Willow is a beautiful name. Meaning slender and graceful, like the tree, it evokes images of a little girl running through the woods with streams of hair behind her. But Willow Cannan, who lives in Mississippi with her parents and two older sisters, can’t run or do very much on her own.
Willow was born on August 21, 2013. At first she seemed fine, except for difficulty nursing.
“Nothing in itself was significant, but a combination of things over time got worse. She crawled a little late. She did walk, but late, at 18 months. She had frequent ear infections, and dry skin that was very bad on her back and her scalp. And she never talked. No words, not even dada. She just made a few sounds,” recalled her mother, Amber Olsen.
The clues started to accrue between 18 and 24 months, when speech therapy didn’t help. Was the problem fluid in her ears, or enlarged adenoids? Willow had her adenoids out the day after she turned 2.
Amber and her husband Tom Cannan probably didn’t know it at the time, but they were about to start the diagnostic odyssey that millions of rare disease families share. It starts with convincing a pediatrician to look beyond the “horses” that are the common childhood conditions to recognize that a child is a zebra or unicorn, with a collection of rare peculiarities that might actually be trumpeting an underlying genetic glitch.
Willow was back at the pediatrician’s three weeks after the adenoid surgery. It hadn’t helped her speak.
“She was walking and running, but she was standing still in time, not progressing like a normal toddler. The pediatrician finally agreed to an endocrinology consult because Willow had been 8 pounds at birth but hadn’t grown at the normal rate, consistently in the 0 percentile,” Amber recalled.
Thyroid tests came back fine. The next stop: a pediatric neurologist, in January 2016. “He looked at her and said there was nothing terribly significant, but she was two and had started having balance issues, and trouble walking. When I said that I had started to see skills undoing, he said ‘ok, we’d better do a genetic panel,” Amber said.
Willow had a chromosomal microarray test, which detects short DNA sequences that are present in extra copies or absent that might explain non-specific findings such as developmental delay or loss of skills. “That test was the only reason we knew what it was,” Amber said. Further single-gene tests confirmed it.
Willow has a gap in both copies of a gene, SUMF1, that normally encodes a protein called sulfatase modifying factor 1, making her one of about 50 people in the world with multiple sulfatase deficiency (MSD). The absence of the one enzyme results in her missing a bunch of enzymes that break down mucopolysaccharides – components of mucus that are mostly sugars with some proteins.
SUMF1 encodes an enzyme, FGE (for formylglycine-generating enzyme), that 17 other enzymes, called sulfatases, require. (Sulfatases remove sulfur atoms from certain proteins.) FGE both activates the sulfatases and ships them to the cells’ garbage disposals, the lysosomes, when they build up. So SUMF1 is a little like a Sprint store activating 17 new iPhones while recycling the old ones. One phone not responding is a problem, but the Sprint store burning down is even worse. Multiple sulfatase deficiency is a big Sprint store on fire.
As a result of the falling domino-like effect of SUMF1 mutations, the urine of kids with Willow’s condition lacks the 17 mucus enzymes, and the child develops symptoms of the other “mucopolysaccharidoses” (MPSs). A good article on the natural history and biochemistry of MSD describes 10 children – 7 from France and one each from Lebanon, Pakistan, and Turkey – who have 13 different mutations among them.
Willow inherited one mutation from each parent. After her official diagnosis in May 2016, things began to move a little faster.
Willow’s pediatrician and endocrinologist had never seen a child with MSD, but the general supportive care, such as physical and speech therapy, was appropriate. Fortunately, the family could get to Keesler Air Force base in Biloxi, where a geneticist had trained with Brian Kirmse, in Jackson, an expert in lysosomal storage diseases, a broader category that includes MSD.
“Dr. Kirmse had seen a child who had passed away before a year of age. He explained about the enzymes and storage material and that Willow’s form is the worst of the worst, although he didn’t use those words. Her body was slowly breaking down and we’d just have to take care of her,” Amber quietly told me.
In the MPSs, stuff (“storage material”) builds up, drowning and eventually destroying cells in many body parts. In the most severe form, MSD, the corneas cloud, hearing vanishes, ears clog, tonsils and adenoids swell, and the windpipe narrows. Swallowing slows. Teeth are widely-spaced with fragile enamel, and a misshapen breastbone constricts breathing. The liver and spleen enlarge. The skin is flaky and scaly, although it doesn’t hurt or itch. Facial features are characteristically coarse, so that kids with different forms of MPS look somewhat alike.
DNA Science has told the stories of several families leading battles against rare genetic diseases. Like them, for Amber, a devastating diagnosis with no hope quickly transitioned from tragedy to challenge. But she was intimidated.
“I flunked biology in high school and hated the discipline and knew crap about genes and DNA. I googled for many nights. I hired a medical student to help interpret papers and compiled a list of every doctor and geneticist and researcher. I emailed them, telling them Willow’s story.”
Amber found other MPS families and learned their tales. She made contacts at scientific meetings. And although Clinicaltrials.gov lists nothing for MSD, she learned that gene therapy is already helping kids with other forms of MPS, such as Eliza O’Neill, featured in several DNA Science posts.
Eventually, Amber’s networking led to Steve Gray, a gene therapy guru at the University of North Carolina, whom I profiled here. Dr. Gray creates the viral vectors that deliver gene therapies. His team at the Gene Therapy Center at UNC has tackled giant axonal neuropathy (GAN), and 5 lysosomal storage diseases are on his to-do list.
Willow’s dual deletions of a master gene that controls a suite of vital enzymes must have seemed daunting, for at first Dr. Gray discouraged the distraught mother sitting before him in his office. “He said it’s in the brain, it’s too complex, I have too much on my plate. I felt like I was hitting my head against a wall. I sat and cried in his office. So he finally said, I’ll help you.”
And Dr. Gray has helped. The first mice with MSD were born on September 2 at UNC, and the first gene transfer experiments are slated for November. Social networking has drawn the community together, and in Argentina a dad, Seba Ballauz, has gotten his daughter Alma’s case into the media in a big way and joined forces with Amber. She knew of only 23 cases when Willow was diagnosed, but today knows of 48, the most recent a boy in Texas.
But time is running out.
“Willow has lost a lot of her skills. She can’t walk or run or even sit up. She can’t roll over and she’s having a hard time swallowing. She had a feeding tube put in a couple of months ago, and she’s gained 3 pounds. She’s super sweet. Her personality is bright and smiley and she’s just happy most of the time. She loves music and songs and that’s how we get her to smile,” said Amber.
The self-described DNA dunce is now talking about mouse models and the cost of developing gene therapy vectors. Amber has come a long way from flunking biology, and if her efforts to mobilize researchers and bring MSD to public attention can’t save Willow, they’ll almost certainly save others.
Thanks to Amber Olsen for photos taken from Facebook.