It is important to understand first the anatomy and developmental processes to fully gauge the concepts behind the disorders. This review covers both before looking initially at the commonly encountered (individual) nerve defects, including abnormal findings, aetiology and pathogenesis (where applicable) and later, the much rarer and specific congenital cranial dysinnervation disorders, which include HGPPS, CFEOM, Duane syndrome, BSAS, ABDS, Mobius syndrome and Marcus Gunn syndrome.
There are 12 bilateral cranial nerves in humans. These carry both afferent (sensory) and efferent (motor) fibres between the brain and peripheral structures - mostly within the head and neck - where they innervate muscles or glands. All cranial nerves exit the cranium via foramina or fissures and are covered by tubular sheaths derived from the cranial meninges. They are named and numbered according to the rostrocaudal sequence in which they attach to the brain.
I - Olfactory II - Optic III - Oculomotor
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IV - Trochlear V - Trigeminal VI - Abducens
VII - Facial VIII - Vestibulocochlear IX - Glossopharyngeal
X - Vagus XI - Accessory XII - Hypoglossal
Cranial nerves carry:
Motor fibres to voluntary (striated) muscles (general somatic efferent) - e.g. muscles of mastication
Motor fibres to involuntary (smooth) muscles or glands (general visceral efferent) - e.g. the sphincter pupillae and lacrimal gland
Sensory fibres transmitting general sensation e.g. touch, pressure etc. from skin and mucous membranes (general somatic afferent)
Sensory fibres carrying sensation from the viscera (general visceral afferent) - information is gathered from the carotid body and sinus, pharynx, larynx, trachea, GI tract etc.
Fibres transmitting unique sensations - including fibres conveying taste and smell (special visceral afferent) and those involved in vision, hearing and balance (special somatic afferent).
Some nerves are purely sensory (CN I, II, VIII), others are purely motor (CN III, IV, VI, XI, XII), and several are mixed (V, VII, IX, X) with both somatic motor and somatic sensory components. It is interesting to note that nerves considered to be purely motor, including the motor root of CN V, contain a small number of sensory fibres for propioception, the cell bodies of which are probably located in the mesencepahlic nucleus of CN V (discussed later) (Moore et al., 2010). Another component of cranial nerve fibres within CN III, VII, IX, and X is presynaptic parasympathetic axons that emerge from the brainstem.
The fibres of cranial nerves connect to cranial nerve nuclei - these are the sites of attachment from which afferent fibres terminate and efferent fibres originate. The first two cranial nerves attach directly to the forebrain (see later). The nuclei of the remaining cranial nerves are located in the brainstem (see Fig 1).
Afferent nuclei of fibres carrying sensory information via the trigeminal nerve (CN V) terminate at the large trigeminal sensory nucleus, which covers the whole length of the brain stem and runs as far down as the cervical spinal cord. The other two afferent nuclei within the brainstem include vestibular & cochlear nuclei and nucleus solitarius. Fibres in the vestibulocochlear nerve involved with the special senses of hearing and motion/positional sense terminate at the cochlear and vestibular nuclei (at the level of the medulla) respectively. Visceral afferents terminate in the nucleus solitarius (medulla).
Efferent nuclei are arranged and can be divided into three discontinuous longitudinal groups according to their embryological derivation, the first of which is the nuclei of the somatic efferent cell column. It contains the nuclei of CN III - oculomotor nucleus at the level of the midbrain, CN IV - trochlear nucleus also at the level of the midbrain, CN VI - abducens nucleus located in the caudal pons and CN XII - hypoglossal nucleus in the medulla. The second column contains the nuclei of the branchiomotor cell. This includes the trigeminal motor nucleus in mid-pons - where fibres of the trigeminal nerve originate, the facial motor nucleus in the caudal pons which supplies fibres to the facial nerve, and the nucleus ambigus within the medulla which sends motor fibres in the glossopharyngeal, vagus and accessory nerves. The final group contains nuclei of preganglionic parasympathetic neurones which send axons into CN III via the Edinger-Westphal nucleus (midbrain), CN VII and IX via the superior and inferior salivatory nuclei (pons) respectively, and CN X via the dorsal motor nucleus of the vagus (medulla) (Crossman and Neary, 2005).
