Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.
When Children’s National pediatric nephrologist Lisa Guay-Woodford, M.D., was an intern at Boston Children’s Hospital, a baby with autosomal recessive polycystic kidney disease (ARPKD) was admitted to one of the hospital’s neonatal intensive care units (NICU). This disease, which causes cysts to form in the kidney and liver, kills about one-fifth of babies within the newborn period due to related problems that affect lung development.
But this baby seemed like a survivor, Dr. Guay-Woodford remembers. The child passed the newborn period and graduated from the NICU, although she went home with severe blood pressure issues. Along with a team of colleagues, Dr. Guay-Woodford helped to manage this patient’s care, juggling normal infant concerns with her ARPKD.
As far as Dr. Guay-Woodford knew at the time, this baby was beating the odds against her, growing and thriving. But one day near the end of her internship period, Dr. Guay-Woodford was called to the emergency department. Her patient was in a hypertensive crisis that ultimately killed her.
“It was absolutely devastating to all of us. This was supposed to be a good news kind of story, that she survived the newborn period and had gone home and was growing and developing,” Dr. Guay-Woodford says. “I realized then that a big part of the tragedy of this disease is how little we knew about it.”
Dr. Guay-Woodford vowed to change that. Since then, she’s devoted her career to studying ARPKD and other inherited kidney diseases.
After finishing her residency and fellowship in Boston, Dr. Guay-Woodford was recruited to the University of Alabama, where she began caring for a cadre of 40 patients with inherited renal disorders. Fueled by the research questions that arose while working with these patients, she and her colleagues searched for PKD-related genes in the cpk mouse model, an animal that mimics many of the features of human ARPKD.
Dr. Guay-Woodford and her team cloned several of the key genes that caused recessive PKD in this mouse and other mouse models and eventually went on to identify the first major genetic modifier of PKD in these animals – a gene that wasn’t directly responsible for the disease but could sway its course. In time, her collaborative group became one of two that co-indentified the major gene responsible for human ARPKD. In 2005, Dr. Guay-Woodford led a team of investigators at the University of Alabama-Birmingham to establish one of just four PKD translational core centers funded by a National Institutes of Health P30 grant.
After moving to Children’s National in 2012, Dr. Guay-Woodford still co-directs this PKD translational core center while also caring for patients at her inherited renal disorders clinic. She and her colleagues here and beyond continue to work with mouse models of this disease, trying to ferret out the vast network of genes that interact in ARPKD and their specific roles.
“You can use a variety of strategies to compare these patients’ gene portfolios with those of healthy patients and pick out the disease genes. But at the end of the day, to me, that’s just the opening chapter,” she says. “To really make a story, you’ve got to understand what is it that gene does, what protein it makes, and how that protein works together with others involved in this disease.”
She and her team also are currently working with a pharmaceutical company to develop the first clinical trial to test a treatment for ARPKD. This effort has relied heavily on a clinical database that Dr. Guay-Woodford and colleagues worldwide maintain to track patients with this and related conditions. Through the extensive collection of clinical information in this database – including a variety of data on patients’ gestation and birth, growth, and kidney structure and function – the team has identified a core cohort of patients whose disease is rapidly progressing, a characteristic that makes them prime candidates to test this potential new treatment.
“Everything I do in the clinic informs the work I do in the lab, and everything I do in the lab is to help the patients I see in the clinic. It’s this constant dance back and forth between our human patients and animal models,” she says. “One day, this dance will help lessen the burden of this disease for these kids and their families.”
https://innovationdistrict.childrensnational.org/wp-content/uploads/2017/02/LGW-Article-Image-e1496347348126.jpg300400Nicole Kresgehttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifNicole Kresge2019-01-14 14:09:402019-01-14 14:17:24Serving patients with polycystic kidney disease
Andrew Dauber, M.D., hosts an AMA chat with Reddit’s science community and offers feedback about height, growth disorders and pediatric endocrinology.
Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National, spoke about epigenetics – how genes are expressed – and about all things related to pediatric endocrinology in a recent Ask Me Anything (AMA) chat with Reddit’s science community.
We’ve selected highlights from several questions Dr. Dauber received. You can view the full AMA discussion on Reddit.
Q1: What will the future of type 1 diabetes treatment look like?
As a pediatric endocrinologist, Dr. Dauber sees a lot of patients with type 1 diabetes. He predicts technology will pave the way for advancements with continuous glucose monitoring and encourage a ‘real-time’ interaction between patients and providers:
“I anticipate that within a few years, everyone will have access to continuous glucose monitoring technology and that these will be seamlessly connected to insulin pumps or artificial pancreas technologies,” types Dr. Dauber in response to the first AMA question. “I also think there will be more virtual interaction between medical providers and patients with doctors and nurses reviewing blood sugar data in the cloud.”
Q2: What height range is considered normal for a growing child? What is the difference between short stature and a height problem?
The Centers for Disease Control and Prevention has a growth chart, which shows ‘normal’ ranges, based on statistical definitions of height in the general population.
“The truth is that I know plenty of people who have heights below the ‘normal’ population, and they don’t think they have a problem at all,” says Dr. Dauber. “From a genetics point of view, the question can be reframed: When do we call a genetic variant a ‘mutation’ versus a rare variant in the population? For example: If there is a genetic change that 1 in a 1,000 people have that causes you to be 2 inches shorter – is that a problem? Is that a disease?”
“From a clinical perspective, I tend to have a discussion with my patients and their families and ask them how their stature is affecting their lives and whether changing that would really make a meaningful difference,” adds Dr. Dauber. “I believe that this is a very personal decision but people need to be realistic about expected outcomes.”
Q3: What are your favorite case studies about atypical growth or height patterns?
Dr. Dauber references two case studies about growth and puberty:
The growth case study refers to the PAPPA2 gene, which was particularly meaningful for Dr. Dauber since he got to know the family and was able to provide answers to a previously undiagnosed medical mystery about short stature. This research is also opening future studies and analysis about the regulation of IGF-1 bioavailability.
The puberty case study looks at the opposite end of growth and development: precocious puberty. In this case an inherited MKRN3 gene mutation resulted in new insight about the regulation of pubertal timing: Deficiency of MKRN3 caused central precocious puberty in humans. Girls who had inherited the mutated genes from their father (an imprint gene) started to develop breasts before age 6. The results were published in The New England Journal of Medicine.
Q4: What are the differences with consistent and inconsistent growth disorders? Could one arm or leg experience accelerated or stunted growth?
“Most genetic disorders that affect growth will have a uniform effect throughout the body as they are likely to affect all aspects of the skeleton,” says Dr. Dauber. “That being said, there are some notable exceptions such as Russell-Silver syndrome which presents with body asymmetry. There are also somatic mutations (mutations which are just present in some cells in the body) that can lead to segmental areas of overgrowth leading to asymmetry.”
Q5: Can you predict height and growth by looking at genetic factors? What are your thoughts about polygenic risk scores?
“Polygenic risk scores will probably play more of a role in the future to help determine risk of a certain disease,” says Dr. Dauber. “Right now, for most conditions, the risk score does not explain a substantial enough fraction of the variation to help with prediction.”
Dr. Dauber discusses how this works for height, a highly hereditable trait, in The Journal for Clinical Endocrinology and Metabolism. In the review, Dr. Dauber and the study co-authors note that individuals with extreme heights are more likely to have abnormal stature as a result of a severe mutation that causes a growth disorder. For these individuals, whole exome sequencing may reveal gene mutations.
However, the study authors note that for now, the role of these technologies in individuals with extreme stature but without any syndromic features has not been rigorously and systematically explored. (Dr. Dauber and a team of endocrinologists from leading children’s hospitals are currently using electronic health records to study and track these types of genetic clues over time.)
