Pigmentary Dystrophy Research Articles

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

РОЛЬ КОМПЕНСАТОРНЫХ МЕХАНИЗМОВ СЕТЧАТКИ В УСЛОВИЯХ ПИГМЕНТНОЙ ДИСТРОФИИ

Researching some aspects of functioning retina performance in conditions of pigmentary dystrophy (PD) will allow revealing a number of features regarding its existence and sequence of restoration both as respector and neural systems.Research objecture. To investigate dynamics of formation of electroretinogram (ERG) in conditions of retina PD. Materials and methods. Chronic experiments were conducted on awake rabbits for a month in the norm and condition of PD. Results. The received results testily that formation a – and b – ERG components in condition of PD was ambiguous. Amplitudes of a – waves higher (76,4%) than those of b – waves (44,4%). Conclusion. Partial recovery of ERG components is a result of the inclusion of retina backup mechanisms capable of withstanding pathological process and restoring vision.

Structural and Functional Reorganization of the Retina in an Experimental Simulation of Age-Related Macular Degeneration and the Melatonin Effect

The aim of the study was to evaluate regularities of morphological and functional reorganization of the rabbit retina in the experimental simulation of age-related macular degeneration (AMD) and the use of melatonin.Material and methods. The study included 21 sexually mature male rabbits (42 eyes) weighed 2800– 3300 g, chinchilla breed. All the animals included in the study were divided into 3 groups: group 1 (experimental) (n=9), group 2 (control) included animals that were simulated AMD (n=9), and group 3 (intact) (n=3). Surgical interventions were performed in sterile conditions using an Opton operating microscope (Germany). Massage of the retina was performed under visual control through fixed caliber ports with a 25 G silicone-tip cannula at 10 and 2 hours in 4 mm from the limb, retreating from the optic nerve disk at a distance equal its one diameter, until the pigment epithelium was destroyed (dispersion). The size of the injury was 3 mm (RF Patent for the invention No. 2480844, 2011). Group 1 (experimental) was orally administered a suspended solution of the drug “Melaxen” (the active substance is melatonin), dosage 10 ml/kg daily once a day from 21.00 to 22.00 h for 3 months. Animals of group 2 did not receive treatment. Experimental animals were removed from the experiment on the 30th, 60th and 90th days. A histological and immunocytochemical study of the retina of experimental, control, and intact (without AMD simulation) animals was performed, including two-stage reactions to identify proteins p-53 and bcl-2.Results. Experimental histological studies allowed us to obtain a model of AMD, which corresponded to the morphological manifestations of the exudative form of chorioretinal dystrophy and destruction with a primary lesion of the choriocapillaris layer of the uveal tract. The use of melatonin for therapeutic purposes resulted in the resistant adaptation of pigment epithelium and retina gliocytes, reduction of pigment dystrophy and hemorrhage, destruction, reduction of apoptotic dominant and plexiform layers of the retina.

Bilateral conjunctival melanocytosis and retinitis pigmentosa

Conjunctival pigmented lesions have varied appearances. It arises from the melanocytic or nonmelanocytes. It is rare to find conjunctival melanocytosis associated with retinal pigmentary dystrophy. We report a case of a 69-year-old male with bilateral typical retinitis pigmentosa with conjunctival melanocytosis. The excessive pigmentation of conjunctiva was recognized when the patient came for cataract surgery. The conjunctival pigment was identified during slit lamp examination. Histopathological section of superior conjunctiva revealed stromal mononuclear infiltrate with melanin pigment in the basal cells. To the best of our knowledge, such an association has not previously been described. Such an association needs to be studied in a large case series. The present of conjunctival pigments may alert the eye surgeon to look for pigmentary disorder of the retina.

Clinical and morphological characteristics of enamel during pigment hypoplasia of tooth tissues.

