Novel Compound Heterozygous Mutations Resulting in Cone

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seemed to be dark. The narrowing of the retinal vessels and disc 2. Kline LB, Kelly CL. Ocular migraine in a patient with cluster headaches. pallor diminished gradually over time. In the late phase of the Headache. 1980;20(5):253-257. attack (after 1 minute 28 seconds), the retinal vessels were di- 3. Winterkorn JMS, Kupersmith MJ, Wirtschafter JD, Forman S. Brief report: treatment of vasospastic amaurosis fugax with calcium-channel blockers. N Engl lated and the disc was hyperemic. Video 2 and Video 3 show J Med. 1993;329(6):396-398. the reperfusion of the retinal circulation in the late phase. The 4. Bernard GA, Bennett JL. Vasospastic amaurosis fugax. Arch Ophthalmol. images obtained immediately after the attack (Figure 2) show 1999;117(11):1568-1569. the dilated retinal vessels in the right eye. The images show that 5. Hill DL, Daroff RB, Ducros A, Newman NJ, Biousse V. Most cases labeled as the retinal veins and arteries in the right eye were more di- “retinal migraine” are not migraine. J Neuroophthalmol. 2007;27(1):3-8. lated than those in the left eye (not shown) or those obtained 6. Petzold A, Islam N, Plant GT. Video reconstruction of vasospastic transient under normal conditions 1 month after the attack. monocular blindness. N Engl J Med. 2003;348(16):1609-1610. No hypercoagulability was identified with hematologic and serologic testing. Findings on neurologic tests and magnetic Novel Compound Heterozygous Mutations Resulting resonance imaging of the brain were normal. The patient was in Cone Dystrophy With Supernormal Rod Response treated with propranolol hydrochloride because of an allergy Cone dystrophy with supernormal rod response (CDSRR) to lomerizine hydrochloride, and the retinal migraines have (RCD3B, OMIM #610356) was first described in 2 siblings by not recurred. Gouras et al1 in 1983. In subsequent reports, it has been characterized as a rare autosomal recessive retinal disorder asso- Discussion | Most cases of previously documented retinal va- ciated with a delayed and markedly decreased cone and rod sospasms have been associated with emboli or systemic response that exhibits an exaggerated, or superthreshold, rod diseases.1,3,4 Most cases reported to be retinal migraine were electroretinogram (ERG) in response to higher stimulus levels.2 cases of presumed retinal vasospasm, and this disorder is ex- Reports of CDSRR commonly describe an early onset of dys- ceedingly rare.5 Because our patient had no systemic disease chromatopsia, photophobia, and central scotoma with poor except migraine and no embolus, the attacks were likely to have best-corrected visual acuity.3 Associated signs and symp- been primary vasospasms. The images clearly show vaso- toms include nyctalopia, nystagmus, and macular retinal pig- spasm in a patient with a history of migraine with aura, which ment epithelium changes.3,4 supports the belief that retinal migraine is a distinct entity. In- Genetic studies have linked CDSRR to mutations in the po- dividual cases of transient monocular vision loss have varied tassium channel, subfamily V,member 2 gene (KCNV2), which in the main component of vasoconstriction.6 In our case, dif- is predominantly expressed in retinal photoreceptors and en- fuse narrowing of the retinal vessels may have represented de- codes a modulatory subunit of the Kv8.2 voltage-gated potas- creased blood flow in the central retinal artery, and disc pal- sium channel.4 Mutations in KCVN2 may inhibit proper as- lor and a dark choroid may have indicated decreased posterior sembly of heteromeric voltage-gated potassium channels with ciliary circulation. Therefore, we speculated that the main com- a subsequent pathologically prolonged outward potassium cur- ponent of the vasoconstriction may be the ophthalmic artery rent in the dark, causing an abnormality in photoreceptor mem- and that marked retinal vasodilation at the end and immedi- brane potentials.5 The exclusive link of CDSRR to KCNV2 mu- ately after the attack may represent compensation for hy- tations is a notable contrast from the majority of inherited poxia of the retinal tissues. retinal disorders, which display genetic heterogeneity.