Q6: The general public is excited about genetics and ongoing research, especially with consumer applications – such as genetic tests, including 23andMe. What misconceptions about genetics do people have? What ethical concerns do geneticists share right now?
“Many people think that genetics is completely deterministic,” says Dr. Dauber. “In reality, most genetic variants influence a person’s predisposition toward a trait or disease but don’t actually determine the outcome. Also, the genetic sequence itself is just the first step. Epigenetics, gene regulation, and gene-environment interactions are all important and we are just scratching the surface of understanding these areas.”
“I think that people engaged in genetics research are very interested in the ethical questions,” adds Dr. Dauber. “The problem is that technology is advancing at such a rapid pace, that often consumers are using technologies in ways that we haven’t yet had time to figure out the ethics for. The medical community is often playing catch up.”
Q7: Aside from using gene modifications to cure diseases, where or when should we draw the line in terms of enhancement?
“I think genetic modification for enhancement is a very dangerous slippery slope that we should avoid,” says Dr. Dauber. “We really don’t know the full effect of many genes and by enhancing them, we could be causing lots of problems that we can’t anticipate. There is a reason that evolution is a slow process that happens over millions of years. I think we need to start with the most devastating diseases and try to cure those first.”
Q8: Would it be ethical to use CRISPR on the genes for short stature to produce tall offspring if the risks are sufficiently small? This would be similar to what Dr. He did, but without the ethical violations.
“This is a fascinating question and it will become more of an issue over time,” says Dr. Dauber. “Where do we draw the line between fixing, preventing disease and enhancing physical function? Personally, I think using genome editing to promote height is a terrible idea. Our current perception that taller height is more desirable is a social construct and varies by culture. This idea also changes over time.”
Q9: Overall, how does this fit into meeting unmet medical needs?
“I would be very wary about trying to design our children’s physical features,” Dr. Dauber notes. “We need to figure out as a society what diseases are sufficiently problematic that we feel comfortable trying to eliminate them via genome editing.”
Q10: How many genes control acromegaly? Is it possible (in theory) to Top of Formselect them just to gain the positive effects of gigantism without the health risks?
Dr. Dauber explains that acromegaly, a condition often referred to as gigantism, is caused by a growth hormone-producing tumor. There are a few genes known to cause these tumors, including the AIP, and there was recently a genetic cause of X-linked gigantism, which was published in The New England Journal of Medicine.
“This basic idea is a good one,” notes Dr. Dauber. “We can find genes that when mutated can cause tall stature – and then try to manipulate those pathways. A great example is the NPR2 gene, which when mutated can cause short or tall stature. This pathway is being targeted for therapeutics related to achondroplasia.”
The National Institutes of Health (NIH) refers to achondroplasia as ‘short-limbed dwarfism,’ which results in an average-sized trunk with short limbs, especially arms and legs, due to a lack of cartilage turning into bone. The average height of an adult male with achondroplasia is 4 feet, 4 inches, while the average height of adult females with achondroplasia is less than 4 feet, 1 inch. In this case, manipulating growth pathways may help alleviate health problems associated with achondroplasia: lack of mobility or range of motion, an enlarged head, apnea, ear infections and spinal stenosis, or a compression or pinching of the spinal cord.
Q11: Give us a history lesson. Why are there variations of height within populations, such as Asia and Latin America?
“The average height in a population is due to the influence of literally thousands of common genetic variants,” says Dr. Dauber. “These population differences have evolved over thousands of years due to a combination of migration and selection. There is a well-known difference in the genetic makeup of various populations which likely underlies the differences across the globe. There are even differences within Europe.”
Q12: Are there examples of pseudoscience or theories about growth, such as recommendations to eat a certain food instead of taking growth hormones to correct for a growth disorder, which runs contrary to scientific evidence, that drive you crazy?
