A team of researchers has discovered a new genetic disorder – developmental split-brain syndrome – characterised by agenesis of corpus callosum, underdevelopment of the brain stem, and clinical manifestations of horizontal gaze palsy, intellectual disability and scoliosis.

The syndrome is caused by homozygous mutations in the gene deleted in colorectal carcinoma (DCC), which is responsible for forming common connections, known as commissures, in the brain.

 

MISSING CONNECTIONS IN THE BRAIN

During normal fetal development, the right and left side of the brain develop independently but share commissures to allow for cross-transmission of electrical impulses. Both brain hemispheres are connected by the main and largest bundle of commissural neurons – the corpus callosum – which helps to coordinate brain function and activity, depth perception, hearing and walking in the individual.

“In contrast, individuals with developmental split-brain syndrome are born without a corpus callosum, and lack connection between the right and left sides of the brain and central nervous system from birth,” explains Dr Saumya Jamuar, Consultant, Genetics Service, KK Women’s and Children’s Hospital (KKH), who led the study during his tenure as a clinical fellow at Harvard Medical School. 

“Through a network of international collaborators, we identified three families from Mexico, the United States and Saudi Arabia, whose children remarkably shared this central defect, amongst other similar clinical and radiological features.”

   

Structural magnetic resonance imaging of the brain of the affected children showed agenesis of corpus callosum (Figure 1E) and an underdeveloped brainstem (Figure 1F), leading to a midline cleft of the medulla with an unusual but characteristic butterfly appearance (Figure 1H).

Diffusion tractography further revealed a disorganised network of not just the commissural fibres, but also the associational, and subcortical fibres (Figure 2B). Fewer fibres were visualised in the affected individuals, with particular depletion of associational and commissural fibres.  

DISCOVERING THE LINK TO THE DCC GENE

Dr Jamuar analysed the DNA of the three affected families to delineate the genetic basis of the disease, mapping it to homozygous mutations in the DCC gene.

“While the DCC gene has been demonstrated in animal models to be responsible for guiding neurons across the midline in the brain, and thus key to the formation of connecting brain tracts, no human had ever been reported with such features,” says Dr Jamuar. “These were the first known human cases.” 


IMPLICATIONS OF A SPLIT IN BRAIN ORGANISATION

Whilst rare, the phenomenon of split brain has been intensely studied with implications on brain organisation. Explicit connections between split brains and neurodevelopmental disorders, including autism and Asperger syndrome, have also been established.

“Split-brain syndrome is often seen in adults and children who have undergone surgical transection of the corpus callosum to manage refractory epilepsy. In these patients, the left and right brain behave as independent organs, developing separate concepts and impulses to act.

“This syndrome can create interesting dilemmas – where one side of the brain may favour an activity while the other side may not – providing a unique perspective into understanding how the brain functions as two separate organs,” shares Dr Jamuar.

“However, as the surgery is performed in mature brains, the effect of lack of connections between the sides of the brain from an embryological perspective is still unknown.”


IMPROVING THE OUTCOME OF PATIENTS WITH RARE GENETIC DISEASES

With the discovery of developmental split-brain syndrome, patients with symptomatic clinical and radiological features and their families can now be identified and recommended to undergo screening for mutations in the DCC gene.

An accurate diagnosis will enable affected patients and their families to be educated on the prognosis and future complications, and engaged on opportunities for management and therapeutics for the syndrome.

Biological relatives at risk of mutations in the DCC gene can also be recommended for genetic testing to confirm their genetic variant and assess their risk of inheriting the syndrome. If they are found to be carriers of this gene mutation, they can receive appropriate counselling on the implications of future reproductive decisions.

“The study findings may also have implications in improving our understanding of how the brain develops, and common disorders such as scoliosis and squint,” Dr Jamuar adds.

“We will continue to search for more patients who may have aberrations along the same genetic pathway, and look forward to discovering answers to longstanding mysteries faced by some patients and their families around the world.”


MOVING FORWARD

Since his return from Harvard Medical School, Dr Jamuar has initiated the Singapore Undiagnosed Disease Endeavour for Kids (SUREKids) programme at KKH, in partnership with Agency for Science, Technology and Research (A*STAR) and National University Hospital.

The programme has recruited over 300 families, and has successfully diagnosed more than 100 families. Some of these families have benefitted from targeted therapeutic interventions initiated on the basis of the genetic findings.

This study was led by Dr Saumya Jamuar, under the supervision of Prof Christopher A. Walsh, an Investigator of the Howard Hughes Medical Institute (HHMI) and Chief of the Division of Genetics at Boston Children's Hospital (BCH), and A/Prof Timothy Yu, Department of Pediatrics, Harvard Medical School. During the study, Dr Jamuar was a clinical fellow at Harvard Medical School and is now Consultant, Genetics Service, KKH. A paper outlining the study findings, entitled ‘Biallelic mutations in human DCC cause developmental split-brain syndrome’, was published online in Nature Genetics on 27 February 2017, in Volume 49 Issue 4 April 2017.