■Congenital cranial dysinnervation disorders (CCDDs) are a group of neurodevelopmental diseases of the brainstem and the cranial nerves.

■Endogenic or exogenic disturbances lead to a primary dysinnervation of structures supplied by cranial nerves. Motility disturbances and potentially structural changes occur.

■Secondary dysinnervation occurs if fibers of other cranial nerves innervate the primarily misinnervated structures. Synkinetic movements or cocontractions of antagonists result and may lead to structural changes in the muscles involved.

■Neurogenetic studies proved congenital fibrosis of the extraocular muscles (CFEOM), isolated and

syndromic forms of Duane syndrome and horizontal gaze palsy with progressive scoliosis (HGPPS) to be related to mutations in genes that play a role in brainstem and cranial nerve development.

■By clinical features and theoretic considerations some forms of congenital ptosis,congenital fourth nerve palsy, Möbius syndrome and Marcus Gunn jaw winking phenomenon are understood as CCDDs.

■Other congenital disturbances of ocular motility with fibrotic features such as congenital Brown syndrome, congenital monocular elevation palsy and vertical retraction syndrome may be discussed as CCDDs.

7.1Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders

Electromyographic, clinicopathologic, neuroradiologic and genetic studies changed the view upon some congenital ocular motor disorders dramatically during the last decades [1–8].

Many of them that were formerly understood as congenital structural anomalies of the extraocular muscles [9] can now be explained as consequent to disorders in brainstem or cranial nerve development.

Neurogenetic studies and amongst them particularly those of the workgroup of E. Engle improved our understanding of classic representatives of congenital eye motility disorders such as congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome [2, 3, 6, 10–15, 21, 22]. In familial cases, mutations were found in genes that play crucial roles in

cranial nerve development. The typical motility patterns in these diseases and the muscular anomalies can now be explained as changes secondary to incomplete, absent or paradoxical innervation of the eye muscles.

7.1.1The Concept of CCDDs: Ocular Motility Disorders as Neurodevelopmental Defects

With the term congenital cranial dysinnervation disorders (CCDDs) coined in 2002 [16] a new entity was established that convincingly encompasses di erent congenital, nonprogressive diseases sharing etiopathologic features.

The underlying concept postulates a defect in the prenatal development of the neuronal structures supplying innervation of the cranial region.

As to the nature of this defect, primary genetic disorders in the neurodevelopmental plan or exogenic influences are a possibility.

So it has to be stressed that although by genetic investigations in familial cases of congenital cranial dysinnervation single gene defects could be found to be responsible for hereditary forms of CCDDs the mechanism by which

7congenital cranial dysinnervations may occur is not necessarily genetic. Nevertheless, the proof that mutations in genes playing a role in brainstem development are causative for the phenotypes of CCDDs was important to elicit the neurodevelopmental nature of the disorders.

Whether the cause of a single disorder in cranial nerve development is genetic or exogenic, the consequences of lack of innervation of the target muscles are common features: the underaction of the nonor underdeveloped cranial nerve is referred to as primary dysinnervation, which may lead to secondary fibrotic changes in the target muscles. Substitutional innervation of the target muscles by cranial nerve fibers originally destined for other muscles is referred to as secondary dysinnervation, in these cases paradoxical and sometimes synkinetic and cocontractive motility patterns result.

As CCDDs of ocular motility namely the development of the third, fourth and sixth cranial nerves and the formation of brainstem structures involved in ocular motor control are of interest.

A brief summary of the steps involved in proper development of the brainstem structures supplying ocular motility may indicate di erent stages at which hazardous influences can induce specific lesions.

7.1.1.1Brainstem and Cranial Nerve Development

From the first induction of neural tissue in the developing organism to the proper innervation of an extraocular eye muscle by a cranial nerve a lot of consecutive steps have to be taken that depend on the inborn genetic plan for development and on the conditions in the surroundings of the organism.

Major steps are anterior–posterior patterning of the neural system as well as dorsal–ventral patterning, segmentation with formation of brainstem nuclei, axon sprouting and axon guidance requiring neuronal interaction with chemoattractants and chemorepellents that interact with axonal receptors and guide the axonal growth cone away from or toward the midline and toward the target muscle.

Some genes involved in these developmental processes are highly conserved during the development of species. That is why insight into the developmental plans of invertebrates helps us to understand the developmental steps in mammals.

The role of so called homeobox genes that form a genomic sequence that is encoding developmental steps in anterior–posterior patterning and segmentation is a

prominent example for this. The hox homeobox cluster encoding sequential processes of di erentiation both in time and space has been studied in the genome of Drosophila melanogaster. In mammals related sequences that encode di erent steps in hindbrain di erentiation are identified on four chromosomes thus multiplying the information for single developmental steps [17–19].

