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Sample records for onset retinal dystrophy

  1. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

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    Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

    2017-01-01

    Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70–80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. PMID:28689169

  2. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions.

    Science.gov (United States)

    Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

    2017-09-01

    Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Prevalence of generalized retinal dystrophy in Denmark

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Bregnhøj, Jesper F;

    2014-01-01

    of this study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in the Danish population. METHODS: A population-based cross-sectional study with data from the Danish Retinitis Pigmentosa Registry that comprises all patients in Denmark with generalized retinal....... RESULTS: Of the 5,602,628 Danish citizens on January 1, 2013, 1622 patients were registered as having a generalized retinal dystrophy and were alive and living in Denmark, corresponding to a prevalence of 1:3,454. In 28% of cases the eye condition was part of a syndrome, while the remaining 72% had eye...... disease only. Aside from simplex cases (45%), the most common hereditary pattern was autosomal recessive (23%). CONCLUSION: This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in the Danish population is 1:3454. Many of the dystrophies are the subjects of clinical...

  4. [Genetic diagnostic testing in inherited retinal dystrophies].

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    Kohl, S; Biskup, S

    2013-03-01

    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  5. [Muscular Dystrophies Involving the Retinal Function].

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    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis.

  6. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

    NARCIS (Netherlands)

    Gerard, X.; Garanto Iglesias, A.; Rozet, J.M.; Collin, R.W.J.

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several

  7. Identification of the CRB1 gene and analysis of its role in autosomal recessive retinal dystrophies

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    Hollander, Antonia Ingrid den

    2002-01-01

    Inherited retinal dystrophies generally lead to severe visual impairment early in life. Most genes involved in retinal dystrophies are expressed exclusively or predominantly in the retina or the RPE. To identify candidate genes for inherited retinal dystrophies, we isolated

  8. An unusual central retinal dystrophy associated with ichthyosis vulgaris.

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    Saatci, O A; Ozbek, Z; Köse, S; Durak, I; Kavukçu, S

    2000-06-01

    A number of ichthyosis syndromes may have retinal abnormalities such as the retinitis pigmentosa-like diffuse rod-cone dystrophy in Refsum's syndrome and the maculopathy in Sjögren-Larsson syndrome. We present two sisters who have an unusual, almost identical, bilaterally symmetric central retinal dystrophy associated with ichthyosis vulgaris in the absence of other systemic disorders. We believe that this dystrophy has not been previously described in patients with any of the known varieties of ichthyosis.

  9. Bietti’ Crystalline Retinal Dystrophy: A Case Report

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    Muhammed Şahin

    2016-03-01

    Full Text Available Bietti’ crystalline retinal dystrophy (BCD is a rare, auto­somal, recessively inherited disorder, characterized by the deposition of yellow crystals in the corneal limbus and retina. In this paper we aimed to present a pediatric case with BCD, with clinical, electrophysiological and spectral domain optical coherence tomography (SD-OCT findings and discuss BCD with the light of the literature. J Clin Exp Invest 2016; 7 (1: 94-97

  10. Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies.

    Science.gov (United States)

    den Hollander, Anneke I; Black, Aaron; Bennett, Jean; Cremers, Frans P M

    2010-09-01

    Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

  11. Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy.

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    Weleber, Richard G; Pennesi, Mark E; Wilson, David J; Kaushal, Shalesh; Erker, Laura R; Jensen, Lauren; McBride, Maureen T; Flotte, Terence R; Humphries, Margaret; Calcedo, Roberto; Hauswirth, William W; Chulay, Jeffrey D; Stout, J Timothy

    2016-07-01

    To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in adults and children with retinal degeneration caused by RPE65 mutations. Nonrandomized, multicenter clinical trial. Eight adults and 4 children, 6 to 39 years of age, with Leber congenital amaurosis (LCA) or severe early-childhood-onset retinal degeneration (SECORD). Patients received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of 2 dose levels, and were followed up for 2 years after treatment. The primary safety measures were ocular and nonocular adverse events. Exploratory efficacy measures included changes in best-corrected visual acuity (BCVA), static perimetry central 30° visual field hill of vision (V30) and total visual field hill of vision (VTOT), kinetic perimetry visual field area, and responses to a quality-of-life questionnaire. All patients tolerated subretinal injections and there were no treatment-related serious adverse events. Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients. In the treated eye, BCVA increased in 5 patients, V30 increased in 6 patients, VTOT increased in 5 patients, and kinetic visual field area improved in 3 patients. One subject showed a decrease in BCVA and 2 patients showed a decrease in kinetic visual field area. Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity. Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  12. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

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    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  13. Retinal arterial but not venous tortuosity correlates with facioscapulohumeral muscular dystrophy severity

    NARCIS (Netherlands)

    Longmuir, Susannah Q.; Mathews, Katherine D.; Longmuir, Reid A.; Joshi, Vinayak; Olson, Richard J.; Abramoff, M.D.

