Search Results (22)

Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft^® Excel^® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression. Full article

Background/Objectives: Joubert syndrome (JS, MIM 213300) is a rare genetic condition characterized by respiratory control disturbances, abnormal eye movements, ataxia, cognitive impairment, and the notable agenesis of the cerebellar vermis. The molar tooth sign visible in magnetic resonance imaging of the brain serves as a diagnostic tool for JS. Variants in the TCTN3 gene can lead to the development of several diseases, including JS type 18, Orofaciodigital syndrome IV, and Meckel–Gruber syndrome. Methods: We performed whole-exome sequencing (WES) in a 49-year-old woman with JS characterized by severe intellectual disability, ataxic gait, agenesis of the cerebellar vermis leading to the molar tooth sign, dystonic movements, strabismus, and nystagmus. Moreover, the patient also showed a thickened corpus callosum. Results: Molecular analysis through WES revealed the heterozygous variants c.182dup (p.G62Wfs*18) and c.1452+4del in the TCTN3 gene, expanding our understanding of the genetic diversity and potential phenotypic implications associated with TCTN3 variations. Conclusions: To our knowledge, this is the first patient with JS and a thickened corpus callosum. Moreover, a thickened corpus callosum has never been identified in patients with pathogenic variants of the TCTN3 gene. Full article

Background and Objectives: Poretti–Boltshauser syndrome (PBS) is a rare, autosomal recessive disorder caused by pathogenic variants in the LAMA1 gene, resulting in laminin dysfunction. This manifests as a cerebellar malformation with cysts, and patients present with developmental delay and ataxia; however, ocular features are not well-characterised. We aimed to summarise the ocular phenotypes of PBS based on cases reported in the literature. Materials and Methods: A literature search was conducted on Medline, Embase, and PubMed on PBS and its ocular associations. Genetically confirmed PBS cases were reviewed, and genotype–phenotype correlations were investigated. Results: Comprehensive reporting of genotypes and associated systemic and ocular phenotypes was available in 51 patients with PBS, who had 52 distinct variants in LAMA1. Most patients carried homozygous variants. The most common genotype was a c.2935delA homozygous mutation, followed by the c.768+1G>A; c.6701delC compound heterozygous mutation. High myopia was the most common ocular phenotype (n = 39), followed by strabismus (n = 27) and ocular motor apraxia (n = 26). A wide range of other ocular manifestations, including retinal dystrophy, retinal neovascularisation, retinal detachment, strabismus, nystagmus, optic disc and iris hypoplasia, were reported. Patients with the same genotype exhibited variable expressivity. Conclusions: PBS has a broad ocular phenotypic spectrum, and characterisation of this variability is important for making an accurate diagnosis and informing genetic counselling. Full article

Purpose: To present the current state of knowledge and our diagnosed patients with congenital stationary night blindness. Material and methods: Data from the PubMed database on CSNB and the presentation of patients with complete and incomplete forms of this condition. Patients underwent routine ophthalmologic examination, optical coherence tomography, and full-field elecroretinogram (ERG-ISCEV), ON-OFF ERG. Results: CSNB is a group of rare, non-progressive retinal diseases characterized by impaired night vision from birth, reduced visual acuity, myopia, nystagmus, and strabismus. Color vision and fundus imaging are most often normal. CSNB is mainly inherited autosomal recessively. Eighteen genes with more than 360 pathogenic variants have been detected in this condition. The effect of gene mutations is to damage the function of rods (Riggs type) and bipolar cells of the retina (Schubert–Bornstein type). The key diagnostic test in CSNB is ERG. In diagnosed cases of complete CSNB the following types have been registered: rod ERG absent, rod–cone response negative (ON bipolar cell defect), and photopic ERG enlarged a-wave. In incomplete CSNB-rod ERG-subnormal, rod-cone response-negative (bipolar cell defect ON, OFF), photopic ERG-subnormal with a double peak in the flicker fusion frequency. Knowledge of the phenotypic changes associated with various gene pathogenic variants is still very limited, hindering the ability to correctly diagnose a patient based on clinical examination and additional ophthalmologic tests. However, some phenotypic features found in our cases were consistent with pathogenic variants previously described in the literature and helped to make a diagnosis that was proven by genetic testing. Conclusions: Congenital stationary night blindness should be considered in the diagnosis of retinal diseases manifesting with impaired night vision. A correct diagnosis is especially important for the patients, as it is nonprogressive, unlike other diseases that should be considered in the differential diagnoses. Full article

Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the smallest of the three, a 23 kb duplication on chromosome 4 (hg38|4:25,554,985-25,578,843). Methods: Using CRISPR and bridging oligos, we introduced the duplication into the Kolf2.1J iPSC line. We differentiated the parent line and the line with the duplication into cortical neurons using a three-dimensional differentiation protocol, and performed bulk RNASeq on neural progenitors (day 14) and differentiated neurons (day 63). Results: We successfully introduced the duplication into Kolf2.1J iPSCs by nucleofecting a bridging oligo for the newly formed junction along with cas9 ribonucleoparticles. We confirmed that the cells had a tandem duplication without inversion or deletion. The parent line and the line with the duplication both differentiated into neurons reliably. There were a total of 37 differentially expressed genes (DEGs) at day 63, 25 downregulated and 12 upregulated. There were 55 DEGs at day 14, 18 of which were also DEGs at day 63. The DEGs included a number of protocadherins, several genes involved in neuronal development, including SLITRK2, CSMD1, and VGF, and several genes of unknown function. Conclusions: A copy number variant (CNV) that confers risk for strabismus affects gene expression of several genes involved in neural development, highlighting that strabismus most likely results from abnormal neural development, and identifying several new genes and pathways for further research into the pathophysiology of strabismus. Full article

Background/Objectives: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in KIDINS220 cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them. Methods: We performed whole exome sequencing (WES) and a literature and mutation databases review. Results: We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in TUBB3 tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G > T) p. Glu 1382* in KIDINS220 that was predicted to be causative of SINO. Conclusions: The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole KIDINS220-related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype. Full article

Background: The dysregulation of extraocular muscles (EOMs) in the strabismus may be partly due to modification in the mitochondrial DNA (mtDNA). Currently, little is known about changes occurring in mtDNA of EOMs in patients with strabismus, therefore the aim of our study was to analyze if there are any changes occurring in the mitochondrial DNA of extraocular muscles in children that underwent strabismus surgery in our clinic. Methods: MtDNA was isolated from the tissue material using the Qiagen kit. Assessment of mtDNA mutations was performed by next-generation sequencing (NGS) using the Illumina MiSeq protocol. Results: The examination revealed the presence of atrophic changes in muscle fibers. NGS evaluation revealed a dominant genetic mutation in the ANT1 gene in 12 of the 15 patients examined. Conclusions: The presented results constitute the beginning of research on changes in mtDNA occurring in the muscles of children with strabismus surgery. Further studies are necessary in the context of resolving the transcriptomic differences between strabismic and non-strabismic EOMs. Better understanding of the molecular genetics of strabismus will lead to improved knowledge of the disease mechanisms and ultimately to a more effective treatment. Full article

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10⁻⁸, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10⁻⁶. In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10⁻⁸ in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus. Full article

Heterozygous mutations in the FOXP1 gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as “intellectual developmental disorder with language impairment with or without autistic features” (OMIM#613670) or FOXP1 syndrome for short. The main features of the condition are global developmental delay/intellectual disability; speech impairment in all individuals, regardless of their level of cognitive abilities; behavioral abnormalities; congenital anomalies, including subtle dysmorphic features; and strabismus, brain, cardiac, and urogenital abnormalities. Here, we present two siblings with a de novo heterozygous FOXP1 variant, namely, a four-year-old boy and 14-month-old girl. Both children have significantly delayed early psychomotor development, hypotonia, and very similar, slightly dysmorphic facial features. A lack of expressive speech was the leading symptom in the case of the four-year-old boy. We performed whole-exome sequencing on the male patient, which identified a pathogenic heterozygous c.1541G>A (p.Arg514His) FOXP1 mutation. His sister’s targeted mutation analysis also showed the same heterozygous FOXP1 variant. Segregation analysis revealed the de novo origin of the mutation, suggesting the presence of parental gonadal mosaicism. To the best of our knowledge, this is the first report of gonadal mosaicism in FOXP1-related neurodevelopmental disorders in the medical literature. Full article

Bovine ocular diseases are typically characterized by the concurrent appearances of both macroscopic and intraocular abnormalities. This study examines the diagnostic efficacy of a combination of ultrasonography and magnetic resonance imaging (MRI) for the bilateral ocular disease observed in a 9-month-old Japanese Black heifer. This case presented with bilateral strabismus and a white-colored lens structure in the right eye. A combination of ultrasonography and MRI revealed formations of corn-like and V-shaped membranous structures within the vitreous cavities of the left and right eyeballs, respectively. In the right eye, a cataract was suspected on both ultrasonogram and MRI. This case involved bilateral retinal detachments and strabismus similar to the signs of an autosomal recessive hereditary ocular disease; however, the cataract in the right eye differed from that hereditary disease. Finally, in genetic analysis, a known mutation of the WFDC1 gene was not detected. Ultrasonography is superior to MRI in demonstrating intraocular pathological changes. On the other hand, MRI is helpful for evaluating invasiveness of the ocular lesions to the peripheral structures. Thus, the combined use of these imaging modalities is recommended for diagnosing various bovine ocular diseases. Full article

