Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT).

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 µg/µg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 µg/µg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 µg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 µg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.

Ethambutol and visual assessment in England: current practice and recommendations.

BACKGROUND: Standard treatment for tuberculosis (TB) in children and adults includes an initial two-month course of ethambutol, a drug that in rare cases can cause optic neuropathy and irreversible vision loss. There is a lack of clear guidance on what vision assessments are needed before and during treatment with ethambutol, with the Royal College of Ophthalmologists, National Institute for Health and Care Excellence, British National Formulary and British Thoracic Society offering different guidance. We aimed to assess how vision is routinely tested in patients treated with ethambutol in TB services across England. METHODS: An online survey developed by Public Health England was sent to all TB services in England in 2018 to assess current practice and inform the development of best practice recommendations for visual assessment of patients treated with ethambutol for TB. RESULTS: Sixty-six TB professionals from across England responded, a response rate of 54%. The results showed variations in practice, including when to omit ethambutol from treatment, the timing and frequency of visual assessment, the type of visual assessment, referral processes and management of visual changes. CONCLUSION: This national survey highlights the need for clear guidelines on the testing of vision for patients taking ethambutol at recommended doses, before and during treatment. We suggest a pragmatic approach to visual assessment to reduce variation in practice, proposing a stepwise pathway for patients on standard TB treatment for local adaptation.

Monitoring compliance to topical therapy in children and young people with uveitis.

BACKGROUND/OBJECTIVES: Uveitis in children and young people (CYP) is a rare but potentially debilitating condition. Steroid eye drops are the first step in treatment and poor compliance may result in vision-threatening complications. This study aims to measure compliance with prescribed eye drops prospectively in a child-specific manner. SUBJECTS/METHODS: Patients aged 0-18 years attending a tertiary paediatric uveitis clinic using steroid drops were recruited. Both the CYP, and person with parental responsibility (PPR) completed questionnaires about compliance. A subgroup had bottles of Prednisolone 1% drops dispensed and weighed at the first appointment and reweighed at follow-up. The weight reduction was compared with expected weight change over the interval. RESULTS: The study was completed by 42 patients of the 50 patients recruited. Thirty-one CYP and their respective PPR completed both questionnaires, 11 completed only one questionnaire (9 CYP, 2 PPR). Drop errors for all eye drops were reported more than "once a week" by 13/39 CYP (33.3%, 95% CI: 19.1%-50.2% of respondents), and 3/31 PPR (9.7%, CI: 19.1%-50.2% of respondents). Many PPR could not recall prescribed drop frequency (n = 13/31, 40.6%, CI: 23.7%-59.4% of respondents). Twelve patients had bottles weighed and returned. Insufficient weight reduction was found in 9 (75%, CI: 42.8%-94.5%). Within the eye drop weighing subgroup three participants (25%, CI: 5.5%-57.2%) used <50% the expected weight of drops. CONCLUSIONS: This study demonstrated poor eye drop compliance in CYP with uveitis. Self-reported compliance was unreliable in this population. Worryingly, some patients miss more than 50% of drops and may suffer sub-optimal disease control.

Update on the systemic management of noninfectious uveitis in children and adolescents.

Noninfectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, along with the risks of vision loss and the need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in pediatric NIU. Adalimumab, an antitumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for the treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary nonresponse/secondary loss of response to anti-TNF treatment, biological switching, and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

The Role of Genetic Testing in Children Requiring Surgery for Ectopia Lentis.

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis.

Changes in Corneal Clouding Over Time in Patients With Mucopolysaccharidosis.

PURPOSE: Mucopolysaccharidoses (MPSs) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems, including the eye. Visual loss occurs in MPS predominantly due to corneal clouding. Despite the success of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) in improving many systemic manifestations of MPS, less is known about their effect on corneal clouding. This study prospectively analyses the effect of both ERT and HSCT on corneal clouding using objective measures over time. METHODS: This is a prospective longitudinal observational study. Corneal clouding was assessed in each participant using slitlamp, digital slit-lamp photographs, and an iris camera (Corneal Opacification Measure [COM] and the Pentacam system). RESULTS: Data were collected for 65 participants: 39 MPS I (Hurler), 5 MPS II (Hunter), 12 MPS IV (Morquio), and 9 MPS VI (Maroteaux-Lamy). Follow-up data are available for 45 participants (29 MPS I, 3 MPS II, 6 MPS IV, and 7 MPS VI). CONCLUSIONS: This study found corneal clouding to be stable in most participants with MPS I, II, IV, and VI over a follow-up period of 5 to 75 months (median of 30 months) when measured with clinical corneal grading systems, graded digital slit-lamp images, and iris camera COMs. For those with Pentacam densitometry measures, there was a progression of corneal clouding, on average, in those with MPS I and MPS VI. There was no apparent difference in progression of corneal clouding between patients who were on ERT, HSCT, or no treatment.

