Congenital Fibrosis of the Extraocular Muscles

Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
Seminars in Ophthalmology (Impact Factor: 0.86). 08/2009; 23(1):3-8. DOI: 10.1080/08820530701745181
Source: PubMed


Congenital fibrosis of the extraocular muscles (CFEOM) is a strabismus syndrome characterized by non-progressive, restrictive ophthalmoplegia of the extraocular muscles and congenital blepharoptosis. Three clinical phenotypes for familial CFEOM (CFEOM1, 2, and 3) have been delineated, for which two genes have been identified to date: KIF21A for CFEOM1 and 3 and PHOX2A/ARIX for CFEOM2. Insights gained from molecular genetics have strengthened the hypothesis that CFEOM results from the dysinnervation of the extraocular muscles supplied by the oculomotor and/or trochlear nerves. Continued study of this syndrome should help to further elucidate the pathogenesis of eye movement disorders.

    • "No genotype–phenotype correlations have been reported that permit distinctions among MCD TUBB3 patients harboring different mutations. CFEOM is a severe congenital form of incomitant, paralytic strabismus with restricted vertical, and typically also horizontal, eye movements together with ptosis [Heidary et al., 2008; Graeber et al., 2013], and results from errors in oculomotor nerve development . CFEOM1 is primarily caused by recurrent heterozygous missense mutations in KIF21A that attenuate autoinhibition of the KIF21A kinesin anterograde motor protein and result in an isolated eye movement disorder [Yamada et al., 2003, 2005; Tischfield et al., 2010; Cheng et al., 2014]. "
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    ABSTRACT: One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Dec 2015 · American Journal of Medical Genetics Part A
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    • "The expression level of KIF21A is high in axon-rich tissues similar to KIF3A and nKHC, molecules known to participate in axonal transport (Marszalek et al., 1999; Hirokawa et al., 2010; Silverman et al., 2010). Point mutations in KIF21A were found in patients of congenital cranial dysinnervation disorders (Yamada et al., 2003; Heidary et al., 2008). Although the genetic disorder implies that KIF21A is involved in axonal transport, no neuronspecific cargo of KIF21A has been identified. "
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    ABSTRACT: We have previously shown that K(+)-dependent Na(+)/Ca(2+) exchanger (NCKX) is a major calcium clearance mechanism at the large axon terminals of central neurons, whereas their somata display little NCKX activity. We investigated mechanisms underlying the axonal polarization of NCKX2 in rat hippocampal neurons. We identified NCKX2 as the first neuron-specific cargo molecule of kinesin family member 21A (KIF21A). The intracellular loop of NCKX2 specifically interacted with the WD-40 repeats, a putative cargo-binding domain, of KIF21A. Dominant-negative mutant or depletion of KIF21A inhibited the transport of NCKX2-GFP to axon fibers. Knockdown of KIF21A caused calcium dysregulation at axonal boutons but not at somatodendritic regions. Despite the axonal polarization of the NCKX activity, both somatodendritic and axonal regions were immunoreactive to NCKX2. The surface expression of NCKX2 revealed by live-cell immunocytochemistry, however, displayed highly polarized distribution to the axon. Inhibition of endocytosis increased the somatodendritic surface NCKX2 and thus abolished the axonal polarization of surface NCKX2. These results indicate that KIF21A-mediated axonal transport and selective somatodendritic endocytosis underlie the axonal polarized surface expression of NCKX2.
    Full-text · Article · Mar 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: • Congenital ptosis typically involves reduced function of the levator palpebrae superioris muscle. • In children with congenital ptosis, amblyopia is common. • When present, amblyopia is usually refractive and caused by “inducedwith-the-rule” astigmatism. Occlusion amblyopia is much less common. • Surgical repair of congenital ptosis and other pediatric eyelid abnormalities involves procedures that require special considerations and techniques that may differ from oculoplastic surgical procedures performed on adults.
    No preview · Article · Jan 2009
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