Mar 02 2015

Finding New Genetic Syndrome Ends Medical Odyssey for Families

LETA_DNA

At 3 foot 8 inches, 66 pounds, Leta Moseley is a tiny teenager with a big personality.

At 3 foot 8 inches, 66 pounds, Leta Moseley is a tiny teenager with a big personality. Seventeen years ago, her family embarked on a medical odyssey in search of a diagnosis for Leta, who has cognitive disabilities, speaks only a few words, and has lung disease and heart irregularities. A bad virus can land her in The Children’s Hospital of Philadelphia (CHOP) for several weeks, at times on a ventilator for breathing support. Yet, when she is healthy, Leta can take over a dance floor with her swirls and smiles.

CHOP medical geneticist and researcher Ian Krantz, MD, has been a tireless detective in his efforts to find out what genetic anomaly could be behind Leta’s constellation of symptoms. She had many characteristics in common with his patients with the rare multi-system disorder Cornelia de Lange Syndrome that Dr. Krantz has long studied. But her clinical features weren’t a perfect fit for this diagnosis, and genetic testing for Cornelia de Lange syndrome was negative. Dr. Krantz, Director of the Individualized Medical Genetics Center at CHOP, took Leta’s clinical history and photos all over the world with him to genetic conferences, in hopes of finding other children who shared Leta’s profile.

Over the past 10 years, Dr. Krantz and his team identified two other unrelated children (who live less than 200 miles away) with clinical features that seemed to match Leta’s. Using samples from all three children, his research team made the groundbreaking discovery “back home” in the genetics lab at CHOP. With the help of a breakthrough in sophisticated gene-sequencing technology that became available two years ago, they analyzed the protein-coding portions of DNA (exomes) and identified mutations in the AFF4 gene in Leta and the other two children. In genetic research, this is the equivalent of finding a needle in a haystack.

“This is a great example of how families and their doctors work together over many years to find answers and advance both science and the care of their children,” Dr. Krantz said. “Although it has been a long road to get to this point, it is really just the beginning, and we still need to work closely with the families to fully understand the significance of this discovery and how best to use this information to take better care of Leta and other children with this diagnosis.”

After years of mystery and misdiagnoses, Leta’s family finally has a name for her disorder — a new diagnosis called CHOPS syndrome. The acronym stands for the group of symptoms seen in the three affected children: Cognitive impairment and coarse facial features, Heart defects, Obesity, Pulmonary involvement, Short stature and skeletal dysplasia (abnormal bone development).

As this novel finding is disseminated in a Nature Genetics report, Dr. Krantz expects that CHOPS syndrome may be the answer for other parents around the world who have been on a hunt for their child’s complex, undiagnosed genetic disorder. They may find reassurance that CHOPS syndrome is a de novo condition — which means that it resulted from a new mutation arising in a single egg or sperm that went on to form the affected child but is not present in the patient’s parents — so it is unlikely to recur in any subsequent children.

“Ending the ‘diagnostic odyssey’ for families has a profound psychological effect, allowing for closure and an understanding of how all of these myriad clinical differences in their child are linked to a single underlying cause,” Dr. Krantz said. “It also ends a very expensive search for an answer often with many unnecessary diagnostic tests and blood draws. It allows us to find other children and adults with the same condition that in turn gives us a better understanding of the clinical issues and best options for management and to provide some idea of prognosis for families. We can more effectively counsel families about recurrence risk for themselves and family members. Most importantly, understanding the underlying molecular basis for the clinical findings in their children is the first step towards identifying targeted therapeutics in the future.” 

In this interview, Leta’s mom, Lainey Moseley, described her family’s steadfast love for Leta along their unpredictable journey to the discovery of CHOPS Syndrome:

Q: Tell me about Leta; she seems to have quite a big personality.

A: It blows me away that so much is going on inside that little body of hers. It is so hard to really know what her potential is because we think she is brilliant and understands what is going on all the time. Yet, Leta has cognitive impairment, is nonverbal, has small stature, and she is pretty medically challenged with lung disease and pulmonary hypertension. Having said that, she does have a big personality given all her disabilities, and she endlessly amuses us with her antics. Life with Leta is chaotic and far from normal — the highs and lows are so extreme — but she gives us so much love in return. I cannot imagine our life without her.

Q: When you describe your search for a medical diagnosis for Leta as a “medical odyssey,” what does that mean to you?