“I don’t really get bothered by crazy theories, but it is upsetting when patients and their families get swindled into spending their money on therapies that aren’t truly effective,” says Dr. Dauber. “People ask me all the time if a certain food or exercise can make their child taller. The bottom line is that in a well-nourished (and healthy) child, there is no magical food that is going to make them tall.”
Q13: According to almost every theory of how life evolved on Earth, from religion to evolution, we all have one common ancestor. In theory doesn’t that make us all cousins?
“Yes, just very distant ones,” says Dr. Dauber. “People always point out the vast number of differences between races but in fact we are all more than 99.9 percent identical on a genetic level.”
https://innovationdistrict.childrensnational.org/wp-content/uploads/2018/12/Dauber-Reddit-AMA.jpg300400Nicole Kresgehttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifNicole Kresge2018-12-27 10:27:082018-12-27 11:57:28Thirteen questions for a pediatric endocrinologist
Children’s National Health System’s Comprehensive Pediatric Epilepsy Program is one of the largest and most experienced multidisciplinary epilepsy programs in the country. With a range of programs specializing in new onset epilepsy, the Ketogenic diet, intractable epilepsy, neuroinflammation, neurogenetics, epilepsy surgery and more. The epilepsy program at Children’s National is continuously working to improve care for patients through clinical innovation, active studies and utilizing the most advanced technologies in epilepsy surgery. Children’s National has one of the best surgical outcomes in the county, aided by advanced structural and functional imaging, minimally invasive techniques, deep brain stimulation, neuronavigation, neurorobotics using the ROSA stereotactic neurosurgical robot and intraoperative MRI.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2018/12/Epilepsy_Infographic-feature.png300400Nicole Kresgehttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifNicole Kresge2018-12-03 10:16:152018-12-03 11:13:05By the Numbers: Comprehensive Pediatric Epilepsy Program
“Who speaks for children?” That’s a question Children’s National President and CEO Kurt Newman, M.D., often asks when he talks to groups around the country. As he sees it, children’s hospitals and their pediatric specialists should follow two main principles: Speak out to our nation’s policy leaders, local government officials and other business leaders about what’s right for the most vulnerable among us, namely our children; and listen to parents, helping them find their voices when it comes to health care decisions.
Pediatric specialists have a unique opportunity to serve as the voice for children and families who are so often lost in state and federal health care policy debates. As the children’s hospital located in the nation’s capital, Children’s National has leveraged both its expertise and close proximity to key decision makers to engage in a dialogue about issues vital to the health and well-being of kids.
Amplifying the CHIP call to action
In a perfect example of politics getting in the way of doing the right thing for children, it took almost four months for Congress to extend funding for the Children’s Health Insurance Plan (CHIP), which provides health coverage for nearly 9 million children of working families in the United States. CHIP often supports the patients with the most medically complex needs – and is pivotal to their care at Children’s National and hospitals around the country.
During the agonizing wait for the extension, Dr. Newman, as well as countless Children’s National pediatricians and government affairs leaders, spent hours encouraging, asking and telling policymakers at every level of government about the importance of investing more in children, not less.
He stresses that it’s not just the right thing to do, it’s a wise investment. Spending dollars on children for prevention, early detection and education means that we have a healthier workforce, military and national community. It’s less expensive to treat mental and behavioral health problems, asthma and diabetes early on, before they become chronic issues.
The steady drumbeat from Children’s National supported national advocacy urging Congress to protect health insurance for the millions of children who rely on CHIP for all their health care needs.
The restored measure makes a world of difference for working families, but additional advocacy is needed as Congress continues to seek agreement on a long-term budget and other important legislation, some of which could have tremendous impacts on children’s health.
Leading a conversation about the needs of military families with terminally ill children
Concurrent care for terminally ill children – where lifesaving treatments such as chemotherapy and physical rehabilitation can take place alongside comfort measures and palliative care like 24-hour nursing – is covered by most insurance programs, including CHIP and Medicaid. However, until recently, military families covered under Tricare with such desperately ill children were forced to choose coverage for one OR the other.