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Fig 1 - Cranial nerve nuclei in brainstem (http://www.instantanatomy.net/headneck/nerves/cranial/nucleiinbrainstem.html)
Cranial nerves and their common disorders/pathology
Olfactory Nerve (CN I)
This nerve is involved in the detection of smell. The receptors of this nerve are specialised, ciliated nerve cells that are located in the olfactory epithelium of the nasal cavity. Their axons give rise to central processes that are assembled into the true olfactory nerves, constituting the right and left CN I. These numerous fascicles enter the cranial cavity through the cribriform plate of the ethmoid bone and attach to the olfactory bulb (containing mitral cells) on the inferior surface of the frontal lobe. Axons from the mitral cells leave the bulb in the olfactory tract and terminate in the primary and associated areas of the cerebral cortex.
Loss of smell (anosmia) is caused by many factors; the majority of cases however can be attributed to upper respiratory infections, sinus disease and head trauma (Deems et al., 1991). Virus-related disorders include infection due to common cold, hepatitis, flu-like infections, and herpes simplex encephalitis. Such dysfunction exhibit no fluctuations over time (c.f. nasal inflammatory disorders) and can sometimes reflect damage to central olfactory structures as a result of viral invasion. Severe head injuries may lead to tearing away of the olfactory bulbs from the olfactory nerves or tearing of olfactory nerve fibres due to a fractured cribriform plate. Age is also considered to be a factor with the elderly having reduced acuity of sensation of smell. The changes in smell function are multifactorial and include ossification of the foramina of the cribriform plate (Kalmey et al., 1998) and progressive reduction of receptors due to damage from repeated insults. Frontal lobe tumours/abscess or meningiomas can also cause anosmia as they can compress the olfactory bulb/tract. A lesion in the lateral olfactory area may cause temporal lobe epilepsy characterised by false and disagreeable perceptions of smell as well as involuntary movements of the lip and tongue (Kohler et al., 2001). A number of neurodegenerative diseases have also been implicated in anosmia including Alzheimer's disease and Parkinson's disease (Doty 2009).
Optic nerve (CN II)
The optic nerve is involved in the special sense of vision. The optic nerve fibres arise from ganglion cells in the retina. The fibres leave the orbit through the optic canal to form the optic chiasm where fibres from the nasal halves of the two retinae decussate and join fibres from the temporal halves of the retina to form the optic tract. The decussation of nerve fibres is required for binocular vision and it results in the left optic tract relaying information from the right visual field and vice versa. Optic tract fibres terminate in the lateral geniculate nucleus of the thalamus from which third order visual fibres are relayed to the primary visual cortex of the occipital lobe. The remaining part of this lobe constitutes the visual association area.
The optic nerves are surrounded by extensions of the cranial meninges which extend all the way to the eyeball. This means that the myelin sheath produced by the oligodendrocytes is susceptible to the effects of demyelinating diseases of the CNS e.g. multiple sclerosis. This can lead to optic neuritis - lesions of the nerve that cause a reduction or complete loss of visual acuity. The pathogenesis is believed to be an inflammatory process which leads to activation of peripheral T-lymphocytes that cross the blood-brain barrier. This causes a delayed hypersensitivity reaction which results in axonal loss (Shams and Plant, 2009). Other causes of optic neuritis include nerve compression and occlusion of the retinal artery e.g. giant cell arteritis, trauma and toxic substances e.g. methyl alcohol, tobacco, ehtambutol. There is also the possibility of lesions occurring at other sites in the visual pathway leading to visual field defects. A defect in the optic chiasm most commonly caused by a pituitary adenoma leads to bitemporal hemianopia as it compresses the fibres decussating from the nasal half of each eye. Defects of the optic tract due to tumour or vascular accident and defects of the occipital cortex due to unilateral posterior cerebral artery infarction can lead to homonymous hemianopic defects (Ballinger and Patchett, 2007).
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Oculomotor nerve (CN III)
CN III carries the majority of somatic motor neurones that innervate four of the six extraocular muscles (superior, medial and inferior recti and inferior oblique) responsible for moving the eye and superior eyelid (levator palpebrae superioris). It also contains preganglionic parasympathetic neurones that, via the ciliary ganglion, control the smooth muscle of the sphincter pupillae. This results in constriction of the pupil and ciliary muscles, which in turn produces accommodation. Fibres from the two nuclei (oculomotor and Edinger-Westphal) emerge medial to the cerebral peduncles and lie in the lateral wall of the cavernous sinus, before entering the orbit through the superior orbital fissures. Here it divides into superior and inferior branches with the latter carrying the parasympathetic fibres to the ciliary ganglion.
