Deb Jensen never wanted her children to suffer from the disease that killed her brother at age 28. The condition, called Duchenne muscular dystrophy, manifests in childhood as muscle weakness and trouble walking, then worsens, causing the muscles that control the heart and lungs to fail. She decided to conceive through IVF so she could select an embryo that didn’t carry the disease mutation. But she ended up with only two viable embryos, one of which carried the mutation, so the clinic encouraged her to transfer both.
The fertilized egg was a girl, and because the Duchenne muscular dystrophy mutation is linked to the X chromosome, Jensen remembers the doctor assuring her that girls with the mutation would have a backup chromosome containing a working copy of the affected gene and would be just as healthy as Jensen. “I had 10 minutes to decide,” Jensen told me. Less than a year later, she gave birth to three babies. Both fertilized eggs implanted normally, then one split into two. When one of the toddlers stood up, spread her legs wide, and walked her arms up her legs, Jensen had a clue which fertilized egg had split. As a child, she’d seen her brother make the same movement, a hallmark of muscular dystrophy.
Jensen suspected at the time that two of her daughters, twins, had the Duchenne variant, and knew in her heart that at least one of them had a genetic predisposition that was already developing into the disease. But it took her about a year and a half to convince doctors to test them. “Girls can’t get Duchenne,” Jensen said.
Of the hundreds of genetic diseases linked to the X chromosome, Duchenne disease is one of the more common, along with some forms of hemophilia. Other so-called X-linked diseases include Fabry disease, which can cause kidney and heart problems that shorten lifespan, and a form of Alport syndrome, another disease that destroys the kidneys. In the past, many doctors thought these diseases only affected men and boys. But what at first seemed like isolated cases started popping up, with women and girls also becoming symptomatic. Now, some in the medical community and many patients argue that there may be more women suffering from symptoms of X-linked diseases than previously thought.
For women and girls, there is little data on what these diseases look like, or even how many women are affected. That’s in part because researchers are only just starting to take the issue seriously. Some women are less affected than men, but others can be just as severely affected. Jensen told me that one of her two daughters, who has the mutation, is 15 and has mild symptoms of Duchenne so far, but her daughter, who first developed symptoms, now uses a wheelchair. But the very fact that they are affected contradicts what many women have been told for years.
Shelley Horowitz, now 51, told me that throughout her childhood, wounds would not heal and her joints hurt so much that she would limp. No one believed her about her constant pain. “Doctors told my parents I was lazy and that I was lying to get away with PE,” she says. Horowitz’s father had hemophilia, a blood-clotting disorder that can cause fatal bleeding if left untreated in severe cases, but her doctors never seriously considered the possibility that she had it, too.
Still, long after her PE was cured, Horowitz suffered from swollen joints and other tissues, and wounds that wouldn’t heal. As an adult, she had a small mole removed, but the bleeding filled a roll of paper towels. Doctors finally gave her replacement clotting factors, a traditional treatment for hemophilia, and the bleeding stopped. It wasn’t until she was in her 40s, after a series of medical procedures and follow-up observations, that Horowitz learned that her body produces only 10 to 20 percent of the clotting factors her body needs. She finally found a specialist who recommended preventive hemophilia therapy.
For years, many practicing physicians had a simplistic view of X-linked diseases: In their view, men and boys’ cells have one X chromosome and one Y chromosome that carries a small set of genes. So when a genetic error on the X chromosome prevents the body from making a vital protein, male patients suffer the consequences. According to this conventional logic, women and girls have another copy of the problem gene on their second X chromosome, a functional one that can compensate for the mutated one. (Women can have two mutated X chromosomes, but this is statistically very rare.)
However, the idea that backup genes always protect people from X-linked diseases has proven to be untrue due to a special phenomenon that occurs on the X chromosome.
In other chromosome pairs, these replacement genes could protect against dangerous mutations. But in the early 1960s, scientists began to understand that as a female embryo develops, its cells undergo a process called X-chromosome inactivation. The idea is roughly this: Cells don’t need two of these particular chromosomes to function, so we chemically silence one at random. If the X chromosome that carries a disease mutation is silenced as the embryo develops, women who carry the disease will have no symptoms. But if the healthy X chromosome is silenced early in development, the mutated X chromosome becomes dominant in many cells of the body from that point on, and becomes dominant as the girl develops.
