Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations.
OBJECTIVE
Orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of motility abnormalities in congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a disorder resulting from missense mutations in TUBB3, which encodes neuron-specific beta-tubulin isotype III.


METHODS
Ophthalmic examinations in 13 volunteers from four CFEOM3 pedigrees and normal control subjects, were correlated with TUBB3 mutation and MRI findings that demonstrated extraocular muscle (EOM) size, location, contractility, and innervation.


RESULTS
Volunteers included clinically affected and clinically unaffected carriers of R262C and D417N TUBB3 amino acid substitutions and one unaffected, mutation-negative family member. Subjects with CFEOM3 frequently had asymmetrical blepharoptosis, limited vertical duction, variable ophthalmoplegia, exotropia, and paradoxical abduction in infraduction. MRI demonstrated variable, asymmetrical levator palpebrae superioris and superior rectus EOM atrophy that correlated with blepharoptosis, deficient supraduction, and small orbital motor nerves. Additional EOMs exhibited variable hypoplasia that correlated with duction deficit, but the superior oblique muscle was spared. Ophthalmoplegia occurred only when the subarachnoid width of CN3 was <1.9 mm. A-pattern exotropia was frequent, correlating with apparent lateral rectus (LR) muscle misinnervation by CN3. Optic nerve (ON) cross sections were subnormal, but rectus pulley locations were normal.


CONCLUSIONS
CFEOM3 caused by TUBB3 R262C and D417N amino acid substitutions features abnormalities of EOM innervation and function that correlate with subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical ON hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Apparent LR innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder leading to secondary EOM atrophy.
Demer
Joseph L
JL
Jules Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles, CA 90095-7002, USA. jld@ucla.edu
Clark
Robert A
RA
Tischfield
Max A
MA
Engle
Elizabeth C
EC
D000010:Abducens Nerve / Q000002:abnormalities / Q000473:pathology; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D005192:Family Health; D005260:Female; D005355:Fibrosis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009133:Muscular Atrophy / Q000151:congenital / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D009801:Oculomotor Muscles / Q000002:abnormalities* / Q000473:pathology*; D009802:Oculomotor Nerve / Q000002:abnormalities / Q000473:pathology; D015840:Oculomotor Nerve Diseases / Q000151:congenital / Q000235:genetics* / Q000473:pathology*; D009900:Optic Nerve / Q000002:abnormalities / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D014404:Tubulin / Q000235:genetics*; D014792:Visual Acuity; D055815:Young Adult
C498585:TUBB3 protein, human; D014404:Tubulin
J AAPOS. 2002 Dec;6(6):337-47
12506273
Invest Ophthalmol Vis Sci. 1998 Jan;39(1):207-12
9430565
Science. 2008 Aug 8;321(5890):839-43
18653847
Ann Neurol. 1997 Mar;41(3):314-25
9066352
BMC Genet. 2002;3:3
11882252
Am J Hum Genet. 1995 Nov;57(5):1086-94
7485159
Am J Hum Genet. 2002 Nov;71(5):1195-9
12395297
Brain. 2006 Sep;129(Pt 9):2363-74
16815872
Development. 1997 Oct;124(20):4065-75
9374403
Am J Ophthalmol. 2010 Dec;150(6):925-31
20801423
Arch Ophthalmol. 2000 Aug;118(8):1090-7
10922204
Invest Ophthalmol Vis Sci. 2007 Apr;48(4):1601-6
17389489
Nat Genet. 2003 Dec;35(4):318-21
14595441
Neuromuscul Disord. 2003 Sep;13(7-8):573-8
12921795
Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2169-78
12091413
Nat Genet. 1994 May;7(1):69-73
8075644
J AAPOS. 1998 Feb;2(1):17-25
10532362
Acta Radiol. 2002 Jul;43(4):349-53
12225473
Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2218-23
15223798
Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3380-6
15452039
Invest Ophthalmol Vis Sci. 2007 Jan;48(1):194-202
17197533
Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3787-97
11053278
Invest Ophthalmol Vis Sci. 2010 Aug;51(8):3864-73
20220051
Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5057-69
19494197
J AAPOS. 2006 Apr;10(2):135-42
16678748
Cell. 2010 Jan 8;140(1):74-87
20074521
Nat Genet. 2001 Nov;29(3):315-20
11600883
Hum Genet. 2002 May;110(5):510-2
12073023
Am J Hum Genet. 1998 Aug;63(2):517-25
9683611
Invest Ophthalmol Vis Sci. 1999 Jul;40(8):1687-94
10393037
Graefes Arch Clin Exp Ophthalmol. 1997 Sep;235(9):545-50
9342602
Neuron. 1999 Nov;24(3):555-66
10595509
Ophthalmology. 1995 Apr;102(4):607-12
7724178
Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1047-51
15037567
Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5505-11
18055799
Invest Ophthalmol Vis Sci. 2005 Feb;46(2):530-9
15671279
Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3856-65
12939301