Stories about: rare disease

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.

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2017 predictions for biomedicine

2017 predictions for biomedicine

David Williams, MD, is Boston Children’s Hospital’s newly appointed Chief Scientific Officer. He is also president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and director of Clinical and Translational Research at Boston Children’s. Vector connected with him to get his forecast on where biomedical research and therapeutic development will go in the year ahead.

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Why we’re glad the Cures Act passed: Its provisions benefit children

Cures Act children
Via @POTUS

Amy Judge DeLong is manager of Federal Government Relations at Boston Children’s Hospital.

In the midst of a seismic shift in Presidential administrations and anticipation of the incoming Congress, a landmark medical research bill with several provisions important to children cleared the lame duck session of Congress. The 21st Century Cures Act (Cures) is the end result of nearly three years of bipartisan Congressional activity. Last week, it was signed into law.

Cures includes scores of provisions aimed at strengthening National Institutes of Health funding for medical research and accelerating review efforts at the Food and Drug Administration. The law cleared Congress with overwhelming majorities, an example of bipartisanship that may be challenged in the months ahead.

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The 21st Century Cures Act: Addressing unmet needs in children with rare disease

21st Century Cures Act and children
Among its other provisions, the Cures Act would advance implementation of the 2013 National Pediatric Research Network Act, boosting therapeutic development for rare childhood diseases.

Medical solutions often require countless hours of investigation, months of testing and monitoring, years of post-trial and market analysis and billions of dollars of investment — with no certainty of success.

Last year, after years of groundwork, the U.S. House of Representatives passed the 21st Century Cures Act. A companion measure is being developed in the Senate, and stakeholders are optimistic that agreement on a package — even a slimmed down bill — could happen this year.

While Congress has addressed research and medical product regulatory needs before, the Cures Act has been unique in its comprehensive approach, looking at all elements of the research spectrum — from basic discovery science to translational research to regulatory review. It would upgrade the National Institutes of Health’s research capabilities and update the Food and Drug Administration’s approval policies to get new drugs and devices to the clinic sooner.

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Citizen science: Genetic bone disease fuels a teen’s passion for research

citizen science

When I was just 3 months old, I was diagnosed with fibular hemimelia, a rare genetic condition that affects about 1 in 50,000 people. It manifests itself as the lack of the fibula bone, a key structural bone in the lower leg that provides major stability in the ankle and knee.

Fibular hemimelia leads to a severe leg length discrepancy — which, in my case, would have amounted to over 6 inches without treatment. Prior to my time at Boston Children’s Hospital, the go-to cure was amputation — replacing my lower leg with a series of prostheses.

Luckily, at the time of my diagnosis, leg-lengthening surgeries were just being approved in the U.S. My parents couldn’t bear to part with my leg, so over the course of 18 years, I have undergone 13 procedures to combat my leg-length difference, starting at age 5. This early exposure to the medical field, coupled with encouragement from teachers, led to a passion for science.

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Citizen science: Giving patients a voice in drug development

citizen science patient voice drug development

There’s a natural tension between wanting the FDA to ensure safety and efficacy before a drug enters the market and wanting to speed up what many view as a glacially slow approval process. The rare disease community tends to fall in the second camp, and has become increasingly vocal in calling for more clinical trials, more flexibility in their design and redefinition of what constitutes a benefit.

ALS advocates, for example, have called for a parallel track, “in which FDA provides an early approval based on limited data, and then continues the learning process in a confirmatory clinical trial and if needed, patient registries to collect additional data from patients receiving the drug outside the clinical trial…”

Recent legislation is encouraging patient engagement in drug development, especially for conditions with profound unmet medical needs. In its 2012 iteration, the Prescription Drug User Fees Act (PDUFA) introduced public meetings to get input from the patient community, captured in a series of informative white papers.

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Hunting rare cancers to ground

rare cancers
(UGREEN 3S / Shutterstock)

As we’ve seen this week on Vector, some rare childhood cancers such as medulloblastoma and neuroblastoma are starting to give up their molecular secrets, raising the possibility (and in medulloblastoma’s case, the reality) of precision treatments. Many cancers, though, are so rare that there aren’t even cell lines in which to study them. Yet they could hold important insights. The first tumor suppressor gene, Rb, was discovered in retinoblastoma, a cancer affecting a mere 500 U.S. children each year.

Doctors often have no clear consensus for diagnosing and treating rare cancers, and outcomes tend to be poor in both children and adults. Andrew Hong, MD, a postdoctoral fellow in the Broad Institute’s Cancer Program and a pediatric oncologist at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, is part of a research team that wants to fix that.

Armed with recent advances in culture technology, the scientists aim to engineer cell lines for as many rare cancers as they can get samples for — and then interrogate them for therapeutic targets. A proof-of-concept published in Nature Communications last month finds a lot of potential in their approach. Read more on Broad Minded, the Broad Institute’s science blog.

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Mom-entrepreneur forms gene therapy company to tackle Sanfilippo syndrome

Karen and Ornella Aiach Sanfilippo gene therapy

Sanfilippo syndrome A is a neurodegenerative condition caused by a genetic error in metabolism: because of a missing enzyme, long-chained sugar molecules cannot be broken down. Toxic substrates accumulate in cells, causing a rapid cognitive decline and, later, motor decline. Most affected children die in their teens or earlier.

There is no treatment, and when Karen Aiach’s daughter Ornella was diagnosed with Sanfilippo syndrome A, no companies were even working on the disease.

As a mother, Aiach could not accept that.

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Expectation vs. reality: Rare disease parents’ mixed feelings about genetic research results

rare disease genetic resultsTypically, when you enroll in a study, it’s not with the expectation that you will receive results. In genomics studies, it’s becoming common to give families the option to get individual results — the newborn sequencing study, Baby Seq, is just one example — as an incentive to participate. Families of children with rare disease, especially undiagnosed illnesses, need no incentive: they’re desperate for answers.

But how do families actually feel once they get genetic results? We conducted interviews with nine rare disease parents (six mothers, three fathers) whose children were enrolled at the hospital’s Manton Center for Orphan Disease Research. What we found is more complexity than we expected.

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Short telomeres, myriad diseases: The complex mystery of dyskeratosis congenita

dyskeratosis congenita
The chromosome tips known as telomeres can be compromised by many different mutations — with many different effects. (vitstudio/Shutterstock)

Genetic diseases largely fall into two overarching camps. You have simple, single-gene alterations that produce a single, recognizable disease. And you have conditions like diabetes or cardiovascular disease, where many variations in many genes all make small contributions that fuel the illness.

Dyskeratosis congenita (DC) doesn’t fit either profile. While this rare genetic condition manifests in certain predictable ways (bone marrow failure among the most common), there is huge variability between patients. Yet genetics has revealed one common thread: the molecular caps that protect the ends of chromosomes, known as telomeres, are shortened in DC patients. This results in cells that age too quickly.

From there things get complicated, because problems with any of 11 different genes can trigger short telomeres in DC. And DC, it appears, is only the beginning.

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