    2010-01-01

    Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease beginning with facial and shoulder girdle weakness with variable progression. Exudative retinal detachment, retinal vessel irregularities on fluorescein angiography, and retinal vessel tortuosity have been foun

  14. RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

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    Li eJiang

    2014-04-01

    Full Text Available RNA interference (RNAi knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F producing a slowly progressing cone/rod dystrophy (CORD. The late onset GCAP1(L151F-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection. In both allele-specific (GCAP1(Y99C-RP and nonallele-specific (GCAP1(L151F-CORD models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a proof of concept toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.

  15. Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy

    NARCIS (Netherlands)

    Astuti, G.D.N; Sun, V.; Bauwens, M.; Zobor, D.; Leroy, B.P.; Omar, A.; Jurklies, B.; Lopez, I.; Ren, H.; Yazar, V.; Hamel, C.; Kellner, U.; Wissinger, B.; Kohl, S.; Baere, E. De; Collin, R.W.J.; Koenekoop, R.K.

    2015-01-01

    Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underw

  16. Novel mutations in two Saudi patients with congenital retinal dystrophy

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    Leen Abu Safieh

    2016-01-01

    Full Text Available To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA and Alström syndrome. Case reports. Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L. Case 2 describes a girl with marked nystagmus, photophobia, and retinal changes in both eyes with short and stubby fingers tapering at the distal phalanges. The electroretinograms were nonrecordable in each eye. She had a hearing aid in the left ear, mid-facial hypoplasia, bilateral enophthalmos, and insulin dependent diabetes. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c. 8441C > A, p.S2814*. Two novel mutations causing phenotypic LCA and Alström syndrome in Saudi patients from consanguineous families expand the genotypic spectrum of congenital retinal dystrophies

  17. Two siblings with late-onset cone–rod dystrophy and no visible macular degeneration

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    Sakuramoto H

    2013-08-01

    Full Text Available Hiroyuki Sakuramoto,1 Kazuki Kuniyoshi,1 Kazushige Tsunoda,2 Masakazu Akahori,2 Takeshi Iwata,2 Yoshikazu Shimomura1 1Department of Ophthalmology, Kinki University Faculty of Medicine, Osaka-Sayama City, Osaka, Japan; 2National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan Background: We report our findings in two siblings with late-onset cone–rod dystrophy (CRD with no visible macular degeneration. Cases and methods: Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes. Conclusion: These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years. Keywords: cone–rod dystrophy, peripheral cone dystrophy, occult macular dystrophy, late onset, macular degeneration, negative ERG

  18. Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.

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    Khan, A O; Budde, B S; Nürnberg, P; Kawalia, A; Lenzner, S; Bolz, H J

    2017-03-30

    To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in 2 siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted 2 homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies.

    NARCIS (Netherlands)

    Hollander, A.I. den; Black, A.; Bennett, J.; Cremers, F.P.M.

    2010-01-01

    Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecul

  20. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.

    NARCIS (Netherlands)

    Klevering, B.J.; Maugeri, A.; Wagner, A.; Go, S.L.; Vink, C.W.; Cremers, F.P.M.; Hoyng, C.B.

    2004-01-01

    OBJECTIVE: To investigate the clinical spectrum and molecular causes of retinal dystrophies in 3 families. DESIGN: Family molecular genetics study. PARTICIPANTS: Sixteen patients and 15 relatives in 3 families. METHODS: Members of 3 families with multiple ABCA4-associated retinal disorders were clin

  1. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.

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    Parry, David A; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V; McKibbin, Martin; Jacobson, Samuel G; Logan, Clare V; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L; Springell, Kelly; Adams, Matthew; Johnson, Colin A; Booth, Adam P; Jafri, Hussain; Rashid, Yasmin; Banin, Eyal; Strom, Tim M; Farber, Debora B; Sharon, Dror; Blobel, Carl P; Pugh, Edward N; Pierce, Eric A; Inglehearn, Chris F

    2009-05-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

  2. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

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    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  3. In-vivo imaging of the photoreceptor mosaic in retinal dystrophies and correlations with visual function

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    Choi, S; Doble, N; Hardy, J; Jones, S; Keltner, J; Olivier, S; Werner, J S

    2005-10-26

    To relate in-vivo microscopic retinal changes to visual function assessed with clinical tests in patients with various forms of retinal dystrophies. The UC Davis Adaptive Optics (AO) Fundus Camera was used to acquire in-vivo retinal images at the cellular level. Visual function tests, consisting of visual field analysis, multifocal electroretinography (mfERG), contrast sensitivity and color vision measures, were performed on all subjects. Five patients with different forms of retinal dystrophies and three control subjects were recruited. Cone densities were quantified for all retinal images. In all images of diseased retinas, there were extensive areas of dark space between groups of photoreceptors, where no cone photoreceptors were evident. These irregular features were not seen in healthy retinas, but were characteristic features in fundi with retinal dystrophies. There was a correlation between functional vision loss and the extent to which the irregularities occurred in retinal images. Cone densities were found to decrease with an associated decrease in retinal function. AO fundus photography is a reliable technique for assessing and quantifying the changes in the photoreceptor layer as disease progresses. Furthermore, this technique can be useful in cases where visual function tests give borderline or ambiguous results, as it allows visualization of individual photoreceptors.

