Nov 26 2014

International Team Finds Blood Disorder Mutation

blood disorderAn international team of gene experts has identified a mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which three generations had blood disorders, the researchers discovered a defect in a gene that regulates telomeres, chromosomal structures with crucial roles in normal cell function.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said the study’s co-leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. Dr. Hakonarson and a number of other CHOP investigators collaborated with Australian scientists on the study, what was published in the journal Blood.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. The investigators identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.Complex structures made of DNA and protein, telomeres are located on the end of chromosomes, where they protect the chromosomes’ stability. They are sometimes compared to shoelaces’ plastic tips.

Telomeres shorten after each cell division, and gradually lose their protective function. Aging cells, with their shortened telomeres, become progressively more vulnerable to DNA damage and cell death. Separately from the aging process, certain inherited and acquired disorders may shorten telomeres and injure rapidly dividing blood-forming cells produced in bone marrow. This leads to bone marrow failure, one example of which is aplastic anemia.

The Australian team investigated the function of the ACD gene. They determined that the mutation shortened telomeres and interrupted the ability of telomeres to attract the enzyme telomerase, which counteracts telomere shortening and thus protects cells. The researchers showed that the mutation in ACD alters the telomere-binding protein TPP1, disrupting the interactions between telomere and telomerase. Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” said Dr. Hakonarson. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

To read more about the innovative work being done at the Center for Applied Genomics, see the Center’s website.

Permanent link to this article: http://www.research.chop.edu/blog/international-team-finds-blood-disorder-mutation/

Nov 24 2014

Research Centers Team Up to Help Teens With ADHD and ASD Drive Safely

ASD

Little is known about how ADHD influences driving and how those factors could vary with gender, age, driving experience, comorbidities, and long-term ADHD medication.

A new teen driver with attention-deficit/hyperactivity disorder (ADHD) jumps behind the wheel and steps on the gas, looking for freedom and adventure. Could his inexperience on the road combined with the inattention, distraction, and impulsivity that are the signature symptoms of his ADHD increase his risk of crashing?

Teen driving safety researchers suspect the answer is, “probably,” but there is a surprising lack of rigorous scientific studies focusing on teen drivers with ADHD, according to Allison Curry, PhD,  a senior scientist and director of epidemiology and biostatistics at the Center for Injury Prevention and Research (CIRP) at The Children’s Hospital of Philadelphia. Using a unique database, Dr. Curry is leading a research project to help fill this knowledge gap from an epidemiological perspective.

As the first study of its kind, the study team will provide a new methodological advancement in the field of young driver research, in order to examine the risk of adverse driving outcomes among a general population of adolescents and young adults ages 16 to 25 diagnosed with ADHD. The database combines two data-rich sources:

  1. electronic health record information for about 1,800 children with ADHD and 10,000 children without ADHD who were born from 1987 to 1995 and patients at CHOP’s Care Network in New Jersey
  2. a linked traffic safety database that contains the full licensing, citation, and crash history of every New Jersey driver from 2004 to the present

“The data are really valuable because they can help us look at teens who are typically developing and other teens who have developmental disabilities to see whether there are differences in when they get licensed and in their risk of crashing,” Dr. Curry said. “If we know what kind of crashes teens with ADHD are getting in, we can begin to develop interventions that are tailored to address the driving skill deficits common among this group of new drivers.”

Motor vehicle crashes are the leading cause of death and disability among adolescents. Inattention, distraction, and unsafe driving behaviors are major contributors to teens’ car accidents, but little is known about how ADHD influences driving and how those factors could vary with gender, age, driving experience, comorbidities, and long-term ADHD medication.

Dr. Curry has spent four years creating NJ’s traffic safety database, and it already has spurred multiple published studies on teen crash rates among the general population in N.J. Her current work includes the ADHD study — funded as a three-year grant by the Eunice Kennedy Shriver National Institute of Child Health & Human Development in August 2014 — and a pilot study of teen drivers with autism spectrum disorder (ASD) that addresses similar research questions funded by a CHOP Foerderer Grant for Excellence.  Dr. Curry hopes findings from the pilot study will provide the basis for a future NIH research project grant application.

