Retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome.

PURPOSE: To describe a case of retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome. METHODS: Fundus photography, total field electroretinogram, ultrasound, computerized visual field examination, biochemical examination and genetic testing were obtained. RESULTS: The fundus exam showed diffuse arteriolar attenuation, optic disc with regular contours, and pigment agglomerates like "bone spicules" in the middle periphery. Ultrasound examination revealed scleral thickening and short axial diameter in both eyes. The total field electroretinogram exam showed a subnormal result with greater impairment of the scotopic phase of the exam. Computerized visual field examination demonstrated a diffuse reduction in retinal sensitivity in the periphery. Biochemical examination showed increased urine glycosaminoglycan excretion and iduronate-2-sulphatase activity (IDS) deficiency in leukocytes, confirming the type II mucopolysaccharidosis. Molecular analysis revealed a novel missense mutation (p.A77D) in the IDS gene. CONCLUSION: The case report is about a patient presented an attenuated form of the syndrome, with no cognitive impairment. Ophthalmologic follow-up is still an important part of multidisciplinary treatment for Hunter's syndrome.

Arthrodesis versus dynamic neutralization: A short/mid- and long-term retrospective evaluation in degenerative disk disease treatment.

Study Design: This was a retrospective comparative study. Objectives: The aim of this study was to perform a clinical and radiological retrospective evaluation of the most used techniques for the lumbar degenerative disk disease (DDD) treatment: arthrodesis versus dynamic neutralization (DN)-Dynesys dynamic stabilization system. Methods: The study included 58 consecutive patients affected by lumbar DDD, 28 treated with rigid stabilization and 30 with DN at our department between 2003 and 2013. The clinical evaluation was performed through the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). The radiographic evaluation was performed through standard and dynamic X-ray projections and magnetic resonance imaging. Results: Both techniques determined a clinical improvement in the postoperative period compared to the preoperative one. There were no significant differences between the postoperative VAS of the two techniques. The DN group postoperative ODI percentage showed a significant improvement (P = 0.026) compared to the arthrodesis group. During the follow-up, no clinically significant differences were highlighted between the two techniques. At a long term follow up period, radiographic results showed, in both groups, a L3-L4 disk mean height reduction and an increase of segmental and lumbar lordosis without significant differences between the two techniques. During an average of 96-month follow-up period, 5 (18%) patients developed an adjacent segment disease in the arthrodesis group and 6 (20%) patients developed this syndrome in the DN group. Conclusions: We are confident in recommending arthrodesis and DN as effective techniques for lumbar DDD treatment. Both techniques are potentially burdened, with similar frequency, by the development of long-term adjacent segment disease.

Treatment of periprosthetic supracondylar fractures after CR total knee arthroplasty with retrograde intramedullary nailing in an elderly population: a long term evaluation.

Retrograde intramedullary fixation has been proposed to improve the rate of union providing greater stability in patients with a posterior cruciate ligament retaining femoral TKA component and decreasing soft-tissue trauma. This study assessed the clinical and radiographical outcome of retrograde intramedullary nailing (RIN) for the treatment of periprosthetic supracondylar fractures of the femur in an elderly population. Between January 2014 and December 2018, 16 patients with PSF underwent RIN. The clinical outcome was evaluated using the Knee Society Score (KSS) and the Short-form health survey (SF-12). The radiographic outcome was evaluated directly on the X-rays. Complications were also described. 13 patients (11 females and 2 males) with a mean age of 84 years old (range, 77-89) were evaluated clinically and radiographically, after a mean of 48.3 months (range, 24-73 months). The SF-12 scores were similar to normative values for subjects in the comparable age group. Radiographic union was obtained in all patients after an average of 14,8 weeks (range, 12-40 weeks) postoperatively. RIN is a safe and effective treatment for PSF, above all in the elderly population. The overall clinical and radiographic result was satisfactory.

Impact of ERT and follow-up of 17 patients from the same family with a mild form of MPS II.

