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Review
. 2017 Aug 1;26(R1):R37-R44.
doi: 10.1093/hmg/ddx168.

Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance

Mary C Whitman  1   2   3 , Elizabeth C Engle  1   2   3   4   5   6
Affiliations
Review

Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance

Mary C Whitman et al. Hum Mol Genet. .

Abstract

Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the β-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system.

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Figures

Figure 1
Figure 1
Anatomy of the ocular motor system. (A) Schematic of the normal anatomy of the ocular motor system. The oculomotor nerve (cranial nerve 3; green) extends from the midbrain to the orbit, where it then divides into superior and inferior divisions and innervates the SR and LPS (not shown), and the IR, MR, IO, respectively. The trochlear nerve (cranial nerve 4; blue) exits the midbrain dorsally, crosses the midline in the tectum, then innervates the contralateral SO. The abducens nerve (cranial nerve 6; pink) exits the hindbrain and innervates the LR. (B) CFEOM1 pathology. The superior division of CN3 is absent, and the nerve displays a proximal bulge formed by stalled, misdirected axons, followed by distal thinning. The SR and LPS (not shown) are hypoplastic. CN4 appears normal and CN6 has mild thinning. (C) Duane syndrome pathology. CN6 is absent, and there is misinnervation of the lateral rectus by axons of CN3. CN3, oculomotor nerve; CN4, trochlear nerve; CN6, abducens nerve; SO, superior oblique; SR, superior rectus; MR, medial rectus; IR, inferior rectus; LR, lateral rectus; IO:= inferior oblique.
Figure 2
Figure 2
Clinical photographs of CCDDs. (A) External ocular photographs in different positions of gaze of an individual with TUBB3-CFEOM3. Top row: up gaze, up-left gaze. Central row: right gaze, straight ahead, left gaze, Botton rom: down-right gaze, down gaze. Unable: photographs could not be obtained in up-right gaze, or down-left gaze. Note the prominent ptosis, limited upgaze and limited horizontal motility. This figure was published previously in (31) and copyright belongs to ARVO. (B) External ocular photographs in horizontal gaze positions of an individual with MAFB-DRS. From left to right: right gaze, straight ahead, left gaze. Note the limited abduction of each eye, and the globe retraction on attempted adduction.
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References

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