Today we held our fourth annual symposium marking Rare Disease Day. As keynote speaker William A. Gahl, M.D., Ph.D., noted, “it takes a village” to diagnose, treat, and care for people with rare diseases. By “village,” he meant parents, advocates, doctors, basic scientists, clinical researchers, government officials, and philanthropists—all of whom were represented at the event. Gahl is clinical director of the National Human Genome Research Institute (NHGRI) and director of the NIH Undiagnosed Diseases Program
A disease is considered “rare” if it affects fewer than 200,000 people in the United States. Many affect far fewer—even just a handful of people. Although these diseases can be devastating, there’s often little incentive for researchers to develop new diagnostics and therapeutics for conditions that affect so few people. The situation has been improving in recent years, but rare disorders are still sometimes called “orphaned” or “neglected” diseases.
There’s no doubt rare disease research is valuable for its own sake—after all, it saves lives. But something else is emerging from these studies. By investigating what happens when something unusual goes wrong in the human body, we are learning new things about the way our genes, proteins, and cells operate. And that information is now benefiting research on many more common health conditions. Here are three examples, the first two presented at Rare Disease Day:
1. Infectious diseases. In his Rare Disease Day keynote presentation, Gahl shared the stories of many patients with rare diseases that he and his team in the NIH Undiagnosed Diseases Program have helped diagnose and treat. Two of these were siblings—a 10-year-old boy and a five-year-old girl. They both had many physical and cognitive problems, but nobody knew what caused them. Gahl’s team narrowed it down to the sugar molecules that coat their proteins. Sugar molecules affect the shape and function of many proteins. Without the proper sugars in the proper places, many systems malfunction, as had happened in these two children. They have what’s known as Congenital Disorders of Glycosylation (CDG). Before these two, there had only ever been one known case of this particular type of CDG.
As a result of their irregular sugar coatings, these children’s immune systems are also unable to make antibodies. Yet Gahl and his team were surprised to find that the children weren’t especially susceptible to infection. They think it’s because pathogens—bacteria and viruses, especially—use those same sugars to attach and invade cells and tissues. Without the proper sugars to grab on to, pathogenic microorganisms don’t have a way to establish themselves in the body. According to Gahl, researchers at the National Institute of Allergy and Infectious Diseases are now investigating this phenomenon as a possible means for fighting infectious diseases in other people.
2. Arteriosclerosis. José Luis Millán, Ph.D. and his lab study hypophosphatasia, a rare disorder in which children are born lacking an enzyme called alkaline phosphatase. Without it, their bones are dangerously weak. Working with Enobia Pharma (now Alexion Pharmaceuticals), Millán and his team helped develop ENB-0040, an enzyme replacement therapy that provides hypophosphatasia patients with the alkaline phosphatase they are missing. The therapy is now being tested in children. Already, many who were previously too fragile to move can now walk and jump.
While children with hypophosphatasia lack alkaline phosphatase, it turns out that people who produce too much of the enzyme can develop arteriosclerosis, or hardening of the arteries, a common age-related condition. Based on their previous studies of hypophosphatasia, Millán and his team are now working on a new drug that inhibits alkaline phosphatase. They hope the therapy will first benefit children with a severe, early onset form of arteriosclerosis. If trials go well, the drug could also benefit many adults with the condition.
3. Autism. Children born with a rare disease called multiple hereditary exostoses (MHE) have inherited defects in a cellular component called heparan sulfate. As a result, they suffer from bone growths that cause pain and disfigurement. Beyond the physical symptoms of this condition, some parents have noticed that their MHE children also experience autism-like social problems. Doctors rarely took those concerns seriously, though, until Yu Yamaguchi, Ph.D., and his team used a mouse model of MHE to investigate cognitive function. With the support of MHE parents, they found that a mouse model of MHE shows symptoms that meet the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior.
Not all autistic children have MHE, nor are all MHE children autistic. There are most likely many different genetic abnormalities that can lead to autism in the general population. But these findings now indicate that for some, autism could be caused by mutations in genes encoding enzymes and proteins involved in making heparan sulfate (the same molecule that causes both bone and cognitive problems in MHE patients). Yamaguchi’s group is now comparing DNA from autistic and non-autistic volunteers to look for mutations in heparan sulfate-related genes. So far, their initial results look promising.
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