  4. Targeted knockdown of Cerkl, a retinal dystrophy gene, causes mild affectation of the retinal ganglion cell layer

    NARCIS (Netherlands)

    Garanto, A.; Vicente-Tejedor, J.; Riera, M.; Villa, P. de la; Gonzalez-Duarte, R.; Blanco, R.; Marfany, G.

    2012-01-01

    In order to approach the function of the retinal dystrophy CERKL gene we generated a novel knockout mouse model by cre-mediated targeted deletion of the Cerkl first exon and proximal promoter. The excised genomic region (2.3kb) encompassed the first Cerkl exon, upstream sequences including the proxi

  5. Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies.

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    Lee, Kristy; Garg, Seema

    2015-04-01

    Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.

  6. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter.

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    Bacchi, Niccolò; Casarosa, Simona; Denti, Michela A

    2014-05-27

    Splicing is an important and highly regulated step in gene expression. The ability to modulate it can offer a therapeutic option for many genetic disorders. Antisense-mediated splicing-correction approaches have recently been successfully exploited for some genetic diseases, and are currently demonstrating safety and efficacy in different clinical trials. Their application for the treatment of retinal dystrophies could potentially solve a vast panel of cases, as illustrated by the abundance of mutations that could be targeted and the versatility of the technique. In this review, we will give an insight of the different therapeutic strategies, focusing on the current status of their application for retinal dystrophies.

  7. Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

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    Yuuki Arai

    2015-01-01

    Full Text Available The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is, ABCA4 for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic. EYS mutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two major EYS mutations identified in this cohort. EYS mutations are the most prevalent among Japanese patients with IRD.

  8. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy.

    NARCIS (Netherlands)

    Swart, B.J.M. de; Engelen, B.G.M. van; Kerkhof, J.P. van de; Maassen, B.A.M.

    2004-01-01

    BACKGROUND: Myotonia and weakness are the most important components of dysarthric speech in myotonic dystrophy. OBJECTIVE: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy. METHODS: Studies on speech production were done on 30 mildly affect

  9. Prevalence and Diagnostic Spectrum of Generalized Retinal Dystrophy in Danish Children

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Larsen, Michael;

    2013-01-01

    Abstract Purpose: The aim of the present population-based cross-sectional study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in Danish children. Methods: The Danish Registry for the Blind and Partially Sighted Children comprises all visually impaired......: Of the 1,204,235 Danish children aged 0-17 years on 1 October 2011, 2017 children were registered as visually impaired. Of these, 153 cases were attributed to generalized retinal dystrophy, corresponding to a prevalence of 13 per 100,000 children. The age-specific prevalence increased prominently...... dystrophy in Danish children is 13 per 100,000, which is a considerable increase compared to the 9.8 per 100,000 reported by Rosenberg in 1988. The prevalence of Leber congenital amaurosis, Usher syndrome, and Bardet-Biedl syndrome doubled, which may be explained by a documented history of consanguinity...

  10. A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13

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    Gerber, S.; Rozet, J.M.; Bonneau, D.; Souied, E.; Camuzat, A.; Munnich, A.; Kaplan, J. [Hopital des Enfants Malades, Paris (France); Dufier, J.L. [Hopital Laeennec, Paris (France); Amalric, P. [Consultation d`Ophtalmologie, Albi (France); Weissenbach, J. [Genethon, Evry (France)

    1995-02-01

    Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217xb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood. 16 refs., 3 figs., 1 tab.

  11. Multimodal Image Analysis in Acquired Vitelliform Lesions and Adult-Onset Foveomacular Vitelliform Dystrophy

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    Ricardo Rocha Bastos

    2016-01-01

    Full Text Available Purpose. To characterize vitelliform lesions (VLs in adult-onset foveomacular vitelliform dystrophy (AOFVD and acquired vitelliform (AVL patients using multimodal image analysis. Methods. Retrospective study of twenty-eight eyes from nineteen patients diagnosed with AVL or AOFVD. They were evaluated by color fundus photographs, fundus autofluorescence (FAF, fluorescein angiography (FA, and spectral-domain optical coherence tomography (SD-OCT. Results. Bilateral VLs were associated with AOFVD (p=0.013. Regular and centered VLs were associated with AOFVD (p=0.004 and p=0.016, whereas irregular and noncentered lesions were more frequent in AVL patients. Visual acuity, greatest linear dimension (GLD, lesion height (LH, and pseudohypopyon were similar between groups. Whereas median LH and GLD in AVL group diminished significantly during follow-up (p=0.009 and p=0.001, AOFVD lesions tended to become larger and thicker. Conclusions. When consulting a patient presenting a VL with unknown age of onset, familial history, or previous retinal diseases, some aspects of multimodal imaging assessment may lead the ophthalmologist to a correct diagnosis.

