August 22, 2017

When Bristol Dunlap was born, she was perfectly healthy. But by the time she was three months old, she was failing to reach her milestones and began showing worrisome symptoms.

“She could not lift her head up or sit upright, her body was unusually floppy, and her left eye began turning inward even though her vision was fine,” said her mother Evonia Dunlap. “As my daughter grew older, she was slow to crawl, stand and walk, and had difficulties in chewing, swallowing and talking.”

Bristol was diagnosed with congenital hypotonia which explained her poor muscle tone throughout her body. While therapy helped her daughter sit, walk and talk, there was one thing Dunlap wanted to know: What caused Bristol to develop hypotonia?

After seeing many specialists and undergoing a battery of diagnostic tests with still no answer, the family’s five-year medical odyssey ended at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s, where they were referred to neurologist Dr. Hsiao-Tuan Chao and Dr. Michael Wangler, geneticist and assistant professor of Human and Molecular Genetics at Baylor College of Medicine.

Through the NIH-funded Undiagnosed Disease Network (UDN), which brings together experts from across the country to help solve mysterious medical conditions by searching for their genetic basis, Chao and Wangler learned of a 7-year-old boy who exhibited symptoms similar to Bristol’s and also carried a point mutation in the Early B-Cell Factor 3 (EBF3) gene.

After re-examining Bristol’s exome sequencing results, they found she, too, carried the same mutation that produces a defective EBF3 protein. Since this protein is a master regulator of hundreds of other genes, even the tiniest alteration in its function could potentially cause widespread damage to the nervous system and muscles.

A referral center for undiagnosed diseases

Like the Dunlaps, many patient families are referred to Texas Children’s because of our renowned expertise and specialization in the diagnosis of diseases that are rarely seen and often unrecognized. Besides bringing together experts in genetics, pediatrics and neurology at Texas Children’s and its academic partner, Baylor College of Medicine, the UDN unites clinicians and scientists from across the country to help solve the most difficult medical cases. It is one of seven UDN sites nationwide.

More than 50 percent of UDN patients exhibit neurological symptoms. Texas Children’s chief of Neurology Dr. Gary Clark is one of the co-leaders of the UDN program at Texas Children’s and Baylor, and works closely with Texas Children’s neurologist Dr. Lisa Emrick in solving these mysterious neurological disorders.

“When a patient is referred to our UDN site, their DNA sample is submitted for sequencing,” said Emrick. “We conduct phenotyping and provide our UDN and NRI partners with the clinical patient data they need to help identify variant genes that may be responsible for a patient’s disease. Before advanced technologies like sequencing, only a small percent of these cases could be diagnosed.”

In addition to state-of-the-art medical imaging, metabolomics, and genetic testing including genome sequencing and exome sequencing, clinicians and researchers in the UDN rely on the Model Organism Screening Center (MOSC), where genes are studied in fruit flies to help diagnose patients. The center is led by Dr. Hugo Bellen, professor of Molecular and Human Genetics and Neuroscience at Baylor; Dr. Shinya Yamamoto, NRI investigator and assistant professor at Baylor; and Wangler. This dynamic team uses fruit flies, Drosophila melanogaster, to study new disease candidate genes and variants. They also closely collaborate with researchers at the University of Oregon in generating zebrafish models to study origins of disease.

In the MOSC, researchers combine bioinformatics analysis and experimentation in these ideal organism models to determine whether a specific variant identified in the genome of the patients may be responsible for the disease. “Integration of human genomics and experiments in simple model organisms such as fruit flies and zebrafish greatly facilitates disease diagnosis and mechanistic studies,” said Bellen.

“An exciting technique we developed is a way to humanize a fly gene,” said Yamamoto. “By knocking out the homologous gene in the fly and replacing it with the human gene, we can test the specific variant found in the patient to see how well it performs.”

Since fruit flies share many similar genes with humans, they have become a powerful model organism for the study of genetics. To study human disease in fruits flies, scientists mutate, or disrupt, the same gene that is known or suspected to cause the disease, and then figure out why mutations with this gene leads to disease.