Isao Ota, MD, PhD Methods | A complete ophthalmic examination by a retinal phy- Kiyomi Kuroshima, MD sician (S.H.T.) was performed, including fundus autofluores- Taiji Nagaoka, MD, PhD cence using scanning laser ophthalmoscopy (Heidelberg retinal angiograph; Heidelberg Engineering), microperimetry (MP1; Author Affiliations: Department of Ophthalmology, Asahikawa Red Cross Nidek Technologies), and spectral-domain optical coherence Hospital, Asahikawa, Japan (Ota); Department of Neurology, Asahikawa Red tomography (Spectralis optical coherence tomography/ Cross Hospital, Asahikawa, Japan (Kuroshima); Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan (Nagaoka). scanning laser ophthalmoscopy; Heidelberg Engineering). An Corresponding Author: Isao Ota, MD, PhD, Department of Ophthalmology, electrophysiological assessment was performed using the Es- Asahikawa Red Cross Hospital, 1-1 Akebono, Asahikawa, 070-8530, Japan pion 5 system (Diagnosys). Full-field electroretinograms (ERGs) ([email protected]). were recorded according to the standards of the International Published Online: September 5, 2013. Society for Clinical Electrophysiology of Vision. doi:10.1001/jamaophthalmol.2013.4686. Blood samples were genetically screened at Casey Eye In- Author Contributions: Study concept and design: All authors. stitute Laboratory, Portland, Oregon, for KCVN2 coding re- Acquisition of data: Ota, Kuroshima. Analysis and interpretation of data: Ota, Kuroshima. gion mutations that cause disease. All exons and flanking in- Drafting of the manuscript: All authors. trons of KCVN2 were directly sequenced on the ABI 3100XL Critical revision of the manuscript for important intellectual content: Ota. DNA sequencer (Applied Biosystems), and detected variants Obtained funding: Ota. Administrative, technical, or material support: Ota, Kuroshima. were analyzed for evolutionary conservation by the predic- Study supervision: Nagaoka. tion programs PolyPhen-2 and SIFT. Conflict of Interest Disclosures: None reported. 1. Humphrey WT. Central retinal artery spasm. Ann Ophthalmol. Report of a Case | A 47-year-old man presented with decreased 1979;11(6):877-881. visual acuity and a history of hemeralopia and photophobia

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Figure 1. Color Photographs, Fundus Autofluorescence Images, and Optical Coherence Tomographic Images

A B

C D

Color photographs of the right (A) and left (B) eyes demonstrate bilateral images of the right (C) and left (D) eyes demonstrate hypoautofluorescent macular atrophy (dotted inset) with pale optic nerves with peripapillary atrophy areas suggestive of central atrophy with a surrounding ring of (white arrowheads) and diffuse retinal pigment epithelial changes. There was hyperautofluorescence corresponding to lipofuscin accumulation in the retinal also a significant amount of asteroid hyalosis (black arrowhead) in the right eye pigment epithelium likely secondary to incomplete degradation of (A). These magnified images of the macula highlight the graduated atrophy photoreceptor outer segments. These autofluorescence findings correlate with corresponding to the bright deposits around the fovea in both eyes (A and B) retinal optical coherence tomographic imaging of the right (E) and left (F) eyes exhibiting a hyperreflective crystalline appearance. Fundus autofluorescence showing diffuse outer retinal atrophy bilaterally.

for several years. Medical, ocular, and family histories were un- domain optical coherence tomography revealed diffuse outer remarkable. Best-corrected visual acuity was 20/150 OD and retinal atrophy as evidenced by loss of inner segment–outer 20/100 OS. Pupils, extraocular movements, confrontational vi- segment continuity and loss of outer nuclear layer–outer plexi- sual fields, intraocular pressures, and anterior segment ex- form layer normal architecture as well as granular changes cor- amination findings were within normal limits. Color vision was responding to the hyperreflective crystalline lesions seen on diminished to 3/6 on Hardy-Rand-Rittler plates in both eyes. fundus examination (Figure 1E and F). Mean full-field ERG re- On fundus examination, there was bilateral macular atro- sults and respective stereotypical tracings showed signifi- phy with retinal pigment epithelium changes and pale optic cant delays and amplitudinal loss in the photopic cone and nerves with peripapillary atrophy (Figure 1A and B). The right 30-Hz flicker ERGs indicating generalized cone system dys- eye had moderately dense asteroid hyalosis (Figure 1A). Fun- function (Figure 2). Bipolar cell-corresponding b-waves were dus autofluorescence demonstrated bilateral patchy, central reduced compared with the photoreceptor-specific a-wave. The hypoautofluorescence surrounded by a ring of high-density hy- dim-flash, scotopic rod ERGs (0.01 candela · s/m2) showed pro- perautofluorescence in the macula (Figure 1C and D). Spectral- foundly delayed b-waves, and the bright-flash, maximum cone

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Figure 2. International Society for Clinical Electrophysiology of Vision–Standardized Full-Field Electroretinograms