Background. Dystrophic changes in enamel and dentin occur as a result of metabolic disturbances in the hard tissues of the tooth and are characterized by its insufficient formation and mineralization, or excessive accumulation of pigments in the form of spots. The accumulation of pigment (qualitative and quantitative) is irreversible, that is, pigmentary dystrophy has no reverse development and remains in the enamel for life. Objectivе. To analyze the structural changes in tooth enamel in case of pigmentary dystrophy. Methods. After extraction, the teeth were embedded with Epon-812 epoxy. After polymerization, the obtained block was cut with a separating disk on thin sections 0.25 mm thick, an aluminum layer was applied to the preparations in vacuum and examined on a scanning electron microscope REM - 102E with an accelerating voltage of 30 kV. Results. It has been established that in case of chronic discolorites the enamel is partially fragmented, the phenomena of lysis of the enamel are determined. Lacunae are observed on the enamel-dentin border. Enamel preparations with congenital discolorations revealed a thickening of enamel prisms, mosaic expressiveness of Retzius lines. In exogenous pigmentary dystrophy, the main changes are established on the enamel surface. The phenomena of focal fragmentation, diffuse thinning of enamel prisms (atrophic changes) were observed. In endogenous pigmental dystrophy, the main changes are determined by the enamel-dentin boundary. Prisms are thinned and fragmented. Conclusion. Congenital dystrophy of pigment has a diffuse nature and affects the entire thickness of the enamel, which is caused by disorders in the process of histogenesis. With acquired discolorites, the localization of pathological changes depends on the etiology - endogenous, or exogenous. In endogenous pigmental dystrophy, morphological changes are found in the surface layers of enamel, developing as a result of disruption of the tertiary mineralization process, which create favorable conditions for the penetration of pigments by reducing the content of inorganic substances. In endogenous pigmental dystrophy, major changes develop in the deep layers of enamel adjacent to the dentine-enamel border. The source of pigment in this case is enamel spindles, which have a low content of inorganic substances and penetrate into the enamel on 1/3 of its thickness.

Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes.

Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.

Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity.

Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here, we report the identification of heterozygous missense mutations in the α-catenin 1 (CTNNA1) gene in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice revealed increased cell shedding and large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, suggests that CTNNA1 is involved in maintaining RPE integrity, and suggests that other components that participate in intercellular adhesion may be implicated in macular disease.

Abstract 440: Activation of the Brain Renin-angiotensin System is Critically Involved in the Hypertension Associated With Bbs

Bardet-Biedl syndrome (BBS) is a human autosomal recessive disorder characterized by a pleiotropic of phenotypes including obesity, renal abnormalities, mental retardation, retinal pigmentary dystrophy, polydactyly and hypogenitalism. Hypertension is also common in BBS patients, except BBS2. Consistent with this, we previously demonstrated that obese Bbs2 knockout mice are normotensive while obese Bbs4 null mice are hypertensive. However, the underlying molecular mechanisms of hypertension in BBS remain poorly defined. Using BBS mice, we tested whether abnormalities in the brain renin-angiotensin system (RAS) may contribute to the increased arterial pressure in BBS. Using real time PCR, we found that mRNA expression of RAS components were differentially altered in Bbs2 -/- and Bbs4 -/- mice. Compared to wild type controls, the hypertensive Bbs4 -/- mice exhibited significantly (P<0.05) elevated expression of renin (160%), angiotensin converting enzyme (ACE, 185%), angiotensin type 1a receptor (AT1aR, 143%) and AT1bR (244%) in the brain. Notably, while the expression of ACE was increased (154%) in the brain of the normotensive Bbs2 -/- mice, the expression of renin, AT1aR and AT1bR were significantly (P<0.05) decreased by 56%, 60% and 36%, respectively, relative to controls. Next, we examined the functional consequences of the elevated brain RAS components in Bbs4 -/- mice. Consistent with our previous findings, radiotelemetric mean arterial pressure was significantly (P<0.05) elevated in the obese Bbs4 -/- mice (114±3 mmHg) relative to wild type controls (101±1 mmHg). Moreover, Bbs4 -/- mice exhibited an exaggerated decrease in arterial pressure in response to intracerebroventricular (ICV) administration of losartan (AT1 receptor antagonist). Indeed, ICV losartan (10 g) decreased mean arterial pressure by 24±7 mmHg in Bbs4 -/- mice vs. 5±10 mmHg in wild type controls (P<0.05). Our data indicate that overactivity of the brain RAS may account for the high blood pressure associated with BBS. This study provides a novel molecular mechanism for the hypertension associated with BBS.

