Jen et al. (2004) carried out high resolution MRI in eight patients from four families with HGPPS including two consanguineous families from Saudi Arabia and a third from unknown Arab origin. Abnormal flattening of the basis pontis and hypoplasia in the pontine tegmentum were evident on sagittal sections. The structural alterations in caudal pons suggested potential involvement of the abducens nuclei, the medial longitudinal fasciculus, and the pontine paramedian reticular formation. The medulla appeared abnormally butterfly-like, with anterior flattening and an unusual midline cleft. The abducens nerves were visualized bilaterally in the extra-axial space, and orbital MRI demonstrated normal extraocular muscle configuration and size, as well as the presence of apparently normal intraorbital motor nerves to the medial and lateral rectus muscles. Jen et al. (2004) concluded that the absence of bulging of abducens nuclei into the fourth ventricle observed in HGPPS patients likely represents hypoplasia rather than absence of the abducens nuclei. These findings distinguish HGPPS from other congenital eye movement disorders in which absence or aberrant motor nerves are associated with hypoplastic extraocular muscles, but normal brain structure.
Khan et al., (2008) describe a a 9-year-old girl affected with substituted convergence for horizontal gaze since birth. She presented at birth with congenital, nonprogressive, abnormal eye movements. She also had asynchronous blinking, conjugate pendular nystagmus, and high myopia. The patient was the fifth child of first-cousin parents. The coding exons in the ROB03 gene were sequenced and a novel homozygous missense p.Pro771Leu (c.2312 CT) mutation in exon 15 was identified in the patient. The parents and both of her sisters were heterozygous for the same mutation. This mutation was not found in 50 healthy Saudi individuals and affected an amino acid that is an evolutionarily conserved in several species.
Abu-Amero et al. (2009) reported four consanguineous families of Saudi Arabian origin affected with HGPPS. Two of these families had one affected child, while two had two affected children each. All patients had grossly normal cognitive function for age and neurologic examination. However, there was complete or almost complete restriction of horizontal gaze in both eyes with full vertical gaze. All patients had scoliosis. All but one had scoliosis surgery. MRI revealed brainstem hypoplasia in all the patients, exemplified by hypoplasia of the pons and a 'butterfly' medulla with deep anterior and posterior midline clefts. Intraoperative SSEP and MEP yielded ipsilateral responses. Each of these families was found to carry a novel mutation in the ROBO3 gene, which was found in homozygous condition in the affected patients and in heterozygous condition in the parents and some of the unaffected siblings.
Oystreck et al. (2011) detailed the phenotypic similarity in five Saudi patients with genetically and pathologically different ocular motility abnormalities involving straight eyes. The first patient was a 47-year-old male with oculopharyngeal muscular dystrophy presented with complete bilateral ophthalmoparesis and ptosis covering the pupillary axis. He had substantial weakness and wasting of facial muscles, frontal balding, moderate proximal and distal muscle weakness, and nasal speech. The second patient was a 12-year-old boy with congenital myasthenic syndrome who developed bilateral ptosis and partial bilateral ophthalmoparesis at the age of 5 months. He had two older brothers affected with the same syndrome caused by a homozygous mutation in the CHRNE gene. A 7-year-old girl, five of her siblings, and their father were diagnosed with congenital fibrosis of the extraocular muscles type 3. The 7-year-old presented with congenital ptosis and restricted eye movements. At the age of 2 years she had bilateral ptosis repair. The 4th patient was an 11-year-old girl with Bosley-Salih-Alorainy syndrome who presented with anomalous horizontal eye movements and complete congenital deafness since birth. Her younger sister also had similar features, their parents were first cousins. The fifth patient was a 4-year-old-boy who presented with a completely absent horizontal gaze without globe retraction or lid fissure changes; he developed severe progressive scoliosis at the age of 2 years. His parents were first cousins. A homozygous mutation in the ROBO3 gene was found in the patient, confirming the diagnosis of HGPPS.
Volk et al. (2011) described four patients with horizontal gaze palsy and progressive scoliosis (aged between 6 months and 13 years), two of them were siblings. The three consanguineous families were unrelated. One of the families was of Saudi origin; the patient was a 13 year old boy who presented with a progressive right-curved thoracolumbar scoliosis. His horizontal eye movements were severely disturbed. He had left microhypertropia with fusion and motor developmental delay. Direct sequencing of the ROBO3 gene revealed a homozygous deletion of 31 base pair including the splice donor site of exon 17; resulting in altered splicing. Both parents were carriers of this mutation.
Abu Amero-et al. (2009) described a consanguineous Sudanese family with one child affected with HGPPS. The clinical features and radiological features were similar to the Saudi patients in the series.
[See also: Saudi Arabia > Abu-Amero et al., 2009].