Third nerve palsies can result from lesions located anywhere along the nerve pathway, and may highlight an underlying neurological emergency such as intracranial aneurysm (of a posterior cerebral or superior cerebellar artery), fracture involving the cavernous sinus, herniating uncus, giant cell arteritis (Bruce et al., 2007) and diabetes mellitus (Singh et al., 2006). Raised intracranial pressure (due to an extradural haematoma for example) can cause compression of CN III against the temporal bone. Another cause of third nerve palsy may be injury or infection of the cavernous sinus. Abnormal findings include dilated pupil, ptosis, eye turned down and out, and loss of papillary reflex on ipsilateral side.
Trochlear nerve (CN IV)
The trochlear nerve contains only somatic motor neurones which supply one extraocular muscle (superior oblique) to abduct, depress and medially rotate the eyeball. This is the only nerve to emerge from the posterior surface of the midbrain, passing anteriorly to gain ventral aspect of the brain. It lies in the lateral wall of the cavernous sinus and enters the orbit through the superior orbital fissure.
Isolated lesions of the trochlear nerve are rare (Brazis, 2009). It may be torn as a result of severe head injuries due to its long intracranial course. The patient complains of diplopia when looking down. This occurs because the superior oblique assists the inferior rectus in depressing the pupil and so directing the gaze downward. It also occurs because extorsion of the eyeball by the inferior oblique is unopposed when the superior oblique is paralysed. This results in two different anteroposterior axis of the eyes when looking down.
Abducent nerve (CN VI)
Similar to CN IV, the abducent nerve contains only somatic motor neurones which supply the last of the extraocular muscles, the lateral rectus. This muscle abducts the eye. The fibres emerge from the pons, pass anteriorly through the cavernous sinus and enter the orbit through the superior orbital fissure.
The nerve has a long intradural course. Raising the intracranial pressure (e.g. space occupying lesion such as brain tumour) can stretch or compress the nerve (Peters et al., 2002). Complete paralysis causes medial deviation of the eye due to the unopposed effect of the medial rectus, and diplopia on lateral gaze. Other causes of CN VI paralysis include aneurysm of the cerebral arterial circle, pressure from an atherosclerotic internal carotid artery and septic thrombosis of the cavernous sinus.
Combined palsies of CN III, IV and VI can also occur from lesions at sites where the nerves run close to each other e.g. the cavernous sinus, superior orbital fissure and within the orbit. The insult is usually caused by tumours, aneurysms and infections.
Trigeminal nerve (CN V)
This important nerve has both sensory and motor components, which originate from the sensory and motor nuclei, respectively. It attaches to the brain stem as a large sensory and a smaller motor root on the pons. The cell bodies of the afferent neurones are located in the trigeminal ganglion. The peripheral processes of the ganglionic neurones form three divisions: ophthalmic nerve (CN V1), maxillary nerve (CN V2) and mandibular nerve (CN V3). The trigeminal ganglion is located at the site of convergence of these three divisions. The motor axons leave the pons in the motor root, run parallel to the sensory root, bypass the ganglion and then join the mandibular nerve. Together the trigeminal nerve innervates the muscles of mastication (masseter, temporalis, lateral and medial pterygoids) and is the main sensory nerve for head (including skin of face, teeth, gingiva, mucous membrane of the nasal cavity, and paranasal sinuses).
Lesions of the trigeminal nerve include infection of the sensory roots of the trigeminal nerve (shingles). Zoster is characterized by severe, sharp, lancinating radicular pain,
and eruption of vesicles restricted to 1-3 dermatomes supplied by the division(s) of the nerve affected. After chickenpox, the virus becomes latent in cranial nerve, dorsal root, and autonomic nervous system ganglia - reactivation results in shingles (Gilden et al., 2003). Trigeminal neuralgia - affecting the sensory root of CN V - causes brief but excruciating pain usually in the area supplied by the maxillary and/or mandibular nerves. This lesion is usually a tumour, (e.g. an acoustic neuroma), or due to demyelination (e.g. multiple sclerosis) (Graff-Radford, 2009). Other causes of injury to trigeminal nerve include trauma, aneurysms and meningeal infections. It may also be involved in poliomyelitis and generalised polyneuropathy affecting several nerves. Findings include loss of pain and touch sensations, paraesthesia, and paralysis of muscles of mastication with deviation of the mandible to the side of the lesion.
