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Show Letters to the Editor Horizontal Gaze Palsy With Progressive Scoliosis: Two Novel ROBO3 Mutations in a Compound Heterozygous Sporadic Case W e read with interest the article by Mendes Marques et al (1), describing 2 patients with the syndrome of horizontal gaze palsy with progressive scoliosis (HGPPS) with mutations of the ROBO3 gene. We evaluated another patient with this syndrome who harbors 2 novel ROBO3 gene mutations. A 34-year-old woman was born at full term from nonconsanguineous parents with normal psychological development and no family history of scoliosis or gaze palsy. At the age of 6 months, her parents and physicians noticed a lack of full ocular motility. At the age 9 years, physical examination demonstrated dorsal lumbar scoliosis and the absence of the horizontal eye movements without nystagmus. Brain MRI showed typical signs of HGPPS. Sequencing of all 28 coding exons of the ROBO3 gene revealed 2 polymorphisms in the exon 8 (rs4935898) and in the intron 22 (rs145185934 deletion), and 2 novel mutations: a heterozygous missense mutation and a splice-site mutation. The missense mutation was a c.1433 C.T transition in the exon 9. To our knowledge, this novel mutation (p.Pro478Leu) has not been reported and it is not present in 1000 genomes database nor in the Exome Variant Server. Furthermore, evidence support the pathogenicity of the mutation found: 1) clinical features were consistent with the HGPPS phenotype; 2) besides the P478L change, the sequence of the entire gene was normal; 3) the proline-478 is well conserved among ROBO3s as predicted by Clustal W2 software (EMBL-EBI, Hinxton, UK) 4) bioinformatic programs predicted that this variant likely has pathological functional effect (PolyPhen [Harvard, Cambridge, MA] with a score of 0.995; Sorting Intolerant From Tolerant software [J. Craig Venter Institute, Rockville, MD] P = 0.02, intolerant threshold of 0.05; SNAP [Rostlab, Munich, Germany] prediction: nonneutral, expected accuracy: 96%; Panther Classification System [Gene Ontology Consortium, Washington, DC] 25.72042, P = 0.938; SNPs & Go [Bologna Biocomputing Group, Bologna, Italy] effect: disease, Reliability Index: 7). The splice-site mutation c.3321-G.A occurs in the acceptor splice site of the intron 22 and probably leads to a missplicing. The in silico analysis (NNNSplice09; Berkeley Drosophila Genome Project, Berkeley, CA) revealed that the transition G.A abolishes the acceptor splice site. This change probably generates a loss of splicing in this region that could lead to an aberrant protein. HGPPS is characterized by a peculiar morphological pattern on MRI, diffusion tensor imaging, and functional MRI (fMRI) that directly or indirectly results in the Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 122-133 absence or only partial decussation of some bundles of white matter in the brainstem (2,3). In this disorder, the internuclear nucleus axons of the sixth nerve nucleus do not cross the midline to ascend in the medial longitudinal fasciculi to synapse with the neurons within the third nerve nucleus complex innervating the medial rectus muscles. The failed decussation of the axons of the interneurons is the primary cause of the defective control on horizontal eye movements. The etiology of progressive scoliosis in patients with HGPPS remains unknown. Neuroimaging and fMRI findings also have shown defective decussation within the brainstem, specifically involving the corticospinal tracts, superior cerebellar peduncles, and transverse fibers in the pons. Although a neurogenic mechanism for scoliosis has been postulated (4), it is unclear whether this is related to mutations of the ROBO3 gene because HGPPS with scoliosis has been described without detectable mutations in that gene (5). This raises epigenetic and/or environmental factors as potentially playing a role in development of scoliosis. Carmine Ungaro, PhD Institute of Neurological Sciences, National Research Council, Mangone, Italy Sergio Valentini, MD Neuroradiology, Azienda Ospedaliera di Cosenza, Cosenza, Italy Antonio Cerasa, PhD Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy S. Anna Institute and Research in Advanced Neurorehabilitation (RAN), Crotone, Italy Pier Luigi Lanza, MD Institute of Neurological Sciences, National Research Council, Mangone, Italy Rosalucia Mazzei, PhD Institute of Neurological Sciences, National Research Council, Mangone, Italy Institute for Agricultural and Forest Systems in the Mediterranean, National Research Council, Rende, Italy 131 Letters to the Editor The authors report no conflicts of interest. P. L. Lanza and R. Mazzei contributed equally. REFERENCES 1. Mendes Marques NBPS, Barros SR, Miranda AF, Nobre Cardoso J, Parreira S, Fonseca T, Donaire NM, Campos N. Horizontal gaze palsy and progressive scoliosis with ROBO 3 mutations in patients from Cape Verde. J Neuroophthalmol. 