  12. Adaptive optics imaging of the outer retinal tubules in Bietti's crystalline dystrophy.

    Science.gov (United States)

    Battu, R; Akkali, M C; Bhanushali, D; Srinivasan, P; Shetty, R; Berendschot, T T J M; Schouten, J S A G; Webers, C A

    2016-05-01

    PurposeTo study the outer retinal tubules using spectral domain optical coherence tomography and adaptive optics and in patients with Bietti's crystalline dystrophy.MethodsTen eyes of five subjects from five independent families with Bietti's crystalline Dystrophy (BCD) were characterized with best-corrected visual acuity (BCVA), full-field electroretinography, and fundus autofluorescence (FAF). High-resolution images were obtained with the spectral domain optical coherence tomography (SD-OCT) and adaptive optics (AO).ResultsSD-OCT showed prominent outer retinal layer loss and outer retinal tubulations at the margin of outer retinal loss. AO images displayed prominent macrotubules and microtubules with characteristic features in eight out of the 10 eyes. Crystals were present in all ten eyes. There was a reduction in the cone count in all eyes in the area outside the outer retinal tubules (ORT).ConclusionsThis study describes the morphology of the outer retinal tubules when imaged enface on the adaptive optics in patients with BCD. These findings provide insight into the macular structure of these patients. This may have prognostic implications and refine the study on the pathogenesis of BCD.

  13. Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration.

    Science.gov (United States)

    Miyadera, Keiko; Kato, Kumiko; Boursnell, Mike; Mellersh, Cathryn S; Sargan, David R

    2012-02-01

    Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1(-/-) dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1(-/-) MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10(-13)) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ~11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1(-/-) alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD.

  14. Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease.

    Science.gov (United States)

    Brais, B

    2003-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)8-13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.

  15. Socio-economic characteristics of patients with generalized retinal dystrophy in Denmark

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Linneberg, Allan; Rosenberg, Thomas

    2015-01-01

    in patients with systemic involvement and patients with an early age at disease presentation. The socio-economic inequalities of this group of blinding diseases emphasize the importance of rehabilitation and need for a substantial and multidisciplinary support from the healthcare, educational and social......PURPOSE: To examine socio-economic characteristics of patients with generalized retinal dystrophy in Denmark. METHODS: Cross-sectional population-based study with analysis of socio-economic characteristics including income, education, employment status and civil status in 2285 patients from...... with a Danish civil registration number were registered as having a generalized retinal dystrophy. At the age of 40 years, less patients than controls had a high education (odds ratio (OR), 0.51; 95% confidence interval (CI95), 0.41-0.62), a high income (OR, 0.21; CI95, 0.17-0.26) and were married (OR, 0.39; CI...

  16. C8orf37 is mutated in Bardet-Biedl syndrome and constitutes a locus allelic to non-syndromic retinal dystrophies.

    Science.gov (United States)

    Khan, Arif O; Decker, Eva; Bachmann, Nadine; Bolz, Hanno J; Bergmann, Carsten

    2016-09-01

    Bardet-Biedl syndrome (BBS) is a pleiotropic and clinically and genetically heterogeneous ciliopathy. Primary features are early-onset retinal dystrophy that is typically rod-cone, obesity, polydactyly, renal abnormalities, hypogonadism, and learning difficulties, but most patients do not present with the full clinical picture. In a BBS patient from a consanguineous marriage we performed next-generation sequencing targeting all known BBS genes and other genes known or hypothesized to cause ciliopathies. While no mutation was present in any of the recognized genes for BBS, we were able to identify the homozygous non-conservative mutation c.529C>T (p.Arg177Trp) in C8orf37 that segregated with the phenotype, affects an evolutionarily highly conserved residue, and is bioinformatically predicted to be pathogenic. The same mutation has been described in unrelated patients with non-syndromic cone-rod dystrophy and other C8orf37 changes were found in individuals with retinitis pigmentosa. We conclude that C8orf37 should be added to BBS screening panels as a probable rare cause of the disease and that individuals with C8orf37-related retinal dystrophy should be screened for BBS features.

  17. North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13

    DEFF Research Database (Denmark)

    Small, Kent W; DeLuca, Adam P; Whitmore, S Scott

    2016-01-01

    PURPOSE: To identify specific mutations causing North Carolina macular dystrophy (NCMD). DESIGN: Whole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells. PARTICIPANTS: A total of 141 members of 12 families...... development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1....

