Characteristics of beta parapapillary atrophy in primary angle-closure suspect.

OBJECTIVE: To investigate the characteristics of beta parapapillary atrophy (ß-PPA) in patients with primary angle-closure suspect (PACS). METHODS AND ANALYSIS: In total, 215 and 259 eyes with PACS and non-PACS (NPACS), respectively, were enrolled in this observational, cross-sectional study. Stereoscopic fundus and optical coherence tomography images were used to characterise ß-PPA; the former was also used to measure the major ß-PPA parameters. Univariate and multiple logistic regression analyses were used to identify the factors correlated with the presence of ß-PPA and with ß-PPA parameters. RESULTS: The ß-PPA occurrence rates were 48.80% and 44.40% in the PACS and NPACS groups, respectively, with no significant difference between groups. Compared with that in the NPACS group, the ß-PPA area was significantly larger (p=0.005) in the PACS group, but the angular extent and maximum radial length did not differ between groups (p=0.110 and 0.657, respectively) after adjusting for age and axial length. The presence of ß-PPA was associated with older age (OR 1.057, 95% CI 1.028 to 1.088, p<0.001) and larger disc area (OR 1.716, 95% CI 1.170 to 2.517, p=0.006). A larger ß-PPA area was associated with older age (p=0.014), greater vertical cup-to-disc ratio (p=0.028), larger disc area (p<0.001) and PACS diagnosis (p=0.035). CONCLUSION: 48.80% of participants with PACS had ß-PPA, which is slightly larger than NPACS. The area of ß-PPA was larger in PACS, while the angular extent and maximum radial length did not differ between groups.

Bilateral optic atrophy in Wilson disease: A case report and literature review.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical manifestations of WD are complex and variable, with Kayser-Fleischer ring (K-F ring) and the sunflower cataract being the most common ocular findings. Visual impairment is rare in patients with WD. We report the case of a 17-year-old female with bilateral optic atrophy associated with WD and summarize the clinical features of previously reported cases of optic neuropathy in WD, Clinicians should be aware that WD is a rare cause of optic neuropathy and that optic neuropathy in patients with WD may need to be recognized and screened.

Optic Nerve MRI T2-Hyperintensity: A Nonspecific Marker of Optic Nerve Damage.

BACKGROUND: MRI abnormalities are common in optic neuropathies, especially on dedicated orbital imaging. In acute optic neuritis, optic nerve T2-hyperintensity associated with optic nerve contrast enhancement is the typical imaging finding. In chronic optic neuropathies, optic nerve T2-hyperintensity and atrophy are regularly seen. Isolated optic nerve T2-hyperintensity is often erroneously presumed to reflect optic neuritis, frequently prompting unnecessary investigations and neuro-ophthalmology consultations. Our goal was to determine the significance of optic nerve/chiasm T2-hyperintensity and/or atrophy on MRI. METHODS: Retrospective study of consecutive patients who underwent brain/orbital MRI with/without contrast at our institution between July 1, 2019, and June 6, 2022. Patients with optic nerve/chiasm T2-hyperintensity and/or atrophy were included. Medical records were reviewed to determine the etiology of the T2-hyperintensity and/or atrophy. RESULTS: Four hundred seventy-seven patients (698 eyes) were included [mean age 52 years (SD ±18 years); 57% women]. Of the 364 of 698 eyes with optic nerve/chiasm T2-hyperintensity without atrophy, the causes were compressive (104), inflammatory (103), multifactorial (49), glaucoma (21), normal (19), and other (68); of the 219 of 698 eyes with optic nerve/chiasm T2-hyperintensity and atrophy, the causes were compressive (57), multifactorial (40), inflammatory (38), glaucoma (33), normal (7), and other (44); of the 115 of 698 eyes with optic nerve/chiasm atrophy without T2-hyperintensity, the causes were glaucoma (34), multifactorial (21), inflammatory (13), compressive (11), normal (10), and other (26). Thirty-six eyes with optic nerve/chiasm T2-hyperintensity or atrophy did not have evidence of optic neuropathy or retinopathy on ophthalmologic examination, and 17 eyes had clinical evidence of severe retinopathy without primary optic neuropathy. CONCLUSIONS: Optic nerve T2-hyperintensity or atrophy can be found with any cause of optic neuropathy and with severe chronic retinopathy. These MRI findings should not automatically prompt optic neuritis diagnosis, workup, and treatment, and caution is advised regarding their use in the diagnostic criteria for multiple sclerosis. Cases of incidentally found MRI optic nerve T2-hyperintensity and/or atrophy without a known underlying optic neuropathy or severe retinopathy are rare. Such patients should receive an ophthalmologic examination before further investigations.

