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Blink reflex (patient 1). R1 was elicited ipsilaterally to the stimulus (Stim) and R2 on both sides.
Source publication
Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations of the ROBO3 gene, which encodes a receptor associated with axonal guidance during development. Although there is evidence for uncrossed cuneatal and corticospinal tracts in HGPPS, it is unclear whether other central nervous system pathways are involved.
To study two pat...
Context in source publication
Citations
... 24 Preclinic and clinic studies revealed that ROBO3 variants also cause impairment in auditory pathways and alterations in brain stem auditory evoked potentials. 29 Sensorineural hearing loss is documented in two of our patients. Based on our findings and previous reports, sensorineural hearing loss can be a component of the clinical phenotype. ...
Objective
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive disorder resulting from axonal midline crossing defect due to variants in ROBO3.
Methods
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.
Results
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.
Interpretation
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.
... However, patients with later-onset eye movement disorders have also been reported (Chan et al., 2006). In contrast to many other case reports, our patient did not present with nystagmus, and no other clinical symptoms associated with HGPPS, such as sensorineural hearing impairment, ipsilateral stroke, and nodding of the head, were observed (Amoiridis et al., 2006;Arlt et al., 2015;Bosley et al., 2005;Ng et al., 2011;Yamada et al., 2015). Approximately one-third of patients present with motor delay and several patients have shown intellectual disability (Xiu et al., 2021). ...
Background:
Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.
Methods:
We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.
Results:
We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10-4 , by a review of our in-house database.
Conclusion:
This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.
... All findings related to the sensory and motor system provided consistent results with dominantly ipsilateral fMRI motor activations in the primary sensorimotor area, and ipsilateral ascending and descending tractography without crossing fibers at the level of the brainstem and superior peduncle. Additionally, ipsilateral SSEPs and MEPs results are consistent with previous investigations [29] . ...
Horizontal gaze palsy with progressive scoliosis is a rare entity with few cases in the literature. Despite the fact the patient will not present with typical symptoms of this syndrome, clinical suspicion should be raised particularly in terms of imaging findings. Imaging findings are characteristic to flag the possibility of this syndrome. Keeping in mind such congenital abnormalities on magnetic resonance imaging particularly for radiologists might help in the management process. Multidisciplinary teams play a crucial role in terms of communication to find the clinical, radiological and genetic studies to reach the diagnosis.
... No cases of comorbid epilepsy or electroencephalographic abnormalities are known. Some authors, however, reported the presence of other neurologic anomalies, such as trunk imbalance, altered walking, coordination and reflexes disturbances, intention tremor, headache, hearing impairment, and head movements as compensations for the horizontal gaze restriction (see Table 1) [6,16,19,[21][22][23][24][25][26]. If, on the one hand, the coexistence of these symptoms could be interpreted as occasional, it could suggest a more widespread brainstem lesion in some HGPPS patients with the possibility that a spectrum of abnormalities might be included [7]. ...
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital disease characterized by the absence of horizontal gaze movements, progressive scoliosis, and typical brain, cerebellum, and medullary malformations. Here we describe a pediatric HGPPS case with overlapping epilepsy and learning difficulties. A 6-year-old girl was admitted to the University Hospital of Bari for the onset of a tonic–clonic seizure. Electroencephalogram showed slow and sharp waves on the right side with the tendency to diffuse. Brain magnetic resonance imaging demonstrated malformations compatible with HGPPS. Ophthalmological and orthopedic evaluations confirmed conjugate horizontal gaze palsy and mild thoracolumbar scoliosis. Neuropsychological assessment attested normal intelligence but serious difficulties in reading and writing. In spite of neuroradiological malformations, visual difficulties, and spinal deformities, literature data are limited about any coexisting neurocognitive HGPPS symptoms. Literature data regarding such topics are very limited. If, on the one hand, the coexistence of such symptoms can be interpreted as occasional, it could support the idea that they could fall within a spectrum of HGPPS anomalies. In addition to the standard investigations, the activation of specific neuropsychological assessment programs could help interventions improve the specialist care and the quality of life of HGPPS patients.