Children’s National brought this challenge to its coalition partners at Tricare for Kids after watching several military families forced to make an agonizing decision between comfort and treatment. The coalition, a collection of military advocacy groups, children’s hospitals and other advocates, then fought hard to add a landmark provision to the National Defense Authorization Act allowing military families concurrent care coverage for their children. Implementing Tricare adjustments that deviate from Medicare provisions has been extremely difficult and politically fraught in the past, but when advocates and lawmakers focused on doing what’s right for kids, there was little to no Capitol Hill opposition and the change was easily passed in both the House and Senate.
In addition to advocacy, every day, a children’s hospital should help parents find their voices as active, empowered and engaged team members when it comes to caring for a sick child.
“It is crucial for a child’s care team to include his or her parents – the people who know them best,” Dr. Newman recently wrote. “I want every parent to feel comfortable being a true champion for their children at the pediatrician’s office or the hospital in the same way they champion them on the playing field or in the classroom.”
“That’s why I wrote the book Healing Children,” he says during book talks and interviews. “If parents knew what I knew, they’d make sure the doctors and nurses caring for their kids were experts in treating children. These stories show the power of pediatric specialty medicine, illustrate why parents should think ahead about how best to demand the care they deserve when something bad happens and show why we should always listen to parents’ concerns.”
Children and their families are at the center of every decision made at Children’s National, from day-to-day care planning to large scale business initiatives. When focusing on doing what’s right for them, everyone – the children, their families, the community AND the healthcare organization – benefits.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2018/02/Kurt-Newman-capitol-building.jpg300400Nicole Kresgehttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifNicole Kresge2018-02-08 11:20:202018-02-08 14:14:58Leading conversations about what’s right for children
The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.
When facing vaccine-hesitant parents, the key for me is to be collaborative and not to dismiss their questions or concerns. That’s why the American Academy of Pediatrics advises pediatricians to talk with parents to determine their individual concerns so we can address them. The decision whether to immunize a child ultimately rests with the parents. It’s understandable for parents to be worried – but it also critical that they get the facts.
The conversation can begin simply.
Here’s what I say to vaccine-hesitant parents: You work hard to protect your child every day. Vaccines are as important as feeding your child healthy foods, using a car seat or seat belt and installing a smoke detector.
Here’s what I ask vaccine-hesitant parents: What information can I provide to help you make an informed decision, or to help you feel comfortable with vaccinating your child? As with most of what we pediatricians do, my goal is to partner with the parent so that we help their child to attain optimal health as a team.
I am a parent. Although my husband and I did not hesitate in vaccinating our daughter, I understand why parents want to feel comfortable about the choices they make for their children.
I also am a pediatrician. I have seen children die from the flu or develop a life-threatening brain infection from chickenpox. Thanks to the herd immunity that results from decades of vaccination, many of these diseases are now rare in the United States, but there are still episodic outbreaks throughout the country that remind us why we vaccinate children.
Vaccinating is the norm. Only about 1 percent of children in the United States receive no vaccinations. Most parents who are hesitant about vaccines are not opposed to immunizing their children; they are unsure or have unanswered questions. Fortunately, most vaccine-hesitant parents are responsive to receiving information about vaccines, consider vaccinating their children and do not oppose all vaccines.
When it comes to vaccine-hesitant parents, one-on-one counseling is effective. The single most important factor in parents deciding to accept vaccines is one-on-one contact with an informed, caring and concerned pediatrician.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2017/04/BabyVaccination.jpg300400Nicole Kresgehttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifNicole Kresge2017-04-13 09:15:512017-10-19 15:14:20How to talk with parents who are vaccine hesitant
Boosting research and innovation to find cures and develop new medical devices for children and adults who carry childhood and rare diseases will transform our health system and save lives.