A Scotopic rod Maximal 30-HZ flicker Photopic cone

0 0 0 0 100 µm 50 ms 0 0 0 0

0 0 0 0 100 µm 50 ms 0 0 0 0 The mean and typical traces in the right (A) and left (B) eyes of the C patient are shown, and electroretinograms from an age-matched control subject with results within 2 SDs of the normal mean values representative of normal traces in this age group are shown for comparison (C). In the patient, photopic cone and 30-Hz Flicker 0 0 0 0 responses were reduced and significantly delayed, the scotopic rod-specific response was delayed and reduced, and the maximal

100 µm response was notably higher and 50 ms 0 0 0 0 more prolonged compared with the normative control.

and rod ERGs (11 candelas · s/m2) showed a significantly in- ditionally, these findings confirm reports in the literature of creased amplitude along with a prolonged b-wave. older patients presenting with fundus autofluorescence im- The diagnosis of CDSRR was suspected based on reports ages with a ringlike area of high density encircling retinal pig- of an association between this unique ERG finding and KCNV2 ment epithelial atrophy.2 It is likely that in patients who pre- mutations. Genetic testing confirmed the diagnosis and also sent later, milder symptoms and more subtle examination revealed 2 novel mutations, p.W46X:c.137G>A and p.C177X: findings are consistent with slowly progressing atrophy out- c.531T>A, in KCVN2 to possibly account for this novel disease ward from the macula, highlighted by complete degradation phenotype. centrally and incomplete degradation of photoreceptor outer segments in a peripheral ring. Discussion | There are several novel conclusions to be drawn Ensembl analysis revealed that pC177X c531T>A is likely from this case of CDSRR. Testing with ERG can focus candi- a nonsense truncating mutation in the N-terminal, cytoplas- date gene screening in patients with dyschromatopsia, nycta- mic tetramerization domain of the Kv8.2 protein, thus impair- lopia, or hemeralopia presenting with distinct bilateral macu- ing its ability to form functional α-unit tetrameric potassium lar atrophy with retinal pigment epithelial changes and diffuse channels (http://www.ensembl.org/). The pW46X c137G>A mu- outer retinal atrophy. This case highlights specific optical co- tation is a nonsense mutation that can also lead to a trun- herence tomographic findings of diffuse outer retinal atro- cated protein. Both are loss-of-function alleles.6 phy that correspond with previously described mechanistic The 2 mutations identified are novel and thus expand the theories detailing preservation of the inner nuclear layer.3 Ad- current knowledge of CDSRR genotype-phenotype descrip-

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tions in the literature. This patient uniquely presented with a study including fundus autofluorescence and extensive electrophysiology. more dramatic macular pattern at a much later age than an Retina. 2010;30(1):51-62. average patient with CDSRR and had neither nyctalopia nor 3. Michaelides M, Holder GE, Webster AR, et al. A detailed phenotypic study of “cone dystrophy with supernormal rod ERG.” Br J Ophthalmol. dyschromatopsia. This would suggest not only that the 2005;89(3):332-339. heterogeneity of phenotypes for CDSRR is much broader than 4. Wissinger B, Dangel S, Jägle H, et al. Cone dystrophy with supernormal rod the literature indicates but also that the patient’s 2 novel response is strictly associated with mutations in KCNV2. Invest Ophthalmol Vis mutations are mild, having resulted in compound heterozy- Sci. 2008;49(2):751-757. gosity associated with a late presenting phenotype. 5. Wissinger B, Schaich S, Baumann B, et al. Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response. Hum Mutat. 2011;32(12):1398-1406. Tamara Lee Lenis, MD, MS 6. Smith KE, Wilkie SE, Tebbs-Warner JT, et al. Functional analysis of missense Elona Dhrami-Gavazi, MD mutations in Kv8.2 causing cone dystrophy with supernormal rod Winston Lee, MA electroretinogram. J Biol Chem. 2012;287(52):43972-43983. Sri Krishna Mukkamala, MD Mirela Raluca Tabacaru, MD Peripapillary Chorioretinal Lacunae in a Girl Lawrence Yannuzzi, MD With 3q21.3 to 3q22.1 Microdeletion Peter Gouras, MD With Features of Aicardi Syndrome Stephen H. Tsang, MD, PhD Aicardi syndrome is characterized by the classic triad of agen- esis of the corpus callosum, seizures, and peripapillary chorio- Author Affiliations: Cleveland Clinic Lerner College of Medicine, Case Western retinal lacunae.1 This disorder occurs exclusively in girls and XXY Reserve University, Cleveland, Ohio (Lenis); Department of Ophthalmology, boys and is presumed to be inherited in an X-linked dominant Columbia University, New York, New York (Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Gouras, Tsang); Department of Pathology and Cell Biology, Columbia pattern, although the causative genes involved have not been University, New York, New York (Lee, Tsang); Vitreous Retina Macula identified. We examined a girl with a microdeletion on chro- Consultants of New York, New York (Mukkamala, Yannuzzi). mosome 3 who was found to have bilateral peripapillary cho- Corresponding Author: Stephen H. Tsang, MD, PhD, Edward S. Harkness Eye rioretinal lacunae with other features of Aicardi syndrome. Institute, 635 W 165th St, Room 218, New York, NY 10032 ([email protected]).

