Tag Archives: Center for Rare Childhood Disorders

Krauss Honored For Science

TGen finds gene giving children appearance of aging

Researchers at the Translational Genomics Research Institute (TGen)have identified a genetic mutation associated with the appearance of premature aging and severe loss of body fat in children.

TGen’s Center for Rare Childhood Disorders found that the appearance of premature aging, a neonatal form of Progeroid syndrome, in a 3-year-old girl was caused by a mutation in the gene CAV1, according to a study published today in the scientific journal PLOS ONE.

The Center for Rare Childhood Disorders was established in 2010 to examine the genetic basis of disease in children with medical conditions that have no definitive diagnosis. Since its inception, the Center has enrolled more than 900 participants and analyzed the genomes of more than 200 families, with a diagnostic success rate of nearly 40 percent.

Progeroid syndromes are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. In this instance, the patient has a triangular appearance to her face, and a large area at the top front of the head where a growing young child’s cranial bones eventually fuse together known as the anterior fontanelle.

The CAV1 mutation was discovered following genomic sequencing of the girl and her parents, in which the billions of pieces of information in their DNA were spelled out, using TGen’s state-of-the-art technologies and capabilities for whole-genome sequencing.

“Having a diagnosis is a major step in the continuing care of our patients,” said Dr. Matt Huentelman, Co-Director of TGen’s Center for Rare Childhood Disorders and the study’s senior author. “This is a unique discovery and a prime example of how children born with rare, undiagnosed conditions may benefit from a diagnosis obtained through genetic sequencing.”

The young patient in this study also has a form of high blood pressure (pulmonary hypertension) that specifically affects the heart and lungs. She also has had a feeding disorder, and a failure to thrive. In addition, she has symptoms of lipodystrophy, a medical condition characterized by a severe loss of body fat. Patients with lipodystrophy have a tendency to develop insulin resistance, diabetes, high triglyceride levels, and fatty liver.

“We characterize further association of CAV1 dysfunction with a syndrome of severe premature aging and lipodystrophy, showing clearly how these specific genetic changes expand the spectrum of CAV1-associated disorders” said Dr. David Craig, Co-Director for TGen’s Center for Rare Childhood Disorders, and another author of the PLOS ONE scientific paper.

The CAV1 gene codes for Caveolin 1, a key protein in the plasma membrane of individual cells. The plasma membrane surrounds the cell and contains a multitude of molecules that enable the cell to send and receive information to and from the environment. Caveolin 1 helps regulate many cellular functions, including tumor suppression; but also vesicle trafficking, the movement of important biochemical signal molecules through vesicles in the cell, or the traffic of molecules between different membrane-enclosed compartments in the cell; and cellular senescence, the phenomenon in which cells stop growing and dividing.

“This study may contribute to a better understanding of the pathogenic mechanisms that contribute to the severe reduction of body fat, the appearance of premature aging, as well as the serious medical problems that affect our patient,” said Dr. Vinodh Narayanan, Medical Director of TGen’s Center for Rare Childhood Disorders, and also an author of the PLOS ONE paper. “Such understanding may lead to better approaches to her treatment, and allow us to anticipate, detect and treat complications before they become severe.”

The patient’s lack of body fat could be due to the cumulative combination of the defective functions not only of the CAV1 gene, but also of the LPIN1 and ADPAT2 genes, the study said.

Despite her premature aging appearance, the patient shows no neurological problems, said Dr. Isabelle Schrauwen, a Research Assistant Professor in Dr. Huentelman’s lab and the lead author of the scientific paper.

“She has been active, playful, interactive and well spoken. In fact it has always been such a treat to see her smiling face at our Center outreach events,” Dr. Schrauwen said. “We really owe a debt of gratitude to her, her family, and all of the families who work with us at the Center. Without their commitment to research we wouldn’t be where we are today.”

The Center for Rare Childhood Disorders is co-directed by Drs. Huentelman, Narayanan and Craig. The Center has established collaborations that stretch across the globe.

The authors of the paper thank the patient and her family for participating in this groundbreaking research as well as the donors who support the ongoing work in TGen’s Center for Rare Childhood Disorders.


Medical miracle girl raises funds for TGen

Shelby Valint, the 12-year-old Phoenix girl whose sequenced genome led her from a wheelchair to walking, is raising funds for the non-profit Translational Genomics Research Institute (TGen).

The “Shelby Valint Inspiration Fundraiser” will generate needed research dollars for TGen’s Center for Rare Childhood Disorders (C4RCD). It was research through this innovative unit at TGen that helped enable Shelby to go from a wheelchair to walking.

“TGen has done so much for me,” Shelby said. “Now, I want to do something for TGen so they can continue to help other children like me with rare medical disorders.”

The fundraiser is being organized by Shelby’s mother, Renee Valint, and by one of Shelby’s 7th Grade teachers, Tracy Livingston, whose husband – the Honorable Rep. David Livingston – is a freshman member of the Arizona House of Representatives, representing the north Valley’s District 22.

“In October, TGen launched their Center for Rare Childhood Disorders, which is helping parents in Arizona find answers and treatment for their children,” said Rep. Livingston, who has invited Gov. Jan Brewer and members of the Arizona Legislature to the fundraiser at the home of Shelby’s parents, Renee and Scott Valint – 1-5 p.m. April 6 at 1517 E. Red Range Way, about a mile south of Carefree Highway, just east of 14th Street.

“In my recent tour of TGen’s facilities, I saw first-hand the cutting-edge research, tools and technology being used to help children like Shelby,” Rep. Livingston said. “My wife, Tracy … has personally seen Shelby’s amazing transformation.”

By sequencing, or spelling out, the nearly 3 billion letters in Shelby’s DNA, TGen researchers found a gene that prevented Shelby from producing sufficient amounts of a brain chemical called dopamine, which is needed for balance and muscle control.

Using a combination of drugs usually given to older persons for treatment of Parkinson’s disease, Shelby was able within several weeks to abandon her wheelchair. She was able to more easily walk, talk, eat and even breathe, generally restoring her to a normal functioning child.

“Before TGen’s discovery, we had been through an enormous amount of despair with all the doctor visits and tests, and I had watched helplessly as Shelby was poked and prodded with a heart-wrenching number of needles and IVs,” Renee Valint said. “Shelby’s newfound ability to walk and talk, and generally lead a normal life, is a testament to the unwavering dedication to helping patients exhibited by the scientists at TGen.”

To see Shelby’s amazing transformation from a girl who was unable to walk, talk and eat to a girl who dances across the room, watch this recent story from CBS 5 News.



TGen Launches Center for Rare Childhood Disorders

The Translational Genomics Research Institute (TGen) today announced the creation of a new center that could have life changing effects on the lives of potentially thousands of children and their families.

The TGen Center for Rare Childhood Disorders (C4RCD) will harness the latest technologic leaps in genome sequencing to pinpoint the causes of rare childhood disorders that largely remain a mystery to modern medicine.

“We envision a Center that leverages today’s genomic technology toward diagnosing children with a baffling array of seriously debilitating, and often lethal, symptoms for which there is no known cause or treatment, let alone a cure. In many cases, it’s merely a collection of symptoms,” said Dr. Jeffrey Trent, President and Scientific Director of TGen. “Through the C4RCD, TGen has a unique opportunity to significantly improve the lives of these children and their families.”

The Honorable Arizona Gov. Jan Brewer praised the new TGen initiative as a major step in meeting the healthcare needs of Arizonans, and as a fundamental building block of the state’s burgeoning biotechnology sector.

“With its new Center for Rare Childhood Disorders, TGen continues to position Arizona as a world-class leader in bioscience and research,” said Gov. Brewer. “More importantly, this program holds the promise of bringing much-needed certainty and hope to the lives of thousands of Arizona children and their families. I commend TGen for its pioneering work that is making a real difference in the lives of Arizonans.”

