Stories about: rare diseases

Patients’ brain tissue unlocks the cellular hideout of Sturge-Weber’s gene mutation

A diagram of the skull and brain showing the leptomeninges, which is affected by Sturge-Weber syndrome
Sturge-Weber syndrome causes capillary malformations in the brain. They occur in the brain’s leptomeninges, which comprise the arachnoid mater and pia mater.

A person born with a port-wine birthmark on his or her face and eyelid(s) has an 8 to 15 percent chance of being diagnosed with Sturge-Weber syndrome. The rare disorder causes malformations in certain regions of the body’s capillaries (small blood vessels). Port-wine birthmarks appear on areas of the face affected by these capillary malformations.

Aside from the visible symptoms of Sturge-Weber, there are also some more subtle and worrisome ones. Sturge-Weber syndrome can be detected by magnetic resonance imaging (MRI). Such images can reveal a telltale series of malformed capillaries in regions of the brain. Brain capillary malformations can have potentially devastating neurological consequences, including epileptic seizures.

Frustratingly, since doctors first described Sturge-Weber syndrome over 100 years ago, the relationship between brain capillary malformations and seizures has remained somewhat unexplained. In 2013, a Johns Hopkins University team found a GNAQ R183Q gene mutation in about 90 percent of sampled Sturge-Weber patients. However, the mutation’s effect on particular cells and its relationship to seizures still remained unknown.

But recently, some new light has been shed on the mystery. At Boston Children’s Hospital, Sturge-Weber patients donated their brain tissue to research after it was removed during a drastic surgery to treat severe epilepsy. An analysis of their tissue, funded by Boston Children’s Translational Neuroscience Center (TNC), has revealed the cellular location of the Sturge-Weber mutation. The discovery brings new hope of finding ways to improve the lives of those with the disorder.

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Hillary Savoie: Parents as citizen scientists

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The author with 3-year-old Esmé at their home in New York. (Tracey Buyce Photography)

In my last post I explained the genetic testing process that led to my daughter Esmé receiving results of two mutations of unknown significance. One, on the gene PCDH19, was discovered in 2012 with the GeneDx infantile epilepsy panel. The other, on SCN8A, was found with whole exome sequencing, also through GeneDx, in 2014.

When we received the SCN8A result, I was fascinated by the notion that it would have been included in our original epilepsy panel had we only waited a handful of months. In fact, in the time since Esmé’s original test in 2012, almost 20 new genes have been added to the GeneDx Infantile Epilepsy panel.

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The changing nature of what it means to be “diagnosed”

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One of a series of posts honoring #RareDiseaseDay (Feb 28, 2015).

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? 

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Restoring muscle function in a rare, devastating disease: Part 1

Will Ward at the NSTAR Walk for Boston Children’s Hospital in 2012.

This two-part series examines two potential treatment approaches for myotubular myopathy, a genetic disorder that causes muscle weakness from birth.

Sixth-grader William Ward cruises the hallways at school with a thumb-driven power chair and participates in class with the help of a DynaVox speech device. Although born with a rare, muscle-weakening disease called X-linked myotubular myopathy, or MTM, leaving him virtually immobile, he hasn’t given up.

Neither has Alan Beggs, PhD, who directs the Manton Center for Orphan Disease Research at Boston Children’s Hospital, and who has known Will since he was a newborn in intensive care.

“From the very beginning, Alan connected with our family in a very human way,” says Will’s mother, Erin Ward. “In the scientific community, he’s been the bridge and the connector of researchers around the world. That makes him unique.”

Since the 1990s, Beggs has enrolled more than 500 patients with congenital myopathies from all over the world in genetic studies, seeking causes and potential treatments for congenital myopathies—rare, often fatal diseases that weaken children’s skeletal muscles from birth, often requiring them to breathe on a ventilator and to receive food through a gastrostomy tube.

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Customized cell therapy for untreatable diseases: Your tax dollars at work

Leonard Zon (top) and Massachusetts Lt. Governor Timothy Murray in the Stem Cell Program's zebrafish facility. (Courtesy MLSC)
Ed. Note: Leonard Zon, MD, is founder and director of the Boston Children’s Hospital Stem Cell Program, which yesterday was awarded $4 million by the Massachusetts Life Sciences Center to build the Children’s Center for Cell Therapy.

As a hematologist, I see all too many children battling blood disorders that are essentially untreatable. Babies with immune deficiencies living life in a virtual bubble, hospitalized again and again for infections their bodies can’t fight. Children disabled by strokes caused by sickle cell disease, or suffering through sickle cell crises that drug treatments can’t completely prevent. Children whose only recourse is to risk a bone marrow transplant—if a suitably matched donor can even be found.