Facial nerve (CN VII)
The facial nerve contains sensory, motor and parasympathetic components. It joins the brain stem at the ventrolateral aspect of the caudal pons, in a region known as the cerebellopontine angle. The nerve emerges as two divisions: the motor root and the intermediate nerve. The more medial motor root innervates the muscles of facial expression and the lateral intermediate root contains sensory and parasympathetic fibres. The sensory fibres are involved in taste sensation from the anterior two-thirds of the tongue, the floor of the mouth and palate and sensation from skin overlying part of the external ear. The cell bodies of the afferent neurones lie in the geniculate ganglion located in the facial canal of the petrous temporal bone. The fibres terminate in the nucleus solitarius. From here, fibres make contact with the sensory cortex of the parietal lobe. The motor fibres of the facial nerve originate in the facial nucleus and pass dorsally leaving the brain stem in the motor root. These fibres innervate muscles of facial expression, posterior bellies of the digastric muscle, stylohyoid and stapedius muscles, and platysma. Interestingly, the facial motor nucleus forms reflex connections through afferent fibres from other parts of the brain stem and cortex. An example of this is the reflex contraction of the stapedius muscle due to loud noise as a result of connections with the superior olivary nucleus (part of the central auditory pathway). Finally, the preganglionic parasympathetic fibres (originating from the superior salivatory nucleus) pass to the pterygopalatine and submandibular ganglia and synapse with postganglionic neurones innervating the lacrimal gland, and the sublingual & submandibular glands, respectively. The former also innervate the nasal and oral mucous membranes.
Fig 2 - Component fibres of the facial nerve and their distribution
Bell's palsy and Ramsay-Hunt syndrome are the most common diseases of peripheral facial paralysis (Nakatani et al., 2010). Evidence suggests that Bell's palsy and Ramsay-Hunt syndrome are caused by reactivation of latent viral infections- often herpes simplex virus type 1/herpes zoster virus and varicella zoster virus, respectively - from the geniculate ganglion. (Murakami et al., 1996, Holland and Weiner, 2004). A study by Furuta et al. (1992) supported the theory relating to Ramsay-Hunt syndrome. They investigated varicella zoster virus DNA in the geniculate ganglion taken from 13 autopsy cases by polymerase chain reaction (PCR). They found that none had symptoms of recent infection, but DNA was found in 9 of them (69%). Bell's palsy causes pain around the ear, paralysis of unilateral facial muscles, an inability to close the eye, an absent corneal reflex, hyperacusis and loss of taste sensation in the anterior two-thirds of the tongue.
Vestibulocochlear nerve (CN VIII)
This nerve is a special sensory nerve involved in hearing and balance. It emerges from the junction of the pons and medulla and enters the internal acoustic meatus, the point at which it separates into its two divisions. The cochlear nerve, sensory to the spinal organ for the sense of hearing, is composed of the central processes of bipolar neurones in the spinal ganglion (the peripheral processes are associated with the spinal organ). The vestibular nerve is similarly composed of the central processes of bipolar neurones but in the vestibular ganglion ganglion. The peripheral processes extend and are sensory to the cristae of the ampullae of the semicircular ducts and the maculae of the saccule and utricle, for the sense of equilibration. Within the internal acoustic meatus, this nerve is related to CN VII and the labyrinthine artery.
Peripheral lesions of this nerve often affect both hearing (loss of hearing or causing tinnitus) and balance (vertigo) due to their close relationship. Central lesions may involve just one of the divisions. The two types of deafness include conductive deafness - involves external or middle ear e.g. otitis media, and sensorineural deafness - may be due to disease in the pathway (including the nerve) from the cochlea to the brain. An acoustic neuroma (also known as vestibular schwannoma) is a benign intracranial tumour of the Schwann's cells of this nerve, which leads to its compression and that of the adjacent structures in the cerebellopontine angle. It has a low lethality rate and is of unknown aetiology (Corona et al., 2009). Currently, it is believed that a possible cause is a defect on the NF-2 gene of the chromosome 22 long arm, which is responsible for schwannonian protein production - regulator of Schwann cell division. This defect can be seen in patients with type II neurofibromatosis, but this link has not yet been proven in patients with unilateral acoustic neuromas (Fontaine et al., 1991).
