Horizontal Gaze Palsy With Progressive Scoliosis Research Articles

Horizontal gaze palsy with progressive scoliosis: Further expanding the ROBO3 spectrum.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive disorder resulting from axonal midline crossing defect due to variants in ROBO3. We retrospectively evaluated demographics, clinical phenotype, course of spinal deformities, and neuroimaging findings of six Turkish patients with HGPPS. We performed targeted gene testing by next-generation sequencing. The median age at symptom onset and diagnosis was 1.5 years (0.5-4), and 11 years (2-16), respectively. Oculomotor signs were the most common presenting symptom (n = 4), followed by scoliosis (n = 2). The course of scoliosis was progressive and accompanied by kyphosis, showed intrafamilial variability, and was corrected surgically in three of the patients. Intellectual disability (n = 4), hypergonadotropic hypogonadism (n = 2), hearing loss (n = 2), and tranisent movement disorders (n = 1) were additional features. Targeted gene sequencing revealed five distinct homozygous variants. Of the four novel variants, two of them were located in the acceptor site of the noncoding region of the gene, remaining two were missense and frameshift variants, located in immunoglobulin-like domain-2, and cytoplasmic signaling motif 2, respectively. Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) showed the absence of decussation of superior cerebellar peduncle and dorsal transverse pontine fibers. Spectrum of HGPPS is further expanded with novel variants in the ROBO3 with clinical and radiological fingerprints. Spinal deformities require close orthopedic screening and individualized approach. Intellectual disability and hearing loss emerge as additional features. Hypogonadism and transient subtle movement disorders require further attention and confirmation from other series.

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations.Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patientsand 15 patientsfrom 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES wasperformed in 122 CCDDspatients.Tenpathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM)and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.

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

HGPPS (horizontal gaze palsy with progressive scoliosis) presents in early childhood ages and one of the cardinal manifestations of the syndrome, progressive scoliosis, is the main disabling feature which usually seeks for orthopedic correction surgeries in early years. Nevertheless, the presence of scoliosis has not been explained yet by the pathogenesis of the disease, the ROBO3 mutation, which is a well-known pathology for gaze palsy by failure of axonal decussation toward the pontomedullary junction. This article highlights a novel case of HGPPS with prominent extrapyramidal findings including torticollis, cervical dystonia and facial spasm along with classic clinical, imaging and genetic correlation. Aiming to investigate the prevalence of extrapyramidal signs in this syndrome, the published cases of HGPPS in the literature have been reviewed in this study. 32% of all HGPPS cases between years of 1975 to 2020 founded to have one or more extrapyramidal features and the dystonia was the most reported sign which even proceed to the presence of scoliosis. Regarding to the fact that the scoliosis could be as a consequence of axial dystonia, its relationship to ROBO3 mutation can be explained by structural and functional changes toward the brainstem and cerebellum, which are involved in this syndrome and known to contribute with the extrapyramidal system. Knowing this possibility, not only could solve the 35-year mystery of scoliosis in the syndrome, but also would be considered as a target of treatment to prevent scoliosis in the future.

Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessively inherited disorder characterized by a congenital absence of conjugated horizontal eye movements with progressive scoliosis developing in childhood and adolescence. HGPPS is caused by mutations of the ROBO3 gene that disrupts the midline crossing of the descending corticospinal and ascending lemniscal sensory tracts in the medulla. We present two siblings, 5-year-old and 2-year-old boys with HGPPS, from non-consanguineous parents. The older brother was brought for the evaluation of moderate psychomotor retardation. He had bilateral horizontal gaze palsy with preserved vertical gaze and convergence. Scoliosis was absent. Cranial MRI showed brainstem abnormalities, and diffusion tensor imaging showed absent decussation of cortico-spinal tracts in the medulla. Clinical diagnosis of HGPPS was confirmed by sequencing of ROBO3 gene, IVS4-1G > A (c.767-1G > A) and c.328_329delinsCCC (p.Asp110Profs*57) compound heterozygous variations were found, and segregated in parents. The younger boy was first reported at 16 months of age and had the same clinical and neuroradiological findings, unlike mild psychomotor retardation. ROBO3 gene analysis showed the same variants in his brother. Our cases show the importance of evaluating eye movements in children with neurodevelopmental abnormalities and looking for brainstem abnormalities in children with bilateral horizontal gaze palsy.