A: Like everyone else, we really wanted to have a healthy child. We realized early on that Leta wasn’t hitting her milestones, and at one year old she was diagnosed with lung disease, but for 16 years no genetics doctors were able to give us a definitive genetics diagnosis. After many years, we gave up caring about a diagnosis; a label wasn’t going to alter the course of Leta’s life. But it was still unsettling not knowing how her disabilities were going to unfold. What was her lifespan going to be? Was the lung disease going to be a degenerative condition? We had no idea what her capacity was for learning or speaking. When you don’t have a diagnosis, you don’t know the end game or what to expect.

Q: How did you feel when Dr. Krantz told you that he had found this genetic glitch in Leta’s exome?

A: When Dr. Krantz called and told us that he had identified her gene mutation and that he actually had found two other kids like Leta, it was beyond exciting. I was so curious what these two other little kids, Liam and Nadira, would look like. Leta is so unique. It was hard to imagine that there were two other people in the world just like her. But the discovery also became important for other reasons. On an emotional level, when I found out her dad and I were not carriers of the AFF4 gene mutation, I realized that Leta’s medical issues were not my fault. All those years, I carried the burden that maybe I had done something wrong in my pregnancy that caused Leta’s genetic condition. A diagnosis let me off the hook of blaming myself. There’s nothing that I could have done differently to prevent it. This was just a random act of nature. That was a big turning point for me.

Q: So far, two other families are known to have the same genetic mutations as Leta. Why is it important for you to have this new connection?

A: It is important because we share a medical bond and now have a support group to compare notes about our kids, like what medicines are the doctors prescribing for their lung disease? What kind of communication devices do we each use? Does your child have the same hyperactive personality as mine? They are all so much alike, it is now almost like having triplets. I really am looking forward to getting to know Liam’s and Nadira’s families better. Having them in my life makes me feel so much less alone in my journey with Leta. Liam’s mom and I have become Facebook friends, and she was with me every step of the way praying for Leta when she was in the hospital last month on a ventilator.

Q: Overall, how has your experience been being part of Dr. Krantz’s research team?

A: The whole team has been phenomenal and so wonderful. They have been really supportive by keeping us informed about the ongoing AFF4 research. The genetics team is organizing a lunch next month so that our families can finally get together as a group. We’ve already learned that the research into the condition that Leta, Liam, and Nadira share could be groundbreaking in genetics and possibly lead to understanding roots of other genetic mutations. So that’s pretty exciting when it’s your child who is on the ground floor of that breakthrough. We’ve always thought that Leta is a superstar, but now she is a trailblazer in genetic research, giving other kids the chance to be born healthy.

Editor’s Note: For more information on how CHOPS syndrome sheds light on key events in human biology, read the press release. Also, learn more about Leta by reading the blog http://savingleta.com/written by her mom, Lainey.

Permanent link to this article: http://www.research.chop.edu/blog/finding-new-genetic-syndrome-ends-medical-odyssey-families/

Feb 27 2015

CHOP HIV Expert Consulted About Novel Vaccine Study

HIVThe Children’s Hospital of Philadelphia Research Institute’s own Philip R. Johnson, MD was consulted for a number of articles about an exciting new HIV vaccine study. The study, published in Nature and led by the Scripps Research Institute’s Michael Farzan, PhD, describes the research team’s creation of a new molecule that prevents monkeys from being infected with simian/human immunodeficiency virus (SHIV).

“What Mike [Farzan] has done very ingeniously is to develop a molecule that attacks HIV in two different spots … [and] is able to neutralize most if not all strains of HIV,” said Dr. Johnson in Newsweek’s article about the project.

Dr. Farzan’s work builds on research by Dr. Johnson. In 2009 he published a study in Nature Medicine in which he worked with simian immunodeficiency virus (SIV) — which is closely related to HIV, and occurs in primates — to develop proteins that act like antibodies called immunoadhesins. These proteins, which Dr. Johnson and his team delivered via adeno-associated virus (AAV) vectors, were designed to prevent SIV from infecting cells. They found the immunoadhesins blocked SIV infection, protecting the primates used in the study.

When the Nature Medicine study was published, Steven Douglas, MD, medical director of CHOP’s Immunogenetics Laboratory, said, “Dr. Johnson’s groundbreaking research represents one of the biggest, most significant findings in the history of research at Children’s Hospital. This approach represents a paradigm shift in HIV research.”

Dr. Farzan’s recent paper, meanwhile, explores the effectiveness of a protein his team created, eCD4-Ig, at protecting against SHIV, a hybrid of HIV and SIV. The researchers — who include the University of Pennsylvania’s Beatrice H. Hahn, MD — found AAV-expressed eCD4-Ig protected macaques against SHIV “for more than 40 weeks” against “several infectious challenges.”