Glossopharyngeal nerve (CN IX)
CN IX is mainly a sensory nerve but it also contains preganglionic parasympathetic and few motor fibres. The afferent fibres relay sensory information from the pharynx, posterior third of the tongue and the middle ear. It is also involved in the sensory information of taste buds in the pharynx and tongue, and of chemoreceptors in the carotid body and baroreceptors in the carotid sinus. Afferent fibres carrying touch information from the pharynx and back of the tongue are required for the gag reflex. This is achieved through connections with the nucleus ambiguus and the hypoglossal nucleus. The motor component of the glossopharyngeal nerve is small and innervates just one muscle, the stylopharyngeus, involved in swallowing. Visceral motor (preganglionic parasympathetic) fibres of CN IX synapse with neurones in the otic ganglion, which go on to innervate the parotid salivary gland.
Isolated lesions of this nerve are rare and do not usually cause disability. Abnormal findings can include loss of taste on posterior third of tongue and loss of sensation on affected side of soft palate. Glossopharyngeal neuralgia, similar to trigeminal neuralgia, does occur rarely. It too consists of a stabbing, lancinating pain, but at the base of the tongue or around the palate, often initiated by swallowing, protruding the tongue or touching the palatine tonsil (Bruyn, 1983)
Vagus nerve (CN X)
The Vagus nerve, like the previous nerve, contains sensory, motor and parasympathetic fibres. It attaches immediately inferior to the glossopharyngeal nerve on the lateral aspect of the medulla. The sensory fibres convey information from the pharynx, larynx, oesophagus, chemo- and baroreceptors and receptors widely distributed throughout the thoracic abdominal viscera. Receptors for general sensation end in the trigeminal sensory nucleus and visceral afferents end in the nucleus solitarius. The motor fibres innervate voluntary muscles of the larynx and superior oesophagus as well as the soft palate and larynx. The nucleus ambiguus, from which these fibres originate, is important in the control of speech and swallowing. The parasympathetic fibres innervate involuntary muscles and glands of the tracheobronchial tree and oesophagus via the pulmonary and oesophageal plexus, the heart via the cardiac plexus and the alimentary tract.
Isolated vagus nerve lesions are also uncommon. Dysphagia can be caused by an insult to the pharyngeal branches of CN X. Paralysis of the recurrent laryngeal nerve (usually from cancer of larynx and thyroid gland or surgery) can cause dysphonia and hoarseness.. Paralysis of both recurrent nerves causes aphonia and an inspiratory stridor.
Accessory nerve (CN XI)
The accessory nerve is purely motor in function. It consists of two parts. The traditional 'cranial root' is in fact a part of CN X and is united with the spinal accessory nerve for a short distance. The spinal root emerges as a series of rootlets from the upper five or six segments of the cervical spinal cord. These fibres join the cranial root briefly as it passes through the jugular foramen but separate once they exit the cranium. The spinal accessory nerves innervate the sternomastoid and trapezius muscles. The cranial component joins the vagus nerve and serves the same function as other vagal nerve fibres.
Due to its superficial passage through the posterior cervical region, CN XI is susceptible to injury during procedures such as lymph node biopsy and cannulation of the internal jugular vein. This causes paralysis of the muscles supplied by the nerve leading to drooping of shoulder.
Hypoglossal nerve (CN XII)
The last of the cranial nerves is also purely motor in function. It supplies somatic motor fibres to the intrinsic and extrinsic muscles of the tongue, serving to move and to change the shape of the tongue. The axons originate in the hypoglossal nucleus and arise by several rootlets between the pyramids and the olives of the medulla. Finally they pass through the hypoglossal canals and between the mylohyoid and the hypoglossus to reach the muscles of the tongue. Its nucleus receives afferents from other nuclei to help control the reflex movements of chewing, sucking and swallowing. It also receives fibres from the contralateral motor cortex, which help voluntary movements of the tongue e.g. in speech.
Injury to this nerve causes paralysis of the ipsilateral half of the tongue. Protruded tongue deviates toward affected side and there is also moderate dysarthria.