Genes for axonal guidance are preserved through the species as well and that is why basic research in this field is helpful to understand disease mechanisms in CCDDs.

A good example is the interaction between slits and netrin as proteins expressed in the midline of the nervous system and growing neurons that express receptors that interact with them. Generally proteins of the slit group act as repellents from the midline and netrin acts as an attractant. In the hindbrain an intricate interplay between slits and the receptors of the robo-group and dcc that is a netrin receptor guides growing axons either away from or across the midline. Further guidance molecules are the semaphorins and ephrins, which interact with various receptor complexes [17–20].

By now we have only narrow insight into some of the genetically determined interactions in normal cranial development. Future investigations with linkage analysis in familial disorders and investigations targeting on candidate genes are likely to elucidate the role of further genes in these processes.

Hitherto mutations in six genes are identified as causative in CCDDs, more gene loci are mapped. Two genes are involved in the pathologic process in CFEOM [21, 22], most probably interacting in axon function and nuclear formation, three genes up to now are found mutated in different subgroups of Duane retraction syndrome [6, 10, 23, 24]. The example of the di erent mutated genes causing Duane retraction syndrome shows that the interference with di erent steps of development may lead to similar phenotypes: one gene is a homeobox gene controlling the development of one hindbrain segment: one gene is a presumed transcription factor and one gene seems to regulate axonal outgrowth in cranial nerves. One gene is found mutated in a complex disorder of horizontal gaze, termed horizontal gaze palsy with progressive scoliosis (HGPPS), this gene encodes for one of the transmembrane receptors in the slit-robo interaction [15].

7.1.1.2Single Disorders Representing CCDDs

Congenital Fibrosis of the Extraocular Muscles (CFEOM)

CFEOM was described already in 1879 by Heuck [25]. This disorder drew the attention of Elizabeth Engle to the

entity of ocular motility disorders [2] and in 2001 it was the first congenital eye motility disorder in which a gene relevant in cranial nerve development was identified to be mutated in familial cases [21].

Clinically, CFEOM is characterized by gross motility disorders and sometimes paradoxical motility [26–28] in eye muscles and in the lid muscle that are supplied by the third cranial nerve and in some forms by the third and fourth cranial nerves (Fig. 7.1). According to clinical traits, three subgroups have been described, and a recent review [29] covers these disorders.

CFEOM1 is an autosomal dominant anomaly characterized by bilateral ptosis and bilateral elevation deficiency of the eyes, both leading to a compensatory chin-up head posture. Intraoperatively passive motility is found to be restricted, and especially the elevation of the globe is hindered. Clinicopathologic studies showed fibrous changes in the eye muscles that formerly led to the assumption that the disorder was primarily myogenic. More recent neuropathologic studies revealed abnormalities in the inferior part of the oculomotor nucleus and absence of the superior part of the nerve and hypoplasia of the target muscles of this nerve, which are the superior rectus and the levator palpebrae [14]. With mutations found in the gene KIF21A [22] in families with this disorder, it could be shown that alterations in a kinesin promoting axonal transport processes in neurons play an etiopathologic role in CFEOM1. Thus clinic, pathologic and genetic findings are consistent in this disorder with the notion of a primary defective innervation in the muscles usually supplied by the superior part of the third nerve, stemming from neurons located in the inferior part of the third nerve nucleus. The fibrous changes in the noninnervated muscles can be understood as secondary changes due to noninnervation of the muscle fibers.

Fig. 7.1 Patient with bilateral congenital fibrosis of the extraocular muscles (CFEOM). After bilateral inferior rectus recession, the patient still adopts a 10° chin-up head posture to fixate due to ptosis and residual elevation deficiency

CFEOM2 is inherited in an autosomal recessive mode; features are bilateral ptosis and an exotropia with adduction deficiency and varying disorders in vertical alignment and motility. In this entity a lack of innervation both of the third and the fourth cranial nerves is presumed [2, 29].

Mutations in the gene ARIX/PHOX2A have been found in several pedigrees. From animal experiments it can be derived that ARIX is necessary for proper third and fourth nerve development [21, 29, 30].

CFEOM3 is an autosomal dominant disorder with varying penetrance and varying symptoms including unilateral or bilateral ptosis and motility deficiencies of the muscles usually supplied by the third nerve. KIF21A has been found mutated in this phenotype but there seems to be a heterogeneous genetic background because linkage analyses in di erent families also indicate other genetic loci. Clinical overlap with congenital motility disorders classified as vertical retraction syndrome is possible [31, 32].

Duane Retraction Syndrome

Duane retraction syndrome represents the most frequent and the most prominent congenital cranial dysinnervation disorder (CCDD). In 1905 Alexander Duane published a paper titled “Congenital deficiency of abduction, associated with impairment of adduction, retraction movements, contraction of the palpebral fissure and oblique movements of the eye” [33]. This title still gives the full description of the main features of the syndrome known today as Duane or retraction syndrome (Fig. 7.2).