Through collaboration with the UDN, Texas Children’s and Baylor continue to make significant strides in helping to accelerate the diagnoses of previously undiagnosed and rare neurological conditions.

For the Dunlap family, this provides a source of encouragement.

“While the journey to find a cure for our daughter’s illness has just begun, we are happy to finally have some answers,” Evonia said. “We are thankful for the pioneering work being done by physicians and researchers at Texas Children’s.”

July 17, 2017

Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Institute at Texas Children’s and professor in the departments of pediatrics, molecular and human genetics, neurology, and neuroscience at Baylor College of Medicine, received the 2017 Switzer Prize from the David Geffen School of Medicine at UCLA for excellence in biological and biomedical sciences research.

The Switzer Prize recognizes discoveries in basic research in the biological and biomedical sciences that have the potential to inspire transformative breakthroughs in medicine. It is awarded annually to an individual investigator whose recent work has revealed new paradigms, illuminated biological processes or pathways, or explained the origins of pathologies or diseases.

The David Geffen School of Medicine at UCLA established the prize to promote the importance of basic sciences research, which advances the understanding of biological systems and human physiology. Such research – a priority at UCLA – is essential to continued improvements in the diagnosis and treatment of a wide variety of illnesses.

The Switzer Prize is named in recognition of the generosity of Irma and Norman Switzer, who made a major gift to the David Geffen School of Medicine at UCLA.

Zoghbi’s research includes identifying a gene mutation that causes Rett syndrome, a severe genetic disorder that mostly affects girls. She will deliver the Switzer Prize lecture at UCLA in February 2018.

June 6, 2017

Dr. Benjamin Arenkiel, a researcher at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s has received a 2017 Michael E. DeBakey, M.D., Excellence in Research Award, a prestigious honor given annually to Baylor College of Medicine faculty who have made the most significant published scientific contribution to clinical or basic biomedical research during the past three years.

“Arenkiel is an extraordinarily gifted scientist who has made many exciting and notable discoveries in the area of neuroscience,” said Dr. Huda Zoghbi, director of the NRI who nominated Arenkiel for this prestigious award. “The papers he published in the last couple of years open up new exciting areas of research into sensory maps as well as the circuits of feeding behavior.”

Since joining the Baylor faculty, Arenkiel and his team have published and/or co-authored 32 manuscripts. In addition, the Arenkiel lab now focuses on three areas of science that each have resulted in publications in high-impact journals including Developmental Cell, Neuron, Nature, and Nature Neuroscience.

Arenkiel was presented with the DeBakey Excellence in Research Award on May 15. To learn more about the scientific research that garnered Arenkiel the DeBakey award, see below:

Nature Neuroscience: Using contemporary genetic approaches, the Arenkiel lab has recently described novel roles for neuropeptide signaling in synaptic remodeling within the adult nervous system. Synapse and circuit formation and function serves as a platform for their ongoing work. Arenkiel and his lab found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.

Developmental Cell: In this paper, Arenkiel capitalizes on the olfactory system circuits system to understand how newly born neurons integrate into an existing network in the adult brain. Using the rodent olfactory system as a model, their work strives to understand how the circuits that comprise and modulate the olfactory bulb contribute to olfaction. This research shows that local corticotropin hormone signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation and integration of new neurons in the adult brain.

Nature: Most recently, Arenkiel has initiated new and creative experiments to further probe neuronal synapse and circuit formation in the mouse brain. His lab has discovered a novel mechanism by which cholinergic signaling in the basal forebrain exerts a strong influence on body weight control. His group has serendipitously uncovered novel circuits that govern convergent hypothalamic circuits that influence feeding behavior, sensory processing and stress. He has since taken a keen interest in the feeding behavior circuits. This manuscript has been positively received by the scientific community as well as the pay press and was highlighted in the Wall Street Journal.

May 23, 2017

Drs. Hsiao-Tuan Chao and Laurie Robak, physician-scientists at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s, received scholarship grants from the American Academy of Neurology (AAN) to support studies on neurodevelopmental and neurodegenerative diseases.

