Please can you describe the new disease entity that you discovered on your quest to map novel human disorders related to brain development?
Our group describes a new entity, which we refer to as “Developmental Split-Brain syndrome” which we discovered affected four individuals from three unrelated families.
All affected individuals showed disruption of communicating tracts between the right and left side of the brain which meant that there is lack of coordination and communication between the two sides of the brain.
What are the main symptoms of Developmental Split-Brain syndrome and who is it thought to affect?
Developmental Split-Brain syndrome can lead to symptoms including intellectual disability, horizontal gaze palsy, mirror movements and scoliosis.
This disorder affects individuals soon after birth (and in case three, even during pregnancy) although the clinical features may not be obvious until an older age.
How much is known about the causes of the syndrome?
Developmental Split-Brain syndrome is a genetic condition caused by mutations in the gene Deleted in colorectal cancer (DCC). DCC acts as a receptor for netrin-1 and, together, guides the developing neurons to cross the midline and form connections between the two halves of the brain.
All the affected patients in our study had mutations in DCC that would lead to disruption in the activity of DCC, which led to failure of developing neurons to form these connections.
This was evident on brain imaging of the tracts in the affected individual from family two. This is similar to work done on animal models, where similar changes are seen in mice with mutations in DCC.
How does your research build on previous studies of the human Deleted in Colorectal Carcinoma (DCC) gene?
This research builds on research dating back to the early 1990s. Mutations in UNC-40 (counterpart of DCC in worms) caused these worms to move awkwardly and erratically. Similarly, severe mutations in DCC in mice led to defects in commissural tracts that were similar to what we see in our human subjects.
Milder mutations in DCC in mice (referred to as Kanga mice) led to a “hopping” gait. These previous studies help us correlate findings in our patients and aided in identifying the cause of this novel syndrome.
Are there any connections between split brains and other neurodevelopmental disorders?
Although, this condition is rare, the phenomenon of split brain has been intensely studied with implications on brain organization. There are also explicit connections between split brains and neurodevelopmental disorders, including autism and Asperger syndrome.
The findings may also have implications in improving our understanding of common disorders such as scoliosis and strabismus.
What impact do you think your findings will have?
These patients could provide interesting insights into how our brains are organized and operate on a day-to-day basis, adding to a growing body of research (including studies of patients undergoing hemispherectomy for severe epilepsy).
What further research is needed?
Identification of more patients with mutations in DCC, as well as other genes associated in this pathway, including NTN-1, will allow us to further characterise this syndrome, as well as gain deeper understanding of the underlying pathological mechanism.
How important was international collaboration to your work?
This research would not have been possible without an international collaboration. The three families were from different parts of the globe- two from the USA (one each of Caucasian and Mexican ancestry) and one from the Middle East (of Arabic ancestry).
Identification of multiple individuals from unrelated and diverse populations allows us to be more confident of our discovery. And similar efforts in discovering novel syndromes will continue to require international efforts and collaboration, especially from under-represented populations of Asia.
What do you think the future holds for patients with neurodevelopmental disorders?
In the past, poor understanding of neurodevelopmental disorders hampered effective treatment. However, recent efforts in mapping out the genetic basis of these disorders and understanding the underlying biology has allowed researchers and pharma to focus on developing drugs that target these specific pathways.
With more of such efforts, the future does look promising as there may be potential treatments for some of these neurodevelopmental disorders.
Where can readers find more information?
About Dr Saumya Jamuar
Dr Saumya Jamuar is a co-founder and co-chief scientific officer at Global Gene Corp. He is also a consultant in the Genetics Service at KK Women’s and Children’s Hospital, Singapore and serves as the Clinical Lead of the Precision Medicine Initiative and Singapore Childhood Undiagnosed Disease Programme.
He completed his Genetics Fellowship at the Harvard Medical School Genetics Training Program and worked as a post-doctoral fellow in Christopher A Walsh lab in Harvard Medical School from January 2012 - December 2013.
He is actively involved in research and has presented at both local and international meetings. He was awarded the Young Investigator Award at the American Epilepsy Society meeting for his work on targeted resequencing on patients with epileptic encephalopathy. He is also the recipient of the 2015 Singhealth Outstanding Young Researcher Award.
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