Congenital monocular elevation deficiency associated with a novelTUBB3gene variant

Abstract

BackgroundThe genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality.MethodsTwo brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members.ResultsBoth affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell’s phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of TUBB3 revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of β-tubulin and is one of three putative kinesin binding sites.ConclusionWe show that familial MED can arise from a TUBB3 variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for TUBB3 mutation screening.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles

“…The pedigrees and characteristics of individuals diagnosed with CFEOM are shown in Figure 1 A and Supplementary Table S1 , respectively. The phenotypes and genotypes associated with families F1 [ 8 ] and F4 [ 15 ] and subject S1:II-1 [ 4 , 16 ] have previously been described.…”

“…Affected subjects in F1 had significant intra-familial clinical variability and each harbored a heterozygous TUBB3 mutation (c.1263G > C, p.Glu421Asp) [ 8 ]. Subject F1:I-1 had bilateral blepharoptosis, left esotropia, and bilateral restriction on elevation ( Figure 1 B); however, both his children (F1:II-1 and F1:II-2) had unilateral restriction without ptosis ( Figure 1 B) [ 8 ].…”

“…CFEOM3 is inherited in an autosomal dominant manner and arises from TUBB3 or TUBB2B mutations [ 5 ]. Recently we have reported that congenital monocular elevation deficiency, or double elevator palsy, can be part of CFEOM3 and arise from TUBB3 mutations [ 8 ].…”

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

“…Affected individuals frequently present additional neurological signs and symptoms in addition to mental abnormalities in CFEOM-3 [ 12 ]. Recently, Thomas et al suggested that some patients diagnosed with congenital monocular elevation deficiency could be included in CFEOM-3 [ 13 ]. CFEOM-4, also known as Tukel syndrome, is characterized by a CFEOM-3 phenotype plus hand oligodactyly [ 14 , 15 ].…”

TUBB3 M323V Syndrome Presents with Infantile Nystagmus

“…The limitation of eye movement in CFEOM3 patients is so various that they range from no or mild to severe ophthalmoplegia and may also show a unilateral or asymmetric presentation [ 21 ]. Interestingly, a recent study showed that the TUBB3 gene variant could cause congenital monocular elevation deficiency [ 22 ]. MCD includes lissencephaly (agyria–pachygyria), polymicrogyria or polymicrogyria-like cortical dysplasia, and cortical gyral simplification.…”