Two-thirds of high functioning adolescents with ASD of legal driving age are either currently driving or plan to drive, according to previous research done at CHOP by Patty Huang, MD, a developmental pediatrician at The Children’s Hospital of Philadelphia. However, little is known about the ability of teens’ with ASD to drive safely. ASD is characterized by deficits in communication and social interaction and can be associated with impairments in body coordination and ability to regulate emotions, which could come into play while driving. The research team will use the novel database to determine rates of licensure, police-reported crashes, and moving violations among 500 to 600 adolescents with autism treated at CHOP who were born from 1987 to 1994 and live in New Jersey and then compare them to rates among all New Jersey adolescents.

“We hope these projects will help to set the scientific foundation for the development of interventions that tailor the learning-to-drive process for teens with developmental disabilities,” Dr. Curry said.

In addition to the robustness of the database, both studies stand out to Dr. Curry because they are being conducted in collaboration with two other research centers at CHOP: The Center for Autism Research and the Center for the Management of ADHD. The research teams are in the process of finding and validating the ADHD and autism cases in the CHOP electronic medical record. Concurrently, they are preparing the licensing and crash database, and by the middle of next year, Dr. Curry expects they will be ready to begin analysis.

Dr. Curry hopes their novel research methods can be used to investigate the effect of other medical conditions or events, such as children who have had concussions or seizures, on driving licensure rates and traffic outcomes.

“The large patient population at CHOP gives us the opportunity to provide a unique perspective on teen drivers,” Dr. Curry said.

Understanding how each of these conditions impacts driving could lead to the development of more personalized driving assessments and educational tools for teens. Teen driver safety research is a major focus of CIRP, and the Center offers many universal resources and tips at www.teendriversource.org for navigating the learning-to-drive process.

Permanent link to this article: http://www.research.chop.edu/blog/research-centers-team-help-teens-adhd-asd-drive-safely/

Nov 21 2014

PolicyLab Study Shows Rise in Pediatric Dental Care

dental care

“We know that dental caries, also known as tooth decay, is the most common chronic pediatric disease in the US,” said Katherine Yun, MD, MHS.

A study conducted by PolicyLab researchers shows the proportion of US-born, Medicaid-enrolled children in Pennsylvania who utilized preventive dental care rose significantly for children ages 5-10 years from 2005-2010, with marked gains among Latino children. The study, published recently in the American Journal of Public Health, found that while overall preventive dental care utilization increased from 2005 to 2010, utilization remained less than 60 percent overall. Latino children in non-immigrant families demonstrated the largest gains over time, with 63 percent of children ages 5-10 years receiving preventive dental care in 2010 compared to 35 percent in 2005.

“We know that dental caries, also known as tooth decay, is the most common chronic pediatric disease in the US,” said Katherine Yun, MD, MHS, the study’s lead author and an attending pediatrician and faculty member at PolicyLab. “We also know that it disproportionally affects poor and minority children, and children in immigrant families.”

Preventive dental care includes routine prophylactic cleaning and the application of fluoride by a dentist. The researchers used state Medicaid claims (2005-2010), birth records (2000-2010), and data from the 2010 American Community Survey. Children who were born in Pennsylvania and enrolled in Medicaid for at least 10 months of any calendar year were eligible for the study

Coverage for preventive dental care is available for Medicaid-enrolled children through Medicaid’s Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) benefit. However, despite this coverage, wide-scale utilization of preventive dental care has lagged in many states. Increasing utilization of preventive dental care by Medicaid-enrolled children has been a public health priority in Pennsylvania.

The study team looked at different groups of children to see if their use of preventive dental care had increased, decreased, or plateaued from 2005 to 2010. The authors also focused on US-born children whose mothers were born outside of the U.S., as prior research has suggested that the children of immigrants have difficulty accessing preventive healthcare. They found that in Pennsylvania disadvantage was not concentrated among the US-born children of immigrants.

Latino children in immigrant families were more likely than their peers in non-immigrant families to receive preventive dental care, while white children in immigrant families were more likely to receive preventive dental care than their peers in non-immigrant families. The researchers also found African American children in immigrant and non-immigrant families had moderate rates of preventive dental utilization and were comparable to each other, and Asian children in both immigrant and non-immigrant families showed relatively high rates of preventive dental utilization at each time point and were also comparable to each other.

“We now need to identify the factors responsible for increasing utilization overall and understand why some groups of children have accessed preventive dental care services more than others,” said Dr. Yun. “This is just the first step in ensuring that all children have access to preventive dental services.”

For more information about the study, see PolicyLab’s website.