BACKGROUND: Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme Iduronate-2- Sulfatase (IDS), leading to progressive accumulation of Glycosaminoglycans (GAGs) in several organs. Over the years, Enzyme Replacement Therapy (ERT) has provided significant benefits for patients, retarding the natural progression of the disease. RESULTS: The authors evaluated 17 patients from the same family with a mild form of MPS type II; the proband had developed acute decompensated heart failure refractory to clinical measurements at 23 years and needed a rather urgent heart transplant; however, he died from surgical complications shortly after the procedure. Nevertheless, subsequent to his tragic death, 16 affected male relatives were detected after biochemical tests identifying the low or absent activity of the IDS enzyme and confirmed by molecular analysis of the IDS gene. Following diagnosis, different options of treatment were chosen: 6 patients started ERT with Elaprase® (Idursulfase) soon after, while the other 10 remained without ERT. Eventually, 4 patients in the latter group began ERT with Hunterase® (Idursulfase Beta). None presented adverse effects to either form of the enzyme. Among the 6 individuals without any ERT, two died of natural causes, after reaching 70 years. Despite the variable phenotype within the same family (mainly heart dysfunctions and carpal tunnel syndrome), all 14 remaining patients were alive with an independent lifestyle. CONCLUSION: Here, the authors report the variable progress of the disease with and without ERT in a large Brazilian family with a slowly progressive form of MPS II, harboring the same missense variant in the IDS gene.

Multimodal image analysis of the retina in Hunter syndrome (mucopolysaccharidosis type II): Case report.

INTRODUCTION: We report a case of retinal and posterior ocular findings in a 33-year-old man diagnosed with Hunter syndrome (Mucopolysaccharidosis type II) in a multimodal imaging way. CASE PRESENTATION: Our patient was complaining of blurred night vision for the past 3 years. He had not received any systemic treatment for Hunter syndrome. Vision acuity was 20/20 in both eyes and corneas were clear. Fundus examination revealed bilateral crowded and hyperemic optic nerve heads (elevated in the ocular ultrasound) and areas of subretinal hypopigmentation. There was hyperautofluorescence at the central fovea and perifovea, and a diffuse bilateral choroidal fluorescence in angiography. Macular SD-OCT showed a thinning of the external retina at the perifovea in both eyes. Visual field testing showed a bilateral ring scotoma. The full field ERG was subnormal, with a negative response in the scotopic phase. Visual Evoked Potencial test and cranial MRI were normal. CONCLUSION: Our multimodal analysis reported here attempted to contribute to the knowledge of the natural history of GAG deposition in the eye, focusing on the retina and retinal pigment epithelium. Defining this natural history is essential for a proper comparison with Hunter patients receiving systemic treatment, thus determining if it can or cannot improve retinal function in humans with this disorder.

Hypotrichosis with juvenile macular dystrophy: a case report with molecular study.

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by sparse scalp hair caused by hair follicle abnormalities as well as progressive retinal degeneration leading to blindness in the second or third decade of life. It is associated with mutations of the cadherin 3 (CDH3) gene, which result in abnormal expression of P-cadherin. Mutations in CDH3 are related to ectodermal dysplasia, ectrodactyly, and macular dystrophy. In this report, we describe an 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes. Genetic testing of the CDH3 gene revealed a homozygous gene variant at exon 6 (640A>T). This novel in-frame mutation converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.

Echocardiographic characteristics of hypertensive patients affected by transient ischemic attack: a cross-sectional study.

Atrial septal aneurysm (ASA), common finding in normal echocardiographies, has been described in association with transient ischemic attacks (TIAs)/strokes, as well as hypertensive end-organ damage such as left ventricular (LV) hypertrophy. Aim of this study was to assess if a cluster of echocardiographic aspects could characterize TIA hypertensive patients. A cross-sectional study on patients with history of TIA, referring to a Hypertension Center echolab, has been performed. A total of 5223 patients received transthoracic echocardiography. TIA patients were 292 (5.6%). A total of 102 age/sex-matched patients without TIA have been collected as controls. The main characteristic of TIA patients resulted ASA/bulging (B) (TIA 61%, controls 6%, P = .0001). Other aspect was LV concentric remodeling (TIA 32.3%, controls 20.8%, P = .029) and mitral flow aspects of diastolic dysfunction. After adjustment for age and hypertension, ASA/B (odds ratio [OR] = 62.4, 95% confidence interval [CI]: 13.6-73.9, P < .001), followed by LV concentric hypertrophy (OR = 2.1, 95% CI: 1.1-4.3, P = .043), was associated with a positive TIA history. A binary logistic regression performed in ASA/B patients, identified relative wall thickness as the strongest TIA-associated aspect (OR = 53.4, 95% CI: 11.9-74.18, P = .001). ASA/B, common finds in general population, could carry a significant incremental possibility of association with TIA when concentric geometry, frequent hypertensive aspect, is present as well.