According to the CDC, more than 1.1 million Americans were living with HIV at the end of 2010, and approximately 35 million people around the world are living with the disease. An estimated 39 million people have died of HIV/AIDS since it was first recognized.

Dr. Johnson told the Wall Street Journal that the molecule described by Dr. Farzan et al. “appears to be an extraordinarily potent molecule,” he said. “It’s further validating of the idea that we should be thinking in alternate terms about how to attack HIV vaccines. To me the nonhuman primate data are outstanding.”

And finally, speaking to Science, Dr. Johnson said eCD4-Ig “is a beautiful thing.”

For more information about Dr. Farzan’s SHIV study, see Nature. And to read an article about Dr. Johnson’s 2009 study that supports the new HIV work, check out the 2009 CHOP Research Annual Report.

Permanent link to this article: http://www.research.chop.edu/blog/chop-hiv-expert-consulted-novel-vaccine-study/

Feb 25 2015

Genetic MEG Study Links Language Delay to Chromosome Deletion

chromosome

As each child heard a series of tones, the MEG machine analyzed changing magnetic fields in the child’s brain, just as electroencephalography (EEG) detects electrical fields.

According to new research, children born with a DNA abnormality on chromosome 16 already linked to neurodevelopmental problems show measurable delays in processing sound and language. By strengthening the case that the deleted gene disrupts a key biological pathway, the study may lay the foundation for future medical treatments for specific subtypes of autism, along with cognitive and language disabilities.

“This study shows an important connection between gene differences and differences in neurophysiology,” said Timothy P.L. Roberts, PhD, vice chair of Radiology Research at The Children’s Hospital of Philadelphia and a researcher at CHOP’s Center for Autism Research. “It may also help to bridge a largely unexplored gap between genetics and behavior.”

Dr. Roberts led the study published recently in Cerebral Cortex, collaborating with a group from the University of California, San Francisco. The researchers examined children with copy number variants — either deletions or duplications­ of DNA — at the genetic site 16p11.2. Previous researchers had found that this location on chromosome 16 was associated with a subset of autism spectrum disorders (ASDs) and with developmental and language delays.

The researchers used magnetoencephalography (MEG), which detects magnetic fields in the brain, just as electroencephalography (EEG) detects electrical fields. As each child heard a series of tones, the MEG machine analyzed changing magnetic fields in the child’s brain, measuring an auditory processing delay called the M100 response latency.

The researchers analyzed 115 children: 43 with the 16p11.2 deletion, 23 with the 16p11.2 duplication, and 49 healthy controls. Only a fraction of the children had ASD diagnoses: 11 of the 43 with the deletion, and 2 of the 23 with the duplication.

In children with the deletion, the researchers found a significant delay: 23 milliseconds (ms), a figure that Dr. Roberts called “stunningly high” compared to the healthy children. There was no such delay among children with the duplication, who actually had a non-significant tendency to process sounds faster than the control subjects.

The 23-ms delay, about one-fortieth of a second, was twice as high as the 11-ms M100 delay that Dr. Roberts found in a 2010 magnetoencephalography study of children with ASDs.

While the 2010 study focused on children diagnosed with autism spectrum disorders, the Cerebral Cortex study took a “genetics first” approach, analyzing children known to have genetic variants with or without ASD diagnoses. “We have approached the problem from both ends,” Dr. Roberts said. The previous study found a link between the brain and behavior, while this new study found a link between genetics and the brain.”

Although not all of the children with CNVs had autism, all of them had some neurological or learning disabilities, he noted. Because the severity of neurodevelopmental symptoms did not correlate with the length of the auditory processing delay, the M100 delay may not become a clear-cut diagnostic biomarker in neurological disorders, but it may be a clue to an important common pathway in neurobiology.

“We don’t yet know the significance of the 23-millisecond delay, but we have established its origin in genetics,” Dr. Roberts said. “It seems to be a proxy for something of biological significance.”

Further studies will investigate other genes previously implicated in autism spectrum disorders  and other psychiatric disorders, to determine whether they also involve M100 response delays. “Our goal is to unify diverse genes along a few common pathways, some of which may be treatable with specific therapies,” said Dr. Roberts.

To read more about the Cerebral Cortex magnetoencephalography study, see a press release about the project.