Permanent link to this article: http://www.research.chop.edu/blog/policylab-study-shows-rise-pediatric-dental-care/

Nov 19 2014

Rescuing Mutation May Operate in Bone Marrow Failure

bone marrowBone marrow failure syndromes are rare disorders in which the bone marrow does not produce enough blood cells, increasing the risk for life-threatening bleeding, anemia, and infections. While children with these conditions usually will need bone marrow transplantation, a small percentage experience spontaneous remission.

Modern genomic approaches are allowing researchers at The Children’s Hospital of Philadelphia to discover how such remission cases occur, which potentially could lead to a novel approach that will transform the way these devastating conditions are understood and managed.

Their hypothesis is that natural mutations in stem cells or progenitor cells could “rescue” them and overcome the effects of inherited or acquired gene mutations linked to bone marrow failure. They suggest that the process behind the correcting mutations is associated with clonal hematopoiesis. While clonal hematopoiesis typically is considered to be a black cloud because it is implicated in the series of genetic changes that lead to cancerous tumor development, this study suggests that clonal hematopoiesis could brighten the chances of recovery for patients with bone marrow failure syndromes.

“If the majority of blood cells are derived from a single stem cell, which is the mother cell of all blood cells, this is called clonal hematopoiesis,” explained Philip Mason, PhD, a senior scientist for CHOP’s Comprehensive Bone Marrow Failure Center (CBMFC). “Normal blood cell production is from many stem cells. We think that it is likely that a mutation takes place in a stem cell, or progenitor cell, which improves its ability to produce blood cells or even corrects the initial defect.”

Stem cells, or hematopoietic cells, develop in the spongy bone marrow and give rise to all blood cells. Progenitor cells are early descendants of stem cells that can differentiate to form one or more kinds of blood cells, such as red blood cells, platelets, or white blood cells. In bone marrow failure syndromes, the stem cells or progenitor cells are damaged and restrict blood production. Rescuing mutations, in contrast, allow the stem cell to grow and divide, thus giving the mutated blood cells a growth advantage — sometimes to the extent that these mutated blood cells, all derived from a single stem cell, replace the entire blood cell production

Dr. Mason is principal investigator of a new study that focuses on an inherited bone marrow failure syndrome called Diamond Blackfan Anemia, which affects 5 to 7 infants per million births worldwide. The study team’s plan is to determine the DNA sequence in the blood cells from bone marrow of 20 study participants with Diamond Blackfan Anemia, and then compare it to the sequence of skin cells from the same participants. Along with experts from CHOP’s Center for Biomedical Informatics, the researchers will pinpoint the sequences that only appear in the bone marrow cells, which will help them to identify clones of cells that are likely to carry the characteristics of the rescuing mutations.

Once this bioinformatics analysis is complete, the researchers will perform extensive validation using targeted deep sequencing methodology. This will help them to select candidate genes to be included in future functional studies to test if and how these mutations are capable of correcting the initial defect in ribosome synthesis seen in Diamond Blackfan Anemia that is responsible for the poor production of red cells.

If the study team finds clonal hematopoiesis due to mutations that increase blood cell survival or proliferation, they propose that similar mechanisms likely operate in all inherited bone marrow failure syndromes and possibly in the scenario of acquired aplastic anemia, although the mutations, genes, and pathways affected may differ. Dr. Mason also is a co-investigator of a larger study involving a multidisciplinary team of clinicians and researchers that focuses on 100 patients with acquired aplastic anemia. The lead principal investigator is Monica Bessler, MD, PhD, director of the CBMFC, a collaborative effort between CHOP and the Hospital of the University of Pennsylvania.

“While the study process is similar, it is more complicated because we don’t exactly know the causes of acquired aplastic anemia,” Dr. Mason said. “DNA sequencing and identifying the correcting mutations will help us to find out the disease’s origins, which may be different from patient to patient.”

Dr. Mason, who has investigated bone marrow failure diseases for 17 years, is enthusiastic about his involvement with both studies, which were awarded funding in August by the National Institute of Diabetes and Digestive and Kidney Diseases.

“This kind of study has only become possible in the last few years because of the technical advances in sequencing,” Dr. Mason said. “I’m excited by the possibility that it could work out and lead to better treatments for these patients.”

Permanent link to this article: http://www.research.chop.edu/blog/rescuing-mutation-may-operate-bone-marrow-failure/

Nov 17 2014

Thrombosis Researcher Set to Deliver American Heart Association Lecture

thrombosis

Sriram Krishnaswamy, PhD, is set to deliver this year’s Sol Sherry Distinguished Lecture in Thrombosis.