Bilateral Central Retinal Vein Occlusion Associated with Axitinib Therapy: A Case Report.

PURPOSE: To describe a case of retinal vascular occlusion and cerebrovascular accident following axitinib therapy. METHODS: A retrospective chart review. RESULT: A 65-year-old gentleman with a history of renal cell carcinoma and subsequent metastases to the brain was on axitinib at an oral daily dose of 10 mg. The patient reported a loss in vision in the right, followed by the left eye, and suffered an episode of cerebrovascular accident. Retinal examination revealed right eye optic nerve pallor with sclerosed vessels, possibly sequelae of central retinal vein occlusion, and left eye showed multiple retinal hemorrhages in all quadrants with macular edema, suggestive of central retinal vein occlusion. He was not a known hypertensive, his renal carcinoma was in remission, and his other systemic parameters were within acceptable limits. CONCLUSIONS: Axitinib can cause retinal vein occlusions, and clinicians, both oncologists, and ophthalmologists need to be aware of this rare but potentially blinding side effect.

Reverse Foster Kennedy Syndrome Caused by an Intra-axial Tumor.

We present a case of a 23-year-old male complaining of painless loss of vision in right eye for 1 year and rapidly progressing vision loss in left eye with bilateral lateral rectus palsy. His fundoscopy revealed optic atrophy on the right side and papilledema on the left. Magnetic resonance imaging (MRI) showed intra-axial contrast-enhancing left frontal tumor. We discuss this first case of reverse Foster-Kennedy syndrome in the English literature with emphasis on the clinico-radiological and clinico-histopathological correlation.

Wolfram syndrome in a young woman with associated hypergonadotropic hypogonadism - A case report.

OBJECTIVES: Wolfram syndrome (WFS) is a rare neurodegenerative disease. Clinical diagnosis is made when nonautoimmune insulin-dependent diabetes is found to be associated with bilateral optic atrophy in a patient early in life. Frequent associations include diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Many other multisystemic associations have been described including menstrual irregularities in female and hypogonadism in male patients. CASE PRESENTATION: We present a first case of WFS associated with hypergonadotropic hypogonadism in a female adolescent diagnosed with WFS both clinically and genetically. Other causes of premature ovarian insufficiency (POI) have been excluded. CONCLUSIONS: This case report shows the importance of gonadal function assessment and follow-up in time for both genders.

Wolfram Syndrome 1: From Genetics to Therapy.

Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1.

Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum.

BACKGROUND: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). METHODS: A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. CONCLUSION: WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.

Optical coherence tomography confirms shunt malfunction and recurrence of raised intracranial pressure in optic atrophy.

BACKGROUND: Investigating potential cerebrospinal fluid (CSF) shunt malfunction can be a challenge. Optical coherence tomography (OCT), a non-invasive imaging technique, is used to monitor changes at the optic nerve head in papilloedema. Conventional teaching suggests that in the presence of optic atrophy the optic nerve head may not re-swell in response to a relapse in raised intracranial pressure (ICP). METHODS: A retrospective case series of three patients who had prior CSF diversion surgery for idiopathic intracranial cranial hypertension (IIH) is presented demonstrating the benefit of non-invasive OCT imaging confirming raised ICP. RESULTS: Recurrence of raised ICP, due to malfunctioning CSF shunt, was diagnosed in three patients requiring further surgical intervention. All re-presented acutely with headache and visual disturbances. All had a prior diagnosis of optic atrophy. In all patients, OCT peripapillary retinal nerve fibre layer qualitative image analysis and quantified progression analysis permitted easy detection of the recurrence of papilloedema. CONCLUSION: OCT imaging supports clinical decision making in shunt malfunction, even in the presence of established optic atrophy secondary to IIH.

