RP2 Rod-Cone Dystrophy Causes Spasmus Nutans-Like Nystagmus

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD RP2 Rod–Cone Dystrophy Causes Spasmus Nutans–Like Nystagmus Tae Keun Yoo, MD, Sueng-Han Han, MD, PhD, Jinu Han, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 05/04/2022 S pasmus nutans is an ocular oscillation beginning in early childhood and presents as disconjugate, high-frequency pendular nystagmus, head nodding, and torticollis. It is a benign disorder with onset in infancy and usually resolves within 2 years. However, childhood nystagmus can also be caused by optic pathway glioma, which is indistinguishable from spasmus nutans on physical examination. In addition, inherited retinal disorders can also masquerade as spasmus nutans. A 27-month-old boy first presented to our clinic with shimmering in the right eye. His mother first noted the nystagmus at the age of 8 months. There was no family history of nystagmus or inherited retinal diseases. On initial examination, a 4-Hz pendular nystagmus with small amplitude was noted in the right eye, while the left eye was quiet. He could fix and follow, but he tended to bring objects close to him to see them. His head was tilted to the right side, but no head titubation was noted. Cycloplegic refraction showed 2sph 7.00 2cyl 3.00 axis 180 in both eyes. Dilated fundus examination was normal at that time. A brain MRI was also negative for optic pathway glioma. However, by the age of 4 years, he was still experiencing problems with his vision. His best-corrected visual acuity was 20/200 in the right eye and 20/100 in the left eye. He came back to our clinic at the age of 17 years, and disconjugate nystagmus was still noted (See Supplemental Digital Content, Video, http://links.lww.com/WNO/A384). Bestcorrected visual acuity was 20/400 in the right eye and 20/ 200 in the left eye. He denied any nyctalopia or poor peripheral vision. Dilated fundus examination showed mild granular pigmentary retinopathy in his retinal periphery (Fig. 1A). Spectralis optical coherence tomography showed diffuse disruption of the photoreceptor band in the outer Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea. Supported by a fund (#2018-ER6902-00) from the Research of Korea Centers for Disease Control and Prevention. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Jinu Han, MD, Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Eonjuro 211, Gangnamgu, Seoul 06273, South Korea; E-mail: [e-mail] Yoo et al: J Neuro-Ophthalmol 2021; 41: e91-e93 retina and epiretinal membrane (Fig. 1B). Electrooculography revealed 4-Hz pendular nystagmus in the right eye, and the left eye was quiet (Fig. 2A). Electroretinography (ERG) showed extinguished dark-adapted response and severely reduced light-adapted response (Fig. 2B), which, together with all the previous results, was consistent with a diagnosis of rod–cone dystrophy. Targeted panel next-generation sequencing consisting of 113 genes known to be involved in nystagmus was ordered. Sequencing and bioinformatic analyses were performed as described previously (1). His results came back as heterozygous for the c.590G . C:p(Arg197Pro) variant in the KCNV2 gene, which codes for a voltage-gated potassium channel important in transmitting neuronal signals. This variant is predicted to be deleterious using 3 different in silico prediction programs (Combined Annotation Dependent Depletion [CADD]: 28.2, SIFT: 0.02-deleterious, Polyphen2: 0.996 probably damaging). This variant is extremely rare in the genome aggregation database (gnomAD minor allele frequency: 2/223282). A previous report linked spasmus nutans–like nystagmus to KCNV2 retinopathy (2); however, our patient did not present with findings consistent with the disease. First, the pathognomonic ERG findings such as supranormal rod response were absent in our patient. Moreover, his fundus findings were not consistent with KCNV2 retinopathy where retinal epithelial depigmentation is found in the central fovea. To find hidden variants in the KCNV2 gene or other genes, whole genome sequencing was performed. There were no other pathogenic variants or copy number variations in the KCNV2 gene; however, we discovered a novel hemizygous c.340delT:p.