The Children’s Hospital of Philadelphia’s Sriram Krishnaswamy, PhD, is set to deliver this year’s Sol Sherry Distinguished Lecture in Thrombosis at this week’s American Heart Association Scientific Sessions annual conference. A thrombosis and hemostasis researcher, Dr. Krishnaswamy investigates the biochemical underpinnings of coagulation.

Held November 15 to 19 in Chicago, the American Heart Association (AHA) conference will bring together approximately 17,000 attendees from over 100 countries. The AHA’s Sol Sherry Lecture honors the late Sol Sherry, MD, who was a pioneer in the field of thrombosis research and spent nearly twenty years at Temple University in Philadelphia. Past Sol Sherry lecturers include the University of Illinois’ James Morrissey, PhD, and the University of Maryland School of Medicine’s Dudley K. Strickland, PhD.

A Professor of Pediatrics in the Division of Hematology, Dr. Krishnaswamy’s research is focused on better understanding “how protein-protein interactions involved in the assembly of the coagulation complexes on membranes modulate function and how the coagulation enzymes achieve narrow and defined specificity.” His lab is supported by a number of grants from the NIH, the most recent of which he received in August of 2014. That award supports his investigation of how platelets and vascular endothelium cells contribute to coagulation.

In addition, Dr. Krishnaswamy contributed to a recent Blood study authored by CHOP’s Lacramioara Ivanciu, PhD, and led by Rodney M. Camire, PhD.

In that study, the researchers examined the development of prothrombinase, the enzyme complex responsible for thrombin formation, which is itself an enzyme that plays a fundamental role in coagulation. They found, to their surprise, that platelets near the site of an injury “do not play the presumed preeminent role in supporting prothrombinase assembly and thrombin formation.” By shedding light on the location of prothrombinase formation, the study lays the ground for future research.

During his Sol Sherry Lecture, Dr. Krishnaswamy plans to discuss prothrombin and thrombin, following an article he wrote last year that was published in the Journal of Thrombosis and Haemostasis. A review of the process by which thrombin is produced by prothrombinase, the article goes into the mechanics of this transition while noting recent developments in the field. “In addition to its fundamental role in coagulation, prothrombin activation embodies key structural and functional features encountered in the other proteolytic activation steps of the cascade,” Dr. Krishnaswamy writes. “Consequently, the wealth of biochemical and biophysical information that has accumulated in this system justifies its consideration as an archetypal reaction of coagulation.”

“I’m honored to have been asked by the AHA to deliver this year’s Sol Sherry lecture,” Dr. Krishnaswamy said. “Dr. Sherry was a thrombosis pioneer, and it’s an honor to follow in his footsteps.”

Permanent link to this article: http://www.research.chop.edu/blog/thrombosis-researcher-set-deliver-american-heart-association-lecture/

Nov 14 2014

Gene-regulating Protein Reaches Multiple Disease Pathways

proteinGenomic scientists at The Children’s Hospital of Philadelphia found strong evidence that the protein family, FOXA2, is a master regulator of genetically vulnerable pathways in multiple diseases.

Study leader Struan F.A. Grant, PhD, holder of the Daniel B. Burke Chair for Diabetes Research at The Children’s Hospital of Philadelphia, has long investigated the genetics of diabetes and obesity. In the current study, he focused on the Forkhead Box A transcription factor, referred to as FOXA2, which was already known to act in the liver in affecting glucose levels. Dr. Grant and colleagues started with the hypothesis that FOXA2 regulated molecular pathways that are important in endocrine biology.

As they performed their analyses, the researchers found that FOXA2 proteins acted on sites in the genome that contained genes affecting endocrine-related traits such as glycemic levels, although not type 2 diabetes. They also found strong genome occupancy patterns associated with cardiovascular traits such as lipid levels, as well as with neuropsychiatric traits and cancer.

“FOXA2 appears to function as a master regulator for over a hundred other transcription factors, so it may play an outsized role in human health and disease,” Dr. Grant said.

This computational analysis leveraged data from a team led by co-author Klaus H. Kaestner, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and used two important tools of next-generation genomic analysis: chromatin immunoprecipitation and massively parallel sequencing, together abbreviated as ChIP-seq. ChIP-seq isolates the pieces of DNA that are bound by proteins such as transcription factors.