Until now, medical research and innovation have been severely limited in the U.S. by regulations and lack of funding. On behalf of healthcare systems and medical innovators across the U.S., we applaud the House and Senate for their tremendous bipartisan effort to pass the 21st Century Cures Act that will transform our health and research system and enable us to more effectively fight diseases.
We are encouraged by the provisions in the act that break down regulatory barriers and expedite the approvals of drugs and devices. We are particularly excited about the provisions to increase funding to the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), as well as the establishment of precision medicine, the cancer moonshot initiatives and new programs that will improve our mental health system and fight the worsening opioid epidemic. Boosting research and innovation to find cures and develop new medical devices for children and adults who carry childhood and rare diseases is at the core of our mission at Children’s National. Our researchers are working to find new biomarkers, map the human genome, develop medical devices for children and personalize medicine to make treatment and cures more targeted and effective. They are also studying pain and looking at new ways to detect the presence of opioids and cannabinoids. Thanks in large part to funding from the NIH, institutions like ours are able to continue groundbreaking biomedical research. This legislation brings hope to our children and their families, especially those who volunteer to participate in research, that our scientific breakthroughs will be translated to drugs, therapeutics and medical devices safer and faster.
Another victory for all of us in the pediatric medical device field is the expansion of the Humanitarian Use Device program to include devices used by up to 8,000 individuals rather than the current 4,000 individual cap. The hard cap at 4,000 individuals was excessively restrictive and was a significant disincentive blocking the development of devices for rare diseases and conditions, especially those affecting children. The 4,000 limit was also an obstacle for the development of diagnostic devices, since the FDA interprets the limitation to apply to the number of patients that would receive the diagnostic test, rather than the number of individuals affected or manifesting the rare disease.
Currently, medical device development for children lags woefully behind adults. Children have medical device needs that are considerably different from adults. The subtleties of developing devices for pediatric patients are fundamentally different than those for adults. The challenges include small markets, scarce financial incentives, regulatory issues, and the procedural dissimilarities of premarket clinical trials and post-market surveillance. The lack of available pediatric devices often forces clinicians to treat pediatric patients by using or modifying adult devices, adjusting implants designed for other purposes, and using implants designed decades ago. Because devices are being used “off-label,” clinicians and regulators are not able to collect information on their effectiveness. This act promises a faster regulatory approval process, which increases the enthusiasm of the venture community in investing in drug and device development, which in turn can help startup companies in the field secure private capital.
Thank you to everyone who worked tirelessly to create this bill and to those who lobbied on its behalf. It’s efforts like the 21st Century Cures Act, that break down regulatory barriers and provide the resources to expedite the approvals of life-saving drugs and devices, that save children’s lives.
About the Author
Kolaleh Eskandanian, Ph.D. Executive Director
Sheikh Zayed Institute for Pediatric Surgical Innovation Research interests: device development, entrepreneurship, innovation in health care
https://innovationdistrict.childrensnational.org/wp-content/uploads/2016/09/PerspectivesImage_What-Rare-Diseases-Teach-Us_sm-2-e1494012190946.jpg300399Kathey Jaucianhttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifKathey Jaucian2017-02-03 08:53:322017-08-15 10:16:34It took an act of Congress to save lives
Think of the urea cycle as a river. A normal river flows to where it empties, similar to the process the body uses to rid itself of harmful ammonia via the urea cycle.
I recently presented at Spotlight Health 2016, the health-focused portion of the Aspen Ideas Festival, about how studying and treating rare diseases can inform innovative treatment approaches for more common medical conditions. Our Division of Genetics and Metabolism sees more than 8,000 patients a year with rare conditions, such as urea cycle disorders and Down syndrome. Through decades of analyzing these diseases and treating children who have them, we have developed therapies that apply not only for the small numbers of patients who have rare diseases but also for more common conditions caused by environmental factors leading to a similar physical response.
