Eye movement disorders

Side view of the extraocular muscles which move the eyeball

Strabismus is misalignment of the eyes; it can severely impact quality of life and lead to partial blindness. It results from failure of the oculomotor nerves controlling eye movements to form correct connections with muscles that rotate the eyeball. Genetic mutations have been identified in some forms of strabismus however we cannot predict the clinical implications based on the mutation. Establishing links between genetic changes and human oculomotor development is essential to inform genetic counselling, prognosis and earlier, more effective intervention. The insights we gain from investigating how these nerves find their correct target will have wider application in understanding axon guidanceas a whole and how brains are wired up.

Duane Syndrome

We have begun to identify the molecular pathways responsible for eye movement disorders working with our colleagues Sarah Guthrie at King's College London and Elizabeth Engle at Harvard. There are many different forms of strabismus recognised clinically, several of which can be linked to genetic mutations. For a review see Gutowski & Chilton (2015).
We have focussed upon Duane Retraction Syndrome (DURS) which broadly refers to an inability to move the eye horizontally outwards. This motion away from the body is called abduction (i.e. to lead away), moving the eye inwards, towards the body is called adduction. In addition, upon attempted abduction the eyeball retracts, hence the full name; there are variations on this theme and anyone interested in the different forms of DURS should consult the review above or the OMIM entry (OMIM is a database of all known human mutations and the conditions they cause). The lateral rectus muscle (pink in figure above) is responsible for abducting the eye, it is innervated by the helpfully named abducens nerve, the sixth of the twelve cranial nerves.

Ab = Abducens nerve;
Oc = Oculomotor nerve;
LR = Lateral rectus muscle;
MR = Medical rectus

(Rollover) The right LR and left MR contract to look right.

(Rollover) In DURS, the abducens sends no signal to the right LR so the eye does not move.

In DURS the abducens nerve fails to grow or to reach the lateral rectus, without any input the muscle simply cannot contract. To make matters worse, it is believed that the oculomotor nerve (the third cranial nerve) can then take advantage of the vacancy and form a connection with the lateral rectus instead. This may seem like a good compensation but the oculomotor nerve also controls the medial rectus, the muscle that directly opposes the lateral rectus and adducts the eye - the result is that signals from one nerve are now simultaneously triggering an antagonistic pair of muscles. Whereas a lateral rectus with no nerve would only passively oppose the medial rectus it is now actively pulling against it.

I suspect that there may be a few ophthalmologists rolling their eyes as they read this, listing the clinical inaccuracies. Real life is indeed much more complicated, people cannot be easily pigeonholed to fit neat textbook definitions or the reductionist approach of scientists. This is why I am indebted to the advice of clinical colleagues, especially Dr. Nick Gutowski, who point out the ambiguities and variations in symptoms they encounter in the course of their work. Unfortunately I have also heard several people, who should know better, dismiss this research as unimportant because "No-one ever died from a squint." This misses the point on so many levels. Most importantly, that is of scant consolation to any individuals affected by strabismus which, irrespective of cosmetic considerations, can have a serious impact on quality of life. The other main reason why this view is misguided is that it overlooks the potential for applying a deeper understanding of the formation and maintenance of oculomotor circuits to the development of less accessible and/or more complex systems.

How does strabismus affect vision?

Strabismus is a visual disturbance and affects sight but it does not include a loss of visual acuity, the ability to detect light that does reach the eyeball. To understand how vision is affected we need to consider how it depends upon eye movements.
Light is detected by a layer of specialised cells in the retina at the back of the eyeball. The retina forms a snapshot of the world and sends this picture to the brain along with information about the motion within that image. These signals make their way through the brain to the visual cortex at the back of the head. Along the way the spatial arrangement of the image is maintained such that adjacent neurons carry adjacent parts of the image. In this way, the area that we can see, our visual field, is mapped directly onto our cortex: there is a specific area that deals with the left side of our view, another registers the righthand side and so on.
The outlines of these maps are primed by our genes but they are defined in detail by visual experience as soon as a newborn’s eyes open and continue to be refined as the child grows. Early in life the brain is plastic, it has the ability to make, break and remodel neuronal connections. As we age this ability is lost until the adult brain becomes hard-wired. There is still scope for change otherwise we wouldn’t be able to learn (or forget) things but it would be rather inconvenient if from day to day the brain ‘forgot’ how to hear, smell or move the body.
To be able to build up a map of the entire visual field the eyes must be able to move fully and scan the whole area. If this movement is restricted then parts of the visual field will not be properly represented in the cortex. Note that the map is made relative to oneself so the critical factor is whether there is a signal coming from, for instance, the left edge of the left eye. If this eye can’t adduct then this signal will be absent. In practice this can be compensated by turning the head but from the brain’s perspective there is a bit missing. Similarly, your right arm is still your right arm even if you hold it on the left side of your body. The fact you can do this and know which arm is which is a result of another map in your brain, this time of your body parts.
As the brain develops, if an area is not receiving input, in the case of strabismus from a certain part of the visual field, then when the map is formed it will not be represented. Our perception of the world depends on the processing carried out in the visual cortex so if these maps are incomplete so is our field of view.Fortunately, the brain is incredibly adaptable and carries out all sorts of corrections, of which we are normally unaware, to build up a consistent and useful picture of the world - optical illusions rely on tricking and confusing these subconscious processes. This means that in the example above the brain can use the information received by the right eye to compensate for the loss of movement in the left. However, the more the eye movements become restricted the less scope there is for the brain to fill in the gaps.

