Horizontal Gaze Palsy and Progressive Scoliosis With ROBO 3 Mutations in Patients From Cape Verde

A 15-year-old boy experienced painless vision loss in the left eye of unknown duration. Leber hereditary optic neuropathy (LHON) was suspected, despite negative testing for the 3 most common pathogenic gene mutations and idebenone 300 mg 3 times daily was prescribed. Nine months later, the patient developed right eye involvement. Complete mitochondrial genome analysis revealed 2 rare variants-m.3890G>A of the MT-ND1 gene and m.8417C>A of the MT-ATP8 gene. The former has been described in severe infantile Leigh syndrome and LHON; the latter is of unknown significance. The patient experienced progressive visual deterioration through 12 months, but improved to 20/20, right eye and 20/25, left eye, at 21 months. Visual recovery can occur in a patient with bilateral optic neuropathy secondary to the rare m.3890G>A point mutation.

Clinical Observation Horizontal Gaze Palsy and Progressive Scoliosis With ROBO 3 Mutations in Patients From Cape Verde Nadine B. P. S. Mendes Marques, MD, Sandra R. Barros, MD, Ana F. Miranda, MD, João Nobre Cardoso, MD, Sónia Parreira, MD, Teresa Fonseca, MD, Nelvia M. Donaire, MD, Nuno Campos, PhD Abstract: Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare and autosomal recessive syndrome. We describe 2 cases of HGPPS which are the first documented in patients of African ancestry from an isolated population in Cape Verde. They demonstrated typical findings on neuroophthalmic examination and brain magnetic resonance imaging. One patient had novel heterozymous mutations of the ROB0 3 gene. Journal of Neuro-Ophthalmology 2017;37:162-165 doi: 10.1097/WNO.0000000000000455 © 2016 by North American Neuro-Ophthalmology Society H orizontal gaze palsy and progressive scoliosis (HGPPS) was first identified in 5 children of 2 families by Dretakis and Kondoyannis in 1974 (1). It is an autosomal recessive disorder associated with biallelic mutation in the Roundabout homolog of Drosophila 3 (ROBO 3) gene and causes a profound anatomical maldevelopment of the brainstem with uncrossing of the corticospinal and dorsal column-medial lemniscus pathways (2). The classic ocular motor sign of HGPPS is the absence of horizontal gaze under conjugate gaze conditions, including smooth pursuit, and optokinetic and vestibuloocular responses. Affected individuals can adduct with convergence and may present with pendular and horizontal nystagmus of low amplitude, at times associated with involuntary head movements. Patients also may show asynchronous blinking. Vertical eye movements, visual fields, pupillary reactions, and anterior and posterior segments remain unaffected. Visual acuity typically is normal but, on occasion, may be reduced due to ametropic amblyopia or nystagmus. Scoliosis in HGPPS generally is detected in the first 2 years of life and tends to progress during the first decade. It is usually symptomatic and requires treatment including physiotherapy, 3-dimensional correction using thermoplastic braces, and corrective spine surgery. The majority of the patients seem to be neurologically unaffected, but a small proportion shows delayed motor and cognitive development. The vast majority of patients reported with HGPPS have mutations of the ROBO 3 gene. This is a biallelic mutation with the unaffected family members harboring a heterozygous ROBO 3 mutation (3). There are characteristic neuroimaging features of HGPPS. Brain magnetic resonance imaging (MRI) typically demonstrates anterior and posterior midline clefts with a flattened medulla with a butterfly-like bifid appearance, a flattened pontine tegmentum, markedly reduced facial colliculi and a reduced diameter of both the pons and medulla (4). The purpose of our study is to describe phenotypic and neuroimaging features of the first 2 cases of HGPPS in patients of African ancestry from Fogo Island, Cape Verde, and report a new ROBO 3 mutation associated with this disorder. Garcia de Orta Hospital, Almada, Portugal. 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 full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Address correspondence to Nadine Bianca Pontes de Sousa Mendes Marques, MD, Garcia de Orta Hospital, Avenida Torrado da Silva, Almada 2801-951, Portugal; E-mail: [e-mail] 162 REPORT OF CASES Two patients from Fogo Island, Cape Verde, were referred to Garcia de Orta Hospital, Lisbon, Portugal, for evaluation of severe scoliosis and eye movement abnormalities. Genetic testing was performed at Dona Estefânia Hospital, Lisbon, Portugal. Mendes Marques et al: J Neuro-Ophthalmol 2017; 37: 162-165 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation Patient 1 was an 8-year-old girl with severe thorocolumbar scoliosis that began early in life. This was associated with compromised motor development, causing back pain and difficulty in walking. She was cognitively intact. Surgery to correct scoliosis was performed at the age of 7 years. Visual acuity, pupillary reactions, and examination of the anterior and posterior segments were normal. Vertical eye movements were unremarkable, but horizontal eye movements were absent with testing saccades and smooth pursuit (Fig. 1). The patient could adduct each eye with convergence. She was orthophoric. There was no nystagmus, and lid position and function were normal. Brain MRI revealed a hypoplastic pons and medulla with a prominent midline cleft and an enlarged fourth ventricle (Fig. 2). Somatosensory evoked potentials revealed abnormal lateralization of responses indicating uncrossed ascending dorsal lemniscal sensory pathways. Motor evoked potentials also demonstrated ipsilateral muscle responses consisted of uncrossed corticospinal tracts in the medulla. The patient had a ROBO3 mutation on genetic testing. Patient 2 was a 16-year-old boy who developed scoliosis early in life and underwent repair for a cleft palate at 1 year of age. He