The genetic basis of incomitant strabismus: consolidation of the current knowledge of the genetic foundations of disease

Abstract

In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept of congenital cranial dysinnervation disorders (CCDDs) was introduced in 2002, and the genetic basis of CCDDs continues to be elucidated. In this review, we aim to provide an update of the genetic and clinical presentation of these disorders. Disorders reviewed include Duane syndrome (DS), HOXA1 and HOXB1 syndromes, Moebius syndrome, congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy with progressive scoliosis (HGPPS).

FIGURE 1

Motility of a patient with a KIF21A mutation. He also has aberrant innervation causing a Marcus Gun jaw wink. Reproduced with permission from Yamada, Hunter, et al., “A novel kif21a mutation in a patient with congenital fibrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon,” Arch Ophthalmol. 2005;123(9):1254–1259.

FIGURE 2

(A–E) and (G, H) Eye manifestations of patients with CFEOM3 and TUBB3 mutations. (F) and (I) Concomitant deformities of the extremities in two patients. (J) MRI of the brainstem at the level of the oculomotor nerve. (K–L) MRI of posterior orbit of a patient with TUBB3 mutation (K) compared with a normal posterior orbit (L). Reproduced with permission from Tischfield MA, Baris HN, Wu C, et al., “Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance,” Cell. Jan 8 2010;140(1):74–87. 153×207mm (300×300 DPI).

FIGURE 3

Motility of a patient with horizontal gaze palsy and progressive scoliosis. MRI of spine revealing profound scoliosis below. Reproduced with permission from Jen JC, Chan WM, Bosley TM, et al., “Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis,” Science. Jun 4 2004;304(5676):1509–1513.

FIGURE 4

MRI studies comparing normal subjects (A–C) with patients with HGPPS (D–F) at similar anatomical levels. CC – corpus callosum, P - pons, M - medulla, * - fourth ventricle. Reproduced with permission from Jen JC, Chan WM, Bosley TM, et al., “Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis,” Science. Jun 4 2004;304(5676):1509–1513. 368×235mm (72×72 DPI).