DURS and the chimaera

In 2008 we showed that mutations in the α2-chimaerin gene (CHN1) cause DURS. Chimaerin helps developing oculomotor nerves respond to axon guidance signals and grow towards the correct muscle. The chimaerin protein can be broadly divided into three functional domains which is the, admittedly rather scant, justification for naming it after the mythical hybrid of lion, goat and snake.
Having isolated the mutations in chimaerin we have the far more difficult task of establishing exactly how they exert their effects and why these appear to be restricted to the oculomotor nerve. We have identified some of the other proteins involved and begun to formulate a model to explain how CHN1 mutations lead to oculomotor defects. We use biochemistry and fluorescent microscopy to study how chimaerin interacts with these proteins to direct neuronal connections. Our work will provide novel insights into oculomotor disorders, linking them to human mutations and may identify novel therapeutic avenues.

A treatment for DURS?

In researching the developmental processes underlying DURS we have two goals. One is to understand how the miswiring arises in order to one day suggest how it may be rectified by means other than surgery. The other is to discover more about the mechanisms that direct motor nerves to form connections with the correct muscle. The two questions are inextricably intertwined. In research we never know what breakthrough might be just around the corner and what insight someone might uncover by accident or design. Despite this it is unlikely we will have a detailed answer to either question in the next decade. This is partly because science rarely advances by ‘Eureka!’ moments instead it inches forward as a result of the combined efforts of many scientists each adding a sliver of additional knowledge. Very often this forward movement only comes after a few lurches sideways or even backwards. Research is not a marathon or a sprint, it’s a drunk trying to find the light switch at the other end of the hall and sometimes we wish we’d just stayed in the pub.

The field of axon guidance has made enormous progress over the past three decades. Much of this has been to demonstrate that certain proteins can act as receptors or cues to steer growth cones, though we know very little about how they do this. Genetic techniques have enabled us to show that gene A or B is necessary for the outgrowth of nerve X or Y – CHN1 being required for oculomotor outgrowth is a case in point. What we don’t know is how to put together these signals in the correct order in space and time to form a specific connection.Stem cells are often heralded as the solution to many incurable conditions. Unlike tissues such as skin or liver, nerve cells generally lose the ability to divide and replace themselves so stem cells are a particularly attractive proposition for nervous system repair. They hold huge potential but there are a number of major hurdles to be overcome become reality matches the hype.

1. That which we call a rose.
The first is a problem of identity. Classifying a particular neuron is fraught with difficulty (see Anatomy of a neuron). It is now relatively straightforward to induce a generic ‘neuron’ from stem cells – something that would have been unthinkable barely a decade ago! – but our excitement at this should not cloud the fact that we still have a long way to go. It is even possible to turn that neuron into a motor neuron but there remains the challenge of making the correct subtype of motor neuron. It may be that we don’t need to. The idea of ‘Nature vs. Nurture’ is a central debate in human genetics and the same argument is happening at the level of neurons. Maybe it is sufficient to make a generic motor neuron and when placed in a certain environment this will respond to its surroundings and grow and behave appropriately.

2. Can't get there from here.
The second is a problem of guidance. This is an extension of the above point. Imagine that from a stem cell we make a neuron of the correct genetic identity, how do we know it will regrow the correct connections? It is true that the instructions to do this lie in its DNA but the execution of this code assumes that the developing neuron is extending its axon in a growing embryo. This is an environment far removed biochemically and physically from the adult brain we wish to repair. The sheer difference in size alone is enormous. Added to this, many of the genes that work together to direct embryonic development are silenced postnatally – which ones do we turn back on and what could be the side-effects of this?

Other research topics:

Gutowski, NJ and Chilton, JK (2015) The congenital cranial dysinnervation disorders.
Arch Dis. Child 100(7):678-681 PubMed

Ferrario JE, Baskaran P, Clark C, Hendry A, Lerner O, Hintze M, Allen J, Chilton JK, Guthrie S. (2012) Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin.
Proc. Natl. Acad. Sci. USA 109(36):14669-74 PubMed