Research Lab

Engle Laboratory

Learn about Duane syndrome

DURS2 locus
DURS1 locus

Research: Duane syndrome

Duane syndrome (DS) is an eye movement disorder present at birth (congenital) characterized by a limited ability to move an eye inward towards the nose (adduction), outward towards the ear (abduction), or in both directions. In addition, when the affected eye(s) move inward towards the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases when the eye attempts to look inward, it moves upwards (upshoot) or downwards (downshoot).

Similar to CFEOM, Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the subclassification of incomitant strabimsus (misalignment of the eyes which varies with gaze directions) and subheading of extraocular muscle fibrosis syndromes (conditions associated with restriction of both active and passive movement of the eyeball). Although "muscle fibrosis" suggests that syndromes under this heading are primary disorders of muscle, evidence suggests that DS (and other Congenital Cranial Dysinnervation Disorders-CCDD's) may actually be primary disorders of nerve innervation21, 22

Clinical classification and description

Duane syndrome is often clinically subdivided into three types: 1-3. Different clinical types may be present within the same family suggesting that the same genetic defect may produce a range of clinical presentations4.

Duane syndrome Type 1: The ability to move the affected eye(s) outward towards the ear (abduction) is limited, but the ability to move the affected eye(s) inward towards the nose (adduction) is normal or nearly so. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when looking inward towards the nose (adduction). When looking outward towards the ear (abduction) the reverse occurs.

Duane syndrome Type 2: The ability to move the affected eye(s) inward towards 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 globe when the affected eye(s) attempt to look inward towards the nose (adduction).

Duane syndrome Type 3: The ability to move the affected eye(s) both inward towards the nose (adduction) and outward towards the ear (abduction) is limited. The eye opening (palpebral fissure) narrows and the eyeball retracts when the affected eye(s) attempt to look inward towards the nose (adduction).

Each of these three types can be further classified into three subgroups designated A, B, and C to describe the eyes when looking straight (in primary gaze)1. In subgroup A the affected eye is turned inward towards the nose (esotropia). In subgroup B the affected eye is turned outward towards the ear (exotropia), and in subgroup C the eyes are in a straight primary position.

The frequency of DS in the general population of individuals with eye movement disorders (strabismus) is approximately 1-5%1. Most individuals are diagnosed by the age of 10 years5. The most common clinical presentation is Type 1 DS (78%) followed by types 3 and 2 (15% and 7% of cases, respectively)1. Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral); approximately 80% of cases are unilateral1,5. Of the unilateral cases, the left eye is more often affected (72%). The female to male ratio of individuals with DS is 60:40, showing a slightly higher preponderance of female patients1,3,5.

Duane syndrome is usually an isolated finding (approximately 70%), but may be associated with other malformations1,3,5,6. Major anomalies associated with DS can be grouped into four 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). DS can also be associated with other well-defined syndromes. These include Okihiro syndrome (Duane syndrome with radial ray anomalies)7, Wildervanck syndrome3, Holt-Oram syndrome8, Morning Glory syndrome6, and Goldenhar syndrome9.

Clinical evaluation

A thorough family history and ocular (eye) examination is conducted, with special attention to the presence of other ocular or systemic malformations. Measurements of vision (visual acuity), the ocular misalignment, ocular range of motion, head turn, globe (eyeball) retraction, palpebral fissure (eye opening) size, and up- and downshoots 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 DS3,13.

Genetics

Both genetic and environmental factors are likely to play a role in the development of Duane syndrome. The majority of Duane syndrome cases are sporadic in origin with only approximately 2-5% of patients showing a familial pattern (running in families)10, and large families are rarely reported. Both dominant 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)11,12. Most familial cases are not associated with other anomalies1.

The first gene for Duane syndrome was identified by members of our laboratory in 2002. This was not for isolated Duane syndrome but for Duane syndrome with radial ray anomalies, a disease that was found to map to Chromosome 20. SALL4 was identified as being the causative gene for the disorder24.