Association of Pattern Dystrophy With an HTRA1 Single-Nucleotide Polymorphism

To evaluate if adult-onset foveomacular vitelliform dystrophy (AOFVD) and butterfly-shaped pigment dystrophy (BSPD) are associated with risk single-nucleotide polymorphisms (SNPs) for age-related macular degeneration (AMD). This was a tertiary referral center-based cross-sectional study including 35 consecutive patients with BSPD and AOFVD, 317 patients with AMD, and 159 unaffected individuals. Demographics, clinical information, and ophthalmic imaging studies were collected. Sequencing was performed for the peripherin/RDS and BEST1 genes, and genotyping was performed for SNPs in the genes for complement factor H (CFH) (rs1061170), HTRA1 (rs11200638), and complement component 3 (C3) (rs2231099). Adult-onset foveomacular vitelliform dystrophy and BSPD were diagnosed in 24 (68.6%) and 11 (31.4%) of the 35 patients, respectively. The mean (SD) age of patients with pattern dystrophy (PD) was 75.3 (10) years and median visual acuity was 0.7. Pattern dystrophy was associated with the HTRA1 risk allele compared with unaffected individuals (odds ratio, 1.72; 95% CI, 1.11-2.66; P = .03). The HTRA1 SNP showed similar prevalence in patients with AMD and PD. The CFH risk allele was significantly less common in patients with PD compared with patients with AMD (odds ratio, 0.47; 95% CI, 0.28-0.76; P = .002). No mutations in peripherin/RDS or BEST1 were detected. The AOFVD and BSPD phenotypes are associated with an HTRA1 risk SNP. These phenotypes often present in elderly individuals who do not carry peripherin/RDS gene mutations and are associated with retinal pigment epithelium alterations and increased risk for choroidal neovascularization. Further research is required to evaluate if AOFVD and BSPD phenotypes in aged individuals are associated with AMD.

Visual impairment in the hearing impaired students

Background:Ocular problems are more common in children with hearing problems than in normal children. Neglected visual impairment could aggravate educational and social disability.Aim:To detect and treat visual impairment, if any, in hearing-impaired children.Setting and Design:Observational, clinical case series of hearing-impaired children in schools providing special education.Materials and Methods:Hearing-impaired children in selected schools underwent detailed visual acuity testing, refraction, external ocular examination and fundoscopy. Ocular motility testing was also performed. Teachers were sensitized and trained to help in the assessment of visual acuity using Snellen's E charts. Refractive errors and squint were treated as per standard practice.Statistical Analysis:Excel software was used for data entry and SSPS for analysis.Results:The study involved 901 hearing-impaired students between four and 21 years of age, from 14 special education schools. A quarter of them (216/901, 24%) had ocular problems. Refractive errors were the most common morbidity 167(18.5%), but only 10 children were using appropriate spectacle correction at presentation. Fifty children had visual acuity less than 20/80 at presentation; after providing refractive correction, this number reduced to three children, all of whom were provided low-vision aids. Other common conditions included strabismus in 12 (1.3%) children, and retinal pigmentary dystrophy in five (0.6%) children.Conclusion:Ocular problems are common in hearing-impaired children. Screening for ocular problems should be made mandatory in hearing-impaired children, as they use their visual sense to compensate for the poor auditory sense.

