Jane Ashworth

The ocular features of the mucopolysaccharidoses

AimsThe mucopolysaccharidoses (MPS) are a heterogeneous group of rare disorders characterised by accumulation of glycosaminoglycans within multiple organ systems. This study aimed to determine the prevalence and severity of ocular complications in patients with MPS.MethodsClinical ophthalmic features and electrodiagnostic results of 50 patients with a diagnosis of MPS were retrospectively reviewed.ResultsA total of 79% of MPS IH patients had a visual acuity of less than 6/12 equivalent in their better eye, compared to 44% of MPS IH/S and 25% of MPS VI patients. In total, 16% of MPS IH and 25% of MPS IH/S had severe corneal opacification, compared to 38% of MPS VI patients. 16% of MPS IH patients had optic atrophy; 21% of MPS VI patients had mild disc swelling, 29% had markedly swollen discs, and 14% had optic atrophy. One patient with MPS IH, one with MPS IH/S and six with MPS VI had ocular hypertension. One MPS VI patient had glaucoma that required topical therapy. Nine patients with MPS IH had electrodiagnostic evidence of retinopathy, as did one MPS VI patient.ConclusionsOcular complications causing significant reduction in vision are common in MPS. The majority of MPS I and MPS VI patients have corneal opacification, which can lead to difficulties in diagnosis and monitoring of glaucoma, optic disc changes, and retinopathy.

Advances in the management of congenital and infantile cataract

Congenital and infantile cataracts produce deprivation amblyopia and can thus cause lifelong visual impairment. Successful management is dependent on early diagnosis and referral for surgery when indicated. Accurate optical rehabilitation and postoperative supervision are essential.The timing of surgery and its relationship to the duration of deprivation is important. Unilateral congenital cataract surgery within 6 weeks of birth produces the best outcomes. The equivalent ‘latent’ period for bilateral visual deprivation may be longer at around 10 weeks.Visual deprivation has a significant impact on the development of fixation stability. Major form deprivation, even after early surgery, leads to nystagmus. This is mostly manifest latent nystagmus (MLN). The latent period for fixation stability may be as short as 3 weeks. Preoperative congenital nystagmus (CN) can convert to more benign MLN after surgery.Infantile IOL implantation is becoming increasingly accepted. A satisfactory long-term refractive result requires that allowance be made for childhood axial growth and myopic shift. In a series of 25 infants (33 eyes) implanted before 12 months of age, the mean myopic shift at 12 months was 4.83 D. This increased to 5.3 D in infants implanted before 10 weeks. The initial desired refractive outcome following IOL implantation is thus hypermetropia, with the degree dependent on the age of the child.Glaucoma or ocular hypertension is a common complication following paediatric cataract surgery. Microphthalmia and surgery in early infancy are risk factors. Tonometry results may be influenced by the increased corneal thickness seen in aphakic and pseudophakic children. The long-term prognosis of eyes with aphakic glaucoma is not necessarily poor but intraocular pressure control may require three or more medications. Surgical intervention appears to be necessary in over a quarter of eyes.Posterior capsule opacification (PCO) is common in infants undergoing primary lens implantation. Primary capsulotomy and anterior vitrectomy reduce the risk of PCO. In the absence of anterior vitrectomy, primary posterior capsulotomy does not prevent visual axis opacification.Further developments will continue to be driven by clinical research. The prevention of capsule opacification and cellular proliferation may in future be achieved by the use of devices to specifically target epithelial cells at surgery.

Fibrillin-rich microfibrils: elastic biopolymers of the extracellular matrix.