Chao, a postdoctoral associate in the laboratory of Dr. Hugo J. Bellen was awarded the 2017 Neurology Research Training Scholarship for her proposed study titled, “Transcriptional Dysregulation of Neural Circuits in Neurodevelopmental Disorders.” Using the laboratory fruit fly and mouse, she will explore how changes in the function of master regulators of gene expression, like EBF3, can cause childhood neurologic diseases. Chao’s discoveries will provide some answers and improve the quality of life for many of these children and families.

Robak is a postdoctoral fellow in the laboratory of Dr. Joshua Shulman. She was awarded the 2017 Clinical Research Training Fellowship in Parkinson’s Disease for her proposal titled, “Elucidating Genetic Links Between Lysosomal Storage Disorders and Parkinson’s Disease.” Her study will identify lysosomal storage disorder genes as risk factors for Parkinson’s Disease, which will hopefully lead to improved diagnosis and risk assessment, and development of novel therapeutic strategies.

Twenty award winners, including Drs. Chao and Robak, were recognized at the 69th Annual Meeting of AAN, the world’s largest association of neurologists in April.

Click here for more information about their proposed research studies.

April 18, 2017

On April 10, more than 600 guests attended the Forum Luncheon at the Marriott Marquis in downtown Houston to meet internationally renowned neurogeneticist Dr. Huda Zoghbi and learn about the remarkable breakthroughs being made at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital and Baylor College of Medicine.

President and CEO Mark A. Wallace delivered opening remarks including a video documenting the unfolding story of the NRI and how Texas Children’s bold vision of establishing the world’s first basic research institute dedicated to the study of childhood neurological diseases became reality as a result of the hospital’s incredible leadership which he describes as Texas Children’s “secret sauce.”

ABC 13 Anchor Melanie Lawson moderated the one-hour long Q-and-A discussion with Zoghbi, director of the NRI. In addition to learning about Zoghbi’s early career before making the transition to neuroscience research, Zoghbi shared her collaborative vision for the NRI and spotlighted some of the exciting new discoveries emerging from the numerous labs at the NRI.

“To understand a disease, you have to know the root cause,” Zoghbi said. “Once you know the root cause, you can then create an animal model of the disease, dive into the mechanism and find an entry to a therapeutic manipulation. Genetics is one way to find the root cause of disease.”

Since the NRI opened in 2010, Zoghbi highlighted several recent discoveries that have opened new doors for developing therapeutic targets for various neurological diseases:

  • Dr. Benjamin Arenkiel found a small group of cells in the basal forebrain play a major role in the control of appetite. In mouse studies, when these cells are manipulated a certain way, the animal either eats constantly and becomes obese or eats little and loses weight. Arenkiel’s discovery paves the way for developing new therapies to treat obesity and other eating disorders in children and adults.
  • In collaboration with Drs. Juan Botas and Zhandong Liu, NRI researchers have identified a potential new strategy to prevent Alzheimer’s disease. They found that an over accumulation of the protein tau can make the brain vulnerable to degeneration. By developing new drugs to keep tau at levels that are not toxic, this could either prevent or delay the development of Alzheimer’s and other degenerative diseases caused by toxic tau accumulation.
  • Drs. Andrea Ballabio and Marco Sardiello discovered the function of a gene called Transcription Factor EB that helps cells clear up accumulated proteins, which is important for nerve cells to survive. Based on this scientific breakthrough, new clinical trials are underway that will help slow down or stop the progression of disease in patients with Batten disease by improving the clearing function of the brain.
  • Drs. John Swann, Anne Anderson and their team found that there are many molecular and biochemical changes that drive the growth and over-activity of brain cells in epilepsy patients. They were able to define a way to treat these seizures based on biochemical studies in cancer, which has helped to eliminate uncontrollable seizures in children.
    The NRI Forum Luncheon also included inspirational stories from several patient families who were present at the event, and who have benefitted from the life-altering research emerging from the NRI to improve the outcomes and quality of life for patients with a myriad of neurological disorders.

Prior to this event, Texas Children’s Development also hosted a reception to unveil a photography exhibit by Karen Sachar honoring the special needs children in the Greater Houston community. The reception included a short presentation from NRI researcher Dr. Christian Schaaf.

