OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel FRMD7 Splice Mutation c.1050 ؉5GϾA Arif O. Khan, MD; Jameela Shinwari, MSc; Latifa Al-Sharif, BSc; Dania S. Khalil, BSc; Nada Al Tassan, PhD Objective: To determine the genotype underlying sus- was identified in the 2 affected brothers and in the 3 asymp- pected X-linked infantile nystagmus in a family and to tomatic women only. Allele sharing analysis further con- correlate genotype with clinical examination in poten- firmed that the aunt’s phenotype was not related to the tial female carriers. FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known Methods: Ophthalmic examination (ophthalmic, or- CFEOM genes (KIF21A, PHOX2A, TUBB3). thoptic, optokinetic [OKN] drum, and electrophysi- ologic when possible) and candidate gene analysis. Conclusions: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consis- Results: Two affected brothers had infantile nystagmus tent with the concept of infantile nystagmus being an ab- with no evidence of associated visual or neurological normally increased pursuit oscillation. Further studies disease. The symptomatic maternal aunt had infantile are required to determine the reproducibility of this po- nystagmus in addition to congenital fibrosis of the ex- tential female carrier sign. Rather than being FRMD7 re- traocular muscles (CFEOM) (bilateral hypotropia, exo- lated, nystagmus in the maternal aunt represented a sec- tropia, ptosis, almost complete ophthalmoplegia, and ond disease in this family, likely related to CFEOM. poorly reactive pupils). A sister, the mother, and the ma- ternal grandmother—all 3 of whom were asymptomatic— Clinical Relevance: Clinicians can use the OKN drum had delayed corrective saccades (prolonged pursuit) dur- to assess obligate female carriers in a family suspected ing OKN drum testing. A brother and the father—both of of having X-linked nystagmus. whom were asymptomatic—had unremarkable examina- tion findings. A FRMD7 splice variant (c.1050ϩ5GϾA) Arch Ophthalmol. 2011;129(7):936-940 YSTAGMUS IS AN EYE MOVE- For familial idiopathic infantile nystag- ment control system ab- mus without associated ocular or neuro- normality characterized logical disease, X-linked inheritance is the by rhythmic involuntary most common inheritance pattern.3,4 Since to-and-fro ocular oscilla- mutation in FRMD7 (FERM domain- tions that can occur with or without asso- containing 7; OMIM 300628) was identi- N 1 ciated visual or neurological disease. Al- fied as a cause for X-linked infantile nys- though nystagmus is most accurately tagmus (OMIM 310700) in 2006,5 at least characterized by waveform analysis, such 40 causative mutations have been de- analysis is not readily available to most oph- scribed, although the specific function of thalmologists.2 Clinicians can describe nys- the gene remains unknown.4,6 As is true for tagmus as jerk (with a fast phase and a slow X-linked disease in general, FRMD7- related nystagmus tends to occur in men. Affected women have been reported more Video available online at commonly in pedigrees with nontruncat- Author Affiliations: Division of www.archophthalmol.com ing mutations as opposed to truncating mu- Pediatric Ophthalmology, King tations, possibly owing to a dominant- Khaled Eye Specialist Hospital phase) or pendular (with apparent equal ve- negative effect of the abnormal protein in (Dr Khan); and Department of locity of the to-and-fro movements).1 In jerk Genetics, King Faisal Specialist the former and nonsense-mediated mRNA Hospital and Research Center nystagmus, directionality (right, left, up- decay (and therefore lack of abnormal pro- 3,4 (Drs Khan and Al Tassan, and beat, downbeat) are based on the fast phase, tein product) in the latter. In addition, Mss Shinwari, Al-Sharif, and although it is the slow phase that is con- skewed X-inactivation toward the mutant Khalil), Riyadh, Saudi Arabia. sidered pathological.1 allele can sometimes be observed in af- ARCH OPHTHALMOL / VOL 129 (NO. 7), JULY 2011 WWW.ARCHOPHTHALMOL.COM 936 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Corrected on July 21, 2011 I:1 I:2 DXS1047 202.1/196 c.8472C > T C/T c.1050 + 5G > A G/A c.1530T > C T/C DXS691 156.5/154.5 II:1 II:2 II:3 II:5 II:6 II:7 II:8 DXS1047 202.1/198.4 c.8472C > T C/C c.1050 + 5G > A G/G c.1530T > C T/T DXS691 156.5/156.5 DXS1047 202.1 DXS1047 198.3/196 c.8472C > T C c.8472C > T C/T c.1050 + 5G > A G c.1050 + 5G > A G/A II:4 II:9 c.1530T > C T c.1530T > C T/C DXS691 154.5 DXS691 156.5/154.5 III:1 III:2 III:3 III:4 III:5 DXS1047 202.1/198.3 196 198.3 196 c.8472C > T C/T T C T c.1050 + 5G > A G/A A G A c.1530T > C T/C C T C DXS691 154.5/154.5 154.5 156.5 154.5 Figure 1. Family pedigree of FRMD7 showing 3 generations and allele-sharing results. The mutant allele is in