  18. Two siblings with late-onset cone–rod dystrophy and no visible macular degeneration

    Science.gov (United States)

    Sakuramoto, Hiroyuki; Kuniyoshi, Kazuki; Tsunoda, Kazushige; Akahori, Masakazu; Iwata, Takeshi; Shimomura, Yoshikazu

    2013-01-01

    Background We report our findings in two siblings with late-onset cone–rod dystrophy (CRD) with no visible macular degeneration. Cases and methods Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs) were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes. Conclusion These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years. PMID:24039390

  19. IROme, a new high-throughput molecular tool for the diagnosis of inherited retinal dystrophies.

    Science.gov (United States)

    Schorderet, Daniel F; Iouranova, Alexandra; Favez, Tatiana; Tiab, Leila; Escher, Pascal

    2013-01-01

    The molecular diagnosis of retinal dystrophies is difficult because of the very important number of genes implicated and is rarely helped by genotype-phenotype correlations. This prompted us to develop IROme, a custom designed in solution-based targeted exon capture assay (SeqCap EZ Choice library, Roche NimbleGen) for 60 retinitis pigmentosa-linked genes and three candidate genes (942 exons). Pyrosequencing was performed on a Roche 454 GS Junior benchtop high-throughput sequencing platform. In total, 23 patients affected by retinitis pigmentosa were analyzed. Per patient, 39.6 Mb were generated, and 1111 sequence variants were detected on average, at a median coverage of 17-fold. After data filtering and sequence variant prioritization, disease-causing mutations were identified in ABCA4, CNGB1, GUCY2D, PROM1, PRPF8, PRPF31, PRPH2, RHO, RP2, and TULP1 for twelve patients (55%), ten mutations having never been reported previously. Potential mutations were identified in 5 additional patients, and in only 6 patients no molecular diagnosis could be established (26%). In conclusion, targeted exon capture and next-generation sequencing are a valuable and efficient approach to identify disease-causing sequence variants in retinal dystrophies.

  20. IROme, a New High-Throughput Molecular Tool for the Diagnosis of Inherited Retinal Dystrophies

    Directory of Open Access Journals (Sweden)

    Daniel F. Schorderet

    2013-01-01

    Full Text Available The molecular diagnosis of retinal dystrophies is difficult because of the very important number of genes implicated and is rarely helped by genotype-phenotype correlations. This prompted us to develop IROme, a custom designed in solution-based targeted exon capture assay (SeqCap EZ Choice library, Roche NimbleGen for 60 retinitis pigmentosa-linked genes and three candidate genes (942 exons. Pyrosequencing was performed on a Roche 454 GS Junior benchtop high-throughput sequencing platform. In total, 23 patients affected by retinitis pigmentosa were analyzed. Per patient, 39.6 Mb were generated, and 1111 sequence variants were detected on average, at a median coverage of 17-fold. After data filtering and sequence variant prioritization, disease-causing mutations were identified in ABCA4, CNGB1, GUCY2D, PROM1, PRPF8, PRPF31, PRPH2, RHO, RP2, and TULP1 for twelve patients (55%, ten mutations having never been reported previously. Potential mutations were identified in 5 additional patients, and in only 6 patients no molecular diagnosis could be established (26%. In conclusion, targeted exon capture and next-generation sequencing are a valuable and efficient approach to identify disease-causing sequence variants in retinal dystrophies.

  1. IROme, a New High-Throughput Molecular Tool for the Diagnosis of Inherited Retinal Dystrophies

    Science.gov (United States)

    Schorderet, Daniel F.; Iouranova, Alexandra; Favez, Tatiana; Tiab, Leila; Escher, Pascal

    2013-01-01

    The molecular diagnosis of retinal dystrophies is difficult because of the very important number of genes implicated and is rarely helped by genotype-phenotype correlations. This prompted us to develop IROme, a custom designed in solution-based targeted exon capture assay (SeqCap EZ Choice library, Roche NimbleGen) for 60 retinitis pigmentosa-linked genes and three candidate genes (942 exons). Pyrosequencing was performed on a Roche 454 GS Junior benchtop high-throughput sequencing platform. In total, 23 patients affected by retinitis pigmentosa were analyzed. Per patient, 39.6 Mb were generated, and 1111 sequence variants were detected on average, at a median coverage of 17-fold. After data filtering and sequence variant prioritization, disease-causing mutations were identified in ABCA4, CNGB1, GUCY2D, PROM1, PRPF8, PRPF31, PRPH2, RHO, RP2, and TULP1 for twelve patients (55%), ten mutations having never been reported previously. Potential mutations were identified in 5 additional patients, and in only 6 patients no molecular diagnosis could be established (26%). In conclusion, targeted exon capture and next-generation sequencing are a valuable and efficient approach to identify disease-causing sequence variants in retinal dystrophies. PMID:23484092

  2. Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis.

