Purpose: High-resolution orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of ocular motility abnormalities in humans with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) due to missense mutations in the developmental kinesin KIF21A.

Methods: Clinical ophthalmic and motility findings in 19 volunteers from six unrelated CFEOM1 pedigrees harboring four of the six reported KIF21A mutations and 23 normal control subjects were correlated with MRI studies demonstrating extraocular muscle (EOM) size, location, contractility, and innervation.

Results: Subjects with CFEOM1 had severe bilateral blepharoptosis, limited supraduction, and variable ophthalmoplegia. In affected subjects, MRI demonstrated atrophy of the levator palpebrae superioris and superior rectus EOMs and small or absent orbital motor nerves. The oculomotor nerve was most severely hypoplastic, but the abducens was also affected. EOMs exhibited variable atrophy and an abnormally bright T1 signal. Subjects with the R954W and R954Q substitutions frequently exhibited A-pattern strabismus, with misinnervation of the lateral rectus muscle by an oculomotor nerve branch. Rectus pulley locations were generally normal. Subjects with CFEOM1 exhibited subclinical but highly significant reduction from normal in mean optic nerve size (P < 0.001). Comparing clinical and MRI phenotypes did not reveal distinguishing features among KIF21A mutations.

Conclusions: Orbital imaging in CFEOM1 due to various amino acid substitutions in the kinesin KIF21A demonstrates consistent abnormalities of motor and sensory innervation in the orbit. These findings suggest that neuronal disease is primary in CFEOM1, with myopathy arising secondary to abnormal innervation and minimal rectus pulley abnormality secondary to reduced EOM forces.