CONGENITAL FIBROSIS OF THE EXTRAOCULAR-MUSCLES TYPE-2, AN INHERITED EXOTROPIC STRABISMUS FIXUS, MAPS TO DISTAL 11Q13

The extraocular fibrosis syndromes are congenital ocular-motility diso rders that arise from dysfunction of the oculomotor, trochlear, and ab ducens nerves and/or the muscles that they innervate. Each is marked b y a specific form of restrictive paralytic ophthalmoplegia with or wit hout ptosis. Individuals with the classic form of congenital fibrosis of the extraocular muscles (CFEOM1) are born with bilateral ptosis and a restrictive infraductive external ophthalmoplegia. We previously de monstrated that CFEOM1 is caused by an autosomal dominant locus on chr omosome 12 and results from a developmental absence of the superior di vision of the oculomotor nerve. We now have mapped a variant of CFEOM, exotropic strabismus fixus (''CFEOM2''). Affected individuals are bor n with bilateral ptosis and restrictive ophthalmoplegia with the globe s ''frozen'' in extreme abduction. This autosomal recessive disorder i s present in members of three consanguineous Saudi Arabian families. G enetic analysis of 70 individuals (20 affected individuals) reveals li nkage to markers on chromosome 11q13, with a combined LOD score of 12. 3 at the single nonrecombinant marker, D11S1314. The 2.5-cM CFEOM2 cri tical region is flanked by D11S4196/D11S4162 and D11S4184/1369. Two of the three families share a common disease-associated haplotype, sugge sting a founder effect for CFEOM2. We hypothesize that CFEOM2 results from an analogous developmental defect to CFEOM1, one that affects bot h the superior and inferior divisions of the oculomotor nerve and thei r corresponding alpha motoneurons and extrascular muscles.