Scoliosis associated with HGPPS syndrome: What do we know?

Horizontal gaze palsy with progressive scoliosis (HGPPS) syndrome is a rare genetic abnormality causing cranial dysinnervation manifesting as absence of conjugate lateral eye movements, nystagmus, and scoliosis. While the genetics, imaging abnormalities, and ocular manifestations have been well described in literature, the spinal deformity has not been addressed adequately. An 11-year-old girl presented with progressive thoracic scoliosis who on evaluation was detected to have all the features of HGPPS syndrome. The patient underwent posterior correction of scoliosis uneventfully. A thorough literature search was performed to understand the descriptors of spinal deformity and its surgery in HGPPS syndrome. The spinal deformity in HGPPS resembles adolescent idiopathic scoliosis. Rapidly progressive right thoracic scoliosis was the usual pattern. Surgical and anesthetic considerations during surgery are similar to idiopathic scoliosis. These children tolerate surgery and anesthesia well. Neuromonitoring changes during surgery need to be interpreted correctly in the background of uncrossed sensory and motor tracts.

Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family

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 1year and scoliosis at the age of 11years. 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.

Mutation in ROBO3 Gene in Patients with Horizontal Gaze Palsy with Progressive Scoliosis Syndrome: A Systematic Review.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, inherited disorder characterized by a congenital absence of conjugate horizontal eye movements with progressive scoliosis developing in childhood and adolescence. Mutations in the Roundabout (ROBO3) gene located on chromosome 11q23–25 are responsible for the development of horizontal gaze palsy and progressive scoliosis. However, some studies redefined the locus responsible for this pathology to a 9-cM region. This study carried out a systematic review in which 25 documents were analyzed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The search was made in the following electronic databases from January 1995 to October 2019: PubMed, Scopus, Web of Science, PEDRO, SPORT Discus, and CINAHL. HGPPS requires a multidisciplinary diagnostic approach, in which magnetic resonance imaging might be the first technique to suggest the diagnosis, which should be verified by an analysis of the ROBO3 gene. This is important to allow for adequate ocular follow up, apply supportive therapies to prevent the rapid progression of scoliosis, and lead to appropriate genetic counseling.

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

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 two-fold; first to assist proper management of the scoliosis and second to protect families at risk.

Signaling from Within: Endocytic Trafficking of the Robo Receptor Is Required for Midline Axon Repulsion.

Signaling from Within: Endocytic Trafficking of the Robo Receptor Is Required for Midline Axon Repulsion.

DTI measurements of non-decussating fibers in defective axon guidance disorders (Horizontal gaze palsy and progressive scoliosis and Joubert syndrome)

Diffusion tensor imaging has been useful in demonstrating non-decussating corticospinal tract (CST) and superior cerebellar peduncles (SCP) in Joubert syndrome (JS) related disorder and in horizontal gaze palsy with progressive scoliosis (HGPPS). However, measurements of fractional anisotropy (FA) and mean diffusivity (MD) have never been performed in these diseases. The aim of our work was to investigate if FA and MD values in uncrossed white matter bundles due to defective axon guidance are different from normal decussating fibers. Two patients with HGPPS and four with JS were included. FA and MD were measured by region of interest manually placed on the CST, the SCP and the posterior rows (PR) of the pons. The same measurements were performed in 59 control patients. Comparison of these values between patients and controls was performed by graphical inspection. MD values were normal in all cases. In all patients with HGPPS and JS, FA measurements in SCP were not different from normal controls. FA values in PR and in CST were not different in JS patients but higher than in controls in HGPPS patients. This difference was statistically significant. Normal MD values seem to indicate that MD and FA values likely represent two very different processes in the developing brain. High FA values in PRs and CST in HGPPS, implicating micro- scopic deficits of axonal structures, is a unique finding in this disease. Abnormal measurements on PR confirm a role of these fibers in the pathogenesis and clinical presentation of HGPPS.