Permanent link to this article: http://www.research.chop.edu/blog/genetic-study-links-language-delay-chromosome-deletion-children/

Feb 23 2015

CPCE Supports New Pilot Projects on Clinical Decision-Making

CPCEThe Center for Pediatric Clinical Effectiveness (CPCE) at The Children’s Hospital of Philadelphia supports outstanding pilot research studies designed to produce evidence for what works best for treating, diagnosing, and preventing disease. Winners chosen for the fall round of the CPCE’s Pilot Grant Program will focus on two projects that aim to have an impact on clinical decision-making.

Maya Dewan, MD, MPH, a fellow in CHOP’s Department of Anesthesiology and Critical Care Medicine, will evaluate a low-cost intervention with the goal of reducing the rates of unnecessary alarm signals. It has been well-established that alarm fatigue is a growing threat to patient safety, but little research has been done that focuses on approaches to solve the problem of excessive alarms in the pediatric setting.

“Often when you’re in the pediatric intensive care unit (PICU), you’re overwhelmed by the amount of noise,” Dr. Dewan said. “You’ll go into a sick patient’s room, and sometimes it’s even hard for you to communicate or hear someone speaking because everything is beeping in the room.”

The barrage of alarms also can be stressful for families, Dr. Dewan added. She recalled sitting at 2 a.m. beside a concerned mother who was fixated on her child’s monitors and would jump at every blip.

Physiologic alarms display heart rate, respiratory rate, blood pressure, and oxygen saturation and are important tools to alert clinicians to signs of instability and prevent cardiac and respiratory arrest. In CHOP’s PICU, patients average 100 to 110 crisis and warning alarms per day, yet the majority are false, which can interrupt patient care and reduce nurses’ trust in the alarms.

“We decided to devise an intervention that could safely decrease alarms that are unnecessary,” Dr. Dewan said. “But our goal isn’t just to get rid of the false alarms. We want to ensure that the alarms you hear are true and people respond to them faster. If you filter out the false alarms, maybe we’ll pay more attention and identify kids who are getter sicker sooner.”

Preliminary data show that 25 percent to 30 percent of the crisis and warning alarms in CHOP’s PICU are caused by just 4 percent to 8 percent of patients who are mainly low acuity and require less complicated care. On a daily basis, Dr. Dewan and her study team will identify one or two low-acuity patients in the PICU who have high physiologic monitor alarm rates. During safety huddles — brief, structured conversations with physicians, nurses, and other staff to mitigate safety risks — they will review the alarm data and determine if the patients could benefit from adjustment of the alarm parameters. Patients recognized during the safety huddles as eligible for intervention will be discussed further during rounds, when their physicians will decide if safe tailoring of alarm limits is warranted.

“We wanted to individualize the approach for every patient,” Dr. Dewan said. “And we didn’t want to take away any of the autonomy of the providers at the bedside who know the patient best.”

Dr. Dewan was excited to receive funding from the CPCE, which will pay for research assistance to help launch the project by early spring. She expects the pilot study to include about 200 intervention patients over a six-month period and anticipates that their alarm rates will decrease by at least 10 percent when compared to control patients.

If the huddle intervention is shown to be safe and effective in the PICU, the next step would be to integrate the data-driven approach into the workflow throughout the hospital. The data they collect eventually could be used to support application for funding from the National Institutes of Health to evaluate the intervention’s effectiveness in a multicenter study of PICUs across the U.S.

Nephrology fellow Aadil Kakajiwala, MBBS, is equally as thrilled to have been chosen by the CPCE to conduct a research project that will focus on the variability in measures of mineral metabolism in pediatric end-stage kidney disease. Chronic kidney disease (CKD) is associated with nearly universal disturbances in metabolism of calcium, phosphate, parathyroid hormone, and vitamin D that present multiple obstacles to children’s bone and cardiovascular health, nutrition, and growth.

As part of his training at CHOP, Dr. Kakajiwala spent six months getting to know the young patients who visited the pediatric hemodialysis center, usually three times a week. As part of the standard of care, the patients were monitored monthly for calcium, phosphate, parathyroid hormone. These measurements aided clinicians in making adjustments to the patients’ medications and growth hormone therapy.  Dr. Kakajiwala and his mentors, including Michelle Denburg, MD, MSCE, an attending physician in the Division of Nephrology, suspect that flux in these parameters may occur often in children on dialysis, so they planned a pilot study to investigate if more frequent assessment of mineral homeostasis could help clinicians to assess bone health more closely.

