Historically, the starting point for making a rare disease diagnosis is the patient’s clinical profile: the set of symptoms and features that together define Diamond Blackfan anemia (DBA), Niemann-Pick disease or any of a thousand other conditions.
For example, anemia and problems absorbing nutrients are features of Pearson marrow pancreas syndrome (PS), whereas oddly shaped fingernails, lacy patterns on the skin and a proneness to cancer point to dyskeratosis congenita (DC).
The resulting diagnoses give the child and family an entry point into a disease community, and is their anchor for understanding what’s happening to them and others: “Yes, my child has that and here’s how it affects her. Does it affect your child this way too?”
But as researchers probe the relationships between genes and their outward expression—between genotype and phenotype—some families are losing that anchor. They may discover that their child doesn’t actually have condition A; rather, genetically they actually have condition B. Or it may be that no diagnosis matches their genetic findings.
What does that mean for patients’ care, and for their sense of who they are?
Evolution is a strange thing: sometimes it favors keeping a mutation in the gene pool, even when a double dose of it is harmful—even fatal. Why? Because a single copy of that mutation is protective in certain situations.
A classic example is the sickle-cell mutation: People carrying a single copy don’t develop sickle cell disease, but they make enough sickled red blood cells to keep the malaria parasite from getting a toe-hold. (Certain other genetic disorders affecting red blood cells have a similar effect.)
Or consider cystic fibrosis. Carriers of mutations in the CFTR gene—some 1 in 25 people of European ancestry—appear to be protected from typhoid fever, cholera and possibly tuberculosis.
Patrice Milos, PhD, is president and CEO of Claritas Genomics, a CLIA-certified genetic diagnostic testing company spun off from Boston Children’s Hospital in 2013.
A child is sick, showing symptoms her parents cannot identify. Something is seriously wrong, but what? The family turns to Boston Children’s Hospital for answers. Yet, even with today’s medical advances, a precise diagnosis often remains elusive.
The Human Genome Project has sparked innovation over the last 14 years, and as President Obama’s Precision Medicine Initiative asserts, today genome science offers patients new hope for answers.
Initially, cancer will be the major medical focus of this initiative, as cancer is a genetic disease—a genomic alternation of the patient’s normal tissue DNA.
Since its causative gene was sequenced in the 1980s, cystic fibrosis (CF) has been the “textbook” genetic disease. Several thousand mutations have been identified in the CFTR protein, which regulates the flow of chloride in and out of cells. When CFTR is lost or abnormal, thick mucus builds up, impairing patients’ lungs, liver, pancreas, and digestive and reproductive systems, and making their lungs prone to opportunistic infections.
But new research could add a chapter to the textbook, pinpointing an unexpected environmental cause of CF-like illness. A study reported in the February 5 New England Journal of Medicine found that people with arsenic poisoning have high chloride levels in their sweat—the classic diagnostic sign of CF.
Olaf Bodamer, MD, PhD, is associate chief of the Division of Genetics and Genomics at Boston Children’s Hospital and is launching a multidisciplinary clinic this spring for lysosomal storage diseases—including Niemann-Pick type C, sometimes referred to as “childhood Alzheimer’s.”
Niemann-Pick disease type C (NP-C) has come a long way since its first description as an entity in the 1960s. Part of a group of rare metabolic disorders known as lysosomal storage diseases, NP-C leaves children unable to break down cholesterol and other lipid molecules. These molecules accumulate in the liver, spleen and brain, causing progressive neurologic deterioration.
I still vividly remember when I diagnosed my first patient with this devastating disease, a 3-year-old boy who had global developmental delay, restricted eye movement, loss of motor coordination and loss of speech. I spent hours with the family, explaining what was known about NP-C. When faced with the question about treatability and outcome, I could barely find the right words, but had to acknowledge that the outcome was inevitably fatal and that there was no specific treatment other than supportive measures to treat his symptoms.
Children’s hospitals face the challenges of a relatively small patient population, regulatory barriers and care outcomes that may not be measurable for decades. But challenges also bring opportunities. This fall 2014 panel, hosted by Children’s Hospital Association President and CEO Mark Wietecha, gathered CEOs from some of the world’s most respected pediatric hospitals:
Rare diseases offer a lot of opportunity for gene discovery, but getting a drug to market presents many challenges, and costs per patient are high. This 50-minute session explored this complicated landscape from multiple angles. The panelists:
Jay Berry, MD, MPH, is a pediatrician and hospitalist in the Complex Care Service at Boston Children’s Hospital.
Growing up, my parents repeatedly reminded me that “money doesn’t grow on trees.” They pleaded with me to spend it wisely. I’ve recently been thinking a lot about my parents and how their advice might apply to health care spending for my patients.
As a general pediatrician with the Complex Care Service at Boston Children’s Hospital, I care for “medically complex” children. These children—numbering an estimated 500,000 in the U.S.— have serious chronic health problems such as severe cerebral palsy and Pompe disease. Many of them rely on medical technology, like feeding and breathing tubes, to help maintain their health.
These children are expensive to take care of. They make frequent health care visits and tend be high utilizers of medications and equipment. Some use the emergency department and the hospital so often that they’ve been dubbed frequent flyers.
The fact that childhood cancer is, thankfully, rare belies the fact that it is the leading cause of disease-related death in U.S. children age 1 to 19. The number of people with a direct stake in expanding research into pediatric cancer is quite large, well beyond the small number of children with cancer and their families. Not only are the life-long contributions of children cured of cancer enormous, but understanding cancers of young children could also hold the key to understanding a broad range of adult cancers. The time is ripe to allocate more resources, public and private, to research on pediatric cancer.
In an age of increased understanding of the genetic basis of diseases, one thing is striking about many childhood cancers. They are relatively “quiet” cancers, with very few mutations of the DNA. Young children haven’t lived long enough to acquire the large number of mutations that create the background “noise” associated with years of living. This makes it much easier to pinpoint the relevant genetic abnormalities in a young child’s cancer.
Add to this the growing realization that biology, including how various tumors use common “pathways,” is a major factor in how the cancer responds to treatment. Thus, a mechanism that’s relatively easier to observe in the cancers of young children could help scientists understand cancers in adults, in whom the same mechanism is hidden amid the clutter of mutations acquired over a longer life.
Saltonstall spoke today with five other panelists at Boston Children’s Hospital’s Global Pediatric Innovation Summit + Awards in a session titled, “Rare diseases: Lessons from the path less chosen.” David Meeker, MD, president and CEO of Genzyme, moderated.