Fibrosis Of Extraocular Muscles, Congenital, 5

A number sign (#) is used with this entry because of evidence that congenital fibrosis of extraocular muscles-5 (CFEOM5) is caused by homozygous or compound heterozygous mutation in the COL25A1 gene (610004) on chromosome 4q25.

For a general phenotypic description and a discussion of genetic heterogeneity of various forms of CFEOM, see CFEOM1 (135700).

Clinical Features

Shinwari et al. (2015) reported 3 sibs, born of consanguineous Saudi Arabian parents, with a congenital cranial dysinnervation disorder affecting the ocular muscles. The patients presented with variable abnormal ocular motility without other systemic defects. Two patients showed congenital ptosis with levator palpebrae muscle dysinnervation of 1 or both orbits. The levator palpebrae muscle is normally innervated by the oculomotor nerve (cranial nerve III). The third sib had no ptosis but presented with bilateral Duane retraction syndrome, exotropic in the right eye and esotropic in the left. This was diagnosed as dysinnervation to the lateral and/or medial rectus muscles of both eyes. The medial rectus muscle is normally innervated by inferior division of the oculomotor nerve, and the lateral rectus muscle is normally innervated by the abducens nerve (cranial nerve VI). An unrelated patient with the disorder presented with exotropic Duane retraction syndrome.

Inheritance

The transmission pattern of CFEOM5 in the family reported by Shinwari et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Saudi Arabian parents, with CFEOM5, Shinwari et al. (2015) identified a homozygous missense mutation affecting a Gly-Pro_X stretch in the COL25A1 gene (G382R; 610004.0001). The mutation, which was found by linkage analysis and candidate gene sequencing and confirmed by whole-exome and Sanger sequencing, segregated with the disorder in the family. Analysis of the COL25A1 gene in 41 additional patients with CFEOM identified compound heterozygous null mutations in 1 individual (610004.0002 and 610004.0003). Shinwari et al. (2015) hypothesized that lack of COL25A1 may adversely affect the signaling cascade involved in axon guidance, resulting in abnormal cytoskeletal microtubule dynamics and atypical ocular motor neuron development.