    Science.gov (United States)

    Ronquillo, C C; Bernstein, P S; Baehr, W

    2012-12-15

    Senior-Løken syndrome (SLS) is an autosomal recessive disease characterized by development of a retinitis pigmentosa (RP)- or Leber congenital amaurosis (LCA)-like retinal dystrophy and a medullary cystic kidney disease, nephronophthisis. Mutations in several genes (called nephrocystins) have been shown to cause SLS. The proteins encoded by these genes are localized in the connecting cilium of photoreceptor cells and in the primary cilium of kidney cells. Nephrocystins are thought to have a role in regulating transport of proteins bound to the outer segment/primary cilium; however, the precise molecular mechanisms are largely undetermined. This review will survey the biochemistry, cell biology and existing animal models for each of the nephrocystins as it relates to photoreceptor biology and pathogenesis of retinal degeneration. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Rocuronium as muscle relaxant for electroconvulsive therapy in a patient with adult-onset muscular dystrophy.

    Science.gov (United States)

    Bryson, Ethan O; Aloysi, Amy S; Katz, Maya; Popeo, Dennis; Kellner, Charles H

    2011-12-01

    Adult-onset muscular dystrophy is an inherited myopathy characterized by a variable degree of progressive muscle weakness and degeneration. Although not usually fatal, significant muscle weakness results in an up-regulation of acetylcholine receptors on the less responsive postjunctional muscles. The resulting profound potassium release when these receptors are stimulated by the depolarizing muscle relaxant succinylcholine can result in potentially fatal cardiac arrhythmias. We report a case of electroconvulsive therapy safely administered in a 61-year-old man with adult-onset muscular dystrophy requiring muscle relaxation with rocuronium.

  4. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement.

    NARCIS (Netherlands)

    Estrada-Cuzcano, A.; Neveling, K.; Kohl, S.; Banin, E.; Rotenstreich, Y.; Sharon, D.; Falik-Zaccai, T.C.; Hipp, S.; Roepman, R.; Wissinger, B.; Letteboer, S.J.F.; Mans, D.A.; Blokland, E.A.W.; Kwint, M.P.; Gijsen, S.J.; Huet, R.A.C. van; Collin, R.W.J.; Scheffer, H.; Veltman, J.A.; Zrenner, E.; Hollander, A.I. den; Klevering, B.J.; Cremers, F.P.M.

    2012-01-01

    Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together

  5. Novel Mutations in Two Saudi Patients with Congenital Retinal Dystrophy

    OpenAIRE

    Leen Abu Safieh; Al-Otaibi, Humoud M.; Richard Alan Lewis; Igor Kozak

    2016-01-01

    To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA) and Alström syndrome. Case reports. Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L). Case 2 describes a girl with marked nystagmus, photophobia, and re...

  6. The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies

    NARCIS (Netherlands)

    Slijkerman, R.W.; Song, F.; Astuti, G.D.; Huijnen, M.A.; WIjk, E.; Stieger, K.; Collin, R.W.

    2015-01-01

    Over the last decade, huge progress has been made in the understanding of the molecular mechanisms underlying inherited retinal dystrophy (IRD), as well as in the development and implementation of novel therapies, especially in the field of gene therapy. The use of mutant animal models, either natur

  7. Bietti crystalline retinal dystrophy with subfoveal neurosensory detachment and congenital tortuosity of retinal vessels: case report.

    Science.gov (United States)

    Padhi, Tapas Ranjan; Kesarwani, Siddharth; Jalali, Subhadra

    2011-06-01

    A 34-year-old man presented with reduction and distortion of vision in both the eyes. The best-corrected vision was 20/20 parts, N6 in either eye. The external and slit lamp examination of both the eyes was unremarkable. The fundus examination showed multiple intraretinal crystalline deposits at the posterior pole, extending up to midperiphery, tortuous retinal blood vessels with S-shaped deflections, and absent foveal reflex in both the eyes. There were no corneal crystals, and the color vision was defective in both the eyes. Fundus autofluorescence and fundus fluorescein angiogram (FFA) were suggestive of geographic areas of retinal pigment epithelium (RPE) and choriocapillary (CC) loss. OCT revealed subfoveal neurosensory detachment. Flash ERG and EOG were normal except for a slight decrease in amplitude and delay in latency of pattern ERG waveforms. The Humphrey's visual field showed paracentral scotoma with reduction in the amplitude of waveforms from the corresponding area in the multifocal ERG in both the eyes. Systemic evaluation for crystalline retinopathy was unremarkable. He was diagnosed to be a case of Bietti crystalline retinopathy (local/regional variant). The subfoveal neurosensory detachment could represent early RPE dysfunction caused by these crystals and could account for the mild visual disturbance in both the eyes. Retinal vascular tortuosity and neurosensory detachment seen in this case is the first time to be reported in literature.

  8. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis.

    Directory of Open Access Journals (Sweden)

    Marta Corton

    Full Text Available Retinal dystrophies (RD are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context.We ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants (∼50% novel mutations in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases.Despite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available.

