On October 9, the Neurology division at Texas Children’s will be recognized not once, but four times at the 44th Annual Child Neurology Society Meeting in Washington, D.C.
Drs. Dana Marafie and Davut Pehlivan are two of the four recipients chosen this year to receive the 2015 Outstanding Junior Member Award. Marafie is being recognized for her work titled, “SCN1A as a candidate gene modifier influencing the severity of epilepsy in autosomal dominant GRIN2A mutation,” and Pehlivan for his study titled, “Mutation analysis in patients with neurodevelopmental delay using next generation sequencing.”
Dr. Jimmy Holder, a researcher at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s, will be honored with the Philip R. Dodge Young Investigator Award which is named after one of the modern founders of the specialty of pediatric neurology. Holder received this prestigious honor for his study titled, “Dissection of the molecular, neuronal and circuit abnormalities of the newly delineated SHANK3 duplication syndrome.”
Dr. Robert Zeller will be honored with the 2015 Arnold P. Gold Foundation Humanism Award that is presented to a physician who exemplifies the qualities of a caring and compassionate mentor in the teaching and advising of medical students and one who demonstrates humanistic attributes in the delivery of patient care.
Texas Children’s congratulates our 2015 CNS award recipients. See below to learn more about their award-winning research studies and to watch a video tribute to Zeller featuring inspiring testimonials from his colleagues and one of his patient families.
Principal Investigator: Dr. Jimmy Holder
Project Title: Dissection of the molecular, neuronal and circuit abnormalities of the newly delineated SHANK3 duplication syndrome
CNS Award: 2015 Phillip R. Dodge Young Investigator Award
The SHANK3 gene provides instructions on how to code a protein that controls the function of synapses, which are the points of communication between neurons in the brain. Defects in this gene can impact the production of SHANK3 protein, which is critical in neural communication.
Mutations in the SHANK3 gene have been associated with neuropsychiatric disorders like schizophrenia and a number of cognitive disorders including autism. Previous research shows that a reduction in the amount of SHANK3 protein produced can cause a form of autism called Phelan-McDermid Syndrome.
However, according to a new study led by Dr. Jimmy Holder and his colleagues at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s – Drs. Huda Zoghbi, Christian Schaaf and Jianrong Tang – the production of too much SHANK3 protein can also be detrimental.
In this groundbreaking study, the researchers created and examined mice that make too much SHANK3 protein and found multiple behavioral, molecular and physiologic abnormalities. Next, they searched patient databases and found individuals with SHANK3 duplications who displayed behavioral abnormalities like hyperactivity and mania which was reminiscent of the behavior found in the lab mice.
Based on the results of this study, Holder’s next step is to determine what neuronal and molecular changes might drive the behavioral abnormalities of these mice. Recently, he found that abnormal function of a portion of the brain called the striatum drives some but not all of the behavioral abnormalities of these mice.
“I hope to identify specific molecular pathways that are dysfunctional due to SHANK3 abnormalities,” Holder said. “This information will help scientists develop targeted therapies for patients with mutations in the SHANK3 gene.”
In addition to receiving the Phillip R. Dodge Investigator Award from the Child Neurology Society, Holder is also the recipient of the K08 – Mentored Clinical Scientist Career Development Award from the National Institute of Neurological Disorders and Stroke.
Principal Investigator: Dr. Dana Marafie
Project Title: SCN1A as a candidate gene modifier influencing the severity of epilepsy in patients with autosomal dominant GRIN2A mutations
CNS Award: 2015 Outstanding Junior Member Award
Childhood epilepsy can vary from mild to severe cases depending on the type of epilepsy syndrome. Some of these childhood epilepsy syndrome are described to be associated with disease-causing changes (mutations) in specific genes.
While mutations in the GRIN2A and SCN1A are known to cause epilepsy, Dr. Dana Marafie’s award-winning study explores the interaction between the two epilepsy genes in a four-generation family with variable degrees of epilepsy, learning disability and language impairment.
The idea for this project began when a previously healthy 6-year-old child presented to Dr. Marafie’s clinic at the Blue Bird Circle with behavioral changes and sudden loss of speech. Her initial testing showed that she had a severe form of epilepsy called Landau Kleffner Syndrome. This syndrome represents a rare form of epilepsy where seizure discharges in the brain during sleep causing the child to lose the ability to speak. Because 12 other family members were affected by some degree of epilepsy, speech and learning problems, genetic testing through Whole Exome Sequencing was performed to identify a genetic cause. The test identified a disease-causing change in a gene called GRIN2A. Changes in this particular gene has been recently described to cause neurodevelopmental disabilities, speech problems and epilepsy. What was interesting is that the same patient had an undescribed change in another epilepsy gene called SCN1A.