Impact of ERT and follow-up of 17 patients from the same family with a mild form of MPS II

Abstract Background: Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme Iduronate-2- Sulfatase (IDS), leading to progressive accumulation of Glycosaminoglycans (GAGs) in several organs. Over the years, Enzyme Replacement Therapy (ERT) has provided significant benefits for patients, retarding the natural progression of the disease. Results: The authors evaluated 17 patients from the same family with a mild form of MPS type II; the proband had developed acute decompensated heart failure refractory to clinical measurements at 23 years and needed a rather urgent heart transplant; however, he died from surgical complications shortly after the procedure. Nevertheless, subsequent to his tragic death, 16 affected male relatives were detected after biochemical tests identifying the low or absent activity of the IDS enzyme and confirmed by molecular analysis of the IDS gene. Following diagnosis, different options of treatment were chosen: 6 patients started ERT with Elaprase® (Idursulfase) soon after, while the other 10 remained without ERT. Eventually, 4 patients in the latter group began ERT with Hunterase® (Idursulfase Beta). None presented adverse effects to either form of the enzyme. Among the 6 individuals without any ERT, two died of natural causes, after reaching 70 years. Despite the variable phenotype within the same family (mainly heart dysfunctions and carpal tunnel syndrome), all 14 remaining patients were alive with an independent lifestyle. Conclusion: Here, the authors report the variable progress of the disease with and without ERT in a large Brazilian family with a slowly progressive form of MPS II, harboring the same missense variant in the IDS gene.

Angiopoietin-1 is required for Schlemm's canal development in mice and humans.

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.

Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.

Posterior polar cataract: genetic analysis of a large family.

Congenital cataracts are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 11q22-q22.3, 16q22, and 20p12-q12. We investigated a large four-generation family with 20 individuals affected with congenital posterior polar cataracts. After exclusion of known loci for posterior polar cataracts, a genome-wide screen was conducted. In this family, we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On haplotype analysis, we identified an 11-cM interval between loci D10S1680 and D10S467, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. Although the same genotype was described in a family with ASMD and cataracts, the common phenotype of this mutation is probably posterior polar cataract; a modifier gene is presumed to cause anterior segment abnormalities in the previously described patients. The same mutation was recently identified in four families with congenital cataracts. This study provides further evidence of genetic heterogeneity of autosomal dominant posterior polar cataract.

Rho kinase inhibitors for glaucoma treatment - Review.

Glaucoma is a progressive optic neuropathy characterized by the loss of ganglion cells and their axons. A major risk factor for glaucomatous visual field loss is elevated intraocular pressure (IOP), and several studies have shown that lowering IOP reduces the risk of glaucomatous progression. Currently, an increasing number of researches involve Rho kinase inhibitors, which are a new pharmacological class of hypotensive agents specifically targeting the diseased trabecular outflow pathway. Rho kinase inhibitors reduce IOP by increasing aqueous humor drainage through the primary outflow pathway in the eye, which is known as the trabecular meshwork. In addition to improving the outflow facility of the trabecular meshwork, Rho kinase inhibitors also enhance retinal ganglion cell survival after ischemic injury and increase ocular blood flow.

Efficacy of topical dorzolamide therapy for cystoid macular edema in a patient with MFRP-related nanophthalmos-retinitis pigmentosa-foveoschisis-optic disk drusen syndrome.