  9. Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Dandan Tan

    Full Text Available This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA-related muscular dystrophy (MD. The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293 cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD. Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

  10. Acute necrotizing retinal vasculitis as onset of systemic lupus erythematosus

    Science.gov (United States)

    Monov, Simeon; Hristova, Ruska; Dacheva, Rositza; Toncheva, Reni; Shumnalieva, Russka; Shoumnalieva-Ivanova, Viara; Monova, Daniela

    2017-01-01

    Abstract Rationale: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production, complement activation, and deposition of immune complexes in tissues and organs. SLE can involve any region of the visual system. Although ocular manifestations are not part of the classification criteria for SLE, they can be observed in up to one-third of the patients with SLE. They are rarely reported at the time of disease onset. Retinal vasculitis is usually associated with active generalized disease. Due to its low frequency, we report a case of acute necrotizing retinal vasculitis as onset of SLE. Patient concerns and diagnosis: A 25-year-old white female was referred to the rheumatology clinic with gradually and rapid deterioration of the vision due to abnormal vessel permeability in the right fundus with edema along the vessels, occlusion of arterial branches in the middle periphery with leakage of the dye in these areas and indentical but less prominent changes with cotton wool spots in the papillomacular area and extensive hemorrhages in the left eye. The onset of malar rash, arthralgias and positive antinuclear, anti-double stranded DNA, anti-ribosomal P and anti-β2 glycoprotein I antibodies with decreased C4 complement levels, as well as the positive lupus-band test confirmed the diagnosis of SLE. Interventions: Aggressive immunomodulating therapy with high-dose methylprednisolone, intravenous immunoglobulin, and cyclophosphamide was used for suppression of the disease activity followed by azathioprine as maintaince therapy. Outcomes: Substantial improvement and partial resorption of the vasculitic changes, including central retinal artery and vein, was achieved prominently in the left eye. The study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from the patient. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary

  11. Oculopharyngeal Muscular Dystrophy and Inherited Retinal Dystrophy in Bukhara Jews Due to Linked Mutations in the PABPN1 and NRL Genes.

    Science.gov (United States)

    Braverman, Itzhak; Blumen, Sergiu C; Newman, Hadas; Rizel, Leah; Khayat, Morad; Hanna, Rana; St Guily, Jean Lacau; Tiosano, Beatrice; Ben-Yosef, Tamar

    2017-07-01

    We have previously described two unrelated Bukhara Jews (BJs) with a combination of oculopharyngeal muscular dystrophy (OPMD) and inherited retinal dystrophy (IRD), because of mutations in two linked genes: PABPN1 and NRL. Here we investigated the prevalence of the NRL mutation among BJs with OPMD. PABPN1 and NRL mutation testing were performed by polymerase chain reaction amplification and direct sequencing on two cohorts of Bukhara Jewish patients: OPMD patients (with or without IRD) and IRD patients (without OPMD). Of 24 unrelated chromosomes from Bukhara Jewish OPMD patients, 19 (79%) harbored the NRL mutation. In contrast, the NRL mutation was not detected in Bukhara Jewish patients diagnosed with IRD but without OPMD. Our findings provide an explanation for the reoccurrence of IRD in Bukhara Jewish OPMD homozygotes. Moreover, they indicate that Bukhara Jewish OPMD patients are at high risk for carrying the NRL mutation, and should be offered appropriate genetic counseling and testing.

  12. Psycho-organic symptoms as early manifestation of adult onset POMT1-related limb girdle muscular dystrophy.

    Science.gov (United States)

    Haberlova, J; Mitrović, Z; Zarković, K; Lovrić, D; Barić, V; Berlengi, L; Bilić, K; Fumić, K; Kranz, K; Huebner, A; von der Hagen, M; Barresi, R; Bushby, K; Straub, V; Barić, I; Lochmüller, H

    2014-11-01

    We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced α-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits.

  13. Late-onset Pompe disease with phenotype of the limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    S. A. Kurbatov

    2015-01-01

    Full Text Available Pompe disease, also known as type II glycogenosis, is a rare autosomal recessive disease. Two main types include early-onset Pompe disease – severe, rapidly progressive multisystem deficency, manifestating on the first year of life, and late-onset Pompe disease (LOPD, with the age of onset ranging from the first year till late adulthood. Both types are caused by the deficiency of lysosomal acid-α-glucosidase due to the mutations in GAA gene, leading to an excessive storage of glycogen in body cells. LOPD is a slowly progressive disease with a primary lesion of a skeletal, respiratory and cardiac muscles, affected in different grade, and moderately elevated сreatine kinase. It is often difficult to perform differential diagnosis with a large group of hereditary and non-hereditary myopathies. We present a case report of LOPD with signs of limb-girdle muscular dystrophy.

  14. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy.

    Science.gov (United States)

    Riisager, M; Duno, M; Hansen, F Juul; Krag, T O; Vissing, C R; Vissing, J

    2013-07-01

    Defects in glycosylations of α-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of α-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far.

  15. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy

    DEFF Research Database (Denmark)

    Riisager, Maria; Duno, M; Hansen, Flemming Juul;

    2013-01-01

    to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due...... to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations...