Published Online: September 12, 2013. Report of a Case | A girl was born at 32 weeks’ gestation to a doi:10.1001/jamaophthalmol.2013.4681. mother with preeclampsia via induced vaginal delivery. At Author Contributions: Study concept and design: Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Yannuzzi, Gouras, Tsang. birth, she was noted to have preaxial polydactyly involving her Acquisition of data: Lenis, Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Yannuzzi, left hand as well as an atrial-septal defect with mild pulmo- Tsang. nary valvular stenosis. At age 18 months, she was evaluated Analysis and interpretation of data: Lenis, Dhrami-Gavazi, Lee, Mukkamala, for speech and motor delay and staring spells. Examination dis- Tabacaru, Yannuzzi, Tsang. Drafting of the manuscript: Lenis, Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, closed a broad flat nasal bridge, epicanthal folds, broad and Gouras, Tsang. wide mouth, retromicrognathia, and truncal hypotonia. A chro- Critical revision of the manuscript for important intellectual content: Lenis, Lee, mosomal microarray study revealed a 6-megabase deletion of Mukkamala, Yannuzzi. chromosome 3, spanning from 3q21.3 to 3q22.1. Obtained funding: Lenis, Mukkamala. Administrative, technical, or material support: Dhrami-Gavazi, Lee, Tabacaru, Ophthalmologic examination showed normal optoki- Yannuzzi, Tsang. netic responses and reactive pupils with no relative afferent Study supervision: Mukkamala, Gouras, Tsang. pupillary defect. She had no strabismus, nystagmus, anterior Conflict of Interest Disclosures: None reported. segment anomalies, or refractive error. Retinal examination Funding/Support: This work was supported by the LuEsther T. Mertz Retinal showed bilateral peripapillary chorioretinal lacunae. In the right Research Center, Manhattan Eye, Ear, and Throat Hospital, Macular Foundation, eye, a normal right optic disc was abutted by a cluster of poorly Inc, core grant 5P30EY019007 from the National Eye Institute, core grant 5P30CA013696 from the National Cancer Institute, and unrestricted funds circumscribed chorioretinal lacunae with hyperpigmented bor- from Research to Prevent Blindness. The Bernard and Shirlee Brown Glaucoma ders superotemporally (Figure 1). In the left eye, a dysplastic Laboratory, Department of Ophthalmology, Columbia University is supported optic disc was encircled by a cluster of well-circumscribed de- by grant R01 EY018213 from the National Institutes of Health, the Foundation pigmented chorioretinal lacunae with variably dense fine pig- Fighting Blindness, Schneeweiss Stem Cell Fund, and the Tistou and Charlotte Kerstan Foundation. Tsang is a member of the RD-CURE Consortium, is a fellow mentation around the borders (Figure 1). The midperipheral of the Burroughs-Wellcome Program in Biomedical Sciences, and has been retinas showed multiple additional streaky areas of focal reti- supported by the Bernard Becker Association of University Professors in nal pigment epithelial depigmentation (Figure 1). Magnetic Ophthalmology Award from Research to Prevent Blindness, the Dennis W. Jahnigen Award from the American Geriatrics Society, the Joel Hoffman resonance imaging showed thinning of the corpus callosum, Scholarship, the Barbara and Donald Jonas Family Fund, and the Professor mildly decreased white matter volume with dilation of the pos- Gertrude Rothschild Stem Cell Foundation. terior aspect of the left lateral ventricle, mild cortical thicken- Role of the Sponsors: The sponsors had no role in the design and conduct of ing with abnormal deep sulcation involving the right parasag- the study; collection, management, analysis, and interpretation of the data; or ittal lobe, and a cavum septum pellucidum (Figure 2). preparation, review, or approval of the manuscript. 1. Gouras P, Eggers HM, MacKay CJ. Cone dystrophy, nyctalopia, and Discussion | In 1946, Krause2 first described the ocular findings supernormal rod responses: a new retinal degeneration. Arch Ophthalmol. 1983;101(5):718-724. of Aicardi syndrome in an infant girl with seizures, develop- 2. Robson AG, Webster AR, Michaelides M, et al. “Cone dystrophy with mental delay, and gray-white plaques in the retina bilaterally. supernormal rod electroretinogram”: a comprehensive genotype/phenotype In 1965, Aicardi et al3 documented the classic findings of this

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