatter started, he blurted, “Let’s go.”
Heiman-Patterson said Gerson and his aunt were negative. But another family member, one who does not yet feel ready to talk publicly about the experience, had the dangerous mutation.
Gerson felt a rush of “total elation and total heartbreak” at the same time. The family sobbed.
Gerson had been so sure he would receive bad news that he went to his own doctor at Penn and asked for another test. The results again were negative. “Daniel,” his doctor said, “I understand. I see your history here. I see the pain that this has caused, but this is the second negative test. Go live your life.”
But Gerson was still struggling with the sadness and uncertainty. “How?” he wondered.
Hopes for a breakthrough
David Rayl knew ALS ran in his family. His grandfather and his mother both died of it, but he was not worried that he would also get it. Even when his oldest sister was diagnosed, he was still “pretty confident” that he would be OK.
His wife, Barbara Bucci, knew the history, too. It worried her enough that she asked the priest to stop their wedding vows after a picture of Rayl in a wheelchair popped into her mind. “I thought, eh, he’s not going to get it, and we continued with the vows. I never really thought he was going to get it.”
But, in late summer 2018, she knew she had been wrong. “I knew he had it,” she said. “He had a very mild drop foot. I didn’t really see it. I heard it when he was walking.”
She couldn’t bear to talk about it. A few months later, the weakness in Rayl’s left leg was bad enough that he saw a doctor. He was diagnosed with ALS the day after his sister died. The couple, who have no children, went to her funeral on their 18th wedding anniversary.
Rayl, who is now 57 and a former Lockheed Martin systems engineer, wanted to know why his family was dying. He learned he had the C9 mutation. To his knowledge, his remaining five siblings have not been tested. Nor have members of the next generation.
Two years into his diagnosis, Rayl has had plenty of angry moments, but he’s glad that his version of ALS seems to be progressing slowly. He uses a walker and doubts he could walk a block. He and Bucci recently moved to Schwenksville to a house they could rehab to accommodate his increasing disability. He still hopes to visit some national parks before he gets worse and he wants to join a clinical trial. “If there’s going to be any breakthrough in ALS, it’s going to be on the familial side,” he said.
Should she have a child?
Amy, a 34-year-old Dayton, Ohio, woman, was considering having a child when she was tested for an ALS gene. Her grandmother had died of the disease and an aunt had it. Her father, who is in his early 60s and does not have symptoms, had the abnormal C9 gene.
Amy had hoped good news would reduce her anxiety about pregnancy. Instead, she learned that she also had the bad form of C9. It felt, at first, like a “death sentence.”
She talked openly about the test, but withheld her full name. “It’s not just my story to tell,” she said. “There are people in my family who are having a very difficult time with this emotionally.”
Amy and her husband decided to have a biological child anyway. She thought about all the love she had experienced in her family. That was valuable, no matter how many years she got. Deciding not to have a child, she thought, would be like saying the lives of her grandmother, aunt and father had not been worth living. She knew they had. Plus, she could never control all the risks her child would encounter.
The couple will let their son decide whether he wants to be tested when he is an adult.
In the meantime, Amy will soon enter a clinical trial for those with familial ALS genes. She has faith that research will find ways to help her.
The genetic test made her more aware of her mortality, and that hasn’t been all bad. She tries to focus on what’s important and to savor each moment. She ponders the meaning of suffering and death. Her belief in an afterlife is a comfort.
“I was always going to die,” she said. “Now I have a better idea of how it’s going to happen. I still have to live my life.”
Changes in treatment are on the way
Doctors are beginning to envision a different future for people with ALS.
Elman said Penn is building the infrastructure it will need to give patients antisense drugs, which are injected into the spinal canal.
She thinks there could be an approved treatment for people with SOD1 mutations within a year and one for people with C9 within three years.
She, Pasinelli and Heiman-Patterson are looking ahead to a time when patients who test positive before they are sick will be monitored carefully for the slightest of symptoms, so they can start treatment fast. “The holy grail, of course, will be to treat people pre-symptomatically,” Elman said.
Researchers badly need biomarkers, physical indicators like blood abnormalities, that can identify people in early stages of the disease. And, while they think what they learn about familial ALS may also benefit those with sporadic ALS, they need better treatments for the majority of patients.
Jeffrey Rothstein, a neurologist who is the director of the Robert Packard Center for ALS Research at Johns Hopkins University, founded Answer ALS, a massive data collection project he hopes will unlock some of the mysteries of sporadic ALS, which likely is actually more than one disease.
The project used stem cells from 1,000 ALS patients to create motor neurons. They provide 6 billion data points per patient, a publicly available treasure trove that Rothstein hopes will speed information about genetics and potential drug targets. “It’s the future of sporadic ALS,” he said.
Another new effort is the Healey ALS Platform Trial, an innovative clinical trial design that allows drug companies to test up to four treatments at a time while sharing a smaller placebo group. Researchers expect these trials to be faster and cheaper than typical trials, while giving patients, who have little time to waste, a better chance of receiving an active treatment. Jefferson, Penn, Temple and Penn State are participating.
Rothstein said it is a hopeful time. More than a dozen treatments are being tested, an unusual amount of firepower directed at a disease that struggled for attention before the Ice Bucket Challenge. “The most trials of my entire life are going on right now,” Rothstein said.
‘It never ends’
Rickie Samuel’s family watched her deteriorate for 17 months, knowing hers might not be the last ALS death they would witness.
She had always had a difficult personality, but she got mean and angry at the end. She started hearing voices, Elkman said, and thought the family had abandoned her. She was able to walk, but was prone to tripping. Her tongue couldn’t move food around. She choked constantly, but refused to give up food she wanted. She lost around 100 pounds. Her breathing grew labored. She stopped being able to talk and then to write. She kept texting, but stopped making sense. She refused tube feeding and extra oxygen.
Gerson could see how much his mother was suffering. “She said over and over again, ‘This disease is taking everything from me,’” he said.
“It was a really terrible way to die. Terrible,” Elkman said. The couple, who work in her Center City marketing company, started The ALS Genius Fund to grow something positive from the family trauma.
Rickie Samuel died last Dec. 2.
Gerson’s voice wavered as he talked about imagining what will happen to other family members who may have the gene.
“That’s the worst part of all this,” he said. “It never ends. It never ends.”
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