PP05.7 – 2639: Horizontal gaze palsy with progressive scoliosis (HGPPS): The role of brain MRI and diffusion tensor imaging in diagnosis

Introduction Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder characterized by congenital absence of conjugate horizontal eye movements and progressive scoliosis. It is caused by mutations in ROBO3, which plays an important role in midline crossing of selected axonal paths during embryonic stages. Patients A 12-year-old girl was referred with abnormal head movements and thoracolumbar scoliosis. Parents were first cousins. Her parents recognized abnormal eye movements and head titubation and progressive scoliosis, at the age of 1 y, and 7 y respectively. Physical examination revealed mild intellectual disability (ID), nystagmus, horizontal gaze palsy, head titubation and thoracolumbar scoliosis. A 4-year-old sister had scoliosis and titubation after the age of 2 years. She was born at term with a birth-weight of 3000 g via C/S due to breech presentation. She had developmental delay and unsteady gait. Physical examination revealed mild ID, bilateral horizontal gaze palsy, in toeing and scoliosis. MRI showed hypoplasia of the brainstem with a so called “butterfly” medulla oblongata and midsagittal cleft extending ventrally from the 4th ventricle, called as “split pons”. Along with the history and physical examination findings, this characteristic appearance led us to the diagnosis of HGPPS. Diffusion tensor imaging and fiber tractography obtained at 3T with 30 gradient encoding directions depicted absence of decussation of brainstem tracts. In this presentation, we aim to document neurologic and high-resolution MRI and DTI/fiber tractography findings of these siblings with HGPPS, a very rare, but also diagnosed straightforward disease. Robo3 mutation analysis is pending. Conclusion Recognizing typical neuroimaging pattern combined with the clinical picture characterized by gaze palsy and scoliosis are clues to consider HGPPS and Robo3 mutations. The age at presentation of scoliosis and severity differ in two siblings reflecting intra-familial clinical variability in this novel clinical entity.

Ipsilateral hemiparesis caused by putaminal hemorrhage in a patient with horizontal gaze palsy with progressive scoliosis: a case report

BackgroundHorizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by mutations in the ROBO3 gene, resulting in a critical absence of crossing fibers in the brainstem.Case presentationWe present a patient with ipsilateral hemiparesis caused by putaminal hemorrhage who had a history of horizontal gaze paralysis and scoliosis since childhood. Diffusion tensor imaging (DTI) tractography confirmed the presence of uncrossed corticospinal tracts. Sequence analysis of the entire ROBO3 coding regions revealed a novel nonsense mutation.ConclusionWe report the first known HGPPS case with intracranial hemorrhage and ROBO3 mutation showing an absence of major crossing pathways by DTI.

Horizontal gaze palsy with progressive scoliosis in a Moroccan family

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare clinical condition characterized by a combination of horizontal gaze palsy, pendular nystagmus and scoliosis. Only a few cases have been previously described in the literature. Our observations serve to document the first cases in Morocco.

The EBAX-type Cullin-RING E3 Ligase and Hsp90 Guard the Protein Quality of the SAX-3/Robo Receptor in Developing Neurons

Although protein quality control (PQC) is generally perceived as important for the development of thenervous system, the specific mechanisms of neuronal PQC have remained poorly understood. Here, we report that C.elegans Elongin BC-binding axon regulator (EBAX-1), a conserved BC-box protein, regulates axon guidance through PQC of the SAX-3/Robo receptor. EBAX-1 buffers guidance errors against temperature variations. As a substrate-recognition subunit in the Elongin BC-containing Cullin-RING ubiquitin ligase (CRL), EBAX-1 also binds to DAF-21, a cytosolic Hsp90 chaperone. The EBAX-type CRL and DAF-21 collaboratively regulate SAX-3-mediated axon pathfinding. Biochemical and imaging assays indicate that EBAX-1 specifically recognizes misfolded SAX-3 and promotes its degradation invitro and invivo. Importantly, vertebrate EBAX also shows substrate preference toward aberrant Robo3 implicated in horizontal gaze palsy with progressive scoliosis (HGPPS). Together, our findings demonstrate a triage PQC mechanism mediated by the EBAX-type CRL and DAF-21/Hsp90 that maintains the accuracy of neuronal wiring.