For instance, we’ve demonstrated that the stress of cardiopulmonary bypass during surgery to correct congenital heart disease creates conditions similar to a critical blockage in the urea cycle, specifically the biochemical creation of citrulline, a key biochemical.
When that cycle is unable to flow, or continuing the river analogy, becomes dammed up due to a genetic defect, as in urea cycle disorders, or an environmental factor, such as the extreme stress of cardiopulmonary bypass, the body is unable to make enough citrulline which is critical for maintaining normal blood pressure. We’ve shown that replacing that citrulline can correct a lot of these problems whether caused by rare genetics or the cardiac OR.
Applying rare disease treatment approaches to more common diseases is not limited to urea cycle disorders. Work by my colleague Carlos Ferreira, MD, demonstrates how a rare genetic calcifying arterial disease (generalized arterial calcification in infancy, GACI) causes the same calcium buildup and blockages as chronic kidney disease. Dr. Ferreira hypothesizes that life-saving drugs developed for use in GACI could help patients with long-term kidney disease by averting organ damage and eventual failure caused by the buildup of calcium crystals.
The more we learn about these rare diseases, the more we come to appreciate the tremendous implications our findings have for patients with the rare disorders and potentially hundreds of thousands of others.
About the Author
Marshall Summar, MD Research interests: The interactions between common genetic variations and the environment.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2016/09/PerspectivesImage_What-Rare-Diseases-Teach-Us_sm-2-e1494012190946.jpg300399Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifInnovation District2016-08-09 19:30:362017-08-15 10:17:44What rare diseases teach us about common ones
Common, lifelong health conditions like diabetes and hypertension have footprints that can be traced back to the womb. With advanced fetal MRI we seek to understand as much as possible about brain development during the time in utero. Non-invasive imaging technology helps us to identify signs of abnormal fetal development that may facilitate earlier diagnoses of chronic conditions and intervention.
We’re exploiting both the power and safety of MRI to develop ways to pick up early signs and signals in fetuses whose brain development may be veering off in the wrong direction. Using this advanced technology we can begin to detect varying signals or other signs of distress. These signs of distress may appear in the form of a brain chemical imbalance or a structural brain abnormality that is too subtle to be seen by an ultrasound or other scan. We now have the ability to leverage magnetic resonance imaging to examine the brain in utero for even the most subtle derailments that can lead to lifelong consequences.
The first nine months of life, when a fetus is in the womb, is a time of unparalleled growth and a critical time for fetal brain development. As we examine the maturation of the fetal brain, we know that each and every cortical fold represents future function lost or gained and lays the fundamental background or platform from which critical functions will emerge such as language and social and behavioral development.
We are developing technology that can quickly and reliably pick up early signals of a fetal brain that’s going off route to provide the ability to access therapeutic windows that are currently inaccessible. Earlier identification and intervention can improve the quality of life for children and potentially could even reverse the abnormality.
Early identification of fetal distress is critical. To be able to provide an intervention you must first be able to know that a fetus is getting into trouble, and you must be able to identify the problem early enough, in order to intervene before it has already caused injury to the fetus.
About the Author
Catherine Limperopoulos, Ph.D. Director, MRI Research of the Developing Brain; Director, Diagnostic Imaging and Radiology/Fetal and Transitional Medicine Research interests: Fetal neonatal brain injury
https://innovationdistrict.childrensnational.org/wp-content/uploads/2016/09/PerspectivesImage_Exploration-of-the-Developing-Brain.jpg16272013Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifInnovation District2016-08-08 18:08:522017-08-15 10:19:59Exploration of the developing brain
Post-mortem image shows significant narrowing of the artery in an infant with GACI due to buildup of calcium crystals between the vessel wall’s inner and middle layers. Inset: Normal non-calcified artery. Patients with GACI lack the protein ENPP1, which is responsible for creating pyrophosphate. Pyrophosphate plays a critical role in preventing calcium crystallization and accumulation.