The lower four cranial nerves which lie in the medulla (the 'bulb') are usually affected together - isolated lesions are rare. Motor neurone disease is a chronic degenerative disorder. It leads to degeneration of the fibres projecting to the ambiguus and hypoglossal nuclei (Kernich, 2009). This can lead to pseudobulbar palsy i.e. an upper motor neurone weakness characterised by dysphonia, dysphagia, dysarthria, and weakness of the tongue. If there is degeneration of the nuclei themselves, it can lead to bulbar palsy instead i.e. lower motor neurone weakness characterised by wasting and fasciculation of the tongue in addition to the signs above (Karam et al., 2010). The four nerves can also be damaged by compression as they exit the cranium via the foramina.
Dysinnervation disorders in humans
So far, the more common acquired disorders of human cranial nerves have been described. Of course, there are a number of disorders that are caused by genetic defects. These are much rarer and consequently less is known about their aetiology, epidemiology, pathogenesis etc. One particularly interesting group of disorders termed 'congenital cranial dysinnervation disorders (CCDD) have been shown to have mutations in genes necessary for the normal development and connectivity of brainstem ocular motor neurons. The next section will look at some of the disorders within this group. However, it is important first to understand the concepts behind motor neuron patterning and axon guidance by investigating the genes that are involved in such processes.
Patterning and axon guidance of cranial motor neurons
As shown above, the cell bodies of motor neurones lie in the brainstem. Developing motor neurones need to travel long distances from the CNS to their targets in the periphery. This is set up early in development so that cranial motor neurones rest in the midbrain and hindbrain - constituting the brainstem. Here they are separated into different nuclei. The axons follow dorsal or ventral pathways from the brainstem - the axial positioning of this site of exit determining the peripheral paths. There are both rostrocaudal and dorsoventral patterning mechanisms involved which determine a specific projection of a motor neuron and its ability to differentiate (Guthrie, 2007).
The three types of motor nuclei (branchiomotor BM, visceral motor VM, and somatic motor SM) form at distinct axial levels. BM and VM neuronal somata migrate dorsally into the dorsal half of the neuroepithelium and SM somata remain ventral in the basal plate (all neurones arise in the hindbrain basal plate). BM and VM axons extend dorsally to large common exit points and SM axons exit the neuroepithelium ventrally in small groups. Individual motor nuclei can contain one or more of BM, VM and SM neuron subsets e.g oculomotor nucleus - contains SM and VM neurons. Cranial motor axons converge to form components of the cranial nerve once they exit into the periphery. BM axons travel through CN V, VII, IX, X and XI. VM axons project towards parasympathetic ganglia and SM axons are part of CN III, IV and VI.
The midbrain is divided into 'arcs' which is thought to be involved in the differentiation of nuclei - the most medial arc contains oculomotor neurons and fibroblast growth factor 8 (FGF8). This growth factor is believed to determine the position of the nucleus. Its differentiation is thought to be dependent on the homeobox gene paired-like homeobox 2a as Phox2a mutant mice were shown to have absent oculomotor neurons (Pattyn et al. 1997).
The hindbrain is divided into rhombomeres, transiently divided segments of the developing neural tube that contain repeating sets of neurons with distinct differentiation programs at different axial levels (Lumsden and Keynes, 1989), e.g. rostral rhombomere one (r1) contains nucleus IV. A number of transcription factors and genes are thought to be involved with rhombomere patterning. These include the zinc finger transcription factor early growth response 2 (EGFR2) and MAFB, which both lie upstream of, and activate transcription of Hox genes. The latter plays an important role in hindbrain patterning through the amount and timing of its expression in a particular rhombomere.
In addition to its crucial role in rostrocaudal patterning, Hox genes are believed to also control motor neuron identity. Hoxa2 is thought to regulate trigeminal motor neuron differentiation as shown by Jungbluth et al. (1999) - trigeminal neurons were generated when Hoxa2 was ectopically expressed in chick r1, which normally lack these neurons.