The Genetic Basis of Incomitant Strabismus: Consolidation of the Current Knowledge of the Genetic Foundations of Disease

In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept of congenital cranial dysinnervation disorders (CCDDs) was introduced in 2002, and the genetic basis of CCDDs continues to be elucidated. In this review, we aim to provide an update of the genetic and clinical presentation of these disorders. Disorders reviewed include Duane syndrome (DS), HOXA1 and HOXB1 syndromes, Moebius syndrome, congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy with progressive scoliosis (HGPPS).

Early-onset or rapidly progressive scoliosis in children: Check the eyes!

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence, caused by mutations in the ROBO3 gene which has an important role in axonal guidance and neuronal migration. We describe two female children aged 12 years and 18 months, with progressive scoliosis, in whom the neurological examination showed absent conjugate horizontal eye movements, but preserved vertical gaze and convergence. Cerebral Magnetic resonance imaging findings included pontine hypoplasia, absent facial colliculi, butterfly configuration of the medulla and a deep midline pontine cleft, while Diffusion tensor imaging (DTI) maps showed the absence of decussating ponto-cerebellar fibers and superior cerebellar peduncles. Somatosensory and motor evoked potential studies demonstrated ipsilateral sensory and motor responses. The diagnosis was confirmed by the identification of bi-allelic mutations in the ROBO3 gene.

Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.

Ipsilateral Stroke in a Patient With Horizontal Gaze Palsy With Progressive Scoliosis and a Subcortical Infarct

horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital disorder caused by mutation in the ROBO3 gene. It is characterized by absent horizontal eye movements with progressive scoliosis developing in childhood and adolescence. To our knowledge, both diffusion tensor imaging evaluation in HGPPS patients who present with stroke and truncating stop codon mutation in the ROBO3 gene have yet to be reported. we present a man with HGPPS who experienced a left pure motor stroke as a result of a left corona radiata infarct on diffusion-weighted imaging. Diffusion tensor imaging tractography confirmed the presence of uncrossed corticospinal tracts, accounting for the ipsilateral deficit. He was also found to possess a novel ROBO3 stop codon mutation on genetic testing. patients with HGPPS may present with stroke symptoms on the ipsilateral side of the infarct in view of uncrossed corticospinal tracts. Truncating mutation in ROBO3 may provide additional pathophysiologic insights.

Genetic Dissection of the Function of Hindbrain Axonal Commissures

Author SummaryCoordination of the left and right sides of the body requires the action of neurons whose axons cross the nervous system midline. The precise contributions of “commissural” neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels. A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations. This led to disruption of specific commissures in the sensory, motor, and sensorimotor systems, and resulted in severe but specific functional deficits. Surprisingly, although rerouted axons do not cross the midline, they still project to their appropriate neuronal targets, suggesting that midline crossing is not required to complete the axonal guidance program of those neurons. Moreover, some of the mouse lines represent good models for human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS), which is characterized by deficits in coordinated eye movements. This study links defects in commissural axon guidance with specific and dramatic behavioral phenotypes.

Diffusion tensor imaging in horizontal gaze palsywith progressive scoliosis

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare disorder characterized by absence of conjugate horizontal eye movements, preservation of vertical gaze and convergence, progressive scoliosis developing in childhood and adolescence. It is caused by mutations in the ROBO3 gene which are critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging on a 14-year-old boy with HGPPS revealed ipsilateral ascending and descending connectivity in the brainstem without any crossing over of the major tracts although normal interhemispheric connections in the corpus callosum was demonstrable. Absent decussation of smaller sized superior cerebellar peduncles but with normal crossing over of the middle cerebellar peduncle was also observed. Tractography is a valuable investigative modality to assess neuronal connections in the brain and is a useful adjunct to the structural magnetic resonance imaging in confirming the diagnosis of HGPPS.