Strabismus, a neuro-ophthalmological condition characterized by misalignment of the eyes, is a common ophthalmic disorder affecting both children and adults. In our previous study, we identified the microsomal glutathione S-transferase 2 (MGST2) gene as one of the potential candidates for comitant strabismus susceptibility in a Japanese population. The MGST2 gene belongs to the membrane-associated protein involved in the generation of pro-inflammatory mediators, and it is also found in the protection against oxidative stress by decreasing the reactivity of oxidized lipids. To look for the roles of the MGST2 gene in the development, eye alignment, and overall morphology of the eye as the possible background of strabismus, MGST2 gene knockout (KO) mice were generated by CRISPR/Cas9-mediated gene editing with guide RNAs targeting the MGST2 exon 2. The ocular morphology of the KO mice was analyzed through high-resolution images obtained by a magnetic resonance imaging (MRI) machine for small animals. The morphometric analyses showed that the height, width, and volume of the eyeballs in MGST2 KO homozygous mice were significantly greater than those of wild-type mice, indicating that the eyes of MGST2 KO homozygous mice were significantly enlarged. There were no significant differences in the axis length and axis angle. These morphological changes may potentially contribute to the development of a subgroup of strabismus. Full article

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise. Full article

Background and Objectives: Heterozygous pathogenic variants in the MED13L gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic MED13L deletion in a proband with clinical features of a MED13L-related disorder through extensive clinical, molecular, and functional characterisation. Materials and Methods: Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband’s gDNA sequence (DECIPHER #430183). Intragenic MED13L deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband’s cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a MED13L-gene-silencing experiment in a culture of the control individual’s skin fibroblasts. After the MED13L-gene-editing experiment, subsequent functional fibroblast culture analyses were performed. Results: The analysis of the proband’s cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of MED13L, which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After MED13L gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the RB1, E2F1, and CCNC gene expression were found to exist. Conclusions: Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in MED13L haploinsufficiency due to the premature termination of protein translation, therefore leading to MED13L haploinsufficiency syndrome. Full article

Background: Mowat-Wilson syndrome (MWS) is extremely rare multisystemic autosomal dominant disorder caused by mutations in the Zinc Finger E-Box Binding Homeobox 2 (ZEB2) gene. Ocular pathologies are one of the symptoms that appear in the clinical picture of MWS individuals, but not many have been described so far. Pathologies such as optic nerve or retinal epithelium atrophy, iris or optic disc coloboma as well as congenital cataracts have been most frequently described until now. Therefore, we would like to report the first case of bilateral developmental cataract in a 9-year-old girl with MWS who underwent successful cataract surgery with intraocular lens implantation. Case Presentation: A 9-year-old girl, diagnosed with p.Gln694Ter mutation in ZEB2 gene and suspicion of MWS was referred to the Children’s Outpatient Ophthalmology Clinic for ophthalmological evaluation. Her previous assessments revealed abnormalities of the optic nerve discs. The patient was diagnosed with atrophy of the optic nerves, convergent strabismus, and with-the-rule astigmatism. One year later, during the follow-up visit, the patient was presented with decreased visual acuity (VA), developmental total cataract in the right eye and a developmental partial cataract in the left eye. This resulted in decreased VA confirmed by deteriorated responses in visual evoked potential (VEP) test. The girl underwent a two-stage procedure of cataract removal, first of one eye and then of the other eye with artificial lens implants. In the 2 years following the operation, no complications were observed and, most remarkably, VA improved significantly. Conclusions: The ZEB2 gene is primarily responsible for encoding the Smad interaction protein 1 (SIP1), which is involved in the proper development of various eye components. When mutated, it results in multilevel abnormalities, also in the proper lens formation, that prevent the child from normal vision development. This typically results in the formation of congenital cataracts in children with MWS syndrome, however, our case shows that it also leads to the formation of developmental cataracts. This is presumably due to the effect of the lack of SIP1 on other genes, altering their downstream expression and is a novel insight into the importance of the SIP1 in the occurrence of ocular pathologies. To the best of our knowledge, this is the first case of bilateral developmental cataract in the context of MWS. Moreover, a novel mutation (p.Gln694Ter) in the ZEB2 gene was found corresponding to this syndrome entity. This report allows us to gain a more comprehensive insight into the genetic spectrum and the corresponding phenotypic features in MWS syndrome patients. Full article

Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, SSTR5-AS1 in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in SSTR5-AS1, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in SSTR5-AS1. In the face of newly-registered SSTR5-AS1 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including SSTR5-AS1 as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy. Full article