Combinations of other homeobox-containing transcription factors are involved in dorsoventral axis patterning. Sonic hedgehog protein (SHH) is thought to cause dose-dependent neuronal differentiation through its ventral-dorsal gradient as well as control differentiation of the midbrain arc. It is proposed to work through a complex mechanism where its signalling produces graded activity of Gli transcription factors, which then either activate or repress homeodomain protein expression in specific domains. The domains then consolidate their identity and produce neurons, which in turn produce more transcription factors for further specification. Litingtung and Chiang (2000) showed that both cranial and spinal cord were missing in SHH-/- mouse mutants, showing that SHH is involved heavily in the formation of cranial nerves. Following these events, domains such as p3 and pMN found in the hindbrain give rise to BM/VM and SM neurons, respectively. Transcription factors such as Nkx2.2 and Nkx2.9 are key regulators of BM and VM fate.
Following these programmes of patterning and specificity, the cranial motor axons must undergo extension, either ventrally or dorsally. The first step involves repulsion from the midline by the floor plate. This is done through axon guidance molecules netrin 1 and the Slit proteins. BM and VM neurons express the UNC5A receptor and the Slit receptors ROBO1 and ROBO2 which mediate the repellent effect of netrin 1 and the Slit proteins. A third Robo receptor, ROBO3, is thought to be involved in midline crossing, but might not be expressed in motor neurons (Sabatier, 2004). Little is known of the molecules that mediate the floor repulsion of SM axons. The next step, projection to the exit point, appears to require the presence of cranial sensory ganglia near the dorsal exit points for BM and VM axons. Once in the periphery, its fate is dependent on a balance of attraction (from HGF, BDNF) and repulsion (from the perinotochordal mesechyme and semaphoring including SEMA3A).
Little is known about how cranial motor neurones recognise their target structures. Warrilow and Guthrie (1999) showed that inappropriate projections of trigeminal motor neurons into the periphery were eliminated, suggesting a specific recognition between BM neurons and their targets.
Congenital cranial dysinnervaion disorders
As mentioned above, these disorders are caused by mutations in genes necessary for the normal development and connectivity of brainstem ocular motor neurons. It is characterised by complex strabismus - misalignment of the eyes causing loss of binocular vision and amblyopia (Engle, 2006). These complex strabismus syndromes include defects such as congenital fibromatosis of the extraocular muscles (CFEOM), Duane syndrome, horizontal gaze palsy with progressive scoliosis (HGPPS), Möbius syndrome and Marcus Gunn syndrome. Genes implicated in some of these syndromes include three transcription factors - HOXA1, PHOX2A and SALL4, one gene involved in axonal transport - KIF21A, and one axon guidance molecule - ROBO3.
This is a rare autosomal recessive disorder and is characterised by absent horizontal eye movements and, in addition, severe progressive scoliosis starting in infancy or childhood. Jen et al. (2004) show that it is caused by mutations in ROBO3 - required for axons to cross the midline and form commissures. Its absence in the brain stems of HGPPS patients results in a failure of the medial longitudinal fasciculus and paramedian reticular formation pathways, such as the paramedian pontine retricular formation, to cross the midline and innervate the correct target i.e. abducens and oculomotor nuclei. It is interesting to note that so few symptoms are attributable to the lack of corticospinal and dorsal column-medial lemniscus tract crossing. This suggests that these axons succeed in finding and innervating the intended targets, but on the incorrect side. Scoliosis is a relatively common disability and its link with ROBO3 mutations supports a neurogenic cause for this disorder.
This is a group of congenital syndromes that involve cranial nerve miswiring and paralysis of the extraocular muscles, often associated with drooping of the upper eyelid. The syndromes can be classified as CFEOM1 or CFEOM2 based on specific phenotypic features. CFEOM2 is characterised by bilateral ptosis with the eyes primarily fixed in an exotropic position, with or without secondary hypertropia or hypotropia (Wang et al., 1998). This eye position suggests that the oculomotor and trochlear nerves are lacking, a phenotype shared by Phox2a mouse mutants (Pattyn et al., 1997) suggesting that the human CFEOM2 phenotype results from a complete loss of function of PHOX2A - transcription factor required for the normal development of the oculomotor and trochlear nuclei. CFEOM1 characterised by nonprogressive bilateral external ophthalmoplegia and congenital bilateral ptosis with the eyes infraducted - unable to raise either eye above the horizontal midline. This is believed to occur due to mutations in the kinesin motor protein KIF21A - which is engaged in anterograde axonal transport (Marszalek et al., 1999). This leads to hypoplasia of the oculomotor nerve and occasionally the abducent nerve.