Still, “it’s a pretty common misconception that women don’t get X-linked diseases,” Caroline Bergner, a neurologist at the Leukodystrophy Outpatient Clinic at the University Hospital Leipzig, told me. While many doctors are still learning that X-linked diseases are essentially limited to boys and men, “genetics is a lot more complicated than they teach you in medical school,” Angela Weyand, a hematologist and professor at the University of Michigan Medical School, told me. The science of X-chromosome inactivation may not be new, but in her experience, “most of it is not well known in the medical community outside of geneticists.” Even if doctors understand that women can get X-linked diseases, they may think these scenarios are too rare to apply to their patients. But Weyand said, “I don’t think anyone who really understands the science can say that the risk to carriers is so small that it can be ignored.”
Variations in X-chromosome inactivation likely help explain why X-linked diseases affect symptomatic women so differently. In the case of Duchenne muscular dystrophy, girls whose cells are biased toward the mutated copy of the X chromosome “can develop symptoms very similar to typical Duchenne muscular dystrophy in boys,” Sharon Hesterly, a principal investigator at the Muscular Dystrophy Association, told me. But because X-chromosome inactivation is random and very difficult to test for, women can’t easily tell what pattern of chromosome inactivation their bodies have, or predict the extent to which they’ll experience symptoms. For example, Horowitz’s body produces only 10 to 20 percent of the normal amount of a clotting factor, whereas her aunt, who has the same X mutation, produces 80 percent of the normal amount and doesn’t need medication.
When researchers looked at women, teeth Affected Specific X-linked diseasethey are astonishingly GeneralBut in a study of women with the Duchenne muscular dystrophy mutation, half of the women in Jensen’s study had evidence of scarring in their hearts, and Jensen was one of the women who showed signs of this heart damage. study The study showed that more than 80 percent of women with the adrenoleukodystrophy mutation, an X-linked disease that can cause fatal hormonal and brain complications in boys and men, will develop neurological dysfunction by the age of 60 or older. While these women may not be at risk of death, they can experience life-altering symptoms, including bowel and bladder problems and mobility problems that may require a wheelchair.
Taylor Kane carries a genetic mutation for adrenoleukodystrophy that claimed the lives of her father and his twin brother when she was a child. Though she still has no obvious signs of the disease, the mutation prompted her to found Remember the Girls, an organization that challenges the conventional wisdom that X-linked disorders rarely occur in women. The group includes about 1,500 women, including Jensen and Horowitz, and collectively represents 50 X-linked disorders. But Kane says many women with X-linked disorders don’t even know they carry the affected gene. They may suffer from symptoms and only find out the cause when they have a son with the condition.
Even if women learn they are carriers of the disease, they don’t necessarily receive treatment. There may not be data proving that certain treatments work for girls with the condition. Gender-specific medications are considered off-label for female patients and aren’t necessarily covered by insurance, says Eric Hoffman, a professor of pharmacy at Binghamton University and CEO of a company that approves medications for Duchenne muscular dystrophy and promotes research into the condition. Doctors may prescribe medications for female patients’ symptoms without diagnosing the underlying disease, which can also frown on insurance companies. Insurance companies may deny coverage because patients don’t have diagnostic codes for X-linked disorders in their records, but some hospital health systems don’t have diagnostic codes for girls or women.
Even after a muscle biopsy confirmed her diagnosis of Duchenne muscular dystrophy, Jensen fought to get her daughter treatment: Because she is a girl, she was unable to participate in drug trials, even though a prominent researcher who was enrolling boys in gene therapy trials acknowledged that gene therapy would be a perfect fit for her, Jensen told me.
One of the gene therapy trials eventually yielded a drug called Elevidys, which was approved by the U.S. Food and Drug Administration in June. Jensen’s family was ecstatic when they learned the agency didn’t limit it to boys. Her daughter’s doctor prescribed it in the hopes that it would help her maintain the independence she still has (like getting out of her wheelchair and into bed, getting dressed, etc.). The family’s insurance company initially refused to cover the treatment, a one-time infusion with a list price of $3.2 million. They appealed, and yesterday the insurer called Jensen to tell them the original decision had been reversed. “It doesn’t seem real,” Jensen told me. While the data on the treatment is promising, it’s not conclusive (there is a lack of data, especially on girls). Still, there’s a sense of hope in Jensen’s voice when he talks about giving the drug to her identical twin (who is less affected) before her prognosis worsens. “It could be cured.”