PURPOSE: Mutations in the MFRP (membrane-type frizzled-related protein) gene leads to an entity characterized by retinitis pigmentosa, nanophthalmos, optic disk drusen, and macular changes, originally described as foveoschisis. Despite the association of MFRP gene mutation and increase in macular thickness, no treatment modality has been described for cystoid macular edema related to this particular entity so far. METHODS: In this case report, a 52-year-old woman presented with nanophthalmos, optic disk drusen, retinitis pigmentosa, and increase in macular thickness. Genetic analysis revealed an MFRP gene mutation. The patient was treated with topical carbonic anhydrase inhibitors. RESULTS: A progressive decrease in macular thickness and cystic changes was observed during the 2-month course of topical carbonic anhydrase inhibitor treatment, and best-corrected visual acuity improved from 20/100 to 20/50. Macular thickness remained stable after 6 months of follow-up. CONCLUSION: Cystoid macular edema is part of the macular changes noted in the MFRP mutation-related nanophthalmos-retinitis pigmentosa-foveoschisis-optic disk drusen, syndrome. Taking into account that resolution of cystoid macular edema in patients with retinitis pigmentosa may delay an irreversible decrease in visual acuity, treatment should be considered when cystic changes are suspected. Topical carbonic anhydrase inhibitor was effective in decreasing macular thickness and cystic changes in the patient reported.

Genotype-Phenotype Correlations in CYP1B1-Associated Primary Congenital Glaucoma Patients Representing Two Large Cohorts from India and Brazil.

BACKGROUND: Primary congenital glaucoma (PCG), occurs due to the developmental defects in the trabecular meshwork and anterior chamber angle in children. PCG exhibits genetic heterogeneity and the CYP1B1 gene has been widely implicated worldwide. Despite the diverse mutation spectra, the clinical implications of these mutations are yet unclear. The present study attempted to delineate the clinical profile of PCG in the background of CYP1B1 mutations from a large cohort of 901 subjects from India (n=601) and Brazil (n=300). METHODS: Genotype-phenotype correlations was undertaken on clinically well characterized PCG cases from India (n=301) and Brazil (n=150) to assess the contributions of CYP1B1 mutation on a set of demographic and clinical parameters. The demographic (gender, and history of consanguinity) and quantitative clinical (presenting intraocular pressure [IOP] and corneal diameter [CD]) parameters were considered as binary and continuous variables, respectively, for PCG patients in the background of the overall mutation spectra and also with respect to the prevalent mutations in India (R368H) and Brazil (4340delG). All these variables were fitted in a multivariate logistic regression model using the Akaike Information Criterion (AIC) to estimate the adjusted odds ratio (OR) using the R software (version 2.14.1). RESULTS: The overall mutation spectrum were similar across the Indian and Brazilian PCG cases, despite significantly higher number of homozygous mutations in the former (p=0.024) and compound heterozygous mutations in the later (p=0.012). A wide allelic heterogeneity was observed and only 6 mutations were infrequently shared between these two populations. The adjusted ORs for the binary (demographic) and continuous (clinical) variables did not indicate any susceptibility to the observed mutations (p>0.05). CONCLUSIONS: The present study demonstrated a lack of genotype-phenotype correlation of the demographic and clinical traits to CYP1B1 mutations in PCG at presentation. However, the susceptibility of these mutations to the long-term progression of these traits are yet to be deciphered.

Hypotrichosis with juvenile macular dystrophy: a case report with molecular study / Hipotricose com distrofia macular juvenil: relato de caso com estudo molecular

ABSTRACT Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by sparse scalp hair caused by hair follicle abnormalities as well as progressive retinal degeneration leading to blindness in the second or third decade of life. It is associated with mutations of the cadherin 3 (CDH3) gene, which result in abnormal expression of P-cadherin. Mutations in CDH3 are related to ectodermal dysplasia, ectrodactyly, and macular dystrophy. In this report, we describe an 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes. Genetic testing of the CDH3 gene revealed a homozygous gene variant at exon 6 (640A>T). This novel in-frame mutation converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.

RESUMO Hipotricose com distrofia macular juvenil (HDMJ) é uma doença autossômica recessiva rara caracterizada por rarefação capilar por alteração nos folículos pilosos e degeneracão progressiva da retina levando a cegueira na segunda e terceira década de vida. Associada a mutações no gene CDH3, resultando em expressão anormal de P-caderina. Mutações no gene CDH3 estão relacionados à displasia ectodérmica, ectrodactilia e distrofia macular. Neste relato descrevemos um menino Iraniano de 11 anos de idade, com ausência da unha na mão esquerda e rarefação capilar desde o nascimento, e que posteriormente apresentou alterações pigmentares maculares. Teste genético do gene CDH3 revelou uma variação homozigótica no exon 6 (640A>T). Essa mutação in-frame troca uma lisina por um codon de parada prematura, alterando a síntese da proteína P-caderina no cromossomo 16q22.