Fibrillin-rich microfibrils are evolutionarily ancient macromolecular assemblies of the extracellular matrix. They have unique extensible properties that endow vascular and other tissues with long-range elasticity. Microfibril extensibility supports the low pressure closed circulations of lower organisms such as crustaceans. In higher vertebrates, microfibrils act as a template for elastin deposition and are components of mature elastic fibres. In man, the importance of microfibrils is highlighted by the linkage of mutations in their principal structural component, fibrillin-1, to the heritable disease Marfan syndrome which is characterised by severe cardiovascular, skeletal and ocular defects. When isolated from tissues, fibrillin-rich microfibrils have a complex ultrastructural organisation with a characteristic ‘beads-on-a-strong’ appearance. X-ray fibre diffraction studies and biomechanical testing have shown that microfibrils are reversibly extensible at tissue extensions of 100%. Ultrastructural analysis and 3D reconstructions of isolated microfibrils using automated electron tomography have revealed new details of how fibrillin molecules are aligned within microfibrils in untensioned and extended states, and delineated the role of calcium in regulating microfibril beaded periodicity, rest length and molecular organisation. The molecular basis of how fibrillin molecules assemble into microfibrils, the central role of cells in regulating this process, and the identity of other molecules that may coassemble into microfibrils are now being elucidated. This information will enhance our understanding of the elastic mechanism of these unique extracellular matrix polymers, and may lead to new microfibril-based strategies for repairing elastic tissues in ageing and disease.

Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly.

Fibrillin-rich microfibrils are a unique class of extensible connective tissue macromolecules. Their critical contribution to the establishment and maintenance of diverse extracellular matrices was underlined by the linkage of their principal structural component fibrillin to Marfan syndrome, a heritable connective tissue disorder with pleiotropic manifestations. Microscopy and preparative techniques have contributed substantially to the understanding of microfibril structure and function. The supramolecular organisation of microfibrillar assemblies in tissues has been examined by tissue sectioning and X-ray diffraction methods. Published findings are discussed and new information reported on the organisation of microfibrils in the ciliary zonular fibrils by environmental scanning electron microscopy. This review summarises microscopy and X-ray diffraction studies that are informing current understanding of the ultrastructure of fibrillin-rich microfibrils.

Personalized diagnosis and management of congenital cataract by next-generation sequencing.

PURPOSE To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC). DESIGN Evaluation of diagnostic technology. PARTICIPANTS Thirty-six individuals diagnosed with nonsyndromic or syndromic bilateral congenital cataract were selected for investigation through a single ophthalmic genetics clinic. METHODS Participants underwent a detailed ophthalmic examination, accompanied by dysmorphology assessment where appropriate. Lenticular, ocular, and systemic phenotypes were recorded. Mutations were detected using a custom-designed target enrichment that permitted parallel analysis of 115 genes associated with CC by high-throughput, next-generation DNA sequencing (NGS). Thirty-six patients and a known positive control were tested. Suspected pathogenic variants were confirmed by bidirectional Sanger sequencing in relevant probands and other affected family members. MAIN OUTCOME MEASURES Molecular genetic results and details of clinical phenotypes were identified. RESULTS Next-generation DNA sequencing technologies are able to determine the precise genetic cause of CC in 75% of individuals, and 85% patients with nonsyndromic CC were found to have likely pathogenic mutations, all of which occurred in highly conserved domains known to be vital for normal protein function. The pick-up rate in patients with syndromic CC also was high, with 63% having potential disease-causing mutations. CONCLUSIONS This analysis demonstrates the clinical utility of this test, providing examples where it altered clinical management, directed care pathways, and enabled more accurate genetic counseling. This comprehensive screen will extend access to genetic testing and lead to improved diagnostic and management outcomes through a stratified medicine approach. Establishing more robust genotype-phenotype correlations will advance knowledge of cataract-forming mechanisms.

Fibrillin and the eye

The glycoprotein fibrillin is the principal component of the ciliary zonule and has an important role in the strength and elasticity of ocular connective tissues. Fibrillin polymers form the structural scaffold of extensible microfibrils1-3 which are present in ocular elastic tissues and are arranged in parallel bundles to form the zonular fibres.4 These fibrillin-rich microfibrils are morphologically identical to those which provide strength and long range elastic recoil to the connective tissues of blood vessels, lung, ligament, and dermis.5 6 In these tissues, fibrillin-rich microfibrils form a scaffold for the deposition and alignment of the elastin precursor tropoelastin during elastic fibre assembly.7 8 However, the microfibrils of the ciliary zonule as well as those of kidney glomerulus, skeletal muscle, heart, and periodontal ligament do not contain significant amounts of elastin.9 Disorders which disrupt fibrillin-rich microfibril structure or function, such as Marfans syndrome and ectopia lentis, result in a spectrum of ocular complications. This review summarises current knowledge of fibrillin and fibrillin-rich microfibrils and their role in the eye, and discusses the pathological processes which may be involved in ocular connective tissue ageing and disease. In addition to the zonules, fibrillin has been immunolocalised to the connective tissues of the anterior segment including the conjunctival, iris and ciliary body stroma, the ciliary processes, the corneal stroma and corneal epithelial basement membrane, and the endothelium of Schlemms canal.10 In the posterior segment, fibrillin has been localised to scleral stroma, lamina cribrosa, Bruchs membrane, and choroid10; beaded microfibrils are also present in vitreous.11-13 The precise role of fibrillin-rich microfibrils in all these ocular tissues is not defined, but they may regulate development and confer strength and elasticity to connective tissues. Fibrillin present in the equatorial region of the lens capsule allows anchorage of the …