This is a congenital eye movement disorder that is characterised by a limitation of abduction and narrowing of the palpebral fissure and retraction of the globe on adduction. Duane syndrome accounts for about 5% of patients presenting with strabismus (Appukuttan et al., 1999). Postmortem studies by Hotchkiss et al. (1980) of two patients with DS have demonstrated hypoplasia of the sixth nerve nucleus and absence of the sixth nerve on the affected side. In some cases (Duane syndrome type 2 -DURS2) the oculomotor nerve innervates the lateral rectus muscle. This is similar to the pattern seen in Hoxa3- and Hoxb3-mutant mice, which also lack the abducent nerve and an unknown nerve branches abberantly into the lateral rectus muscle. A number of potential loci have also been identified including chromosome 2q31, 8q13, 4q and 22q. However, there is no clear evidence to link a gene with DURS2.
Okihiro syndrome is a variant of Duane syndrome that is associated with cervical spine and radial ray abnormalities and deafness. It has an autosomal dominant mode of inheritance. This disorder has been mapped to chromosome 20q13, with mutations identified in SALL4- a zinc finger transcription factor (Kohlhase et al., 2003).
Bosley-Salih-Alorainy syndrome and Athabascan brainstem dysgenesis syndrome
Tischfield et al. (2005) found a new recessive congenital cranial dysinnervation disorder syndrome, named Bosley-Salih-Alorainy syndrome (BSAS). It is characterised by bilateral Duane syndrome in addition to congenital sensorineural deafness, malformations of the internal carotid arteries and in some case, autism or mental retardation. This syndrome is similar to Athabascan brainstem dysgenesis syndrome (ABDS), but patients may also have central hypoventilation, mental retardation, in addition to facial weakness, vocal cord paralysis, and conotruncal heart defects. (Holve et al., 2003). They occur due to mutations in the HOXA1 gene found on chromosome 7. The phenotypes reported in the two Hoxa1-/- mouse models are similar to the BSAS and ABDS syndromes. The mice have abnormal rhombomere segmentation with errors in neural patterning of the hindbrain, resulting in aberrant abducent development. This suggests that these disorders result from an error in hindbrain segmentation. Phenotypic variability between the two disorders may be due to genetic and/or environmental differences in populations.
Mobius syndrome is a rare congenital disorder caused by abnormal cranial nerve development, resulting in paralysis of facial muscles and sixth nerve palsy. Other abnormalities include limb malformations, dental anomalies as well as other cranial nerve palsies. A postmortem study by Lammens et al. (1998) demonstrated brainstem abnormalities including hypoplasia of the CN VI, VII and XII and/or their nuclei. Although mostly sporadic, Mobius syndrome may be inherited in an autosomal dominant, autosomal recessive, and X linked fashion. Potential gene loci include chromosome 3q23 and the gene SOX14 has been suggested as a possible candidate gene due to its chromosomal localisation to 3q23, and its expression in the apical ectodermal ridge (Michaelides and Moore, 2004). No mutations have been identified thus far.
Marcus Gunn syndrome
Also known as jaw-winking syndrome, this disorder is characterised by elevation or depression on chewing and/or suckling. It is thought to be the result of aberrant innervation of branches of CN III and V.
The 12 cranial nerves are important structures within the head. Each nerve has the potential to be the victim of an insult or injury - congenital and acquired. The phenotypes of the individual nerve defects can vary tremendously and serve as a demonstration of the vast role and influence of each cranial nerve.
The manner in which the fates of these nerves are decided is truly astounding. Great progress has been made thus far in understanding the processes before and during nerve formation. Such information has proven to be invaluable in uncovering the aetiology of the much rarer disorders such as congenital cranial dysinnervation disorders.
However, it must be noted that despite the great advancements neuroscience has made over the last few decades, there is still a sizeable gap in our knowledge. There are many individual cranial nerve defects which have unknown aetiology and/or pathogenesis e.g. Ramsay-Hunt syndrome (latter applies). Within the congenital disorders, there is even more room for research. Through better understanding of, for example, guidance cues, information regarding patterning will become clearer possibly leading to the aetiology of currently unknown disorders (such as Marcus Gunn syndrome).
Developmental neurobiology is an exciting field as its research will have many ramifications for human health. As more information is gathered through various studies on animal models about signalling cascades and pathfinding strategies of the cranial nerves, we will become better equipped to address the related clinical problems.