A few months shy of her 13th birthday, Katelyn Denbow is not quite child and not yet woman. She's stylishly dressed in teen standard garb of leggings, denim skirt and glittery T-shirt, but on a tour of her room she goes straight to her immaculately organized collection of American Girl® dolls.
Picking up a brown-skinned doll, Katelyn says, "Addie's one of my favorites, because I'm very interested in black history and the Civil War." With the confidence of a history professor, Katelyn describes Addie's life growing up on a plantation and her escape via the Underground Railroad.
"I'm very excited because when we go to Georgia in June, we're going to visit a real plantation," she adds with a big smile.
The main reason for the Denbow family trip to Georgia is to attend the triennial International Family Conference, Medical Research Clinic and Scientific Symposium organized by Alström Syndrome International (ASI), a nonprofit organization. Katelyn lives with Alström syndrome, a rare genetic disorder. It results from a defect in just a single gene, but the impact is profound. It affects vision, hearing, heart, liver, kidneys and other systems. It also greatly shortens life expectancy.
Katelyn's love of reading, her astonishing recall of historical facts and her shelf full of public-speaking trophies make her one of the top students in her class. She's growing up in a unique environment: Campobello Island, a tiny, picturesque community on the Canadian side of a land bridge near Lubec, Maine. Her father is in the fishing industry and her mother, Gina, teaches in Katelyn's school—in fact, she teaches both Katelyn and her brother Cody.
Mother and daughter sit close together on Katelyn's bed, alternating between affectionate hugs and teasing banter. "At school I try to ignore her," Katelyn says. "Typical," her mom responds. Away from school, the two often read together, mother reading aloud to daughter when the Braille books run out ("she reads them faster than they can send them"). But sometimes a girl just has to hang out with her friends and watch TV (current obsession: "I, Carly").
Alström syndrome is a recessive disorder, meaning that a child must inherit the gene variant for the disease from both parents. It's rare even by rare-disease standards, with fewer than 700 patients identified worldwide and only 266 cases reported in the medical literature. Yet the Alström community—the families affected by the disorder and the researchers who study it—is vast, spanning 47 countries. And the hub of this community is only about 100 miles from Campobello Island, at The Jackson Laboratory in Bar Harbor, Maine.
In 1996, Jackson Laboratory Professor Jürgen Naggert and his collaborator and wife, Professor Patsy Nishina, published a paper on their discovery of a genetic mutation that causes a cluster of symptoms similar to those found in Alström syndrome in a mouse model known as tubby, including obesity, blindness and hearing deficit. At that time, Jan Marshall, a research assistant to Naggert, conducted the laborious genealogical study that traced Alström syndrome back through 13 generations to an ancestral couple, who emigrated to what is now Nova Scotia in the 1600s. Since then, mutations in the gene have been identified in hundreds more unrelated families.
Today Jan Marshall also serves on the board of ASI; her husband, Robin, is the executive director and runs the organization out of their home in the woods of Mount Desert, Maine, a few miles from The Jackson Laboratory. As part of ASI's outreach efforts to Alström patients and their families, Marshall has known the Denbows since Katelyn was a little girl of 4.
"One of the blessings of working with a really rare disorder," Marshall says, "is that you get to know these kids personally. They're all my kids! Of course all people are different—some are shy, some are anything but shy—but the Alström kids I know are all so bright and loving, with a great sense of humor."
She adds that many of the Alström patients check in with her to ask how the research is going. "Every once in a while I'll get an email from a kid asking, 'How's the mouse?' We have a running joke that there's just one mouse, and his name is Carl-Henry," after Carl-Henry Alström, the Swedish doctor who first identified the syndrome.
"One young man used to call me and, when I picked up the phone, would say, 'Why are you answering the phone? Why aren't you working?'" The smile fades from Marshall's bright blue eyes. "That boy has since died. The hardest part of my job is when we lose a patient. We know them all, we've hugged them, we've been a part of their lives. And then you lose them. We lose them too young."
At The Jackson Laboratory, in a small instrument room with a window view of Frenchman Bay, Gayle Collin studies a computer screen attached to a microscope. Like Marshall, Collin has been involved in studying Alström syndrome for most of her professional life. It was she who, in 1996, successfully pinpointed the gene responsible for Alström syndrome, ALMS1, to a location on chromosome 2.
Pointing at a pink-and-purple histology image on the screen, Collin says, "This is a retina in a 3-month-old mouse with a mutation in the ALMS1 gene, and it's already showing significant degeneration in the photoreceptor layer. Normally we don't see this kind of damage until 9 to 12 months of age. This is because we have placed the disrupted gene on a different genetic background, and that background is clearly making the condition worse."
The genetic "background" is made up of all the different genes that mice (and humans) have that aren't directly related to the disease being researched. Different mouse strains have different backgrounds, and, as with Alström syndrome, they have a significant effect on many diseases. Understanding just how the "background" genes of a mouse interact with the ALMS1 gene to make Alström syndrome symptoms more or less severe, Collin says, could provide insight into possible paths for treatments.
In Alström patients, modifying effects of other genes could explain why some experience earlier onset or worse symptoms, or why others survive longer with fewer medical problems. "There are so many ways that this gene can go wrong," Collin says, "and so many ways the background can make it worse or compensate for it."
As Collin removes her white lab coat, a clear, teardrop-shaped glass pendant swings from her neck on a black cord. "This is a damlaya," Collin says. "We wear them to remember that small steps lead to big results."
Marshall explains, "One of ASI's board members, Nevin Bengur, once mentioned a Turkish proverb when we were having a tough day. "Damlaya damlaya göl olur" means 'Drop by drop a lake is formed,' and this has become a slogan for us. We found these glass drops to symbolize our community, and started wearing them everywhere."
What's surprising is how often people recognize the symbol of this very rare syndrome.
"So many people at The Jackson Laboratory and around the world are working together to help patients with Alström syndrome," Marshall says, "and the patients themselves are wonderful ambassadors, fundraisers and awareness-raisers.
"Dollar by dollar, drop by drop, we can all make a difference."