In primary gaze, esotropia is the most common finding but a considerable number of patients are orthotropic and about 20% are exotropic [34]. Many patients adopt a head posture to maintain binocular single vision. Although this constellation of ocular motility disorders had been described earlier by others, it was the merit of Alexander Duane to set up a large series of own and published cases, thus accumulating the data of 54 patients.

The early etiopathologic theories put forward mainly focused on mechanical changes in the horizontal rectus muscles. In 1959, Breinin performed electromyographic examinations in Duane retraction syndrome and found no potential in the lateral rectus muscle on abduction but a response in the lateral rectus on intended adduction [1]. Thus a paradoxical innervation of the lateral rectus was realized.A further milestone were clinicopathologic studies by Hotchkiss and Miller who found absent sixth nerves in Duane retraction syndrome and confirmed pathologic findings by Mantucci dating from 1946 where a hypoplastic sixth nerve nucleus and absence of the sixth nerve were described. Miller showed that lateral rectus innervation was taken over by fibers of the third nerve [4, 7, 8].

Fig. 7.2 Patient with Duane syndrome in the left eye. Near alignment in primary gaze (b), adduction deficiency and downward

7movement on right gaze (a), abduction deficiency on left gaze (c). Lateral view of the globe on left gaze (d), retraction of the globe on right gaze (e)

a

b

c

d

e

Neuroradiologic studies later on also diagnosed hypoplasia of the sixth nerve in Duane syndrome [35–37].

In a thorough review De Respinis [34] gives data on demographic and epidemiologic features of the disease. Duane syndrome is estimated to account for 1–4% of strabismus cases. Pooled data of major studies showed a predilection of left eyes with 59%; 23% occurred in the right eye and 18% were bilateral cases. Sixty percent of the patients were female.

The spectrum of associated nonocular findings encompasses miswiring syndromes as Marcus Gunn phenomenon and crocodile tears, vertebral anomalies as the Klippel-Feil anomaly and hearing problems. Syndromes encompassing Duane syndrome are Wildervanck or cer- vico-oculo-acoustic syndrome with Duane syndrome, sensorineural deafness and the Klippel-Feil anomaly as traits and Okihiro syndrome that combines Duane syndrome with radial ray anomalies.

An induction of Duane syndrome by teratogens is possible; some patients with thalidomide embryopathy su er from unior bilateral Duane syndrome [34, 86].

The first mutation to be identified as causative for Duane retraction syndrome was found in patients with familial Okihiro syndrome or Duane radial ray syndrome (DRRS) [6, 10] in SALL4, a gene that encodes a transcription factor. The molecular mechanisms by which Duane syndrome and radial anomalies are induced are not yet clear. In sporadic cases of Duane syndrome up to now no mutations in SALL4 were found [39].

In the recently described Bosley-Salih-Alorainy syndrome (BSAS), bilateral Duane syndrome combines variably with sensorineural deafness, carotid artery malformations, delayed motor development and sometimes autistic disorders. The syndrome is inherited in an autosomal recessive mode. In di erent pedigrees, mutations

in HOXA1 were found to be causative [2, 38, 40, 41]. HOXA1 encodes one homeobox gene that is important for hindbrain segmentation. Individuals su ering from the Athabascan brainstem dysgenesis syndrome (ABDS), a sporadic disorder that beyond the traits of BSAS causes central hypoventilation, mental retardation and varying accompanying signs including cardiac anomalies and facial weakness were found to have homozygous HOXA1 mutations.

In patients with isolated Duane anomaly, no abnormalities in the HOXA1 gene were found [38, 42].

The third gene involved in the genesis of Duane syndrome is CHN1. It has been found mutated in several pedigrees with familial Duane syndrome inherited as a dominant trait [23]. Clinically these patients displayed not only reduced abduction and the pattern of often bilateral Duane syndrome but also some abnormalities in the vertically acting eye muscles innervated by the third nerve. The gene CHN1 encodes a2-Chimaerin, a protein that plays a role in the information flow induced by ephrin and ephrin-receptor interaction that leads to growth cone changes influencing the guidance of a growing axon [44]. In a chick in ovo model, it could be shown that changes comparable with those induced by the gain of function mutations found in CHN1 lead to incomplete outgrowth of ocular motoneurons [23].

The current pathophysiologic concept for Duane syndrome putting together clinical, electrophysiologic, clinicopathologic, neuroradiologic and genetic findings looks upon the disorder as a CCDD in which innervation of the lateral rectus by sixth nerve fibers is not full or absent and third nerve fibers, mainly those primarily intended for the medial rectus take over some innervation of the lateral rectus. Thus, in primary position the underlying paresis is partly or fully compensated for the lateral rectus