2017;37:162-165. 2. Sicotte NL, Salamon G, Shattuck DW, Hageman N, Rüb U, Salamon N, Drain AE, Demer JL, Engle EC, Alger JR, Baloh RW, Deller T, Jen JC. Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations. Neurology. 2006;67:519-521. An Evaluation of Educational Neurological Eye Movement Disorder Video Posted on Internet Video Sharing Sites: Comment W e found the article by Hickman (1) both enlightening and frightening. To find that less than onequarter of the eye movement videos posted on internet video sharing websites contained excellent educational value is disturbing. Although there is some reassurance in the statistically significant finding that a greater number of "likes" was found on higher-quality videos, this is not a practical or reliable screening technique for the clinician working through a busy clinic. As pointed out by Hossain et al (2), in the United States, we are experiencing a steady decline in ophthalmic education in medical schools (3). Although many of us in academic medicine are working to re-engage in the curriculum within our respective medical schools, there is still a need for improving the access and availability of peer-reviewed online ophthalmic educational materials. For this reason, we created an open access website through the Moran Eye Center at the University of Utah with a dedicated outline for medical students (http:// morancore.utah.edu). This outline is based on an Association of University Professors of Ophthalmology (AUPO) Medical Education Task Force editorial that identified the core ophthalmologic knowledge and skills expected of all United States medical school graduates (4). As ophthalmologists, we have a responsibility to take ownership over the education of our nonophthalmologic colleagues. They serve on the frontline screening for eye disease and making appropriate and timely referrals. So often the educational materials produced by ophthalmologists are targeted toward only those who have completed ophthalmic training, and the materials can be difficult to understand for nonophthalmologists. The articles in the medical student outline in the Moran CORE (clinical ophthalmology resource for education) take a novel approach. First, they have gone through a peer review and are posted through a reputable institution. 132 3. Salamon N, Sicotte N, Alger J, Shattuck D, Perlman S, Sinha U, Schultze-Haakh H, Salamon G. Analysis of the brain-stem whitematter tracts with diffusion tensor imaging. Neuroradiology. 2005;47:895-902. 4. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rüb U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wag Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304:1509-1513. 5. Abu-Amero KK, Kapoor S, Hellani A, Monga S, Bosley TM. Horizontal gaze palsy and progressive scoliosis due to a deleterious mutation in ROBO3. Ophthalmic Genet. 2011;32:231-236. Second, these articles have been written by medical students who have a unique insight into identifying what is of greatest benefit to their classmates while making it conceptually accessible. Although these articles are edited and reviewed by staff, we have been impressed how medical students explain topics in clear terms with understandable concepts. We know that both clinicians and patients will increasingly use the internet for self-directed learning, diagnosis, and management of eye diseases. It is hoped that the resource we are providing will give users the confidence and peace of mind that they are accessing accurate and reliable information. We welcome any feedback. Griffin Jardine, MD Pediatric Ophthalmology, University of Utah, Salt Lake City, Utah Nancy T. Lombardo, MLS Christy Jarvis, MLIS, AHIP Eccles Health Sciences Library, University of Utah, Salt Lake City, Utah Kathleen Digre, MD Neurology, Ophthalmology, University of Utah, Salt Lake City, Utah The authors report no conflicts of interest. REFERENCES 1. Hickman SJ. An evaluation of educational neurological eye movement disorder videos posted on internet video sharing sites. J Neuroophthalmol. 2016;36: 33-36. 2. Hossain IT, Malik HH, Iqbal SS. An evaluation of educational neurological eye movement disorder videos posted on internet video sharing sites: Comment. J Neuroophthalmol. 2016;36:352. Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 122-133 |
