A:SCID is a group of disorders that compromise the blood’s T cells, a key component of the immune system that helps the body fight common viral infections, other opportunistic infections and fungal infections. T-cells are also important for the development of antibody responses to bacteria and other microorganisms. A baby born with SCID appears healthy at birth, but once the maternal antibodies that the baby is born with start to wane, the infant is at risk for life-threatening infections. Unless diagnosed and treated—with a stem cell transplant from a healthy donor or a more experimental therapy like gene therapy—babies with SCID typically die before their first birthday.
Our genes can mutate at any point in our lives. In rare cases, a mutation randomly occurs in a single cell of an embryo and gets carried forward only in the descendants of that particular cell, leaving its mark in some tissues, but not in others. This pattern of mutation, called somatic mosaicsm, can have complicated consequences down the road.
From new longer-acting drugs to promising gene therapy trials, much is changing in the treatment of hemophilia, the inherited bleeding disorder in which the blood does not clot. Hemophilia Awareness Month comes at a time of both progress and remaining challenges.
1. Many more treatment products are being introduced, including some that last longer.
People with hemophilia lack or have defects in a “factor”—a blood protein that helps normal clots form. Of the approximately 20,000 people with hemophilia in the U.S., about 80 percent have hemophilia A, caused by an abnormally low level of factor VIII, and most of the rest have hemophilia B, caused by abnormally low levels of factor IX. Many patients with severe hemophilia give themselves prophylactic IV infusions of the missing factor to prevent bleeding (which otherwise can lead to crippling joint disease when blood seeps into the joint and enzymes released from blood cells erode the cartilage).
Hemophilia factors traditionally have such a short half-life that we tend to treat patients every other day with factor VIII and twice a week with factor IX. The first two longer-lasting products came onto the market within the past year, and more are on the way. So now, with factor IX, it is possible to get an infusion just once a week and not bleed. This is really changing how we think about the disease. So far, the longer-acting factor VIII products are not yet long-lasting enough to make as dramatic a difference in the frequency of infusions. And creating really long-acting factors remains a challenge.
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: