Researchers Examine Obesity, Cardiovascular Risks in Down Syndrome

Children with Down syndrome (also known as Trisomy 21) are prone to obesity. Their families may be concerned about their future risks for cardiovascular problems as well as their quality of life. 

Although Down syndrome is the most common chromosomal anomaly in humans, affecting about 5,000 babies born each year and more than 350,000 people in the U.S., the population is understudied, according to Andrea Kelly, MD, MSCE, an attending physician in the division of Endocrinology and Diabetes at The Children’s Hospital of Philadelphia, and Sheela N. Magge, MD, MSCE, director of research in the division of Endocrinology and Diabetes at Children’s National Health System.

They are both principal investigators of a multidisciplinary team — including experts in pediatric growth and metabolism, psychology, cardiology, and statistics — that is studying body composition measures and cardiometabolic risk factors in 150 adolescents with Down syndrome and in a matched control group.

In the typically developing pediatric population, body mass index (BMI, a calculation based on weight and height) is the standard way in the U.S. to screen for obesity. If a child or teen’s BMI is high, it could be an indicator of higher risk for certain health problems such as heart disease, high blood pressure, and type 2 diabetes. Yet, the usefulness of BMI in individuals with Down syndrome is not known in that it might not be appropriate as a one-size-fits-all marker for obesity.

“Children and adults with Down syndrome tend to have short stature,” Dr. Kelly said. “We don’t know if BMI truly reflects body fat or adiposity in a group with altered body proportions. We wanted to explore that a little bit more, especially since older data suggested they might be protected from cardiovascular disease.”

The first-ever BMI charts for children with Down syndrome became available in the fall based on previous research conducted at CHOP by Babette Zemel, PhD, (also a co-investigator on the current study). The charts do not represent an ideal distribution of BMI, but only describe BMI distribution among the study participants. The current investigations should help to put these charts into better context and will compare them to the Centers for Disease Control and Prevention’s BMI charts, in order to give clinicians more guidance on how to screen patients with Down syndrome for excess body fat and associated health symptoms.

The study team aims to determine if BMI is the best way to define obesity in teens with Down syndrome or if there is another measure of body composition that could better predict cardiovascular and metabolic risk in this patient population. For example, the researchers are performing dual-energy X-ray absorptiometry scans to estimate study participants’ body fat. They also are looking at novel markers of cardiometabolic risk by performing subparticle analysis of the participants’ lipids and blood sugars. And they are using technology called pulse wave velocity to assess cardiac end organ injury.

“We are exploring these traditional and novel markers because if children with Down syndrome and obesity need to be more aggressively managed, we need to pay attention to that,” said Dr. Kelly, who also is an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania

Based on pathology studies conducted in the late 1970s, a belief that individuals with Down syndrome are protected from cardiovascular disease has persisted. But more recent research has contradicted this theory, suggesting that death from cardiovascular disease was more than six times great in the Down syndrome population, Drs. Kelly and Magge pointed out.

In addition to taking a comprehensive look at the relationship between BMI and cardiovascular risk factors, the study team wants to know more about the teens’ perceptions of their quality of life and if families identify any barriers to promoting exercise and a healthy lifestyle for their children with Down syndrome. The study participants will wear an armband accelerometer that monitors their physical activity for a week.

Eventually, the investigators hope to use this research to build a foundation for future weight loss interventions and prevention programs that are targeted to pediatric populations with special needs.

“We’d like to work with the study team and ask, how can we prevent this from happening?” Dr. Kelly said. “Most families are very aware that their children are at risk for gaining excess weight, but we don’t know the best way for them to minimize that risk.”

At a Trisomy 21 Research Initiative meeting in October, Drs. Kelly and Magge gave an update on their research project to colleagues from the Intellectual and Developmental Disabilities Research Center at CHOP and Penn as well as other investigators from Kennedy Krieger Institute, Boston University, and University of California, Irvine. This meeting fostered a dialogue between these institutions and examined the Trisomy 21 research being done, in order to find potential extensions or amplifications of this work.

For more information on the IDDRC, contact Kristen Hearty at heartyk@email.chop.edu.

CHOP/ Penn IDDRC Renewed for Another 5-Year Cycle

The Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) has announced the renewal of the Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/Penn for the next 5 years. This award marks the sixth successful grant application for support by the IDDRC, which has enjoyed uninterrupted funding since its establishment in 1990.

Created by Congress in 1963, the 15 Centers in the IDDRC Network represent the nation's first and foremost sustained effort to prevent and treat disabilities through biomedical and behavioral research. The 15 Centers contribute to the development and implementation of evidence-based practices by evaluating the effectiveness of biological, biochemical, and behavioral interventions; developing assistive technologies; and advancing prenatal diagnosis and newborn screening.

In 2014, the NICHD transitioned the IDDRC Network to a U54 mechanism (“Cooperative Agreement”) which creates an ongoing partnership between the Centers and the Intellectual and Developmental Disabilities (IDD) Branch at NICHD. This partnership emphasizes multidisciplinary research into the causes and treatments of the developmental disabilities. A novel feature of the U54 mechanism is the sponsorship at each Center of a research project which addresses a crucial aspect of the IDD. At CHOP/Penn, we are supporting a study to develop a novel brain biomarker using magnetoencephalography to diagnose and evaluate minimally verbal people with an autistic spectrum disorder.