Rho kinase inhibitors for glaucoma treatment - Review / Inibidores da Rho-Quinase para o tratamento do glaucoma - Revisão

ABSTRACT Glaucoma is a progressive optic neuropathy characterized by the loss of ganglion cells and their axons. A major risk factor for glaucomatous visual field loss is elevated intraocular pressure (IOP), and several studies have shown that lowering IOP reduces the risk of glaucomatous progression. Currently, an increasing number of researches involve Rho kinase inhibitors, which are a new pharmacological class of hypotensive agents specifically targeting the diseased trabecular outflow pathway. Rho kinase inhibitors reduce IOP by increasing aqueous humor drainage through the primary outflow pathway in the eye, which is known as the trabecular meshwork. In addition to improving the outflow facility of the trabecular meshwork, Rho kinase inhibitors also enhance retinal ganglion cell survival after ischemic injury and increase ocular blood flow.

RESUMO Glaucoma é uma neuropatia óptica progressiva, caracterizada pela perda de células ganglionares e seus axônios. O principal fator de risco que leva à perda de campo visual relacionada ao glaucoma é a elevação da pressão intraocular (PIO) e vários estudos mostraram que a redução da pressão intraocular diminui o risco de progressão do glaucoma. Atualmente, uma nova classe de drogas hipotensoras foi desenvolvida e tem sido cada vez mais estudada, os inibidores da Rho-Kinase. Essas drogas reduzem a pressão intraocular aumentando a drenagem de humor aquoso através da via de drenagem primária do humor aquoso no olho, a malha trabecular. Além de aumentar o escoamento pela malha trabecular, inibidores da Rho-kinase também aumentam a sobrevivência das células ganglionares retinianas após isquemia e aumentam o fluxo ocular sanguíneo.

Correçäo de hipotropia na posiçäo primária do olhar mediante a tenectomia unilateral do músculo oblíquo superior próximo a inserçäo em estrabismo essencial / Correction of hypotropia in the primary position with unilateral superior oblique tenectomy close to the scleral insertion

Objetivo: Os estrabismos horizontais essenciais estäo freqüentemente associados a desvios verticais. A patogênese desse desvio vertical pode resultar da disfunçäo de músculos retos verticais, de músculos oblíquos ou da combinaçäo de ambos. Na presença de hiperfunçäo do músculo oblíquo superior (OS), nota-se hipotropia (HoT) na posiçäo primária do olhar (PPO). O presente estudo objetivou avaliar a magnitude da correçäo da HoT, na PPO, mediante a tenectomia unilateral do OS. Pacientes e Método: Foi realizado um estudo retrospectivo, 1977 a 1996, de 15 pacientes portadores de hiperfunçäo unilateral do OS e hipotropia na posiçäo primária do olhar maior que 4 deltas, submetidos a tenectomia unilateral do OS, realizada na Santa Casa de Säo Paulo (12 pacientes), Universidade de Santo Amaro (2 pacientes) e na clínica particular de um dos autores (CSD, 1 paciente). A média de desvio pré-operatória era de 9 deltas. A hiperfunçäo média pré-operatória do músculo oblíquo superior era 1,7 cruzes. Resultados: A correçäo média da HoT obtida foi de 4,67 deltas ñ 5,09 deltas (- 5 deltas a 15 deltas), (H=6,032;p=0,014). A modificaçäo média da hiperfunçäo do OS foi de 0,87ñ0,88 cruzes (0 a 2 cruzes). De acordo com o desvio horizontal, ET e XT, näo houve diferença estatisticamente significante na comparaçäo entre os resultados obtidos na correçäo da HoT. Comentários: Os resultados revelaram que para HoT até 15 deltas na PPO, houve em média correçäo de 51,82 por cento do seu valor pré-operatório. Para amostra estudada, a técnica de tenectomia unilateral do OS mostrou-se eficaz na correçäo do desvio vertical na posiçäo primária do olhar.