NORD gratefully acknowledges N.J. Gutowski, MD, Consultant Neurologist and Associate Professor, Royal Devon and Exeter Hospital and University of Exeter Medical School, Exeter, UK, for assistance in the preparation of this report.
The three types of Duane syndrome present as follows:
Duane syndrome Type 1: The ability to move the affected eye(s) outward toward the ear (abduction) is limited, but the ability to move the affected eye(s) inward toward the nose (adduction) is normal or nearly so. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when looking inward toward the nose (adduction). When looking outward toward the ear (abduction), the reverse occurs.
Duane syndrome Type 2: The ability to move the affected eye(s) inward toward the nose (adduction) is limited, whereas the ability to move the eye outward (abduction) is normal or only slightly limited. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when the affected eye(s) attempts to look inward toward the nose (adduction).
Duane syndrome Type 3: The ability to move the affected eye(s) both inward toward the nose (adduction) and outward toward the ear (abduction) is limited. The eye opening narrows and the eyeball retracts when the affected eye(s) attempts to look inward toward the nose (adduction).
Each of these three types has been further classified into three subgroups designated A, B, and C to describe the eyes when looking straight (in primary gaze). In subgroup A, the affected eye is turned inward toward the nose (esotropia). In subgroup B, the affected eye is turned outward toward the ear (exotropia), and in subgroup C, the eyes are in a straight primary position.
Different clinical types may be present within the same family, suggesting that the same genetic defect may produce a range of clinical presentations.
The most common clinical presentation is Type 1 DS (78 percent of cases) followed by Type 3 (15 percent) and Type 2 (7 percent). Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral). Approximately 80-90 percent of cases are unilateral. Of the unilateral cases, the left eye is more often affected (72 percent). Amblyopia (reduced visual acuity in an eye) due to a lack of binocular vision occurs in about 10% of DS cases and is more common in familial autosomal dominant CHN1 gene familial cases.
Duane syndrome is usually an isolated finding (approximately 70 percent), but may be associated with other malformations. Major anomalies associated with DS can be grouped into five categories: skeletal, auricular (having to do with the ears), ocular (having to do with the eyes) and neural (having to do with the nervous system) and renal (having to do with the kidneys and urinary tract).
DS can also be associated with other well-defined syndromes. These include Okihiro’s, Wildervanck, Holt-Oram, Goldenhar and Möbius syndromes.
The majority of Duane syndrome cases are sporadic in origin, with only approximately ten percent of patients showing a familial pattern (running in families). Both dominant (most common) and recessive forms of DS have been documented. In some families with dominant DS, it has skipped a generation (shown reduced penetrance) and ranged in severity within the same family (shown variable expressivity). Most familial cases are not associated with other anomalies.
DS is a Congenital Cranial Dysinnervation Disorder (CCDD), see earlier. Genetic, and possibly environmental factors, are known to play a role.
Data to support abnormal development of cranial nerve VI (abducens nerve) in DS come from neuropathological, neuroradiological, and neurophysiological evidence. Neuropathological evidence comes from autopsies of individuals with DS. Such autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence of the abducens nerve (cranial nerve VI), which normally supplies the lateral rectus muscle. In place of the abducens nerve was a nerve branch from the oculomotor nerve (cranial nerve III), which normally supplies other ocular muscles. Recent neuroradiological studies in DS support the postmortem findings and also show, by magnetic resonance imaging (MRI) studies, an absence of the abducens nerve (cranial nerve VI).
Neurophysiological evidence for neuronal involvement in DS comes from electromyographic (EMG) studies, which show that the medial and lateral recti muscles are electrically active in individuals with DS. When individuals with DS attempt to move their eyes inward, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening narrowing.
Genetic linkage studies of two large DS families (with affected members having type 1 and/or type 3 DS inherited autosomal dominantly) without associated abnormalities established the location of a DS gene on chromosome 2. Mutations in the CHN1 gene are the cause, hyperactivating a2-chimaerin, and mutations have been found in further families.
A genetic cause for individuals with DRRS (Duane radial ray syndrome; Okihiro Syndrome), that is Duane syndrome (unilateral or bilateral) with a skeletal change of radial dysplasia (unilateral or bilateral) ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide cases), has been found. Other features include deafness, renal and ocular manifestations. Inheritance is autosomal dominant. Truncating mutations and SALL4 gene deletions have been identified in DRRS families, there is haploinsufficiency (the level of the protein is not sufficient for normal functioning). No SALL4 gene mutations were found in 25 sporadic cases of isolated DS.
DS can also be found as part of a complex autosomal recessive disorder that can include deafness, facial weakness, vascular malformations and leaning difficulties due to homozygous mutations in the HOXA1 gene.
In addition, cytogenetic results (a study of chromosomes) of individuals with Duane syndrome and other abnormalities have, in rare cases, shown abnormalities that suggest other locations for genes responsible for causing DS. Deletions of chromosomal material on chromosomes 1, 4, 5 and 8, and the presence of an extra marker chromosome thought to be derived from chromosome 22, have been documented in DS individuals. In addition DS has been reported with chromosomal duplications.
Given the evidence that DS results from an absence of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some cases, it is thought that DS results from a disturbance of normal embryonic development by either a genetic or an environmental factor at the time when the cranial nerves and ocular muscles are developing (between the third and sixth week of pregnancy).
Duane syndrome has been seen in diverse ethnic groups. The frequency of DS in the general population of individuals with eye movement disorders (strabismus) is approximately one to 5 percent. Most individuals are diagnosed by the age of 10 years. The female to male ratio of individuals with DS is approximately 60:40, showing a slightly higher preponderance of female patients.
When the presence of DS is suspected, a thorough ocular (eye) examination is required, with special attention to the presence of other ocular or systemic malformations. Measurements of the ocular misalignment, ocular range of motion, head turn, globe (eyeball) retraction, palpebral fissure (eye opening) size, upshoots and downshoots and visual acuity are indicated. In addition, an examination of the cervical (neck) and thoracic (chest) spine, palate (roof of mouth), vertebrae, hands, and a hearing test is recommended to rule out disorders associated with DS.
The standard management of Duane syndrome may involve observation, treatment of amblyopia (such as patching of the better seeing eye) or possibly surgery. The goal of surgery is the elimination or improvement of an unacceptable head turn, the elimination or reduction of significant misalignment of the eyes, the reduction of severe retraction, and the improvement of upshoots and downshoots. Surgery does not eliminate the fundamental abnormality of innervation and no surgical technique has been completely successful in eliminating the abnormal eye movements. Simple horizontal muscle recession procedures, vertical rectus muscle transposition procedures, or combinations of the two may be successful in improving or eliminating head turns and misalignment of the eyes. The choice of procedure must be individualized.
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