“Our concern is that patients on dialysis have vitamin D and parathyroid hormone levels that are variable, and they need a lot of fine-tuning and management,” Dr. Kakajiwala said. “What we want to show from this study is whether we need to check these levels more than just every month, with the intention that we can intervene quicker and not lead to any bone or cardiovascular issues.”

As a major goal of the study is to see how decision-making would differ based on serial measures, the study will not alter usual care in any way except that an extra 3 mL of blood will be drawn pre-dialysis twice weekly from about 10 study participants over a 12-week period during the winter season. The study team will collect, store, and then analyze the blood samples, also taking note of any medication changes that were made based on the usual monthly laboratory results.

The investigators will determine how many times an intervention would have been made based on the weekly results. Dr. Kakajiwala noted that a similar study of adults showed that almost 25 percent to 40 percent of the time, the physician would have made changes to the patient’s care plan.

Dr. Kakajiwala is especially thankful for the guidance from Dr. Denburg, an assistant professor of pediatrics for the Perelman School of Medicine at the University of Pennsylvania, during his application for the CPCE grant.

“With Dr. Denburg’s expertise in chronic kidney disease and metabolic bone health, and my passion for the dialysis patients, I think this is going to be a fantastic study,” Dr. Kakajiwala said.

The CPCE accepts proposals for its pilot grant program twice a year, and promising projects undergo at least two rounds of reviews to determine that they fully meet the selection criteria. Read more about the program’s winners chosen in spring 2014: http://www.research.chop.edu/blog/investigators-excited-receive-cpce-pilot-grant-awards/

Permanent link to this article: http://www.research.chop.edu/blog/cpce-supports-new-pilot-projects-clinical-decision-making/

Feb 20 2015

Pediatric Medical Device Innovators Receive PPDC Seed Grants

medical device

The Bili-Hut is a portable phototherapy device for treating newborns with neonatal jaundice.

The Philadelphia Pediatric Medical Device Consortium (PPDC) announced that it will provide seed grants of $25,000 each to three companies to transform their innovative ideas into commercial devices that benefit young patients.

The PPDC brings together engineers and biomedical researchers from The Children’s Hospital of Philadelphia, Drexel University, and the University of Pennsylvania to address the shortage of medical devices designed for children. In addition to financial support, they provide clinical, business, and regulatory expertise to help overcome common hurdles of commercialization. Nineteen organizations responded to the PPDC’s first request for proposals in June 2014.

“Our request for proposals sought projects from academia and industry from around the globe,” said bioengineer Matthew R. Maltese, PhD, the PPDC’s executive director and principal investigator. Dr. Maltese also is director of Biomechanics Research in the Department of Anesthesiology and Critical Care Medicine at The Children’s Hospital of Philadelphia, as well as an adjunct assistant professor in the University of Pennsylvania’s Perelman School of Medicine. “All projects were rigorously reviewed by our clinical and industry experts, and we are excited to fund these innovators of promising medical devices for children.”

The three PPDC awards will help to advance the development of medical devices that aim to improve pediatric care for jaundice, ear infections, and prosthetic limbs:

  • The Bili-Hut, proposed by Little Sparrows Technologies, is a portable, high-intensity phototherapy device designed for use in medically underserved areas to treat newborns with neonatal jaundice. The condition responds to phototherapy, typically provided by fluorescent lights. The Bili-Hut offers a three-pound, collapsible enclosure that uses low-energy-requiring LED lights, enabling use with either line power or alternative sources such as a 12-volt battery.
  • OtoNexus Medical Technologies designed a handheld ultrasound tool to detect and identify the type of fluid behind a child’s eardrum, which is crucial to correctly diagnosing middle ear infections, called otitis media. Obtaining more accurate diagnoses for otitis media — currently half of diagnoses are in error — could lower unnecessary antibiotic usage and reduce medical costs.
  • RasLabs is using a polymer-based material to line the socket of a pediatric-sized artificial leg or other limb in order to provide a more snug fit during normal daily use. The material contracts or expands like muscle, in response to low-voltage electricity.

The PPDC is one of seven regional pediatric device consortia that received funding from the U.S. Food and Drug Administration to address the unmet need for child-specific medical devices. Pediatric medical device innovators’ next opportunity to apply for a PPDC grant will be in March.

Read the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/pediatric-medical-device-innovators-receive-ppdc-seed-grants/

Feb 18 2015

Transparent Microelectrodes Allow for Dynamic Imaging to Study Epilepsy

epilepsyThe brain is the body’s control center, and it relies on an intricate circuitry of thousands of neurons that communicate with each other through electrical and chemical signals. An electroencephalogram (EEG), which is a recording of brain activity using small button electrodes, helps neuroscience researchers to better understand the cellular mechanisms involved with brain disorders, such as how epileptic seizures occur.

