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

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.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.Congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DS) are complex strabismus disorders that present with congenital restrictive ophthalmoplegia with or without ptosis. These disorders were traditionally believed to reflect primary structural extraocular muscle (EOM) anomalies and have been referred to as 'congenital fibrosis syndromes' [1]. Neuropathology studies of DS [2,3] and one form of CFEOM (CFEOM1) [4], and the identification of ARIX as the gene mutated in a second form of CFEOM (CFEOM2) [5], however, support our hypothesis that CFEOM results from maldevelopment of the oculomotor (nIII) and/or trochlear (nIV) nuclei and DS results from maldevelopment of the abducens (nVI) nucleus. The continued definition of these phenotypes and identification of the underlying disease genes will assist clinical diagnostics and lead to a better understanding of the unique developmental features of the oculomotor lower motor neuron unit.Although several distinct CFEOM phenotypes have been defined [6-8], each likely resulting from maldevelopment of a unique combination of alpha motor neurons in nIII and/or nIV, most reports of CFEOM families describe a stereotypical clinical phenotype. The affected members