Tubulointerstitial nephritis and uveitis in children during the COVID-19 pandemic: report of four cases.

Tubulointerstitial nephritis and uveitis (TINU) is a rare autoimmune disorder often triggered by drugs and infections. Since the onset of the COVID-19 pandemic, we have observed an unusual cluster of paediatric cases. Four children (3 females) were diagnosed with TINU (median age 13 years) following a kidney biopsy and ophthalmologic assessment. Presenting symptoms included abdominal pain (3 cases), fatigue, weight loss and vomiting (2 cases). At presentation, median eGFR was 50.3 ml/min/1.73m2 (range 19.2-69.3). Anaemia was common (3 cases) with median haemoglobin of 10.45 g/dL (range 8.4-12.1). Two patients were hypokalaemic and 3 had non-hyperglycaemic glycosuria. Median urine protein:creatinine ratio was 117 mg/mmol (range 68-167). SARS-CoV-2 antibodies were detected in 3 cases at presentation. All were asymptomatic for COVID-19 with a negative PCR. Kidney function improved following high-dose steroids. However, disease relapse was observed during steroid tapering (2 cases) and upon discontinuation (2 cases). All patients responded well to further high dose steroids. Mycophenolate mofetil was introduced as a steroid-sparing agent. At latest follow up (range 11-16 months), median eGFR was 109.8 ml/min/1.73m2. All four patients continue on mycophenolate mofetil, with 2 patients applying topical steroids for uveitis. Our data suggest that SARS-CoV-2 infection might be a trigger for TINU.

Paracentral Acute Middle Maculopathy in A Young Girl Treated with Interferon-Beta for Nasopharyngeal Carcinoma.

PURPOSE: To describe a case of interferon-beta retinopathy associated with paracentral acute middle maculopathy. CASE REPORT: A 15-year-old girl with Epstein-Barr virus-positive advanced nasopharyngeal carcinoma WAS REFERRED with reduced visual acuity. Multimodal imaging findings, including optical coherence tomography angiography, at presentation and evolution following cessation of interferon therapy are presented. CONCLUSION: The presentation of paracentral acute middle maculopathy in this patient supports the presumed ischaemic pathogenesis in interferon retinopathy. The imaging findings provide evidence of deep capillary plexus involvement in interferon retinopathy with evolution to permanent structural damage within the inner nuclear layer.

Bi-allelic mutation of CTNNB1 causes a severe form of syndromic microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia.

BACKGROUND: Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/ß-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. METHODS: Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. RESULTS: In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/ß-catenin pathway. The proband's parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of ß-catenin activity. CONCLUSIONS: This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

Management of Corneal Clouding in Patients with Mucopolysaccharidosis.

Mucopolysaccharidoses (MPS) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems including the eye. Visual loss occurs in MPS predominantly due to corneal clouding and retinopathy, but the sclera, trabecular meshwork and optic nerve may all be affected. Despite the success of therapies such as enzyme replacement therapy (ERT) and hematopoietic stem-cell transplantation (HSCT) in improving many of the systemic manifestations of MPS, their effect on corneal clouding is minimal. The only current definitive treatment for corneal clouding is corneal transplantation, usually in the form of a penetrating keratoplasty or a deep anterior lamellar keratoplasty. This article aims to provide an overview of corneal clouding, its current clinical and surgical management, and significant research progress.

Favourable outcome in paediatric endogenous endophthalmitis secondary to Neisseria meningitidis following pars plana vitrectomy.

Paediatric endogenous endophthalmitis is an uncommon but potentially devastating intraocular infection which should not be missed. Often cases present to the accident and emergency department. Accurate and prompt assessment is key in saving sight and life. We present one such case and how it was surgically managed.

Areas of agreement in the management of childhood non-infectious chronic anterior uveitis in the UK.