Ocular manifestations as key features for diagnosing mucopolysaccharidoses

Diagnosis of mucopolysaccharidosis (MPS) requires awareness of the multisystem disease manifestations and their diverse presentation in terms of time of onset and severity. Many patients with MPS remain undiagnosed for years and progressively develop irreversible pathologies, which ultimately lead to premature death. To foster timely treatment and ensure a better outcome, it is of utmost importance to recognize and evaluate the typical ocular features that present fairly early in the course of the disease in many children with MPS. These include corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic disc swelling and optic nerve atrophy. Other associations include pseudo-exophthalmos, amblyopia, strabismus and large refractive errors requiring spectacle correction. While some ocular manifestations require specialized equipment for detecting abnormalities, light sensitivity, pseudo-exophthalmos and strabismus are often apparent on a routine physical examination. In addition, patients may be symptomatic from vision impairment, photosensitivity, night blindness and visual field constriction. Combined with the skeletal/joint complications and other manifestations, these ocular features are key in the differential diagnosis of children with joint abnormalities. Rheumatologists should have a high index of suspicion for MPS to facilitate early diagnosis. Referral to a geneticist, a metabolic specialist or physician who specializes in MPS can confirm the diagnosis and provide disease management. Consultation with an ophthalmologist who has expertise in MPS is also needed for thorough examination of the eyes and regular follow-up care.

Refractive outcomes after primary intraocular lens implantation in infants

Background: Intraocular lens (IOL) implantation is becoming increasingly accepted as a primary procedure in infants. Aim: To evaluate the accuracy of IOL power calculation, the rate of myopic shift and the refractive outcome after primary IOL implantation in infants aged <12 months at the time of cataract surgery. Method: A retrospective case review of 25 patients (8 with bilateral cataracts and 17 with unilateral cataracts) who underwent cataract surgery with primary IOL implantation at <12 months of age. Outcomes measured were actual early postoperative refraction, lens power calculation error, myopic shift and refractive outcome. Results: In 83% of cases, actual postoperative refraction was within 2 dioptres (D) of the target refraction. Lens power calculation error did not depend on axial length, age at surgery or target refraction. Mean (SD) myopic shift was 5.43 (3.7) D in the first 12 months after surgery, but was significantly greater when surgery was performed at <10 weeks of age. Conclusion: This study demonstrates that IOL power can be calculated with reasonable accuracy in infants using current formulas. Factors such as age at the time of surgery, axial length, whether surgery is unilateral or bilateral, and the presence of systemic pathologies do not seem to influence the accuracy of lens power calculation or myopic shift up to 36 months of age.

Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans in several tissues and organs. This accumulation results in an array of clinical manifestations and premature death in severe cases. Ocular problems are very common in children with MPS and may involve the cornea, sclera, trabecular meshwork, retina, optic nerve and also the posterior visual pathways. The aims of this study are to give an overview of ocular problems in MPS and to provide clinical guidelines for paediatric ophthalmologists for early diagnosis and management of ocular manifestations in children with MPS. Diagnostic problems may arise in children with severe corneal clouding, hampering visualization of the fundus. Intraocular pressures may be falsely high, even leading to suspicion and unnecessary pressure‐lowering treatment. Simple interventions such as the use of prescription glasses or photochromatic glasses can considerably improve quality of life in children with MPS.

Combined trabeculotomy–trabeculectomy augmented with 5‐fluorouracil in paediatric glaucoma

Background:  To describe our experience of combined trabeculotomy–trabeculectomy in paediatric glaucomas with a special emphasis on the use of 5‐fluorouracil and releasable sutures.