Danon disease presenting with dilated cardiomyopathy and a complex phenotype

X-linked dilated cardiomyopathy (XLCM) was first described in 1987 and associated with dystrophin gene (DMD) mutations a decade later in one of the original two families. Here we report long-term follow-up of the second family (XLCM-2), for which a DMD mutation was never found. Analysis of the lysosome-associated membrane protein-2 (LAMP-2) gene detected a novel mutation, confirming a diagnosis of Danon disease. The broad phenotype in this family included dilated and hypertrophic cardiomyopathy, cardiac pre-excitation, skeletal myopathy with high serum creatinine kinase, cognitive impairement (in males), and and a pigmentary retinopathy in affected females. Cardiac biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. We conclude that XLCM may be the presenting sign of Danon disease and, in the presence of familial history of HCM, pre-excitation, skeletal muscle involvement and retinal pigmentary dystrophy should prompt LAMP-2 clinical testing. Furthermore, the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.

Spinocerebellar ataxia type 7 mimicking Kearns–Sayre syndrome: A clinical diagnosis is desirable

Spinocerebellar ataxias are a group of autosomal dominant cerebellar degenerative disorders, which are characterized by clinical and genetic variability. Spinocerebellar ataxia type 7 (SCA7) is less variable in clinical presentation than other SCAs. We present a pediatric patient with 13 and 70 trinucleotide CAG repeats within SCA7 gene and no family history, whose presentation mimicked Kearns-Sayre syndrome (KSS). We review the differential diagnosis of cerebellar ataxia with vision loss secondary to retinal pigmentary dystrophy. This paper supports concept of a desirable clinical diagnosis to avoid multiple genetic or invasive testing in children with neurodegenerative disorders.

Obesity and Male Reproductive Potential

Obesity and Male Reproductive Potential

Ataxia espinocerebelosa tipo 7: descripción de una familia mexicana

Spinocerebellar ataxias (SCA) constitute a group of neurodegenerative diseases characterized by cerebellar disfunction alone or associated with other neurological anomalies. The combination of progressive cerebellar ataxia, macular pigment dystrophy, ophtalmoplegia, spasticity and an autosomal dominant pattern of transmission is characteristic of SCA 7. Genome wide linkage analysis mapped the defective gene to 3p12 13. To describe a Mexican family with SCA 7. We present a family pedigree of 13 individuals with ataxia and other neurologic findings in 3 generations. The evaluation consisted of a complete clinical and neurologic examination; neuropsychologic, neurophysiologic, ophthalmologic, neuroradiologic assessments and a molecular genetic study. The first 2 generations had a history of gait disturbance and visual loss. We objectively found a global cerebellar syndrome, pyramidal signs, visual impairment and ophtalmoparesis in variable grades in all members of the third generation All had progressive retinal degeneration, cerebellar, brainstem and hemispheric atrophy. We observed anticipation phenomena. Genetic analysis of the father of the third generation showed expansion of CAG triplet repeats at the SCA 7 gene. The clinical and genetic findings confirmed the diagnosis of SCA 7, and this is the first report in a Mexican family.

Effect of epithalon on age-specific changes in the retina in rats with hereditary pigmentary dystrophy.

The effect of peptide bioregulator Epithalon on the course of hereditary pigmentary retinal degeneration was studied in Campbell rats. Administration of epithalon starting from birth protected morphological structure, increased its bioelectrical activity, and improved its function.

Uncombable Hair (cheveux incoiffables, pili trianguli et canaliculi) Syndrome: Brief Review and Role of Scanning Electron Microscopy in Diagnosis

