Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases

Abstract

Background: Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. HGPPS is associated with mutations of the ROBO3 gene. In this study, the objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations. Methods: Thirteen Tunisian patients from six unrelated consanguineous families all manifesting HGPPS were genetically investigated. We searched for the causative variants for HGPPS using classical Sanger and whole exome sequencing. Results: Four distinct homozygous mutations were identified in ROBO3 gene. Two of these were newly identified homozygous and non-synonymous mutations, causing effectively damage to the protein by in silico analysis. The other two mutations were previously reported in Tunisian patients with HGPPS. Mutations were validated by Sanger sequencing in parents and affected individuals. Conclusion: To the best of our knowledge, this is the largest ever reported cohort on families with HGPPS in whom ROBO3 mutations were identified. These molecular findings have expanded our knowledge of the ROBO3 mutational spectrum. The relevance of our current study is twofold ; first to assist proper management of the scoliosis and second to protect families at risk.

Horizontal Gaze Palsy with Progressive Scoliosis with Overlapping Epilepsy and Learning Difficulties: A Case Report

“…When better reported, progressive scoliosis is in the thoracic or thoracolumbar area [18] and presents with varying levels of severity that justify physical therapy, braces, and, more often, spinal surgery.…”

Extrapyramidal Involvement as a Manifestation of ROBO3 Mutation in HGPPS: A Case Report and Review of Literatures

“…From the first published case of HGPPS in 1975 to the recent, extrapyramidal signs have been occasionally reported along with cardinal manifestations of the disease, as facial myokymia was one of the significant signs of the very first reported patient with HGPPS [6] and some other extrapyramidal findings such as torticollis and head titubation, mentioned in many of afterward case reports; Nevertheless, not only the pathophysiology of these signs has not been fully explained, but also in some level ignored to be considered as a part of the syndrome. Although some authors have been focusing on extrapyramidal findings in HGPPS by arranging them into different categories [5,7], but there is no further investigation to any of those.…”

“…30 cases had a sign of extrapyramidal involvement, consisting 32% of total reports. Torticollis was the most reported clinical finding corelate with extrapyramidal manifestation, observed in 43% of these cases [5,[8][9][10][11], followed by dystonic head tremor detected in 40% of cases [7,[12][13][14][15] and facial contraction developed in 20% of cases [7,15,16]. One patient showed the combination of facial spasm along with dystonic head tremor [6].…”

“…Furthermore, persistence of some unusual clinical findings reported in various published cases such as torticollis, facial spasm and cervical dystonia, have not been favorably explained or linked to the disease. Recently it has been addressed that torticollis which has been reported in several studies, can be a reason for discovery [5].…”

Utility of Whole-Exome Sequencing in Pediatric and Medical Diagnosis

“…It was found that four distinct homozygous mutations in the ROBO3 gene were responsible. Two of those mutations novel homozygous, causing effective damage to the protein by in-silico analysis [65]. Another disease with genetic heterogeneity is cerebral palsy (CP) a common, clinically heterogeneous set of disorders that affects the movement and posture of an individual.…”