Genetic linkage studies of a single large family with isolated DS has established the location of a DS gene on chromosome 24, the DURS2 region. This finding was followed up with a report in 200023 of a 4-generation family with Duane syndrome in the U.K. that was linked to this locus and refined the region to an interval of 8.8-cM.

Cytogenetic results (a study of chromosomes) of individuals with Duane syndrome have, in rare cases, shown abnormalities that suggest that there may be more than one gene responsible for causing DS. Deletions of chromosomal material on chromosomes 418 and 819, and the presence of an extra marker chromosome thought to be derived from chromosome 2220 have been documented in DS individuals.

Pathology

Both neuropathologic, neuroradiologic, and neurophysiologic studies support the hypothesis that Duane syndrome results from an absence of cranial nerve VI (abducens nerve). Neuropathologic evidence comes from postmortem examinations of individuals who had DS14,15. These studies have shown an absence of cranial nerve VI and its correponding alpha motor neurons in the pons, and aberrant innervation of the lateral rectus muscle (the muscle that moves the eye outward towards the ear) by a branch of cranial nerve III. Magnetic resonance imaging (MRI) studies of an individual with DS also revealed the absence of the abducens nerve (cranial nerve VI)16. 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 (adduct), however, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening (palpebral fissure) narrowing5,10,17. These findings support the aberrant innervation of the lateral rectus muscle.

Given the evidence that DS results from an absence of the abducens nerve (cranial nerve VI) 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 3-8 weeks gestation3,10.

Standard therapies

The standard management of Duane syndrome may involve 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 downshoots3,10,17. 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.

Please contact Caroline Andrews to obtain further information on the genetic studies that we are undertaking and if you are interested in enrolling a patient or participating yourself.

References

Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last edit date 3/3/2005 (entry number 126800 and 3/18/2004 (entry number 604356). Home page: http://www3.ncbi.nlm.nih.gov/Omim/

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  3. Pfaffenbach, D., Cross, H. & Kearns, T. Congenital anomalies in Duane's retraction syndrome. Archives of Ophthalmology 88;635 (1972).
  4. Appukuttan, B. et al. Localization of a gene for Duane retraction syndrome to chromosome 2q31. American Journal of Human Genetics 65;1639-1646 (1999).
  5. Kowal, V.O. & McKeown, C.A. Duane Syndrome. International Ophthalmology32;51-62 (1992).
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  15. Hotchkiss, M.G., Miller, N.R., Clark, A.W. & Green, W.G. Bilateral Duane's retraction syndrome: A clinical-pathological case report. Archives of Ophthalmology 98;870-874 (1980).
  16. Parsa, C., Grant, E., Dillon, W.J., du Lac, S. & Hoyt, W. Absence of the abducens nerve in Duane syndrome verified by magnetic resonance imaging. American Journal of Ophthalmology 125;399-401 (1998).
  17. Hoyt, W. & Nachtigaller, H. Anomalies of ocular motor nerves. American Journal of Ophthalmology 60;443-448 (1965).
  18. Chew, C., Foster, P., Hurst, J. & Salmon, J. Duane's retraction syndrome associated with chromosome 4q27-31 segment deletion. American Journal of Ophthalmology 119;807-809 (1995).
  19. Vincent, C. et al. A proposed new contiguous gene syndrome on 8q consists of branchio-oto-renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Human Molecular Genetics 3;1859-1866 (1994).
  20. Cullen, P. et al. Association of familial Duane anomaly and urogenital abnormalities with a bisatellited marker derived from chromosome 22. American Journal of Medical Genetics 47;925-930 (1993).
  21. Engle, E. The genetics of strabismus: Duane, Moebius, and fibrosis syndromes. In Genetic diseases of the eye: a textbook and atlas.(ed. Traboulsi, E.) 477-512 (Oxford University Press, New York, 1998).
  22. Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25-27 October, 2002. Neuromuscul Disord. 2003 Sep;13(7-8):573-8.
  23. Evans JC, Frayling TM, Ellard S, Gutowski NJ. Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31. Hum Genet. 2000 Jun;106(6):636-8.
  24. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002 Nov;71(5):1195-9. Epub 2002 Oct 22.