One of the most common disorders of the nervous system, epilepsy affects 2.7 million Americans of all ages, races, and ethnic background. A seizure takes place when spontaneous high-frequency bursting of neural networks appears that temporarily interrupts normal electrical brain function.

Neuroscience researcher Hajime Takano, PhD, who works in Douglas Coulter, PhD’s, epilepsy research laboratory at The Children’s Hospital of Philadelphia, is especially interested in which specific neurons could be inciting the neural network. But pinpointing those neurons’ locations and plotting the intensity of their activity in real time has been problematic because traditional metal electrodes cause interference when used in conjunction with sophisticated, multicellular calcium imaging techniques that investigators couple with high-speed microscopes to see and record when neurons are firing.

Dr. Takano, who is also a research assistant professor in the Neurology Department in the Perelman School of Medicine at the University of Pennsylvania, collaborated with other Penn researchers from the School of Engineering to test a new type of transparent, flexible microelectrode they developed that could solve this problem. It is made of the strongest material known to man: graphene, a two-dimensional form of carbon only one atom thick. Because it is see-through, the graphene microelectrode allows for simultaneous optical imaging and electrophysiological recordings of neural circuits.

“The idea of applying this technology to basic neuroscience for brain recording is something new and very exciting,” said Dr. Takano, who also has an engineering background.

In a study published in Nature Communications, Dr. Takano; senior author Brian Litt, PhD; Penn Engineering Postdoc Duygu Kuzum; and colleagues described how they were able to use the graphene microelectrode technology in combination with calcium imaging involving confocal and two-photon microscopy to observe seizure-like activity that they induced in neural tissue from rats. The investigators were able to obtain both high spatial and temporal resolution, which is the ability to discriminate between two points in space and time.

Neurons and their processes are small, with a spatial extent measured in micrometers. In contrast, the circuits within which neurons function may extend millimeters to a centimeter or more. The new microelectrode allows for dynamic imaging that can provide valuable information on individual cells, while at the same time probing the regions that they may span.

“By monitoring a seizure with the transparent electrodes and imaging individual neurons at the same time, we can try to pinpoint where a seizure started,” Dr. Takano said. “If there are repeated seizures, we can see if the seizure-initiating cell is always the same or not. And if there is an initiating cell, what is different about it?”

At the Society for Neuroscience’s Annual Meeting held Nov. 15-19 in Washington, D.C., Dr. Takano presented a poster describing how the study team used the graphene electrodes to record high-frequency bursting activity. The response from attendees was overwhelmingly positive, Dr. Takano said.

In the future, Dr. Takano plans to use the graphene electrodes in conjunction with other advanced imaging approaches to provide new insights into the functions of neural circuits during seizures. For example, they will allow him to use chloride imaging to explore factors that control the level of electrical activation in cellular regions.

Development of the transparent microelectrode technology involved a multidisciplinary effort from Penn’s new Center for NeuroEngineering and Therapeutics, Penn’s departments of Neuroscience, Pediatrics, and Materials Science, and the Division of Neurology at CHOP.

Permanent link to this article: http://www.research.chop.edu/blog/transparent-microelectrodes-allow-dynamic-imaging-study-epilepsy/

Feb 16 2015

New Gene Test to Improve Transplantation, Research

geneThe Children’s Hospital of Philadelphia has long been a leader in the world of genomic medicine. CHOP Research investigators regularly publish groundbreaking studies that span the gamut of childhood disease, from those focused on autism to studies of the childhood cancer neuroblastoma, to investigations of common conditions like obesity and more rare diseases.

During fiscal 2013, Children’s Hospital immunogenetics experts developed a unique laboratory test to characterize the genes that encode human leukocyte antigen (HLA) molecules, which are complex proteins on cell surfaces that are essential to immune function. By using faster, more comprehensive gene sequencing technology to type HLAs, the new test may improve transplantation outcomes through a more refined assessment of donor compatibility.

“This faster, more thorough technology allows us to better account for subtle genetic differences between individuals,” said Dimitri Monos, PhD, director of the Immunogenetics Laboratory in the Division of Genomic Diagnostics, and professor of Pathology and Laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania.

“We expect this knowledge to yield clinical benefits, by facilitating more precise matches between transplant donors and recipients, and assessing the significance of mismatches in genomic regions of the HLAs that were previously uncharacterized,” Dr. Monos added.

