Abstract
Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by ROBO3 gene mutations. To date, the number of confirmed HGPPS cases caused by gene mutations is estimated at 76. However, HGPPS caused by ROBO3 gene mutation has not been reported in the Chinese population. In this study, the clinical data, brain imaging features, somatosensory evoked potentials (SEP), and ROBO3 gene mutations were obtained for two Chinese patients with HGPPS. The proband was an 11-year-old boy. He developed horizontal eye movement disorder at the age of 1 year and scoliosis at the age of 11 years. Two eyeballs fixed in the midline position were revealed by neurological examination. A dorsal cleft in the pons and a butterfly-shaped medulla were shown by brain magnetic resonance imaging. Again, most corticospinal bundles did not cross in the brainstem, as revealed by diffusion tensor imaging. SEP confirmed that most somatosensory projections were uncrossed. The proband’s 7-year-old brother exhibited similar clinical manifestations and imaging features. The brothers had compound heterozygous mutations c.3165G>A (p.W1055X) and c.955G>A (p.E319K) of the ROBO3 gene. The c.3165G>A mutation is a novel nonsense mutation that has not been previously reported. This study reports the first two cases of HGPPS carrying a novel ROBO3 gene mutation in patients from a Chinese family, thereby expanding the disease spectrum. Reports from the literature show that missense mutation is the most common mutational type in the ROBO3 gene. Early ROBO3 gene detection is required for patients exhibiting early-onset eyeball movement disorder to confirm HGPPS disease.
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References
Abu-Amero KK, Kapoor S, Hellani A, Monga S, Bosley TM (2011) Horizontal gaze palsy and progressive scoliosis due to a deleterious mutation in ROBO3. Ophthalmic Genet 32(4):231–236
Abu-Amero KK, al Dhalaan H, al Zayed Z, Hellani A, Monga S, Bosley TM (2009) Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations. J Neurol Sci 276:22–26
Amoiridis G, Tzagournissakis M, Christodoulou P, Karampekios S, Latsoudis H, Panou T, Simos P, Plaitakis A (2006) Patients with horizontal gaze palsy and progressive scoliosis due to ROBO3 E319K mutation have both uncrossed and crossed central nervous system pathways and perform normally on neuropsychological testing. J Neurol Neurosurg Psychiatry 77:1047–1053
Amouri R, Nehdi H, Bouhlal Y, Kefi M, Larnaout A, Hentati F (2009) Allelic ROBO3 heterogeneity in Tunisian patients with horizontal gaze palsy with progressive scoliosis. J Mol Neurosci 39:337–341
Arlt EM, Keindl TK, Grabner G, Krall EM, Meissnitzer MW (2015) Horizontal gaze palsy with progressive scoliosis. Klin Monatsbl Augenheilkd 232:281–282
Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, AbuAmero KK, MacDonald DB, al Zayed Z, al Dhalaan H, KansuT SB, Baloh RW (2005) Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology 64:1196–1203
Bozdogan ST, Dinc E, Sari AA, Ozgur A, Bisgin A (2017) A novel mutation of ROBO3 in horizontal gaze palsy with progressive scoliosis. Ophthalmic Genet 38:284–285
Chan WM, Traboulsi EI, Arthur B, Friedman N, Andrews C, Engle EC (2006) Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3. J Med Genet 43:e11
Fernandez-Vega Cueto A, JJ R-EE, Rodriguez-Maiztegui I (2016) Horizontal gaze palsy and progressive scoliosis in a patient with congenital esotropia and inability to abduct. A case report. Arch Soc Esp Oftalmol 91:592–595
Haller S, Wetzel SG, Lutschg J (2008) Functional MRI, DTI and neurophysiology in horizontal gaze palsy with progressive scoliosis. Neuroradiology 50:453–459
Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, ShattuckD SG, 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, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, KarimS AJR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Egle EC (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304:1509–1513
Khan AO, Abu-Amero K (2014) Infantile esotropia with cross-fixation, inability to abduct, and underlying horizontal gaze palsy with progressive scoliosis. J AAPOS 18:389–391
Khan AO, Oystreck DT, Al-Tassan N, Al-Sharif L, Bosley TM (2008) Synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu). Ophthalmology 115:2262–2265
Kurian M, Megevand C, De Haller R, Merlini L, Boex C, Truffert A, Kaelin A, Burglen L, Korffa CM (2013) Early-onset or rapidly progressive scoliosis in children: check the eyes! Eur J Paediatr Neurol 17:671–675
Mendes Marques N, Barros SR, Miranda AF, Nobre Cardoso J, Parreira S, Fonseca T, Donaire NM, Campos N (2017) Horizontal gaze palsy and progressive scoliosis with ROBO 3 mutations in patients from Cape Verde. J Neuroophthalmol 37:162–165
Ng AS, Sitoh YY, Zhao Y, Teng EW, Tan EK, Tan LC (2011) Ipsilateral stroke in a patient with horizontal gaze palsy with progressive scoliosis and a subcortical infarct. Stroke 42:e1–e3
Rossi A, Catala M, Biancheri R, Di Comite R, Tortori-Donati P (2004) MR imaging of brain-stem hypoplasia in horizontal gaze palsy with progressive scoliosis. AJNR Am J Neuroradiol 25:1046–1048
Rousan LA, Qased ABL, Audat ZA (2019) Horizontal gaze palsy and progressive scoliosis with two novel ROBO3 gene mutations in two Jordanian families. Ophthalmic Genet 40:1–7
Sabatier C, Plump AS, Le M, Brose K, Tamada A, Murakami F, Lee EY, Tessier-Lavigne M (2004) The divergent Robo family protein Rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117:157–169
Sharpe JA, Silversides JL, BLAIR RDG (1975) Familial paralysis of horizontal gaze: associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia. Neurology 25:1035–1040
Sicotte NL, Salamon G, Shattuck DW, Hageman N, Rub U, Salamon N, Drain AE, Demer JL, Engle EC, Alger JR, Baloh RW, Deller T, Jen JC (2006) Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations. Neurology 67:519–521
Ungaro C, Valentini S, Cerasa A, Lanza PL, Mazzei R (2018) Horizontal gaze palsy with progressive scoliosis two novel ROBO3 mutations in a compound heterozygous sporadic case. J Neuroophthalmol 38:131–132
Volk AE, Borck G, Carter O, Fricke J, Herkenrath P, Poggenborg J, Demant AW, Ivo R, Eysel P, Kubisch C, Neugebauer A (2011) Horizontal gaze palsy with progressive scoliosis three novel ROBO3 mutations and descriptions of the phenotypes of four patients. Mol Vis 17:1978–1986
Yamada S, Okita Y, Shofuda T, Yoshioka E, Nonaka M, Mori K, Nakajima S, Kanemura Y (2015) Ipsilateral hemiparesis caused by putaminal hemorrhage in a patient with horizontal gaze palsy with progressive scoliosis: a case report. BMC Neurol 15:1–4
Funding
This study was financially supported by grants from the Department of Science and Technology of Fujian Province (Science and Technology Project, Grant No. 2018D0015), the Medical Elite Cultivation Program of Fujian, P.R.C (2019-ZQNB-37), and industry university collaboration between Ningde city and Xiamen University.
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Xiu, Y., Lv, Z., Wang, D. et al. Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family. J Mol Neurosci 71, 293–301 (2021). https://doi.org/10.1007/s12031-020-01650-4
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DOI: https://doi.org/10.1007/s12031-020-01650-4