Doctors Said These Women’s Mutated Genes Wouldn’t Harm Them

Deb Jenssen never wanted her children to suffer from the disease that killed her brother at 28. The illness, Duchenne muscular dystrophy, initially manifests in childhood as trouble with strength and walking, then worsens until the heart or the muscles controlling the lungs stop working. She decided to get pregnant using IVF so that she could select embryos without the mutation for the disorder. But when she ended up with just two viable embryos—one with the mutation—the clinic urged her to transfer both.

The embryos were female, and Jenssen remembers the doctors assuring her that, because the Duchenne mutation is linked to the X chromosome, a girl who carried it would have a backup chromosome, with a working copy of the affected gene, and would be as healthy as Jenssen was. “I had 10 minutes to decide,” Jenssen told me; less than a year later, she had three babies. Both embryos had successfully implanted, then one split into two. Jenssen had a clue which embryo had divided when one of her toddlers stood up by spreading her feet out wide and walking her hands up her legs: She’d seen her brother do that same move, a hallmark of muscular dystrophy, as a child.

Jenssen guessed then that two of her daughters, the twins, had a Duchenne mutation, and she knew in her heart that, for at least one of them, that genetic legacy was already developing into disease. But persuading doctors to test for it took about a year and a half. She said they kept telling her, “Girls don’t get Duchenne.”

Of the hundreds of genetic diseases linked to the X chromosome, Duchenne is among the more common, along with certain forms of hemophilia. Other so-called X-linked disorders include Fabry disease, which can cause life-shortening kidney and heart problems, and types of Alport syndrome, another kidney-destroying disease. In the past, many doctors believed that these diseases affected only men and boys. But what seemed at first like isolated cases kept cropping up, in which women and girls showed symptoms, too. Parts of the medical community and many patients now argue that more women might be affected with symptoms of X-linked disorders than previously appreciated.

Data about what these diseases look like in women and girls, or even how many women are affected, are scarce, in part because researchers are only now taking this problem seriously. For some women, the symptoms appear less severely than in men, but for others they are similarly devastating: Jenssen told me that, at 15, one of her two daughters with the mutation so far has only mild symptoms of Duchenne, but the one who first showed signs of the disease now uses a wheelchair. That they are affected at all, though, goes against what many women were told for years.

Shellye Horowitz, now 51, told me that, throughout her childhood, her wounds never healed well or quickly, and her joints hurt so much that she limped. No one believed what she said about her constant pain. “The doctors told my parents that I was lazy and that I was faking it to get out of PE,” she said. Horowitz’s dad had hemophilia, a blood-clotting disorder that, in severe forms, can cause fatal bleeds if left untreated, but her doctors never took seriously the possibility that she did too.

Still, long after she was done with PE, Horowitz suffered from swelling joints and other tissues, and wounds that wouldn’t heal. As an adult, she had a small mole removed, and bled through an entire roll of paper towels. Finally, the doctors gave her replacement clotting factor, a classic treatment for hemophilia, and the bleeding stopped. Only as she entered her 40s, after a series of medical procedures and follow-ups, did Horowitz learn that she makes just 10 to 20 percent of the amount of clotting factor the body needs. And she finally found a specialist who put her on preventative therapy for hemophilia.

For years, many practicing doctors’ thinking about X-linked diseases has been simple. In their view, men and boys have one X chromosome in their cells and one Y, which carries only a paltry set of genes. So if a genetic error on the X chromosome disrupts production of important proteins in the body, male patients suffer the consequence. According to this traditional logic, women and girls have another copy of the genes in question on their second X chromosome—working genes that can make up for mutated ones. (Women might have two mutated X chromosomes, but that is statistically ultrarare.)

The idea that those backup genes would always shield someone from an X-linked disease, however, has proved untrue, in part because of a special thing that happens with X chromosomes.

In other pairs of chromosomes, those alternative genes can protect against some dangerous mutations. But beginning in the 1960s, scientists began to appreciate that, as female embryos develop, their cells undergo a process known as X-chromosome inactivation. The thinking goes roughly like this: Because cells do not need two of these particular chromosomes to function, they chemically silence one at random. If the X chromosome carrying a mutation for a disease is silenced as the embryo grows, then a woman carrying the disorder will be symptom-free. But if the healthy X chromosome is silenced early in development, then the mutated X chromosome can prevail in many of the body’s cells from that point on, and dominate as the girl grows.