One of the first patients I ever saw with generalized arterial calcification of infancy (GACI) was actually the third child with this condition born to the same parents. GACI is a rare genetic disease, occurring in 1 of 200,000 live births. Unfortunately, as is common in GACI, two of the family’s children previously succumbed to the disorder within the first 6 weeks of life.
GACI causes calcium to build up in the arteries, causing critical blockages that reduce blood flow to organs leading to diminished function, including stroke, heart attack, and death.
Etidronate, a pyrophosphate analog developed to treat osteoporosis, has shown limited success at replacing the pyrophosphate for patients with GACI. However, more than 55 percent of children with GACI still die before their first birthday.
We need more effective solutions. Several treatment options are in development, including the administration of ENPP1 bound to an antibody, which has shown to provide a marked survival improvement in a mouse model of the disease.
These new solutions could translate to more effective treatment of GACI but also other conditions causing calcification in the arteries, particularly the calcium buildup associated with long-term kidney disease. A treatment that potentially reduces morbidity for the estimated 20 million plus Americans with chronic kidney disease would have tremendous health and economic benefits.
Developing more targeted therapies for GACI could allow this to be the outcome for many more patients, both children with GACI and potentially also patients affected by chronic kidney disease.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2016/09/PerspectivesImage_How-a-Rare-Disease-Treatment_sm-3.jpg373600Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifInnovation District2016-08-07 18:11:062017-08-15 10:21:50How a rare disease treatment could impact millions
Changes or errors in an individual’s DNA are often at the root of many disorders. Personalized Sequencing is a fast, cost-effective way to look at a region of the genome without repeat tests and blood draws.
Until recently, doctors and patients had two choices for ordering genetic sequencing panels to identify underlying causes of disease—Individual Gene Testing (single genes and gene panels) or Whole Exome Sequencing.
Individual gene testing is the standard testing modality. Physicians identify a single gene to analyze for change or mutation. If results are negative, they order another individual test, requiring a repeat visit and another blood draw. The process is repeated again and again based on likely candidate genes for a specific disease or symptom. If a physician is very lucky, it takes only a few rounds of tests to find the culprit. More likely, however, the number of individual tests grows large, taking months of patients’ time and increasing healthcare costs significantly. By contrast, Whole Exome Sequencing includes sequencing and analyses of 25,000 genes. It is more expensive when compared with individual gene testing and takes three to six months to complete. When complete, the results often can be more than the doctor and patient bargained for: Potentially revealing a genetic problem that is unrelated to the patient’s current symptoms. A 3-year-old with seizures also may come up positive for BRCA1, the breast cancer gene. Knowing that doesn’t help understand what causes the seizures or how to best treat them. In this model, you receive everything you could ever want. Because there is so much information, however, the results are difficult to interpret or to inform treatment decisions.
We’ve come up with a different way: Personalized Sequencing Panels, a precision medicine initiative at Children’s National Health System. We offer physicians a menu of genetic regions from which to choose when they order a sequencing analysis. While a medical exome is still sequenced, we only analyze a subset of genes that the physician and geneticist think are the most likely targets, which reduces the cost and time for analysis compared to Whole Exome Sequencing. Targeting regions in this approach shortens our turnaround time for results to two or three weeks. If the first identified region shows nothing, we can return to data we’ve already collected for a second look.
We’ve been using the model for 18 months and have tested more than 1,000 patients this way. Eighty percent of physicians prefer to “create their own test” using our menu of options. Rather than bringing a one-size-fits-all test to the patient, we bring the patient their very own personalized test.
About the Author
Sean Hofherr Laboratory Medicine Specialist
https://innovationdistrict.childrensnational.org/wp-content/uploads/2016/09/PerspectivesImage_Personalized-Sequencing-Tailors_sm-2.jpg402600Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2018/11/idlogo1-tagline-Advances-in-Medicine.gifInnovation District2016-08-06 18:12:362017-08-15 10:05:25Personalized sequencing tailors genetic tests for each patient