The IDDRC has become a key agency on the CHOP/Penn campus for the promotion of IDD-related research. It does so with a three-pronged strategy:

• Advocacy - in order to recruit talented investigators and maintain a substantial research infrastructure
• Education – to support promising young scholars entering the field; and
• Research Support – to provide eligible CHOP/Penn investigators with core laboratory services which otherwise would be inaccessible.

The CHOP/ Penn IDDRC sponsors 5 research core facilities:

Analytical Neurochemistry Core
Director: Michael Robinson, PhD; Co-Directors: Marni Falk, MD; Harry Ischiropoulous, PhD; Itzhak Nissim, PhD; Marc Yudkoff, MD) Services: proteomics, bioenergetics assays, metabolomics, stable isotopes, biogenic amines.

Biostatistics and Bioinformatics Core
Director: Mary Putt, PhD; Co-Directors: Hakon Hakonarson, MD, PhD; Douglas Wallace, PhD). Services: statistical analysis, experimental design consultation, bioinformatics analysis for GWAS, CNV, sequencing (both nuclear and mDNA), RNA profiling.

Clinical Translational Core
Director: Robert Schultz, PhD; Co-Director: Nate Blum, MD. Services: assistance with recruitment, phenotyping, database and patient registry creation, websites. 

Neurocircuitry and Neuroimaging Core
Director: Tim Roberts, PhD; Co-Directors: Doug Coulter, PhD; Eric Marsh, MD.
Services: magnetoencephalography, MRI, MRS, multiphoton microscopy, voltage-sensitive dye & Ca2+ indicator imaging; EEG interpretation.

Preclinical Models Core
Director: Ted Abel, PhD; Co-Directors: Deborah French, PhD; Judith Grinspan, PhD Services: animal behavioral testing, EEG implantation, stereotaxic drug delivery, microdissection, neural tissue culture consultation, IPSC consultation, CRISPR-Cas technology

In addition to the above, an Administrative Core is responsible for our educational program, including the IDDRC Monthly Seminar and the administration of the Alavi-Dabiri Postdoctoral Fellowship Award for post-doctoral trainees and the Training Grant in Neurodevelopmental Disabilities.

Access to the core laboratory facilities is available to all CHOP/Penn investigators who are recipients of NIH and/or NSF funding that is relevant to Intellectual and Developmental Disabilities (including training grants). To apply, please contact Ms. Kristen Hearty, Center Administrator (215-590-3728; heartyk@email.chop.edu).  

Alavi-Dabiri Postdoctoral Fellowship Awardee: Dr. Rebecca Ahrens-Nicklas

The Alavi-Dabiri fellowship was created in 1997 by Drs. Abass and Jane Alavi to honor their nephew, Ramin Dabiri, who has a developmental disability, and his parents, Maryam Alavi and John Dabiri. This award, which is administered by the IDDRC, provides one year of support to a postdoctoral fellow who works under the mentorship of one or more members of the IDDRC.
 

Rebecca Ahrens-Nicklas, MD,PhD,
was awarded the Alavi-Dabiri
Fellowship

The 2015 awardee is Dr. Rebecca Ahrens-Nicklas, a fellow in the Divisions of Human Genetics and Metabolism at CHOP. She received her MD/PhD in 2010 from the Cornell/Sloan-Kettering/Rockefeller tri-institutional program. Her mentors are Dr. Eric Marsh, Assistant Professor of Neurology, and Dr. Beverly Davidson, Professor of Pathology and Laboratory Medicine and Director of the CHOP Center for Cellular and Molecular Therapeutics.

Dr. Ahrens-Nicklas' proposal, “Electrophysiologic Consequences of Inborn Errors of Metabolism,” focuses on Juvenile Batten Disease (JBD), a lysosomal storage disorder which causes vision loss, seizures and relentless neurologic decline. Affected patients harbor mutations in the gene coding for CLN3, a lysosomal membrane-associated protein. Proposed functions of CLN3 in the central nervous system include autophagy, vacuolar maturation, endocytosis, and vesicle transport. It is still unclear how mutations in this disease give rise to the devastating phenotype, but it is known that the brain suffers the intra-lysosomal accumulation of toxic substances. Dr. Ahrens-Nicklas will carefully characterize disease manifestations in a mouse model of JBD by deploying EEG monitoring, behavioral analysis, histopathology and electrophysiologic study of neural networks utilizing voltage-sensitive dye imaging technology. This information, Dr. Ahrens-Nicklas notes, is necessary to evaluate the efficacy of selected therapeutic interventions, including gene therapy. As the Alavi-Dabiri awardee, Dr. Ahrens-Nicklas will enjoy access to several IDDRC research core facilities, including the Neuroimaging andNeurocircuitry Core, the Preclinical Models Core (animal behavioral testing) and the Biostatistics and Bioinformatics Core (statistical analysis and experimental design).

 

Dr. Ahrens-Nicklas writes: “Ultimately, I am interested in understanding how inborn errors affect neuronal networks, and if therapies can normalize nervous system function. Given that these networks are established during fetal development, postnatal treatment may never fully reverse neurologic phenotypes. One could imagine that early (perhaps even prenatal) intervention may be more efficacious, albeit technically challenging. Therefore, in the future, I would like to investigate the utility of pre-symptomatic or prenatal therapeutics in JBD and other metabolic disorders.”