Wolfram-like syndrome with bicuspid aortic valve due to a homozygous missense variant in CDK13.

BACKGROUND: Wolfram syndrome (WFS) is characterized by deafness, diabetes mellitus, and diabetes insipidus along with optic atrophy. WFS has an autosomal recessive mode of inheritance and is due to variants in WFS1 and CISD2. METHODS: We evaluated the underlying molecular etiology of three affected members of a consanguineous family with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities via exome sequencing approach. We correlated clinical and imaging data with the genetic findings and their associated phenotypes. RESULTS: We identified a homozygous missense variant p.(Asn1097Lys) in CDK13, a gene previously associated with autosomal dominant congenital heart defects, dysmorphic facial features, clinodactyly, gastrointestinal tract abnormalities, intellectual developmental disorder, and seizures with variable phenotypic features. CONCLUSION: We report a homozygous variant in CDK13 and suggest that this gene causes an autosomal recessive disorder with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities.

Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia.

POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.

A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment.

Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.

RTN4IP1 pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the RTN4IP1 gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.

Characteristics of Focal Gamma Zone Parapapillary Atrophy.

Purpose: The purpose of this study was to investigate the characteristics of focal γ-zone parapapillary atrophy (focal γPPA) in patients with primary open-angle glaucoma (POAG) using spectral-domain optical coherence tomography (SD-OCT). Methods: Three groups of POAG eyes (n = 214) were defined according to the circumferential extent of Bruch's membrane (BM) within the ß-zone PPA, as follows: (1) no γPPA (intact BM; n = 81), (2) conventional γPPA (γPPA involving the fovea-BM-opening axis; n = 89), and (3) focal γPPA (γPPA not involving the fovea-BM-opening axis; n = 44). Clinical and ocular characteristics, including age, axial length (AXL), and focal lamina cribrosa (LC) defects were compared among the three groups. Results: The focal γPPA group was significantly older (60.6 ± 11.0 years) and had shorter AXL (24.10 ± 1.34 mm) than those of the conventional γPPA group (46.2 ± 13.8 years and 26.53 ± 1.61 mm, respectively; P < 0.001). These values of the focal γPPA group were similar to those of the no γPPA group (23.73 ± 0.97 mm for AXL and 64.0 ± 13.0 years for age). The focal γPPA group had a significantly higher prevalence of focal LC defects than did the other two groups (70.5% [31/44] for the focal γPPA group versus 46.1% [41/89] for the conventional γPPA group versus 37.0% [30/81] for the no γPPA group; P = 0.002). Conclusions: Focal γPPA was differentiated from conventional γPPA by older age and shorter AXL. Further, focal γPPA was frequently accompanied by focal LC defects. Longitudinal studies elucidating whether focal LC defects and focal γPPA share common pathogenesis are warranted.

Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report.

BACKGROUND: Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM. CASE PRESENTATION: In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene. CONCLUSIONS: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.

The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2.

PURPOSE: To identify symptoms and health care interactions with patients with riboflavin transporter deficiency (RTD) type 2 prior to diagnosis. METHODS: Parents of children with riboflavin transporter deficiency type 2 (n = 10) were interviewed to collect data on the patient's clinical journey. RESULTS: The average diagnostic delay was 27.6 months. Neurologists were the most commonly visited clinician (90%). Common symptoms during the first year of the patient's clinical journey included abnormal gait and/or ataxia (70%), nystagmus (50%), and upper body muscle weakness (40%). Prior to diagnosis, optic atrophy, sleep apnea, breath-holding spells, and dysphagia were commonly observed. Hearing loss was only reported in 40% of subjects prior to diagnosis. Riboflavin responsive megaloblastic anemia is reported for the first time. Mitochondrial disease was the most common suspected diagnosis (30%). CONCLUSION: Despite clinical variability, common early symptoms of riboflavin transporter deficiency type 2 exist that can better allow clinicians to more rapidly identify riboflavin transporter deficiency type 2.