For more information about this groundbreaking program, see the Research Annual Report.

Permanent link to this article: http://www.research.chop.edu/blog/new-gene-test-improve-transplantation-research/

Feb 13 2015

Young Girls Help Inform Breast Cancer Prevention

breast cancerWith a megawatt smile and adventurous spirit, Marlena Penn, 16, is a high school junior, master scuba diver, and talented underwater photographer. She has been eye-to-eye with an octopus and captured its spectacular changes in color. Evidently, her bravery and glossy, auburn curls come from her mother, Norma Roth, who is a writer, speaker, volunteer extraordinaire, and breast cancer survivor.

Put them together in an interview room, and you can feel the girl power about to burst through the door.

Even though they have a packed schedule, twice a year the pair travels from Cherry Hill, N.J., to visit The Children’s Hospital of Philadelphia as participants in the “Lessons in Epidemiology and Genetics of Adult Cancer from Youth” (LEGACY Girls Study).

Funded by the National Cancer Institute, the LEGACY study is unique in its focus on healthy, young girls and how their habits and development are related to breast health. LEGACY researchers hope to identify risk factors and lifestyle modifications that could potentially be addressed early enough to prevent or diminish the effects of cancer.

“We’ve seen a lot of death on both sides of my mother’s family from breast cancer, but as detection and treatment has advanced, we’ve seen better outcomes,” Norma said. “I always thought there also was some kind of environmental link. So it was interesting to me to see that the LEGACY study was tracking the health and diet of young girls to see what effects it might have on breast cancer development in the future.”

To learn more about this exciting program, see the 2014 Research Annual Report!

Permanent link to this article: http://www.research.chop.edu/blog/young-girls-help-inform-breast-cancer-prevention/

Feb 11 2015

Genetic Clues Found in Food Allergy Eosinophilic Esophagitis

Eosinophilic EsophagitisScientists have identified four new genes associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the findings may point toward potential new treatments for EoE.

“This research adds to the evidence that genetic factors play key roles in EoE, and broadens our knowledge of biological networks that may offer attractive targets for therapy,” said study leader Hakon Hakonarson, MD, PhD, director of The Children’s Hospital of Philadelphia’s Center for Applied Genomics.

The study team — which included researchers from CHOP, the University of Pennsylvania, and Rady Children’s Hospital-San Diego — published the study recently in Nature Communications. The research builds on a 2010 study by Dr. Hakonarson and colleagues that identified TSLP as the first major gene associated with EoE. Children’s Hospital’s Patrick M.A. Sleiman, PhD, also of the Center for Applied Genomics, was the first author of the study, and performed the data analysis.

Only recently recognized as a distinct condition, eosinophilic esophagitis has been rapidly increasing in prevalence over the past 20 years. Its hallmark is inflammation and painful swelling in the esophagus, along with high levels of immune cells called eosinophils. It can affect people of any age, but is more common among young men who have a history of other allergic diseases such as asthma and eczema.

EoE is often first discovered in children with feeding difficulties and failure to thrive. Because children with EoE are often allergic to many foods, they may be placed on a highly restricted diet containing no large food proteins, to allow time for their symptoms to resolve. Physicians then perform tests to determine which foods a child can or cannot eat.

In the current research, the investigators performed a genome-wide association study (GWAS), first in a discovery cohort of 603 EoE patients compared to 3,637 control subjects, then in a replication cohort of 333 patients versus 675 controls. All the subjects were of European ancestry. The study team identified four novel- loci significantly associated with EoE. Two of them, STAT6 and c11orf30, previously were found in association with both allergies and autoimmune diseases. Two other gene loci, ANKRD27 and CAPN14, were specific to EoE.

CAPN14 may be of particular interest, said co-author Jonathan Spergel, MD, PhD, a pediatric allergist-immunologist at CHOP. The gene appears to be expressed only in the esophagus. “A recent study in a mouse model for asthma showed that a drug that inhibits a related protein reduces inflammation and improves airway functioning in animals,” he said.

While a similar drug might relieve esophageal inflammation in children with EoE, he added, “However, the finding of four genes indicates that a single drug might not work for all patients with EoE, and we may need a tailored approach to treatment, based on patients’ genetic profiles.”

Dr. Spergel was a co-author with Dr. Hakonarson on the 2010 study that identified the first EoE-associated gene. He directs CHOP’s Center for Pediatric Eosinophilic Disorders, one of the nation’s premier programs for such diseases. The CHOP center recently joined a new NIH-funded network, the Consortium of Eosinophilic Gastrointestinal Disease Researchers, which brings together leading centers in the field.