(Cys113AlafsTer42) variant in the X-linked RP2 gene that results in a frameshift mutation in exon 2. The RP2 protein regulates the trafficking of ciliary tip kinesin from the inner segment to the outer segment of photoreceptors (3). This variant is absent from the gnomAD; it is predicted to be deleterious based on an in silico prediction program (CADD: 34) and is considered pathogenic according to the guidelines of the American College of Medical Genetics and Genomics. Presentation of nystagmus in patients with inherited retinal disease is not unusual. In fact, various retinal diseases such as Leber congenital amaurosis, congenital stationary night blindness, or achromatopsia are associated with nystagmus (4). Previous studies have also shown that e91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Fundus photographs showed granular pigmentary retinopathy in the retinal periphery. B. Spectralis optical coherence tomography revealed diffuse disruption of the ellipsoid zone and thinning of the outer retinal layer. spasmus nutans–like nystagmus can be seen in various forms of retinal dystrophies (5). In fact, in a study of 22 consecutive patients with spasmus nutans, 4 of 22 patients (18%) had cone or rod–cone dystrophy (6). Another study found that 3 of 8 patients with spasmus nutans had abnormal ERG, indicating that electrophysiology study is FIG. 2. A. Electrooculography showed 4-Hz pendular nystagmus in the right eye, while the left eye was quiet. B. Electroretinography showed extinguished dark-adapted responses and severely attenuated light-adapted responses, which was consistent with rod–cone dystrophy. e92 Yoo et al: J Neuro-Ophthalmol 2021; 41: e91-e93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence necessary to make a correct diagnosis (7). This suggests that full-field ERG should be performed routinely to exclude retinal pathology in patients with spasmus nutans. Genetic investigation of spasmus nutans–like nystagmus with retinal dystrophy has not been previously reported. Khan et al reported that KCNV2-related retinopathy can be mistaken as spasmus nutans (2,8). Patients with KCNV2 mutations have abnormal head posture, head nodding, and nystagmus. In our study, we applied next-generation sequencing in a patient with retinal degeneration who presented with spasmus nutans–like nystagmus and discovered that RP2 retinopathy can be associated with spasmus nutans–like nystagmus. A previous study reported that 4 patients with RP2 mutations had early-onset severe visual loss, myopia, and nystagmus (9). Another study found that truncation mutations in RP2 caused severe visual loss at early age likely due to loss of protein function (10). Thus, our patient’s frameshift mutation in exon 2 of the RP2 gene might be associated with his early-onset visual loss and nystagmus. However, it is still not clear why this mutation specifically caused spasmus nutans–like nystagmus. Because patients with spasmus nutans usually present at early infancy, meticulous fundus examination including the peripheral retina is usually difficult. Sometimes, ERG is inconclusive due to poor cooperation, and it may lead to misdiagnosis (11). Moreover, a neonate with Pelizaeus– Merzbacher disease or Leigh disease has an intermittent nodding movement of the head and pendular nystagmus (12). Head nodding or head titubation may be seen in other diseases including Joubert syndrome, “bobble-head doll” syndrome, and STXBP1 encephalopathy (13). These neurological disorders should be suspected in children with spasmus nutans–like nystagmus and clinical signs of ataxia or developmental delay. Rod–cone dystrophy is a clinically and genetically heterogeneous group of retinal dystrophies, which lead to progressive loss of rod cells predominantly. RP2 (MIM 312600) consists of 5 exons spanning approximately 45 kb on chromosome Xp11.3-11.23. Frameshift mutations or nonsense mutations in the RP2 gene may cause severe visual impairment in early life, and this may be related to the development of nystagmus. Ophthalmologists should keep in mind that RP2 rod–cone dystrophy can cause early vision loss and nystagmus, and it should be included in the differential diagnosis of spasmus nutans. In addition to KCNV2 retinopathy, RP2 rod–cone dystrophy can present in infancy with smallamplitude high-frequency asymmetric nystagmus and a normal appearing fundus at early ages. This highlights the fact Yoo et al: J Neuro-Ophthalmol 2021; 41: e91-e93 that inherited retinal diseases such as KCNV2 retinopathy, congenital stationary night blindness, or RP2 rod–cone dystrophy should be ruled out before making a final diagnosis of spasmus nutans. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Han; b. Acquisition of data: T. K. Yoo and J. Han; c. Analysis and interpretation of data: T. K. Yoo and J. Han. Category 2: a. Drafting the manuscript: T. K. Yoo and J. Han; b. Revising it for intellectual content: S.-H. Han. Category 3: a. Final approval of the completed manuscript: J. Han. 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