Motor impairment in a rare form of spastic paraplegia (Spoan syndrome): a 10-year follow-up.

BACKGROUND: Spastic paraplegia, optic atrophy and neuropathy (Spoan syndrome) is an autosomal recessive disease with approximately 70 cases recorded in Brazil and Egypt. METHODS: This is a prospective longitudinal study performed with 47 patients affected with Spoan syndrome of seven communities of Rio Grande do Norte (Brazil) to investigate changes in motor function based on comparative data obtained from a 10-year follow-up. RESULTS: The mean age of the participants was 47.21 ± 12.42 years old, and the mean age at loss of ambulation and hand function were 10.78 ± 5.55 and 33.58 ± 17.47 years old, respectively. Spearman's correlation analysis between the score on the Modified Barthel Index and the investigated variables evidenced statistical significance for age (p < 0.001) and right- and left-hand grip strength (p = 0.042 and p = 0.021, respectively). Statistical significance was not evidenced for the remainder of the variables, including age at onset of symptoms (p = 0.634), age at loss of ambulation (p = 0.664) and age at loss of hand function (p = 0.118). CONCLUSIONS: Our analysis allows asserting that the participants exhibited slight dependence until age 35. The greatest losses occurred from ages 35 to 41, and starting at 50, practically all patients become completely dependent. These findings are relevant for determining the prognosis as well as suitable treatment, rehabilitation and assistive technology for these individuals.

Binasal hemianopia caused by pneumosinus dilatans of the sphenoid sinuses.

Bitemporal hemianopia is a significant pathological hallmark of a pituitary lesion; however, binasal hemianopia is rarely reported, except for its known association with other ocular diseases rather than with brain lesions. We report a 24-year-old male with binasal hemianopia caused by pneumosinus dilatans of the sphenoid sinuses.

Clinical Profile of Low Vision Patients Attending in Low Vision Clinic in a Tertiary Care Hospital.

The purpose of the study was to determine the disease profile of patients attending the low vision clinic of a tertiary eye care hospital at National Institute of Ophthalmology & Hospital (NIO&H), Dhaka, Bangladesh July 2016 to June 2017. Low vision and blindness are major causes of morbidity and an economic burden on the individual, family and the country. Low vision service has emerged as a major challenge faced by the developing countries .so prompt diagnosis; early treatment and early use of low vision devices can improve the quality of life. It was a prospective observational study conducted in low vision clinic at a tertiary care hospital in Bangladesh for one year. A total 419 patient, aged 6-60 years among them 267(63.7%) were male and 152(36.3%) were female. The leading causes of low vision in patient attending the low vision clinic were Retinitis pigmentosa (31.3%) macular dystrophy/stargards diseases & maculopathy (20.3%) and myopia with macular degeneration (14.8%). The percentage of visual impaired (6/18-6/60) were 38.3%, severely visual impaired (<6/60-3/60) were 24.4% & (<3/60) 37.3%. Almost all the patient was prescribed spectacles and Telescope for distant vision, Hand held magnifier and video magnifier were prescribed for near vision. Vision improved with low vision devices (6/18 or better) in 49.5%, (6/18-6/60) in 47.3%, (<6/60-3/60) in 2.8%, (<3/60) in 0.3% patient. Vision with low vision devices were significantly changes (p=0.001). The present study shows that hereditary ocular anomalies (Retinitis pigmentosa, macular dystrophy, myopic degeneration) and amblyopia were more common causes of low vision in this part of world.