was noted to have absent horizontal eye movements as an infant. At 18 months, he developed bacterial menigitis resulting in cognitive impairment, reduced muscle tone and strength, and difficulties with speech and coordination. On our examination, visual acuity was normal with normal pupillary testing and unremarkable appearance of the anterior and posterior segments. Vertical gaze was intact, but horizontal eye movements were absent on saccadic and pursuit testing. Eye alignment in primary gaze was normal. In addition, nystagmus was not detected, and lid position and function were unremarkable. Brain MRI revealed similar brainstem abnormalities as detected in Patient 1. Evoked potentials were not performed. Spinal MRI showed profound scoliosis primarily in the thoracic segment with spinal cord normal in caliber and morphology (Fig. 3). Genetic testing of ROBO 3 revealed 2 unique and novel heterozygous out-of-frame deletions, each one affecting a different ROBO 3 allele: IV55-5del CATAG; 767-775delAGCGTCCCT. Both patients were from Fogo Island in Cape Verde. Family history revealed African ancestry. There was no history of consanguinity or contact with other ethnicities. Interview of family members of each patient revealed that no family member had been diagnosed with HGPPS, and none had symptoms related to severe scoliosis or horizontal gaze palsy. DISCUSSION Our 2 patients had many of the phenotypic findings of HGPPS including severe scoliosis and horizontal gaze palsy. Typical neuroimaging findings also were present including midline brainstem clefts, abnormal flattening of the basis pontis, and hypoplasia in the pontine tegmentum and butterfly-like configuration of the medulla. Evoked potential testing in Patient 1 confirmed uncrossed corticospinal and dorsal column-medial lemniscal pathways (5). There are several reports of HGPPS cases in patients from Africa. The first report is that of an 11-month-old patient with similar clinical neuroimaging manifestations as our patients. This infant also had 2 older siblings with horizontal gaze palsy, amblyopia, and scoliosis. However, no cranial or axial skeletal imaging had been performed on the siblings and ROBO 3 mutation was not described (6). The other cases reported included patients from Tunisian and Sudanese families and revealed a similar clinical history and different ROBO 3 mutations compared with our second patient (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A213) (6). The MRI abnormalities in patients with HGPPS suggest involvement of the sixth nerve nuclei, paramedian pontine reticular formations and medial longitudinal fasciculi. These patients have normal facial nerve function and normal facial nerve roots on MRI. It is likely that agenesis of the sixth nerve nuclei with hypoplasia of the pontine tegmentum is the cause of horizontal gaze palsy. FIG. 1. Patient 1. Vertical eye movements are intact but horizontal gaze is absent. Mendes Marques et al: J Neuro-Ophthalmol 2017; 37: 162-165 163 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 2. Patient 1. A. Axial T2 MRI shows butterfly-like configuration of the medulla, and (B) there is a midline cleft in the pons (arrow) and absence of the surface contour of the facial colliculi. C. Sagittal T1 scan reveals depression of the floor of the fourth ventricle (arrow) and reduced diameter of the medulla and pons. Our 2 patients demonstrated a progressive thoracolumbar scoliosis beginning in early infancy and progressing during the first decade of life. It is unknown if the cause of the scoliosis development in HGPPS is associated with neurogenic or musculoskeletal alterations. It has been proposed that scoliosis is due to maldevelopment of extrapyramidal projections in reticular formation of patients with HGPPS, leading to alterations in muscle tone (2,7,8). Patient 2 had a cleft palate that was surgically repaired. We are unaware of this association in other patients with HGPPS. Currently, there are 24 identified mutations for ROBO 3 causing HGPPS. Most of the families with history of HGPPS have Arabic, Saudi, Turkish, Greek, Italian, American, and Chinese ethnicities (3). Despite the different ROBO 3 mutations and diverse ethnicities affected, there were no significant differences in clinical and imaging manifestations of HGPPS. Our Patient 2 had a novel deletion in each ROBO 3 allele (IV55-5del CATAG; 767-775del AGCGTCCCT). The mother of Patient 2 had a IV55-5del CATAG deletion in one of the alleles of the ROBO 3 gene. This mutation in both the patient and his mother may have occurred de novo, since there is no common ancestral pool associated with other patients with HGPPS previously reported. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: João Cardoso, Nadine Marques, and Ana Miranda; b. Acquisition of data: Sandra Barros, Sónia Parreira, and Nadine Marques; c. Analysis and interpretation of data: Nadine Marques, Nelvia Donaire, Teresa Fonseca, and Nuno Campos. Category 2: a. Drafting the manuscript: Nadine Marques, Ana Miranda, Sandra Barros, and Sónia Parreira; b. Revising it for intellectual content: João Cardoso, Nelvia Donaire, Teresa Fonseca, and Nuno Campos. Category 3: a. Final approval of the completed manuscript: João Cardoso, Nelvia Donaire, Teresa Fonseca, Nuno Campos, and Nadine Marques. REFERENCES FIG. 3. Patient 2. Coronal T2 spinal MRI demonstrates severe thoracolumbar scoliosis. 164 1. Dretakis EK, Kondoyannis PN. Congenital scoliosis associated with encephalopathy in five children of two families. J Bone Joint Surg Am. 1974;56:1747-1750. 2. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub 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, Wang Q, Wang L, Andrews C, Yamada K, Dremer 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. 3. Bowley TM, Salih MA, Jen JC, Lin D, Oystreck KK, AbuAmero DB, MacDonald Z, Zayed H, Dhalaan T, Kansu B, Stigsby RW. 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