Fibrosis Of Extraocular Muscles, Congenital, 3a, With Or Without Extraocular Involvement
A number sign (#) is used with this entry because of evidence that congenital fibrosis of extraocular muscles-3A (CFEOM3A) with or without extraocular involvement is caused by heterozygous mutation in the TUBB3 gene (602661) on chromosome 16q24.
For a general phenotypic description and a discussion of phenotypic and genetic heterogeneity of CFEOM, see CFEOM1 (135700).
Mutation in the TUBB3 gene can also cause complex cortical dysplasia with other brain malformations (CDCBM; 614039), a more severe disorder of aberrant neuronal migration and disturbed axonal guidance resulting in mental retardation.
DescriptionCongenital fibrosis of the extraocular muscles (CFEOM) encompasses several different inherited strabismus syndromes characterized by congenital restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. If all affected members of a family have classic CFEOM with bilateral involvement and inability to raise the eyes above midline, the phenotype is classified as CFEOM1 (135700). CFEOM2 (602078) shows autosomal recessive inheritance. CFEOM3 is characterized by autosomal dominant inheritance of a more variable phenotype than classic CFEOM1. Individuals with CFEOM3 may not have bilateral involvement, may be able to raise the eyes above midline, or may not have blepharoptosis (reviews by Yamada et al., 2004 and Heidary et al., 2008).
Yamada et al. (2003) concluded that CFEOM3 is a relatively rare form of CFEOM.
Genetic Heterogeneity of CFEOM3
The CFEOM3 phenotype is genetically heterogeneous; see also CFEOM3B (135700), caused by mutation in the KIF21A gene on chromosome 12q12, and CFEOM3C (609384), which maps to chromosome 13q.
Clinical FeaturesKhodadoust and von Noorden (1967) described a family in which a bilateral vertical retraction syndrome was present in 2 of 5 sibs. Although ocular motility was normal in the remainder of the family, 1 of the children with the vertical retraction syndrome and 1 without had incomplete situs inversus of the optic nerve head. The clinical features of the vertical retraction syndrome were similar to those of Duane syndrome (126800), although they affected different muscles.
Doherty et al. (1999) identified a large Canadian family with CFEOM. Affected individuals were born with a nonprogressive eye movement disorder characterized by variable expression of ptosis and restrictive external ophthalmoplegia. Severely affected individuals had ptosis, primary gaze fixed in a hypo- and exotropic position, and marked restriction of eye movement bilaterally. Mildly affected individuals had normally positioned globes with a limitation of vertical gaze. Moderately affected individuals had asymmetric involvement with one eye severely and one eye mildly affected.
Gillies et al. (1995) described a family in which members of 3 generations (and by implication a fourth) showed complete loss of vertical ocular movement but largely free horizontal movement except for variable restriction of adduction in some affected members. A variable degree of ptosis was present, ranging from gross to none, but with poor levator function and an absent Bell phenomenon in all affected members. All showed superficial keratopathy, many with corneal scarring. Ocular alignment, refractive error, and amblyopia were variable. Computed tomographic scan indicated reduction in size of the extraocular muscles, particularly the superior recti with intracranial ventricular asymmetry in 3 of 5 patients examined, and abnormality in shape of the eye globes in 2 patients. There was one instance in which an affected male had 2 affected sons. In general, the pedigree was consistent with autosomal dominant inheritance. Mackey et al. (2002) restudied the family of Gillies et al. (1995). In affected individuals, the primary position of the eyes was vertically neutral (not infraducted) with secondary exotropia or esotropia. Vertical movements were absent, horizontal movements were variably restricted, and forced duction testing was positive for restriction. Ptosis ranged from bilaterally severe to absent. Thus, the phenotype of this family met the criteria for CFEOM3. Computerized tomography demonstrated a reduction in size of the extraocular muscles, most marked in the superior rectus.
Congenital Fibrosis of Extraocular Muscles 3A with Extraocular Involvement
Tischfield et al. (2010) reported 17 unrelated families and 12 unrelated individuals with CFEOM3 caused by heterozygous mutations in the TUBB3 gene (see, e.g., 602661.0001-602661.0005). The pedigrees included those reported by Abeloos et al. (1990), Doherty et al. (1999), Gillies et al. (1995), Mackey et al. (2002), and some by Yamada et al. (2004). Fifteen of the families and some of the single patients had a phenotype consistent with isolated CFEOM3. However, 14 families, including most of the individual patients with a sporadic disorder, had additional neurologic symptoms, including facial weakness, axonal peripheral neuropathy, contractures of the wrist and fingers, delayed development, and learning disabilities. Some patients had abnormalities on brain imaging, including dysgenesis of the corpus callosum, dysgenesis of the anterior commissure, dysmorphic basal ganglia, and hypoplasia of the internal capsule. In 1 family, several mutation carriers had isolated peripheral neuropathy without CFEOM. The findings expanded the clinical phenotype associated with CFEOM3, and with TUBB3 mutations in particular. Tischfield et al. (2010) concluded that these 'TUBB3 syndromes' result from a common defect in axonal guidance during development, which can result in additional neurologic involvement.
InheritanceThe transmission pattern of CFEOM in a large Canadian family reported by Doherty et al. (1999) was compatible with autosomal dominant inheritance with variable expression and probable incomplete penetrance.
Mackey et al. (2002) concluded that the CFEOM phenotype in the family reported by Gillies et al. (1995) segregated as an autosomal dominant trait with full penetrance.
MappingBy linkage analysis of a Canadian family with CFEOM, Doherty et al. (1999) found linkage to markers on chromosome 16q24.2-q24.3. The maximum lod score of 5.8 occurred at markers D16S3063 and D16S689, and the CFEOM3 disease gene was located within a region of approximately 5.6 cM flanked by D16S486 and D16S671. Doherty et al. (1999) hypothesized that CFEOM3 results from a defect analogous to, but distinct from, that of CFEOM1.
Mackey et al. (2002) restudied the family of Gillies et al. (1995) and demonstrated that the phenotype not only satisfied that of CFEOM3 but also that it mapped to the FEOM3 locus on 16q, with a maximum lod score of 6.0, between D16S498 and 16qter.
Molecular GeneticsTischfield et al. (2010) identified 8 different heterozygous mutations in the TUBB3 gene (see, e.g., 602661.0001-602661.0005) in affected individuals with autosomal dominant or sporadic congenital CFEOM3 (CFEOM3A). The most common mutation, R262C (602661.0001), was identified in the families reported by Doherty et al. (1999), Gillies et al. (1995), and Mackey et al. (2002). Approximately half of the patients had isolated CFEOM3, whereas the other half had additional neurologic involvement, including facial weakness, delayed development, peripheral axonal sensorimotor neuropathy, contractures of the wrist or fingers, and dysgenesis of the corpus callosum. In vitro functional expression studies, mutant mouse studies, and yeast studies by Tischfield et al. (2010) showed that the mutations all resulted in altered microtubule dynamics and stability, and some showed various loss of kinesin microtubule interactions. There were some genotype/phenotype correlations: those with the E410K (602661.0005) and D417H (602661.0003) mutations had a severe phenotype with additional features, including facial weakness and learning disabilities, whereas those with the D417N (602661.0004) mutation had peripheral neuropathy and hypoplasia of the corpus callosum, and those with the common R262C (602661.0001) mutation had isolated CFEOM. Overall, the findings were consistent with defects in axonal guidance, suggesting that the TUBB3 gene is critical for normal microtubule dynamics, axonal guidance, and brain development.