Still, “it is a rather common misconception that women are not affected by X-linked disorders,” Caroline Bergner, a neurologist in the Leukodystrophy Outpatient Clinic at the University Hospital Leipzig, told me. Many doctors still learn that X-linked diseases are essentially restricted to boys and men, but “genetics is a lot more complicated than what we are taught in medical school,” Angela Weyand, a hematologist and professor at the University of Michigan Medical School, told me. The science of X inactivation might not be new, but in her experience, “most of it isn’t well known within the medical community outside of geneticists.” Even if a doctor does understand that a woman could be affected by X-linked disorders, they might think these scenarios are too rare to be applicable to their patients. But, Weyand said, “I don’t believe that people who truly understand the science can say that risks to carriers are negligible.”

The variability of X inactivation likely helps explain why an X-linked disease’s effects on women who do have symptoms can vary widely. With Duchenne, a girl whose cells skew toward the mutated copy of the X chromosome “can develop symptoms that look very much like classical Duchenne muscular dystrophy in boys,” Sharon Hesterlee, the chief research officer at the Muscular Dystrophy Association, told me. But because X inactivation is random and exceedingly difficult to test for, women cannot readily know the pattern of chromosome inactivation in their body or predict the degree to which they will experience symptoms. For example, even though Horowitz’s body produces only 10 to 20 percent of the normal amount of clotting factor, she says her aunt with the same X mutation makes 80 percent of the normal amount, and does not need medication.

When researchers have looked at how women are affected by certain X-linked diseases, they’ve found that symptoms are surprisingly common, though. For instance, a study of women with Duchenne mutations—in which Jenssen participated—found that half of them had evidence of tissue scarring in their heart. Jenssen was among those with signs of this cardiac damage. A study of adrenoleukodystrophy, an X-linked disease that can cause deadly hormonal and cerebral complications in boys and men, indicated that upwards of 80 percent of women with mutations for adrenoleukodystrophy show neurological dysfunction by age 60 or older. These women might not be at risk of death, but they can experience life-altering symptoms, including bowel and bladder issues and mobility issues that cause some to need a wheelchair.

Taylor Kane has the mutation for adrenoleukodystrophy, which claimed the life of her father and his twin brother when she was a child. She has not yet had any clear signs of the disease, but her mutation inspired her to start Remember the Girls, an organization that pushes against the dogma that X-linked diseases rarely affect women. About 1,500 women who collectively represent 50 X-linked disorders have joined, including Jenssen and Horowitz. But many women with X-linked disorders are unaware that they even have an affected gene, Kane said. They might suffer symptoms and discover the cause only when they have a son born with the condition.

Knowing that they’re a carrier of the disease doesn’t necessarily help women get treatment. Data might not exist to prove that a particular treatment works in symptomatic girls; if a treatment is sex-limited, then prescribing it for female patients is considered off-label and not always covered by insurance, says Eric Hoffman, a pharmaceutical-sciences professor at Binghamton University and the CEO of a company that has an approved Duchenne therapy and another that facilitates research on treatments for the disease. A doctor might also prescribe a treatment for a female patient’s symptoms without diagnosing the disease as the root cause, which could also cause an insurance company to balk. A company might also deny coverage because a patient’s record is missing the diagnostic code for an X-linked disease—which some hospital medical systems simply don’t have for girls and women.

Jenssen has struggled to get her daughter treated for Duchenne even after a muscle biopsy confirmed the diagnosis. Being a girl disqualified her daughter from drug trials, even though a respected researcher who was enrolling boys in a gene-therapy trial once allowed that “gene therapy would be perfect for her,” Jenssen told me.

One gene-therapy trial eventually produced the medication Elevidys, which received approval from the U.S. Food and Drug Administration in June. Jenssen’s family cheered when they saw that the agency hadn’t limited the drug to boys. Her daughter’s doctor prescribed the medication, with the hope that it would preserve the autonomy her daughter still has—lifting herself into bed from her wheelchair; dressing herself. The family’s insurance provider initially denied coverage of the treatment, a onetime infusion with a list price of $3.2 million. They appealed, and yesterday the company called Jenssen to tell her that the original decision had been overturned. “I feel like it’s unreal,” Jenssen told me. The data on the treatment have been promising but not definitive (and is lacking for girls in particular). Still, Jenssen had hope in her voice when she talked about getting her daughter’s identical twin—the one with more mild symptoms—the medication as well, before her prognosis has a chance to get worse: “She could maybe be cured.”