Researchers then pass those fragments through automated sequencing machines to pinpoint and inventory the regions of the genome that specific transcription factors occupy. This knowledge allows investigators to better understand how transcription factors may activate or repress genes along important biological networks, and further study of those pathways may point the way to various novel therapies.

Grant and colleagues published their study in the The Journal of Clinical Endocrinology & Metabolism.

Study funding came from the National Institutes of Health and the Ethel Brown Foerderer Fund for Excellence from CHOP.

Permanent link to this article: http://www.research.chop.edu/blog/gene-regulating-protein-reaches-multiple-disease-pathways/

Nov 12 2014

CHOP Research Leader Named to Brain Tumor Panel

brain tumorThe Children’s Hospital of Philadelphia Research Institute’s Tom Curran, PhD, FRS, was recently named to a panel of experts who will advise the Pediatric Brain Tumor Foundation (PBTF). A pediatric brain tumor expert and Deputy Scientific Director of the Research Institute,

Dr. Curran was one of seventeen volunteers appointed to the PBTF’s newly created Research Advisory Network.

Per a statement put out by the PBTF, the “Research Advisory Network will contribute insights that help shape the PBTF’s funding priorities and evaluate the impact of its research investment on the lives of children diagnosed with a brain tumor, as well as on the disease that threatens them.” Panel members come from several other children’s hospitals—including St. Jude’s, Boston Children’s, and Children’s National—as well as academic centers and industry.

“The members of the Research Advisory Network, or RAN, will provide highly informed perspectives on the biomedical research enterprise,” said the Pediatric Brain Tumor Foundation’s Dr. Joanne Salcido. According to its website, the PBTF is “the world’s largest nonprofit funder of childhood brain tumor research,” and in addition to funding studies the Foundation hosts events, offers brain tumor-related resources, and offers scholarships.

Before joining Children’s Hospital in 2006, Dr. Curran was the founding chairman of the Department of Developmental Biology at St. Jude’s Research Hospital in Memphis, Tenn. In addition to his role as deputy scientific director of CHOP Research, Dr. Curran is also a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

He is also one of the leaders of the recently established Children’s Brain Tissue Tumor Consortium (CBTTC). A multi-institutional, collaborative research organization dedicated to the collection, annotation, and analysis of children’s brain tumors, the CBTTC’s ultimate goal is to improve outcomes for children with brain tumors. The CBTTC is comprised of CHOP, the Children’s Hospital of Pittsburgh of UPMC, Seattle Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago. The consortium’s operations center is housed at Children’s Hospital.

“I am honored to serve as a member of the Pediatric Brain Tumor Foundation’s Research Advisory Network,” Dr. Curran said. “I look forward to working with the Foundation, as well as my fellow Network members, to advance brain tumor research and improve the lives of children with brain tumors.”

To learn more about brain tumors and cancer care at The Children’s Hospital of Philadelphia, see the Cancer Center at CHOP. For more information about cancer research at CHOP, see the Center for Childhood Cancer Research.

Permanent link to this article: http://www.research.chop.edu/blog/chop-research-leader-named-brain-tumor-panel/

Nov 10 2014

New Autism Roadmap Website One-stop Resource for Families

autism_roadmapWith one in 68 children now thought to be affected by an autism spectrum disorder (ASD), more and more parents are struggling to understand an autism diagnosis and find the resources their children need. “Where do I begin?” families often ask.

The answer is the Autism Roadmap, a new website developed entirely as a result of philanthropy and with the expertise of nearly a dozen of the nation’s top autism experts at The Center for Autism Research (CAR) at The Children’s Hospital of Philadelphia.

Families using the Roadmap will find directories of service providers, community resources, government programs, ideas for various stages of childhood and beyond, and explanations of the latest research on ASD treatments and interventions.

“This tool has the potential to greatly improve the lives of families struggling with the maze of government, medical, and community service providers and as such, enables CAR to be a great service to the broader community,” said Robert Schultz, PhD, director of The Center for Autism Research.

Susan Wenger, who funded the website’s development along with her husband, Don, and other family members, witnessed firsthand the difficulty of finding reliable information the internet and locating autism-specific resources for their grandson. They understand how a family’s life can be turned upside down by a diagnosis of ASD.