... Active forms of MMP have been found in ME effusions, particularly in mucoid versus serous effusions. [47][48][49] Several additional genes associated with the axonal guidance pathway, including EPHA7, GNG11, HHIP, NGF, NTF3, PDGFB, ROBO3, SEMA, SLIT, and WNT gene families, are involved in auditory development and otoprotection, [50][51][52][53][54][55][56][57][58][59][60][61][62][63] and several genes share common pathways. ...
Objectives
Otitis media (OM) is the most common pediatric diagnosis in the United States. However, our understanding of the molecular pathogenesis of OM remains relatively poor. Investigation of molecular pathways involved in OM may improve the understanding of this disease process and elucidate novel therapeutic targets. In this study, RNA sequencing (RNA‐Seq) was used to discern cellular changes associated with OME compared to healthy middle ear epithelium (MEE).
Study Design
Ex vivo case‐control translational.
Methods
Middle ear epithelia was collected from five pediatric patients diagnosed with OME undergoing tympanostomy tube placement and five otherwise healthy pediatric patients undergoing cochlear implantation. Specimens underwent RNA‐Seq and pathways analyses.
Results
A total of 1,292 genes exhibited differential expression in MEE from OME patients compared to controls including genes involved in inflammation, immune response to bacterial OM pathogens, mucociliary clearance, regulation of proliferation and transformation, and auditory cell differentiation. Top networks identified in OME were organismal injury and abnormalities, cell morphology, and auditory disease. Top Ingenuity canonical pathways identified were axonal guidance signaling, which contains genes associated with auditory development and disease and nicotine degradation II and III pathways. Associated upstream regulators included β‐estradiol, dexamethasone, and G‐protein‐coupled estrogen receptor‐1 (GPER1), which are associated with otoprotection or inflammation during insult.
Conclusions
RNA‐Seq demonstrates differential gene expression in MEE from patients with OME compared to healthy controls with important implications for infection susceptibility, hearing loss, and a role for tobacco exposure in the development and/or severity of OME in pediatric patients.
Level of Evidence
4 Laryngoscope, 2021
... Thirty-two patients had previous reports of nystagmus, 31 of which showed horizontal eyeball vibration and 1 showed vertical eyeball vibration (Haller et al. 2008). In addition to the typical symptoms, patients also showed strabismus, bilateral early-onset sensorineural hearing impairment, ipsilateral stroke, and intermittent nodding and shaking of the head (Amoiridis et al. 2006;Yamada et al. 2015;Ng et al. 2011;Arlt et al. 2015;Bosley et al. 2005). It is possible for patients to develop motor developmental delays though their intelligence is normal. ...
... It is possible for patients to develop motor developmental delays though their intelligence is normal. Out of the 76 patients, 25 had previous reports of retarded motor development, while 5 patients had previously reported mental retardation (Mendes Marques et al. 2017;Kurian et al. 2013;Amoiridis et al. 2006;Bosley et al. 2005). Despite most patients manifesting horizontal gaze palsy at an early stage, there were delays in HGPPS diagnosis. ...
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.
... Jen et al.'s [1] study did demonstrate that the ascending and descending spinal tracts do not cross over on neurophysiologic studies in patients with axon guidance anomalies of the neural system. Amoiridis et al. [8] have reported that electrophysiological studies show both crossed and uncrossed tracts in HGPPS cases. Haller et al. [9] have also recorded that SSEPs and MEPs can detect the uncrossed sensory and motor spinal tracts, and these appear to be partial and often asymmetric in their patients. ...
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.
... Currently, the treatment is through spinal surgery [4,5]. These patients appear to have few functional consequences, but results from standardized neuropsychological tests are currently unknown [6]. In 2004, this pathogenesis was linked to mutations on ROBO3 genes in consanguineous families with autosomal recessive inheritance pattern of the disease [7]. ...
... Forty-three different mutations located in diverse encoded protein domains have also been identified and are believed to decrease the axon-guidance receptor function [3]. Neuroimaging and neurophysiologic studies provide non-crossed motor and sensory pathways evidence in patients with HGPP [6]. Horizontal gaze palsy may be due to defects in the abducens nuclei (CN VI), which contain ipsilaterally and interneuronal motor neurons that project contralaterally, or supranuclear control regions, such as the paramedian pontine reticular formation (PPRF), which project to the abducens and oculomotor nuclei [7]. ...