Click here to watch the video of the entire Luncheon Forum program.

Click here to watch specific patient story videos that were featured at the event.

April 4, 2017

The Baylor College of Medicine Department of Pediatrics and Texas Children’s Hospital hosted the 2017 Pediatric Fellows’ Research Symposium on March 21 at the Pavilion for Women Conference Center.

Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute, provided the keynote research presentation, “Protein Levels and Neurological Diseases: Insights and Opportunities.” Besides advancing our understanding of the genetic causes of spinocerebellar ataxia and Rett syndrome, she has been instrumental in other important neurological medical breakthroughs including her recent discovery of how lowering toxic levels of tau in the brain could potentially lead to new therapies to reverse or prevent Alzheimer’s disease.

Dr. Will Parsons, director for the Center for Precision Oncology at Texas Children’s Cancer Center, followed with the keynote scholarship presentation, “Precision Oncology: Deconvoluting One Trainee’s Path from the Bench to the Clinic.”

This year’s research symposium included more than 135 poster presentations from pediatric fellows and included an awards presentation featuring the top four abstracts submitted this year:

  • Bile duct ligation induces ATZ globule clearance in a mouse model Alpha-1 antitrypsin deficiency

Dr. Zahida Khan

  • Respiratory severity score on day of life 15 is higher in premature infants requiring mechanical ventilation at day of life 60

Dr. Matthew Maruna

  • Pharmacogenomic association with neurotoxicity in Hispanic children with acute lymphoblastic leukemia (ALL)

Dr. Claire McClain

  • Inflammatory regulation promotes angiogenesis in chronic renal diseases models

Dr. Xinyi Wang

A fellows’ workshop session was offered as well. Dr. Eric Williams, associate professor of Critical Care at Baylor and Texas Children’s chief medical information officer, led the session on Innovation.

The symposium is an important forum for sharing research results and achievements, as well as for networking and establishing new collaborations. The symposium provides a venue to address topics that may be relevant to the trainee’s career development as they transition to more advanced or faculty positions.

March 29, 2017

Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s and Baylor College of Medicine, is being honored by the Gairdner Foundation with the 2017 Canada Gairdner International Award for seminal discoveries and contributions to biomedical science. This award recognizes some of the most significant medical discoveries from around the world.

Zoghbi, who also is professor and Howard Hughes Medical Institute Investigator at Baylor, is one of five individuals given this award. She is being recognized for her work surrounding the discovery of the gene responsible for Rett syndrome.

After years of treating patients, Zoghbi began to focus on finding the genetic causes of the disease, which strikes after a year of normal development and presents with developmental regression, social withdrawal, loss of hand use and compulsive wringing of the hands, seizures and a variety of neurobehavioral symptoms.

Zoghbi identified that mutations in MECP2 are the cause of Rett syndrome, revealing the importance of MeCP2 for the function of various neuronal subtypes. Her work showed just how sensitive the brain is to the levels of MeCP2 and that doubling MeCP2 levels causes progressive neurological deficits. This disorder is now recognized as MECP2 Duplication Syndrome in humans.

Her recent work showed the symptoms of adult mice modeling the duplication disorder can be reversed using antisense oligonucleotides that normalize MeCP2 levels.

The discovery of the Rett syndrome gene provided a straightforward diagnostic genetic test, allowing early and accurate diagnosis of the syndrome. It also revealed that mutations in MECP2 also can cause a host of other neuropsychiatric features ranging from autism to juvenile onset schizophrenia. Further, it provided evidence that an autism spectrum disorder or an intellectual disability disorder can be genetic even if it is not inherited.

Her discovery opened up a new area of research on the role of epigenetics in neuropsychiatric phenotypes. Her use of an antisense oligonucleotide to lower MECP2 levels provides a potential therapeutic strategy for the MECP2 duplication syndrome and inspires similar studies for other duplication disorders.

Zoghbi will be presented her award at a gala in Toronto on Thursday, October 26. Each award carries an honorarium of $100,000 to support continued research.