Over the past 20 years, my lab and that of George Daley, MD, PhD, at Boston Children’s Hospital have worked hard to give these children a one-time, potentially curative option—a treatment that begins with patients’ own cells and doesn’t require finding a match.

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Cold case: Hospital DNA sequencing program open for business

Mary Elizabeth Stone and her son John, with genetic counselor Meghan Connolly and Pankaj Agrawal, principal investigator of the Gene Discovery Core. (Courtesy ME Stone)

Sequencing a patient’s genome to figure out the exact source of his or her disease isn’t standard operating procedure — yet. But falling sequencing costs and a growing number of successes are starting to bring this approach into the mainstream, helping patients and families while advancing a broader understanding of their diseases.

The Stone family is a case in point. When John and Warren Stone were born, their parents were envisioning life raising identical twins, when suddenly everything changed. On their second day of life, the twins started to have seizures with stiffening of their arms and legs; more alarmingly, they would stop breathing from time to time, requiring a ventilator to help them breathe. Further work-up revealed that both John and Warren were having persistent seizures consistent with Ohtahara syndrome, a rare, debilitating seizure disorder.

Warren died a few weeks later, and the family transferred John’s care to Boston Children’s Hospital. An extensive clinical and genetic work-up here and at several other hospitals involved in his care — including sequencing all the genes known to cause Ohtahara syndrome – identified no cause for John’s unique seizures.

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NOT all in the family: Tackling rare genetic diseases that aren’t inherited

Finding the genetic cause of a non-inherited disorder is a challenge–especially when the gene is abnormal in only some of a person’s cells.

How do you find the genetic cause of a disease that doesn’t appear to be inherited, presents with a variety of symptoms—and has been diagnosed in just a few hundred people worldwide? Add to that the fact that the genetic defect occurs in only a portion of a patient’s cells, and a formidable challenge emerges.

As a team of researchers from Boston Children’s Hospital has discovered, and as is true in many rare diseases, depth and breadth of clinical experience can prove pivotal.

It all started in 2006. That’s when, after poring over years’ worth of patient records and photos, Ahmad Alomari, MD, an interventional radiologist at Boston Children’s and co-director of its Vascular Anomalies Center, defined a condition he called CLOVES syndrome. CLOVES is complex and looks somewhat different in every patient, causing a combination of vascular, skin, spinal and bone or joint abnormalities. It’s a rare and progressive disease for which no known cure or “one-size-fits-all” treatment exists.

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Newly approved Berlin Heart helps patients waiting for a transplant

On the Berlin Heart, Alina Siman, 4, has regained her energy which will make her a better transplant candidate when a new organ becomes available

Four-year-old Alina Siman is being kept alive on a device that gained approval in the U.S. just two weeks ago. The Berlin Heart Group’s EXCOR, a ventricular assist device manufactured in Berlin, Germany, takes over the normal function of a heart by pumping blood directly to the pulmonary artery and into the lungs.

With FDA approval granted on December 16, the U.S. joins Europe and Canada in offering the device for children of all ages with end stage heart failure.

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Reinventing therapeutic development: Systems pharmacology

As Children’s Hospital Boston holds its 2nd Annual Rare Disease Symposium today, here’s a reminder that drug development is incredibly difficult: many initially promising drugs ultimately prove ineffective or have unacceptible toxicity—typically at a late stage of a clinical trial. But it needn’t be that way. In this 10-minute video, introducing its Initiative in Systems Pharmacology, Harvard Medical School makes the argument that focusing on a drug’s action on a single cellular target is a flawed approach — rather, we need to understand and predict its activity in all body systems.

Today’s symposium, co-sponsored by the Technology and Innovation Development Office and the Manton Center for Orphan Disease Research, will address therapeutic development and for rare, often fatal diseases, focusing on moving discoveries to clinical trial and models for partnerships between academia, industry, the FDA and NIH, foundations and patient advocacy groups. Use this link to watch the proceedings live starting at 9 a.m. You can also follow the symposium on Twitter, using the hashtag #CHBRare. Click here for the full agenda.

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Meeting industry halfway on orphan diseases

Credit: Tracy Hunter (via Flickr)

Earlier this week we discussed why, though it may seem counterintuitive, orphan diseases are now good business for Big Pharma. To the delight of hospitals like ours, which care for children with rare diseases lacking good treatments, industry is starting to come to the table. It now falls to us to lay out the banquet.

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