BACKGROUND/AIMS: There is a paucity of high-level evidence to support the management of childhood uveitis, particularly for those children without juvenile idiopathic arthritis uveitis (JIA). We undertook a modified Delphi consensus exercise to identify agreement in the management of chronic anterior uveitis (CAU), the most common manifestation of childhood disease. METHODS: A four-round, two-panel process was undertaken between June and December 2017. Paediatric uveitis specialists identified through multiple sources, including a multicentre network (the Paediatric Ocular Inflammation Group), were invited to participate. They were asked whether they agreed with items derived from existing guidelines on the management of JIA-U when extrapolated to the population of all children with CAU. Consensus was defined as agreement greater than or equal to 75% of respondents. RESULTS: 26 of the 38 (68%) invited specialists participated with the exercise, and response rates were 100% for rounds one to three, and 92% for round four. Consensus was reached on 23 of the 44 items. Items for which consensus was not reached included management at presentation, use of systemic and periocular steroids for children with severe disease and the role of conventional steroid sparing immunosuppressants beyond methotrexate. CONCLUSION: The areas of management uncertainty at the level of the group, as indicated by absence of consensus, reflect the areas where the evidence base is particularly poor. Our findings identify the key areas for the future research needed to ensure better outcomes for this blinding childhood ocular inflammatory disorders.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders.

PURPOSE: A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). METHODS: Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. RESULTS: The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). CONCLUSION: Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease.

Thirty percent of all inherited retinal disease (IRD) is accounted for by conditions with extra-ocular features. This study aimed to establish the genetic diagnostic pick-up rate for IRD patients with one or more extra-ocular features undergoing panel-based screening in a clinical setting. One hundred and six participants, tested on a gene panel which contained both isolated and syndromic IRD genes, were retrospectively ascertained from the Manchester Genomic Diagnostics Laboratory database spanning 6 years (2012-2017). Phenotypic features were extracted from the clinical notes and classified according to Human Phenotype Ontology; all identified genetic variants were interpreted in accordance to the American College of Medical Genetics and Genomics guidelines. Overall, 49% (n = 52) of patients received a probable genetic diagnosis. A further 6% (n = 6) had a single disease-associated variant in an autosomal recessive disease-relevant gene. Fifty-two percent (n = 55) of patients had a clinical diagnosis at the time of testing. Of these, 71% (n = 39) received a probable genetic diagnosis. By contrast, for those without a provisional clinical diagnosis (n = 51), only 25% (n = 13) received a probable genetic diagnosis. The clinical diagnosis of Usher (n = 33) and Bardet-Biedl syndrome (n = 10) was confirmed in 67% (n = 22) and 80% (n = 8), respectively. The testing diagnostic rate in patients with clinically diagnosed multisystemic IRD conditions was significantly higher than those without one (71% versus 25%; p value < 0.001). The lower pick-up rate in patients without a clinical diagnosis suggests that panel-based approaches are unlikely to be the most effective means of achieving a molecular diagnosis for this group. Here, we suggest that genome-wide approaches (whole exome or genome) are more appropriate.

Clinical and genetic variability in children with partial albinism.

Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 - a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.

Traboulsi syndrome due to ASPH mutation: an under-recognised cause of ectopia lentis.

Traboulsi syndrome is an extremely rare ophthalmological disorder characterised by facial dysmorphism, lens dislocation, anterior segment abnormalities and spontaneous filtering blebs. It is caused by pathogenic variants in the ASPH gene. To date, only 13 individuals with Traboulsi syndrome from three families have been reported in the literature. We report the first UK family with Traboulsi syndrome associated with two novel ASPH variants. This condition, which has some phenotypic overlap with both Marfan syndrome and homocystinuria, is most likely under ascertained, and we further delineate the clinical features to aid its recognition.

An update on the modern management of paediatric uveitis.

Uveitis in children and young people (CYP) is often painless, chronic and persistent. It is an often silent blinding condition. Uveitis can be isolated or develop as a manifestation of a systemic disease. Due to the symptomless nature, it can present late with advanced ocular comorbidities such as band keratopathy, hypotony, cataracts. Inadequate control of the eye inflammation can result in permanent and severe ocular complications, structural damage and visual loss. One of the most common systemic associations is juvenile idiopathic arthritis where uveitis has a cumulative incidence of approximately 10%-14% (though wide variation in incidence is reported) after 5 years. Appropriately targeted uveitis screening is recommended to continue for at least 7 years in some subgroups. Paediatric uveitis poses multiple diagnostic and therapeutic challenges. Clinical manifestation and disease course may differ significantly from adult-onset uveitis. However, some CYP are still managed by adult specialists alone, without the opportunity for the prompt use of National Health Service England approved therapy. Optimal management of paediatric uveitis requires a multidisciplinary approach involving coordinated working of different specialities and healthcare professionals. This article highlights the evidence-based practice for the contemporary management of paediatric uveitis to readers in different specialities who may come across this condition. It raises awareness of early systemic treatment aiming to achieve early and complete disease inactivity thereby improving the chances of a long-term positive outcome.

Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability.

BACKGROUND: A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. METHODS: An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. RESULTS: Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. CONCLUSION: The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.