Patients with a rare disease often are in a race against the clock. According to the Rare Genomics Institute, half of today’s rare disease patients are young children, one-third of whom are unlikely to live long enough to celebrate their fifth birthday – unless a cure can be found for their illness.
Rare diseases are by definition conditions that affect a small percentage of the population. The Canadian Organization for Rare Diseases defines a rare disease as one affecting fewer than one in 2,000 people, although the number varies among countries. Researchers have so far counted more than 7,000 rare diseases with many more discovered each year. The conditions are often chronic, severely debilitating, and life-threatening, making research into the diseases urgent.
But while individually rare, the collective impact of research into these ailments has enormous implications for the general population.
Tiina Urv, director of the rare diseases clinical research network at the National Center for Advancing Translational Sciences in Bethesda, Md., explained in an interview that, “a really good way to understand how a system in the body functions is to compare one where something is out of alignment and causing illness with a healthy system. Such side-by-side comparisons not only help us to identify what is causing a disease but also teach us how specific biological systems work.
“In this way, the value of rare disease research extends beyond patients with a rare disease, but also touches everyone.”
Thus, research into rare diseases can hold the key to unlocking the secrets of far more common ailments.
Take John Despota, who, as a 12-year-old boy in the 1970s, was diagnosed with a serious form of familial hypercholesterolemia, commonly known as homozygous FH. This rare genetic disease strikes just one in a million people, leaving them with abnormally high levels of low-density lipoproteins (LDL), or bad cholesterol, in their blood and raises the risk of a premature heart attack, even in childhood.
At the time, the only treatment available to him included hour-long dialysis sessions to remove LDL from his blood. Given his family history of heart disease, John’s cardiologist decided to send his cells for genetic analysis to two experts in cholesterol biology, Michael Brown and Joseph Goldstein, at UT Southwestern Medical Center in Dallas.
The two doctors’ research laid the groundwork for developing the world’s most commonly prescribed cholesterol-lowering medications, known as statins, that have prolonged millions of lives. Their discovery earned Brown and Goldstein the Nobel Prize for Medicine in 1985.
Wong-Rieger notes that the vast majority of rare diseases have a genetic origin. This means that “in many cases, we’re dealing not with individuals, we’re dealing with families, and we’re dealing with generations of families. From a scientific point of view, it’s exciting. Rare diseases are teaching us how we can humanize health care and personalize treatment.”
Rare diseases are teaching us how we can humanize health care and personalize treatment.
As most rare diseases result from a single gene defect and often run-in families, they are called monogenic or mendelian disorders. These single-gene disorders provide valuable clues for understanding an array of ailments because they give researchers an unusually clear understanding of cause (gene) and effect (disease). In contrast, the underlying biology of common ailments is typically far more complex, involving many genes as well as environmental and lifestyle factors like smoking, diet, and pollution.
The link between Rett syndrome and autism is another example of how research into a rare disease has cast light on a more common condition.
Rett is a rare genetic disorder affecting about one in 10,000 girls. Like autism, it is a brain development disorder that causes significant physical and mental challenges.
Huda Zoghbi, professor of molecular and human genetics and pediatrics at the Baylor College of Medicine, in Houston, discovered that Rett syndrome is caused by defects in a gene called MECP2.
Zoghbi explained in an email how Rett syndrome is helping scientists unlock the secrets of autism: “The MECP2 protein is important for the function of all brain cells where it regulates the expression level of many genes in the brain. Severe mutations in MECP2 result in Rett syndrome features whereas milder mutations cause classical autism. More importantly, many of the genes whose expression levels are changed in Rett brain due to altered MECP2 function include autism-causing genes, highlighting why Rett syndrome can inform us on autism.”
Zoghbi points to a landmark study on reversing Rett syndrome symptoms in mice conducted by Adrian Bird, professor of genetics at the University of Edinburgh. She notes “the fact that restoring the normal levels of MECP2 by genetic approaches in mice can reverse Rett syndrome in adulthood after symptoms have set in, is very encouraging and suggests that features of autism are potentially reversible in other types of genetically determined autism spectrum disorders.”
One treatment used on mice with Rett syndrome is deep brain stimulation, which successfully normalized the rodents’ learning and memory. Zoghbi and her colleagues are hoping that if deep brain stimulation can enhance brain functions in other animal models of autism spectrum disorders, it can be applied to many common neurological conditions in humans, irrespective of their genetic cause.
Research on animals has also shown that early behaviour therapy, before the onset of symptoms, has a marked impact on performance, and can delay the symptoms of Rett syndrome by months. “These findings are very promising and consistent with the accumulating evidence showing that the earlier the behavioral therapy is implemented in autism, the more the benefit,” Zoghbi said.
Ellen Sidransky, head of molecular neurogenetics at the National Human Genome Research Institute in Bethesda, studies a rare disorder known as Gaucher disease that affects one in 40,000 people. Gaucher disease is an inherited metabolic disorder caused by a defective gene, known as GBA1 that leads to an abnormal accumulation of body fat, mainly in the liver and spleen.
Sidransky’s research has led to key breakthroughs in understanding Parkinson’s disease, a far more common and complex neurological disorder.
“Through our long-standing longitudinal natural history clinical study, I noted that some rare patients with Gaucher disease also developed Parkinson’s,” Sidransky said in an email. “We determined that mutations in the gene GBA1 are the most common genetic risk factor for Parkinson’s. This discovery resulted from our clinical insights from this rare disorder, as the gene had not been uncovered in large genetic studies of Parkinson’s disease. It’s a nice example of why we study rare disorders.”