red, normal alleles are in black. Arrows point to the individuals who participated in this study. fected women.7-9 To the best of our knowledge, prior stud- sis, exotropia, poorly reactive pupils, and almost com- ies have not assessed asymptomatic female carriers of plete ophthalmoloplegia.11 Congenital fibrosis of the FRMD7 mutation for potential eye movement control sys- extraocular muscles type 3 (OMIM 600638) is an asym- tem abnormalities by tools readily available to clinicians metric variable form of CFEOM that typically does not in- such as the optokinetic (OKN) drum.3,4 As a near target, volve the pupils and can be due to heterozygous muta- the alternating black-and-white strips of the OKN drum tion in TUBB3 (Tubulin beta-3; OMIM 602661)13,14 or stimulate smooth pursuit toward the direction of rotation KIF21A. There are rare reports of patients with CFEOM and a rapid-onset corrective horizontal saccades in the op- with obvious neurological disease15 but none to our knowl- posite direction. There is one prior study10 that assessed edge with documented constant nystagmus.11-15 asymptomatic female FRMD7 mutation carriers for OKN The purpose of this study is (1) to determine the un- abnormality but not by OKN drum testing. That study, derlying genotype for apparent X-linked infantile nys- which assessed OKN using rear projection screens or liq- tagmus in a family with 2 affected brothers and 1 symp- uid crystal display monitors as a stimulus and eye move- tomatic maternal aunt and (2) to correlate the genotype ment waveform analysis as an endpoint, reported that some with clinical examination and clinical OKN drum test- asymptomatic female carriers showed abnormality. ing in potential female carriers. There is higher incidence of strabismus in patients with FRMD7-related nystagmus than the general popula- METHODS tion10; however, the cranial dysinnervation disorder con- genital fibrosis of the extraocular muscles (CFEOM) is not associated with FRMD7 mutation, and infantile nystag- CLINICAL EVALUATIONS mus is not associated with CFEOM.11 Congenital fibrosis of the extraocular muscles is a rare form of congenital in- The family of 2 affected male siblings with possible X-linked comitant strabismus caused by orbital dysinnervation.12 infantile nystagmus was invited to participate in this prospec- Congenital fibrosis of the extraocular muscles type 1 tive genetic study, which was approved by our institutional re- (OMIM 135700), due to heterozygous mutation in KIF21A view boards. Family history was significant for similar “shak- (kinesin family member 21A; OMIM 608283), is charac- ing eyes” in a maternal aunt and uncle, one of whom (the aunt) also had large-angle obvious congenital strabismus with lim- terized by bilateral ptosis, exotropia, hypotropia, and al- ited voluntary eye movements since birth. Available family mem- most complete ophthalmoloplegia. Congenital fibrosis of bers (Figure 1) participated after informed consent: the 2 af- the extraocular muscles type 2 (OMIM 602078), due to fected brothers (III:2, III:4), the symptomatic maternal aunt (II: homozygous mutation in PHOX2A (paired-like homeo- 5), the unaffected sister (III:1), an unaffected brother (III:3), box 2a; OMIM 602753), is characterized by bilateral pto- the 2 unaffected parents (II:4, II:9), and the unaffected mater- ARCH OPHTHALMOL / VOL 129 (NO. 7), JULY 2011 WWW.ARCHOPHTHALMOL.COM 937 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Corrected on July 21, 2011 nal grandmother (I:2). Participants underwent comprehen- cycloplegic refraction were unremarkable. Findings of sive ophthalmic and orthoptic examination by a pediatric oph- electroretinography and visual evoked potentials were thalmologist; the examination included detailed slitlamp within reference limits. Patient III.2 was a 10-year-old examination to exclude signs of albinism and foveal hypopla- ϩ boy with 20/40 visual acuity in either eye. He preferred sia. Visual acuity was measured using a 10-diopter occluder a moderate right face turn, mild left head tilt, and mild over the contralateral eye. Pursuit and saccades were specifi- cally assessed by OKN drum testing (Model 450; Ophthal- chin depression. Moderate amplitude conjugate pendu- medica Ltd, Winchester, England) at near horizontally and ver- lar nystagmus was observable in the forced primary po- tically in both directions. Full-field electroretinography and sition (Video 1; http://www.archophthalmol.com) and visual evoked potentials were performed in the affected broth- other gaze positions without significant change, al- ers and the unaffected mother according to International So- though the preferred head position suggested dampen- ciety for Clinical Electrophysiology of Vision standards.16 ing with that head position.