Resolving the plight of one 12-year-old Phoenix girl named Shelby helped pave the way for C4RCD. Shelby was once a wheelchair-bound patient who for nearly a decade had difficulty walking, talking, holding her head up, and who had difficulty swallowing, and even breathing.

Shelby’s sequenced genome showed she had a problem making dopamine, a key brain chemical that helps regulate movement, muscle control and balance. Within a few months of receiving a medication to address her dopamine deficiency, Shelby was able to do away with her wheelchair. Now, she can talk, walk; enjoy restaurants, shopping and school.

“For us, TGen has been a miracle,” said Shelby’s mother, Renee, who hopes TGen’s C4RCD will bring hope to other parents, as well. “I am truly ecstatic. Shelby and I are very happy about it. It gives parents a place to go when it may seem that they’ve lost all hope. The scientists at TGen are amazing.”

Often, there are just a few children, or even a single child, with a particular set of symptoms. Collectively, according to the National Institutes of Health, there are close to 7,000 rare diseases and about 25 million people in the U.S. have one.

“Too often, the parents of these children are left with nowhere to turn. They often are simply prescribed medications for their child, such as anti-seizure drugs, that only address the symptoms,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics and Co-Director of the C4RCD.

“At TGen, we now have the tools to sequence the entire genome of these children, in a relatively short time and at ever-lower costs. Through this examination of the billions of chemical letters that spell out each human being’s unique genome, and analyzing all the potential genetic changes, or mutations, we now have the ability to potentially identify the root cause of each child’s condition,” said Dr. Craig.

Understanding what is causing the disease or condition enables TGen to consider treatment options that could best help each child.

“Largely, these families have not had many answers. They’ve seen a lot of doctors. They’ve run a lot of tests. If they’re lucky, their disease might have a name,” said Dr. Matthew Huentelman, Head of TGen’s Neurobehavioral Research Unit and Co-Director with Dr. Craig of the C4RCD. “We hope to provide these families — first and foremost — with answers. We strongly believe those answers will be found in their genome.”

Once a genetic target is identified, C4RCD will look for an existing FDA-approved drug that could be repurposed to treat the rare disorder.

If there is no obvious approved drug, C4RCD will develop a custom screening approach to prioritize approved drugs in order of their potential effectiveness. In this fashion, it may be possible to help improve the quality of life for these children quickly without the time-consuming development of an entirely new pharmaceutical agent.

TGen’s C4RCD has four major components: 1) Clinical evaluation and genomic diagnosis. 2) Counseling, and optimizing conventional therapy. 3) Novel therapy development. 4) Community outreach.

Each child will be clinically evaluated and have their genome tested, including the use of whole genome sequencing, which spells out the entire 3 billion letters of each individual’s DNA genetic code.

“One of the important things is to collect available clinical information, and accurately define the phenotype, or problem, causing the child’s issues. That has to be framed very carefully, correctly. This initial step is critical in order to analyze the genome sequencing data,” said Dr. Vinodh Narayanan, Medical Director of C4RCD.

“A precise genetic or molecular diagnosis is of vital importance for the entire family of our patients. But that is just the beginning. We want to use this genetic information to understand more about the particular disorder, and develop novel approaches to treatment. That is what is going to differentiate us from other services — complete integration of the clinical center and the genomic research lab,” said Dr. Narayanan.

Dr. Trent said that there is a critical unmet need in the medical community, which only now can begin to be addressed through the advent of new genomic technologies.

“We continue to be amazed at the way families of children with debilitating conditions are able to find each other, share stories of their victories and of what is wrong, and try to come up with answers,” said Dr. Trent. “We hope to become an active partner and leader in these communities as we learn from the families and patients, and then try to come up with new and better answers for these children — today.”

For information about TGen’s Center for Rare Childhood Disorders, please go to c4rcd.org or call 1-855-343-8611.