To learn more about eosinophilic esophagitis, see Children’s Hospital’s website.

Permanent link to this article: http://www.research.chop.edu/blog/genetic-clues-found-food-allergy-eosinophilic-esophagitis/

Feb 09 2015

Researchers Developing Reliable Measures of Children’s Sleep Health

sleep healthHealthy sleep is essential for children’s happiness, attentiveness, and energy, yet estimates suggest that up to 30 percent of children are affected by sleep problems. While parents usually have no difficulty describing their poor sleepers’ crankiness and fussiness, physicians have not had a standard, reliable way to measure these patient reports of children’s sleep.

Patient reported outcome measures are ways of obtaining information about your health or your well-being from your own perspective, without any translation from a clinician or an interviewer. The National Institutes of Health offers assessment tools called the Patient Reported Outcomes Measurement Information System (PROMIS) to help physicians precisely measure what patients are able to do and how they feel by asking a set of questions that have undergone rigorous scientific testing.

The PROMIS Pediatric Profile has core measures covering domains such as anxiety, depression, fatigue, pain, physical function, and social participation, but the big missing piece of the portfolio is sleep health. Christopher B. Forrest, MD, PhD, a CHOP pediatrician and professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania, recently received a two-year grant from the Patient-Centered Outcomes Research Institute (PCORI) to develop PROMIS pediatric sleep health measures that will fill this gap and enable patients and their families to express exactly how health conditions and treatments affect their sleep.

“These questions address the dimensions of life that I like to call feelings, doings, and beings,” said Dr. Forrest, who has been involved with the PROMIS initiative since 2009. “It’s how you feel about yourself and your life, what you can do in life, and then your ‘beings’ is what you become — your personal growth and development. You cannot get that information unless you ask somebody, and what we’ve done through the National Institutes of Health PROMIS program is standardize the methodology.”

For example, “In the past seven days, I fell asleep during school,” is one of the PROMIS items being considered to measure wakefulness and sleep-related impairment. A section of questions on sleep practices includes, “In the past seven days, what time did you go to bed on school nights?”

Once the set of PROMIS pediatric sleep health measures are developed, the idea is for the questionnaires to be offered on tablets, computer kiosks, or paper forms in physicians’ waiting rooms. Two versions will be available for child self-report (ages 8 and up) and parent-proxy (children ages 5 and up).

At CHOP, efforts are underway to eventually incorporate answers to the sleep bank items and other patient-reported outcomes measures as part of the electronic health record. In addition to giving clinicians a standardized way to assess sleep quality and address pediatric sleep concerns as they change over time, the sleep health measures could be used as clinical trial endpoints.

“A medical treatment ought to make kids feel better, but they are not fully recovered until they are able to do things better, like go to school, interact with friends, have sleepovers,” Dr. Forrest said. “Those tend to be the kinds of concerns that families have, but often they don’t get brought up at conventional medical encounters.”

An innovative facet of how the pediatric sleep health item banks are being created is the project’s engagement model. Twenty individuals from five stakeholder groups — parents, youth, advocates, clinicians, and researchers — help to design and oversee the research. One leader from each group plus the project staff make operational decisions.

The team already has accomplished a substantial part of the groundwork. They have interviewed sleep experts, parents, and children, as well as conducted a literature search to identify pediatric sleep measures that were developed previously. Based on the information that they gathered, they generated a preliminary list of 180 pediatric sleep measures. Their next step is to test and validate the questions by surveying about 4,000 children and parents from across the country. They will be recruiting children from CHOP’s Sleep Center, and another group of children with autism being treated at CHOP have agreed to participate in the research.

Dr. Forrest expects the PROMIS pediatric sleep measures will be narrowed down to about 100 items that will be ready for the engagement team to disseminate within the next two years. The final set of measures will be posted on the PROMIS website for free access.

“In addition to publishing papers, we will want to make known across the country through advocacy groups, through scientific communities, and clinical societies that these measures are available,” Dr. Forrest said. “Our hope is that they get used by thousands of researchers and tens of thousands of clinicians and patients.”

Dr. Forrest also serves as the principal investigator of PEDSnet, which is part of the PCORnet  national patient-centered research network established by PCORI to reduce the time and effort needed to launch new studies and focus research on questions and outcomes especially useful to patients and those who care for them.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-developing-reliable-measures-childrens-sleep-health/

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