“I wondered why, with so many kids affected by autism, wasn’t there a single clearinghouse for information,” Wenger said. “A tool like this is just so needed — it will make life so much easier for parents and grandparents to help get children diagnosed with an autism spectrum disorder the resources they need as quickly as possible.”

Families, researchers, mental and behavioral health workers, and others gave extensive input and tested the website to ensure that it was comprehensive and easy to use. Autism Roadmap provides customized information based on what families need, whether their child has been diagnosed recently or is navigating developmental milestones, from toilet training and school to adolescence and adulthood. The website will be continuously updated as new information becomes available or as resources and community information change.

“We’re extremely grateful for the Wenger’s support to help transform a longtime vision into a reality,” Dr. Schultz said.

A news report about the launch of the comprehensive, one-stop website appeared on 6abc Action News. View the broadcast here:

For more information about the CAR Autism Roadmap, visit www.carautismroadmap.org.

Permanent link to this article: http://www.research.chop.edu/blog/new-autism-roadmap-website-one-stop-resource-families/

Nov 07 2014

New Jersey’s Graduated Driver Decals Linked to Fewer Crashes

decal provisionA new study from the Center for Injury Research and Prevention provides evidence that New Jersey’s Graduated Driver Licensing (GDL) decal provision is associated with a sustained decline in crash rates among provisional teen drivers. The study, which linked New Jersey’s licensing and crash record databases to measure effects of the requirement, was published recently in the American Journal of Preventive Medicine. Crash involvement of an estimated 3,197 intermediate drivers was prevented in the first two years after the decal’s implementation.

In May 2010, New Jersey implemented Kyleigh’s Law, requiring all youth 16 to 20 years of age holding a learner’s permit or intermediate license to display a reflective decal on the front and back license plates of vehicles they are operating. On any given day there are more than 170,000 intermediate drivers on New Jersey’s roadways. The decal was intended to facilitate police enforcement of GDL restrictions and reduce teen crash rates.

While many other countries have had decals for decades, New Jersey is the first state to implement them in the U.S. And CHOP researchers are the first in any country to evaluate the long-term changes in crash rates after a decal provision went into effect.

“Decal provisions now have the support of science. The provision may encourage safer driving behaviors, both among teens and other drivers sharing the road with them,” said the study’s lead author, Allison Curry, PhD, MPH, the Center for Injury Research and Prevention’s director of Epidemiology and Biostatistics.

Dr. Curry and the study team linked New Jersey’s licensing and motor vehicle crash databases from January 2006 through June 2012 to compare monthly rates of police-reported crashes for intermediate drivers in the four years before the decal’s implementation and in the two years after. The researchers showed in the first two years after the new decal requirement took effect the crash rate for young intermediate drivers declined 9.5 percent, as compared to the previous four years before decal implementation.

More dramatic effects were observed for single-vehicle crashes involving older intermediate drivers, with rates decreasing 13 percent per year for 18-year-olds and nearly 17 percent for 19-year-olds. In the previous four years before the decal was put into practice, the rate of single-vehicle crashes did not significantly decrease in either group.

A previous study on the decal’s first year of implementation found a 14 percent increase in the rate of GDL-related citations issued to intermediate drivers, but the increase seemed to be concentrated in the few months after implementation.

“There is definitely more we need to learn, in particular with respect to the specific mechanisms by which the decals reduced crashes,” noted Dr. Curry. “The end result, however, is that many fewer teens crashed.”

To learn more about the Center for Injury Research and Prevention work on teen driver safety and other topics, visit the Center’s website.

Permanent link to this article: http://www.research.chop.edu/blog/new-jerseys-graduated-driver-decals-linked-fewer-crashes/

Nov 05 2014

Collaborative International Study Finds Childhood Epilepsy Genes

childhood epilepsy

The study adds to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies.

An international team of researchers recently identified gene mutations that can cause severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, MD, director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and one of the study’s co-authors. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the United States. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results recently in the American Journal of Human Genetics. Two international research consortia collaborated on the study: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS), and the European EuroEPINOMICS consortium.

The study adds to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations — those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

But the most surprising finding is related to a gene called DNM1, which was found to be mutated in five patients. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dr. Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

To read more about this study, see the full press release. To learn more about The Children’s Hospital of Philadelphia’s epilepsy resources and research, see the Pediatric Regional Epilepsy Program website.

Permanent link to this article: http://www.research.chop.edu/blog/collaborative-international-study-finds-childhood-epilepsy-genes/

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