Rare blood disorder sideroblastic anemia slowly reveals its genetic secrets

congenital sideroblastic anemia
Regardless of the gene, all patients with sideroblastic anemia have sideroblasts: red blood cell precursors with abnormal iron deposits in mitochondria, shown here ringing the cell nucleus. (Paulo Henrique Orlandi Mourao/Wikimedia)

A decade ago, Brooks McMurray’s routine check-up was anything but routine. The suburban Boston boy’s spleen was enlarged. His red blood cell count was low and the cells were very small and very pale, which suggested a serious iron deficiency anemia. The family pediatrician referred McMurray, now a 19-year-old college freshman, to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

There hematologists discovered the boy had unexpectedly high iron levels. Together with pathologist Mark Fleming, MD, DPhil, they solved the mystery. McMurray has congenital sideroblastic anemia, an inherited blood disorder so rare that fewer than 1,000 cases have been reported worldwide. Iron was getting stuck in the wrong place in the precursor red blood cells developing in his bone marrow.

Sideroblastic anemia can lead to iron overload, which can damage organs and tissues, as well as fatigue, an enlarged spleen and fevers. The disorder can become life threatening; for McMurray, management includes medication and regular monitoring.

Sometimes giving a precise diagnosis tells you what not to do. Meanwhile Fleming and Matthew Heeney, MD, clinical director of the Blood Disorders Center at Dana-Farber/Boston Children’s, have launched a quest to uncover the disease’s secrets. McMurray has the most common form of congenital sideroblastic anemia. When Fleming determined his genetic mutation, only 40 percent of congenital sideroblastic anemia cases had a known genetic cause. Since then, Fleming and Heeney have discovered six additional mutated genes, bringing that proportion to nearly 70 percent.

“Brooks was the first X-linked sideroblastic anemia patient that I saw. He spurred us to ask about the causes of the disease that were still unknown,” recalls Fleming, who is now pathologist-in-chief at Boston Children’s Hospital. “These are very rare diseases; the last disease-associated gene we discovered involved five patients in four families. Nevertheless, by studying these unusual patients we may discover relatively simple therapies.”

The hunt continues as patients and their families submit blood for Fleming to analyze. Along the way, Heeney is gaining clinical expertise in treating a group of rare diseases that few physicians ever see and that are often misdiagnosed.

Different mutations, different treatments

Whatever the mutation, sideroblastic anemias look similar under a microscope. Iron in the patient’s red blood precursor cells forms a telltale ring around the cell nucleus. That’s a hint that the iron is stuck in a place where it should not accumulate — in mitochondria, cells’ energy-creating power plants.

congenital sideroblastic anemia Brooks McMurray
Brooks McMurray’s case spurred research on sideroblastic anemia.

“Often, doctors initially assume that a patient has garden-variety anemia,” Heeney says. “But somewhere along the line it’s severe enough and stubborn enough that the patient has some bone marrow aspirated to see what’s going on in the blood-making factory. The factory is not producing red cells, so you have to look into the factory to see if there’s a fire or a strike or another problem.

“With sideroblastic anemia, iron is stuck in the wrong place in the cells. Even though a patient is anemic, the condition is not due to iron deficiency. His body is actually absorbing too much iron and it’s landing in all the wrong places, like the liver, so he might need chelation medications to remove the excess.”

Sometimes the disease is severe enough that the patient needs a stem cell transplant. However, here is where the genetics matter. Clinicians now know that patients with a particular form of sideroblastic anemia should not undergo transplant because the treatment can trigger a lethal reaction. Meanwhile, patients with the most commonly mutated gene often respond well to high doses of vitamin B6 that stabilize the enzyme made defective by the mutation. More treatment clues remain to be discovered.

“This is obviously a first step,” Heeney says. “We’re getting more hints about what underlies various forms of sideroblastic anemia.”

Experience with the disorder matters, too. Fleming recalls an out-of-state referral of a young patient diagnosed with a pre-leukemia condition called myelodysplastic syndrome. He was scheduled for a stem cell transplant, but with a less-than-ideal donor that carried substantial risk. When his physician sent his records, Fleming realized the boy had congenital sideroblastic anemia in its most common form. He needed vitamins, not a rigorous and toxic stem cell transplant, and is doing well today.

“Sometimes giving a precise diagnosis tells you what not to do,” Fleming says. Patients with enlarged spleens are an example. “Historically, the temptation was to take out the spleen because it was big and caused abdominal discomfort and poor nutrition. However, in many forms of congenital sideroblastic anemia, if surgeons remove the spleen, some patients will die from pulmonary emboli or chronic lung disease years later because the spleen has a role in protecting them from some secondary effects of the anemia.”

Living with a rare disease

Today Brooks McMurray is studying finance at the University of Massachusetts/Amherst. He’s careful not to eat too much red meat, for fear of taking in too much iron, and comes to Heeney every six months to monitor his blood levels. When he played football in middle school, McMurray wore extra padding to protect his enlarged spleen. He took chelation medicine for a year to treat iron overload and learned that the vitamins that often help patients with his type of sideroblastic anemia don’t work well for him. When he got mononucleosis at the end of high school, he needed a blood transfusion.

While Fleming and Heeney continue to probe the mysteries of sideroblastic anemia, patients like McMurray await the results of their quest.

“It’s definitely weird and disconcerting to have such a rare disease,” McMurray says. “I can’t compare notes with other people. I don’t like the fact that there’s not a medicine that can get rid of it, but I’m glad they’re learning more about it.”

Learn more about congenital sideroblastic anemia at Dana-Farber/Boston Children’s.