By Tim Edwards – QBI

I am a medical student doing a PhD in Linda Richards’ Lab and am one of the authors of a review on dysgenesis of the corpus callosum (DCC). Dysgenesis of the corpus callosum includes complete and partial agenesis and thinning (hypoplasia) of the corpus callosum. I have written a brief summary of this paper, which is an up-to-the-minute review of what we know about DCC and corpus callosum development; it also establishes the first classification system for syndromes with DCC. A syndrome is where the corpus callosum is affected plus something else.

This may be another disorder in other regions of the brain or in other organ systems. Some syndromes are very rare, but they are identified when more than one person presents with exactly the same or very similar set of problems. There are also people where only the corpus callosum is affected as an isolated problem. Currently there are no known genes published for this group of people and so these are not covered in our review which focuses only on syndromes with DCC.

Linda’s lab has been interested in the corpus callosum for several reasons. First, the formation of the corpus callosum during development is a very complex process that can help us to understand broader principles of how the brain develops. Second, one of the most remarkable features of DCC is the variability in how it can affect brain function. Part of our research is aimed at understanding why some people with DCC can be so severely affected, others are high functioning. To do this, we have engaged with Australian adult DCC patients who have generously donated their time to become involved in our studies. Third, there are many people who have been diagnosed with DCC, and potentially many more who either have not yet been diagnosed, or who have been told later in life that they have DCC. Much of the problem is that DCC can be difficult to identify, and even if it is diagnosed, it can be difficult to predict how it will affect cognitive functions. We’re hoping to provide more information on this issue through our research.

Put simply, we want to know:

1. How does the corpus callosum form normally?
2. How does the wiring of the corpus callosum relate to a person’s cognitive abilities?
3. Why does the corpus callosum fail to form in some people?
4. How is connectivity of the brain altered in DCC, and can this account for some of the challenges faced by these individuals?

 

Answering these questions will, in the future, enable myself and other clinicians to more easily diagnose DCC early in development or shortly after birth, and provide information to parents about how they can expect this to affect their child’s development. In the future, we hope that what we are discovering will lead to the development of therapies for people with DCC.

The spectrum of disorders associated with the corpus callosum is vast, and we needed a way to bring all this information together in one place to help inform doctors and scientists. We wrote this review to methodically outline the features of all known DCC syndromes, and to correlate these with their genetic cause. We expect this to make it easier for clinicians to perform a diagnosis, and provide counselling for people with DCC syndromes and their families. We separated the genetic causes of DCC into two categories: small mutations that affect a single gene, and large deletions or duplications in a person’s DNA (called copy number variants) that can affect multiple genes.

Another way to classify DCC syndromes is to group them according to what developmental event might be disrupted that caused the DCC. We found that the genes that are affected in individuals with be classified according to the stage in development of the brain that we know they are associated with. If we know what stage of development is affected in a person with DCC, in the future we may be able to make reasonable predictions as to how their behaviour and learning maybe affected. These groups of genes are:

1. Neuronal and glial proliferation genes – one of the earliest steps in brain development is the generation of the cells that will make up the adult brain (neurons and glia). Problems in generating these cells can cause DCC, and more severe brain problems.

2. Midline patterning genes – the corpus callosum is a midline structure and for it to form initially, the midline of the brain must be properly developed and ready for axons to pass through it. Otherwise, these axons will stall at the midline. These disorders lie on a spectrum of severity from isolated DCC to a severe condition called holoprosencephaly, which often causes stillbirth.

3. Genes affecting neuronal migration and specification – once neurons are born, they have to migrate to where they are needed. If they fail to, grey matter can end up in the wrong places (called grey matter heterotopia). Once neurons have reached their correct target, they send out axons which will target other areas of the brain depending on which genes they express. Disorders in neuronal migration are often associated with epilepsy, Lissencephaly (a “smooth brain‟ that lacks the normal foldings) and intellectual disability.

4. Axon guidance genes – one of the big questions of brain development is how axons that arise from neurons and form the “white matter‟ of the brain know where to grow during development. Many of these genes code for proteins that diffuse into the space surrounding axons, and signal for axons.

5. Genes affecting synapse development–once the axons travel through the brain to their “target‟ region, they have to make contact with the neurons that reside there. This process is remarkably exact, and several molecules have been shown to be important. It is, however, still not well understood.

A helpful way to think of these genes is to imagine neurons in the developing brain as a car driving from one place to another. If Group 1 genes are affected, there is no car to travel in. Group 2: the highway is undergoing construction and no traffic can get through. Group 3: the car has broken down in the garage. Group 4, the signposts are wrong and the car ends up in a completely different place. Group 5: the car makes it all the way to its destination but the driver’s friend won’t let her inside the house.

Unlike these single gene mutations, copy number variants are much larger deletions or duplications that can stretch across many genes; they are usually entirely normal, but can also result in syndromes if important gene(s) are affected. These are a particularly important area of current research, as improved detection methods mean that many new syndromes resulting from specific deletions or duplications of regions of DNA are being found. Some genes within these regions are promising candidates for causes of DCC, but other regions are poorly understood. To understand which genes within these regions are important for corpus callosum development, more people with these syndromes must be identified and their copy number variants mapped so that we can find the affected gene/s that are common to all.

We think this is an exciting paper because it is one of the first to report that DCC syndromes can be recognized based on what developmental process is likely to be disturbed, and it sets the stage for future discoveries in DCC research. We also hope that it will provide a useful summary for clinicians, people with DCC and their families who wish to know more about the condition. I hope this summary was useful. Please email me if you have any questions or queries about our research.