Uncombable hair syndrome was first described some 3 decades ago as "cheveux incoiffables" and is also known as spun-glass hair and pili trianguli et canaliculi. Both inherited (autosomal dominant and recessive with variable levels of penetrance) and sporadic forms of uncombable hair syndrome have been described, both being characterized by scalp hair that is impossible to comb due to the haphazard arrangement of the hair bundles. A characteristic morphologic feature of hair in this syndrome is a triangular to reniform to heart shape on cross-sections, and a groove, canal or flattening along the entire length of the hair in at least 50%of hairs examined by scanning electron microscopy. Most individuals are affected early in childhood and the hair takeson a spun-glassappearance with the hair becoming dry, curly, glossy, lighter in color, and progressively uncombable. Only the scalp hair is affected. Several conditions are associated with uncombable hair, such as ectodermal dysplasia, retinal dysplasia/ pigmentary dystrophy, juvenile cataract, digit abnormalities, tooth enamel anomalies, oligodontia, and phalangoepiphyseal dysplasia. Other syndromes with hair abnormalities may also mimic uncombable hair syndrome clinically and these include, Rapp-Hodgkin ectodermal dysplasia; loose anagen hair syndrome; ectodermal dysplasia, ectrodatyly, cleft lip/ palate (EEC) syndrome; and familial tricho-odonto-onchyial ectodermal dysplasia with syndactyly. Unlike other conditions with an uncombable hair component, uncombable hair syndrome alone (cheveux incoiffables, pili trianguli etcanaliculi) is not associated with physical, neurologic, or mental abnormalities. In most cases of uncombable hair syndrome, the hair is grossly abnormal in infancy and early childhood, but may have improved manageability later in life. Scanning electron microscopy of hair samples provides definitive evidence for diagnosis of clinically suspected uncombable hair syndrome and eliminates other hair abnormalities from the differential diagnosis.

The prevalence of Usher syndrome and other retinal dystrophy-hearing impairment associations.

The study was undertaken to procure population-based prevalence data on the various types of Usher syndrome and other retinal dystrophy-hearing impairment associations. The medical files on 646 patients with a panretinal pigmentary dystrophy aged 20-49 years derived from the Danish Retinitis Pigmentosa (RP) register were scrutinised. The data were supplemented by a prior investigation on hearing ability in a part of the study population. After exclusion of patients with possibly extrinsic causes of hearing impairments, 118 patients, including 89 cases of Usher syndrome were allocated to one of five clinically defined groups. We calculated the following prevalence rates: Usher syndrome type I: 1.5/100,000, Usher syndrome type II: 2.2/100,000, and Usher syndrome type III: 0.1/100,000 corresponding to a 2:3 ratio between Usher syndrome type I and II. The overall prevalence rate of Usher syndrome was estimated to 5/100,000 in the Danish population, devoid of genetic isolates. The material comprised 11 cases with retinal dystrophy, hearing impairment, and additional syndromic features. Finally, 18 subjects with various retinal dystrophy-hearing impairment associations without syndromic features were identified, corresponding to a prevalence rate of 0.8/100,000. This group had a significant overrepresentation of X-linked RP, including two persons harboring a mutation in the retinitis pigmentosa GTP-ase regulator (RPGR) gene.

The retina.

Prominent amongst last year's diverse papers on the retina were a study of the clinical manifestations of dominant cerebellar ataxia with pigmentary macular dystrophy, a review of the pathogenesis of carcinoma associated retinopathy, the Ischaemic Optic Neuropathy Decompression Trial, and a review of congenital optic disc anomalies. Ocular complications of several neurosurgical procedures were also reported during this period.

A 2 base pair deletion in the RDS gene associated with butterfly-shaped pigment dystrophy of the fovea.

A 2 base pair deletion in the RDS gene associated with butterfly-shaped pigment dystrophy of the fovea.

RETINAL HEMANGIOMA-LIKE LESIONS IN EYES WITH RETINITIS PIGMENTOSA

The authors report two patients with bilateral vascular masses of the peripheral retina associated with primary pigmentary dystrophy of the retina (retinitis pigmentosa). Although they are most similar to the retinal capillary hemangiomas of von Hippel, the affected patients had no clinical history or clinical findings suggestive of that syndrome. They differ from the calcified retinal hamartomas that have been associated with retinitis pigmentosa because they do not show the extensive telangiectasia and exudation seen with the exudative retinopathy that has been described with retinitis pigmentosa. They do not show the fluorescein angiographic pattern that characterizes peripheral choroidal neovascularization. Their main complication seems to be vitreous hemorrhage rather than exudative retinopathy. The authors discuss the possible relationship of these acquired retinal vascular masses to the retinitis pigmentosa.