Summary: Researchers have identified a new syndrome caused by mutations in the DCC gene which can lead to a range of disabilities.
Source: Apollo Strategic Communications.
A new disease entity has been discovered in the quest to map novel human disorders related to brain development. The findings were published in Nature Genetics, by Dr Saumya Jamuar, co-founder of Global Gene Corp and a visiting scientist at Harvard Medical School, under the supervision of Prof Christopher Walsh and Prof Timothy Yu of Harvard Medical School.
The new syndrome, referred to as ‘Developmental Split-Brain syndrome’ is caused by biallelic mutations in the human Deleted in Colorectal Carcinoma (DCC) gene. It can lead to symptoms including intellectual disability, horizontal gaze palsy, mirror movements and scoliosis. This disorder affects individuals soon after birth (and in case 3, even during pregnancy) although the clinical features may not be obvious until an older age.
The hallmark feature of this syndrome is the distinct pattern on brain imaging, and includes agenesis of corpus callosum, absent anterior and hippocampal commissures and ventral midline brain malformations.
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.
The discovery is as a result of an international collaborative effort to study the DCC gene in three families from different regions of the globe (Mexico, USA and Saudi Arabia) who remarkably shared similar clinical and radiological features. On detailed neuroimaging, the team discovered that the central defect was lack of connection between the right and left side of the brain (technical term: disruption of midline commissural tracts).
“This work highlights the need for international collaborative work by building networks and integrating deep clinical and radiological information into research.” says Dr Jamuar. “After working on family 1, we reached out to our collaborators and were struck by the similarity between the images of family 1 and family 2. That’s when we realized that we had found a novel disease entity. The imaging, plus other findings in our patients, demonstrates that the left and right halves of the brain lack the structures necessary to talk to one another — effectively splitting it into two separate halves.”
“It was really exciting when we saw the mutation in DCC— a reunion with an old scientific friend,” says Yu, who studied the gene in roundworms as a graduate student in the 1990s. “At a symposium nearly 20 years ago, I had to explain to an audience full of parents and pediatricians how this really elementary work might relate to their children and patients with autism and ADHD. I talked about how one day we may find that the fundamental mechanisms controlling the wiring of neural circuitry could be disrupted in human neurodevelopmental disorders, too — but it was all theoretical. Finding the complete knockout now feels like it completes the circle.”
The researchers will continue to search for more such patients who may have aberrations along the same genetic pathway, and hope that their findings will help improve the understanding of how the brain develops.
Funding: This research was supported in part by the Repository Core for Neurological Disorders, Department of Neurology, Boston Children’s Hospital, and the IDDRC (NIH P30HD018655). S.S.J. is supported by the National Medical Research Council, Singapore, and the Singhealth-Duke NUS Paediatric Academic Programme Nurturing Clinician Scientist Scheme. A.M.D. is supported by the National Institute of General Medical Sciences (T32GM07753) and a National Institutes of Health Ruth L. Kirschstein National Research Service Award (5T32 GM007226-39). E.C.E.’s contributions to this work were supported by NEI R01EY12498, IDDRC grant P30 HD018655, and the Manton Center for Orphan Disease Research. C.A.W. is supported by grants from the National Institute of Mental Health (R01MH083565), the National Institute of Neurological Disorders and Stroke (R01NS032457 and R01NS035129), the Simons Foundation, and the Manton Center for Orphan Disease Research. C.A.W. and E.C.E. are supported as Investigators of the Howard Hughes Medical Institute. T.W.Y.’s contributions to this work were supported by grants from the National Institute of Mental Health (R01MH083565), the Simons Foundation, and the Nancy Lurie Marks Foundation.
NeuroscienceNews would like to thank Ishara Bhasi Callan for submitting this neurology research news directly to us.
Source: Ishara Bhasi Callan – Apollo Strategic Communications
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Original Research: Abstract for “Biallelic mutations in human DCC cause developmental split-brain syndrome” by Saumya S Jamuar, Klaus Schmitz-Abe, Alissa M D’Gama, Marie Drottar, Wai-Man Chan, Maya Peeva, Sarah Servattalab, Anh-Thu N Lam, Mauricio R Delgado, Nancy J Clegg, Zayed Al Zayed, Mohammad Asif Dogar, Ibrahim A Alorainy, Abdullah Abu Jamea, Khaled Abu-Amero, May Griebel, Wendy Ward, Ed S Lein, Kyriacos Markianos, A James Barkovich, Caroline D Robson, P Ellen Grant, Thomas M Bosley, Elizabeth C Engle, Christopher A Walsh & Timothy W Yu in Nature Genetics. Published online February 27 2017 doi:10.1038/ng.3804
Biallelic mutations in human DCC cause developmental split-brain syndrome
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor ‘deleted in colorectal carcinoma’ (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
“Biallelic mutations in human DCC cause developmental split-brain syndrome” by Saumya S Jamuar, Klaus Schmitz-Abe, Alissa M D’Gama, Marie Drottar, Wai-Man Chan, Maya Peeva, Sarah Servattalab, Anh-Thu N Lam, Mauricio R Delgado, Nancy J Clegg, Zayed Al Zayed, Mohammad Asif Dogar, Ibrahim A Alorainy, Abdullah Abu Jamea, Khaled Abu-Amero, May Griebel, Wendy Ward, Ed S Lein, Kyriacos Markianos, A James Barkovich, Caroline D Robson, P Ellen Grant, Thomas M Bosley, Elizabeth C Engle, Christopher A Walsh & Timothy W Yu in Nature Genetics. Published online February 27 2017 doi:10.1038/ng.3804