... The initial extracted data items comprised the following: (1) authors and publication year; (2) study design (case report or retrospective case series); (3) conflict of interest declaration (yes or no; if yes, which?); (4) subjects' age (in years), and if the study had several The systematic review data information was extracted according to study characteristics and main outcome measures. The initial extracted data items comprised the following: (1) authors and publication year; (2) study design (case report or retrospective case series); (3) conflict of interest declaration (yes or no; if yes, which?); (4) subjects' age (in years), and if the study had several subjects, the average was reported; (5) the percentage of females in the study; (6) relationship between the cases (if the study did not precisely report the family relationship, it was described as family); (7) ethnicity of the subjects; (8) parents' relationship (if the study did not report the parents' exact relationship, it was described as consanguineous); (9) best corrected visual acuity (BCVA) expressed on the Snellen scale; (10) visual axis alignment (the magnitude, eye, and orientation of the tropia was described when the study reported it); (11) horizontal gaze status (absence, palsy, restricted or convergence status); (12) vertical gaze status (limited or normal); (13) magnetic resonance imaging (MRI) findings with a description of brainstem and medulla characteristics; and (14) spine characteristics with scoliosis Cobb's angle reported when available. ...
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.
... In fact, several previous studies had reported patients without congenital decussation of corticospinal tract, but the lack of crossing fibers of those patients often was associated with congenital malformations, such as horizontal gaze palsy with progressive scoliosis (HGPSS), lissencephaly or Dandy Walker malformations [11,[13][14][15][16]. In a literature review of ipsilateral hemiparesis in stroke [5], three patients (18%/n = 17) showed structural defect, such as HGPSS and corpus callosum agenesis. ...
Background:
Cerebral infarction occurs when the arteries to brain are obstructed, and motor impairment contralateral to responsible lesion is commonly recognized. Few studies have profiled the characteristics of cases with ipsilateral motor impairment. We sought to characterize clinical features of patients with motor dysfunction caused by ipsilateral ischemic stroke.
Methods:
We retrieved and analyzed the medical data for patients with ipsilateral cerebral infarction. Patients were regarded as having ipsilateral cerebral infarction if motor impairment is ipsilateral to recent stroke lesions.
Results:
Only 22 patients with unusual ipsilateral cerebral infarction were included in this study. Ipsilateral limb paralysis was observed in all cases, and one case showed central facioplegia. Majority of patients with limb paralysis (90.9%, 20/22) presented with mild muscle strength deficits (MRC grading of 4 or more). Most of the patients (72.7%, 16/22) had a past history of stroke, and previous strokes were contralateral to the side of the recent stroke in 14 out of 16 patients (87.5%). No history of stroke or cerebral injury was identified in seven patients. With aspect of MRI findings, recent infarct lesions of all cases were located along the corticospinal tract.
Conclusions:
History of stroke plays an important role in the pathogenesis of ipsilateral motor impairment, and cortical reorganization in the unaffected hemisphere may contribute to the compensation of motor function after stroke. Besides that, some cases with first stroke may be due to impairment of ipsilateral uncrossed corticospinal fibers.
... Imaging studies revealed that midline crossing is disrupted for the superior cerebellar peduncles and pontine axons, that normally project contralaterally through the middle cerebellar peduncles [154]. The auditory pathways are also compromised [155,156]. Axon projection analysis in robo3 mutant mice has shown a reduction in cochlear nucleus projections that normally cross the midline [36], suggesting that defects in this pathway may contribute to the auditory deficits observed in human disease. ...
... Studies in robo3 mutant mice have similarly reported the persistence of forebrain commissures [149] as well as commissures continuing to be present in the dorsal spinal cord [9]. Functionally, HGPPS patients generally perform well on neuropsychological testing and do not exhibit mirror movements [155], suggesting that a non-decussating CST alone is insufficient to produce mirror movements. Instead, the development of these mirror movements may require the contralateral sprouting of CST axons in the spinal cord as in Klippel-Feil syndrome [29], raising the intriguing possibility that ROBO3 may be required for this contralateral sprouting. ...
During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.