Under the supervision of her mentors – Drs. Gary Clark, Lisa Emrick – Dr. Marafie coordinated genetic testing for these two genetic changes for nine other family members.
The results suggest that the two gene changes are more likely to occur in family members with more severe epilepsy and learning problem. “These findings suggest that the interaction between the two genes may play a role in determining the severity of epilepsy syndrome,” Marafie said.
The next step is to collaborate with other investigators to further examine the function of the change in the SCN1A gene and the interaction between the two gene changes in cell lines.
Principal investigator: Dr. Davut Pehlivan
Project Title: Mutation analysis in patients with neurodevelopmental delay using next generation sequencing
CNS Award: 2015 Outstanding Junior Member Award
In his award-winning study, Dr. Davut Pehlivan analyzed genetic mutations in patients with brain malformation, seizure disorder and neurodevelopmetal delay using next generation sequencing.
With this advanced genetic technology, researchers can screen the sequence of millions of pieces of DNA that comprise genes found in human chromosomes. They can also discover new genes that may be associated with specific diseases a lot easier with next generation sequencing.
Under the supervision of Dr. James Lupski, a senior physician scientist in the Department of Molecular and Human Genetics at Baylor College of Medicine, Pehlivan screened the genetic information of 125 families from Turkey enrolled in the study and identified 10 new genes that play a critical role in brain development.
Besides finding genes that were previously known to cause brain malformation and neurodevelopmental delay, Pehlivan discovered new genes that had not been associated with these types of neurological conditions until now. Interestingly, further bioinformatic analysis revealed that three highly connected gene subnetworks significantly enriched in brain development, RNA metabolism and cytoskeletal organization.
“Our findings provide incredible insights into the biology of brain malformations and the genomics of neurogenetic disease,” Pehlivan said. “Our next step is to discover potential treatment options for patients with developmental delay and seizure disorder.”
Pehlivan’s study was conducted through the Center for Mendelian Genomics at Baylor, a joint program with the Johns Hopkins University School of Medicine funded by the National Human Genome Research Institute.
Neurology colleagues, patient family share inspirational testimonials of Zeller’s humanistic approach to patient care
Dr. Robert Zeller, medical director of Texas Children’s Blue Bird Circle Clinic, received the 2015 Arnold P. Gold Humanism in Medicine Award from the Child Neurology Society. Texas Children’s Chief of Neurology Dr. Gary Clark nominated him for this prestigious honor.
“Dr. Zeller is driven to serve others and really driven by this humanistic approach to medicine and to life,” Clark said. “We can be in important meetings, but Dr. Zeller will drop everything and make sure the needs of his family, patients and coworkers are met.”
Texas Children’s neurologist Dr. Carlos Rivera met Zeller 30 years ago when he was a pediatric resident at Texas Children’s. As a young physician, he recalled how Zeller was well-loved and respected by his patients, family and co-workers. Fast forward 30 years later, Rivera looks up to Zeller as an inspirational mentor, friend and colleague.
“Dr. Zeller exhibits qualities that we as physicians all aspire to have,” Rivera said. “Some physicians will be really good with their intellectual skills, but at the same time, their bedside skills may not be the best. He excels at all of them.”
Joseph and Catherine Reznicek’s exhausting search for their daughter’s physician ended when they met Zeller. They had dealt with so many doctors who were exceptional but very clinical. They chose Zeller because of his compassionate approach to caring for their daughter, Maranda, who suffers from a myriad of medical conditions including tuberous sclerosis, polycystic kidney disease, seizure disorders and a failed kidney transplant.
“A doctor that tells you what’s going on is one thing,” Joseph Reznicek said. “A doctor who can make you understand everything that’s going on in the darkest of hours when you feel like there is just no other options left, for him to say, ‘Yeah, there is a light at the end of the tunnel. It may be a fair way off but we are going to get there.”
Zeller’s compassion goes beyond caring for patients in the clinic.
“I started a camp for children with epilepsy called Camp Spike N’ Wave because one of my patients was rejected from a private camp because of his medical condition,” Zeller said. “This prompted me to develop a camp for disabled children who can discover life without barriers.”
Zeller collaborated with other physicians and organizations to create a barrier-free camp called Camp for All in 1993. More than $10 million was raised to build this camp which now serves more than 100,000 children with complex medical conditions each year.
“Now my kids and everybody else’s kids can go to Camp for All,” Zeller said. “It’s my way of giving back to my patients.”
After more than 40 years in medicine, what motivates Zeller to keep on going? His answer is simple: caring for his patients.
“I see some parents in the elevators now that say, “Oh, Dr. Zeller, you took care of Johnny when he was 4 years old and he is 35 and he is doing just fine,” Zeller recalled. “That’s what makes me happy. My legacy is to have compassion and treat patients well, and that is what I teach medical students and young physicians to do too.”