Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Functional and structural outcomes following lensectomy for ectopia lentis.

PURPOSE: High refractive errors and optical aberrations reduce vision when the lens edge bisects the pupil. We studied outcomes of eyes with ectopia lentis following lensectomy. METHODS: Charts of 11 consecutive patients with bilateral ectopia lentis who underwent lensectomy-anterior vitrectomy in at least one eye from 1985 to 2004 were reviewed. Eighteen eyes were operated. One eye was excluded due to short-term follow-up (<2 years). RESULTS: Mean age at surgery was 7.7 years (2 to 17 years). Median follow-up after lensectomy was 10 years (range 2 to 16 years). Six eyes were followed for 6 to 10 years, and another six eyes were followed for 11 to 16 years. Patient diagnoses included Marfan syndrome (nine eyes), ectopia lentis et pupillae (three eyes), simple ectopia lentis (two eyes), homocystinuria (two eyes), and sporadic spherophakia (one eye). Preoperative best-corrected visual acuity (BCVA) ranged from 20/60 to light perception, and postoperative BCVA ranged from 20/20 to 20/100 (14 eyes were at least 20/30). Complications included posterior vitreous detachment (two eyes, 12%), glaucoma (one eye, 6%), transient ocular hypertension (one eye, 6%), wound dehiscence with iris incarceration (one eye, 6%), transient vitreous hemorrhage (one eye, 6%), and peripheral anterior synechiae (one eye, 6%). No retina detached. CONCLUSIONS: Our cohort of patients with long-term follow-up shows that pars plana lensectomy can be successful in restoring vision when conservative measures fail.

CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX.

BACKGROUND: To learn about the molecular etiology of strabismus, we are studying the genetic basis of 'congenital fibrosis of the extraocular muscles' (CFEOM). These syndromes are characterized by congenital restrictive ophthalmoplegia affecting muscles in the oculomotor and trochlear nerve distribution. Individuals with the classic form of CFEOM are born with bilateral ptosis and infraducted globes. When all affected members of a family have classic CFEOM, we classify the family as a CFEOM1 pedigree. We have previously determined that a CFEOM1 gene maps to the FEOM1 locus on chromosome 12cen. We now identify additional pedigrees with CFEOM1 to determine if the disorder is genetically heterogeneous and, if so, if any affected members of CFEOM1 pedigrees or sporadic cases of classic CFEOM harbor mutations in ARIX, the CFEOM2 disease gene. RESULTS: Eleven new CFEOM1 pedigrees were identified. All demonstrated autosomal dominant inheritance, and nine were consistent with linkage to FEOM1. Two small CFEOM1 families were not linked to FEOM1, and both were consistent with linkage to FEOM3. We screened two CFEOM1 families consistent with linkage to FEOM2 and 5 sporadic individuals with classic CFEOM and did not detect ARIX mutations. CONCLUSIONS: The phenotype of two small CFEOM1 families does not map to FEOM1, establishing genetic heterogeneity for this disorder. These two families may harbor mutations in the FEOM3 gene, as their phenotype is consistent with linkage to this locus. Thus far, we have not identified ARIX mutations in any affected members of CFEOM1 pedigrees or in any sporadic cases of classic CFEOM.