  16. A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

    Directory of Open Access Journals (Sweden)

    Susanne Roosing

    2017-08-01

    Full Text Available Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT, a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM (n = 23 and autosomal recessive or isolated cone dystrophy (CD; n = 145. Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151* and c.4723A>T; p.(Lys1575* in CEP290 were found. Previously, p.(Arg151* was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del and p.(Leu148_Lys172del. mRNA analysis for p.(Lys1575* confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del. No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype.

  17. A novel early onset phenotype in a zebrafish model of merosin deficient congenital muscular dystrophy

    Science.gov (United States)

    Smith, Sarah J.; Wang, Jeffrey C.; Gupta, Vandana A.; Dowling, James J.

    2017-01-01

    Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening. Our goal in this study was to elucidate novel, early onset abnormalities in the candyfloss (caf) zebrafish, a model of MDC1A. We uncovered and characterize abnormalities in spontaneous coiling, the earliest motor movement in the zebrafish, as a fully penetrant change specific to caf mutants that is ideal for future drug testing. PMID:28241031

  18. NRL S50T mutation and the importance of 'founder effects' in inherited retinal dystrophies.

    Science.gov (United States)

    Bessant, D A; Payne, A M; Plant, C; Bird, A C; Swaroop, A; Bhattacharya, S S

    2000-10-01

    The aim of this work was to identify NRL mutations in a panel of 200 autosomal dominant retinitis pigmentosa (adRP) families. All samples were subjected to heteroduplex analysis of the three exons of the NRL gene, and HphI restriction digest analysis of exon 2 (to identify the S50T mutation). Families found to have the S50T mutation, and six additional larger pedigrees (which had previously been excluded from the other nine adRP loci) underwent linkage analysis using polymorphic markers located in the region of 14q11. HphI restriction analysis followed by direct sequencing of the amplified NRL exon 2 product demonstrated the presence of the NRL S50T sequence change in three adRP families. Comparison of marker haplotypes in affected individuals from these families with those of affected members of the original 14q11 linked family revealed a common disease haplotype for markers within the adRP locus. Recombination events observed in these families define an adRP critical interval of 14.9 cM between D13S72 and D14S1041. Linkage analysis enabled all six of the larger adRP pedigrees to be excluded from the 14q11 locus. The NRL S50T mutation represents another example of a 'founder effect' in a dominantly inherited retinal dystrophy. Identification of such 'founder effects' may greatly simplify diagnostic genetic screening and lead to better prognostic counselling. The exclusion of several adRP families from all ten adRP loci indicates that at least one further adRP locus remains to be found.

  19. RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy.

    Science.gov (United States)

    Davidson, Alice E; Sergouniotis, Panagiotis I; Mackay, Donna S; Wright, Genevieve A; Waseem, Naushin H; Michaelides, Michel; Holder, Graham E; Robson, Anthony G; Moore, Anthony T; Plagnol, Vincent; Webster, Andrew R

    2013-03-01

    In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1-like1, a photoreceptor-specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease.

  20. The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies.

    Science.gov (United States)

    Slijkerman, Ralph W N; Song, Fei; Astuti, Galuh D N; Huynen, Martijn A; van Wijk, Erwin; Stieger, Knut; Collin, Rob W J

    2015-09-01

    Over the last decade, huge progress has been made in the understanding of the molecular mechanisms underlying inherited retinal dystrophy (IRD), as well as in the development and implementation of novel therapies, especially in the field of gene therapy. The use of mutant animal models, either naturally occurring or generated by genetic modification, have contributed greatly to our knowledge on IRD. Yet, these mutant animal models do not always mimic the retinal phenotype that is observed in humans with mutations in the orthologous gene, often due to species-specific characteristics of the retina, and/or diverse functions of the gene products in different species. In this manuscript, we compare general and ocular characteristics of a series of widely used vertebrate animal models, i.e. zebrafish, chicken, rodents, cats, dogs, sheep, pigs and monkeys, in terms of genetic architecture and sequence homology, methods to modify genomes, anatomy of the eye, and structural details of the retina. Furthermore, we present an overview of mutant vertebrate animal models that have been used to study or develop treatments for the various genetic subtypes of IRD, and correlate the suitability of these models to the specific characteristics of each animal. Herewith, we provide tools that will help to select the most suitable animal model for specific research questions on IRDs in the future, and thereby assist in an optimal use of animals and resources to further increase our understanding of inherited retinal dystrophies, and develop novel treatments for these disorders.

  1. Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy

    DEFF Research Database (Denmark)

    Andersen, Søren P; Sveen, Marie-Louise; Hansen, Regitze S

    2013-01-01

    We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies.......We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies....

  2. Is there a relationship between outer retinal destruction and choroidal changes in cone dystrophy?

    Directory of Open Access Journals (Sweden)

    Onder Ayyildiz

    Full Text Available ABSTRACT Purpose: The aim of the present study was to use enhanced depth imaging optical coherence tomography (EDI-OCT to investigate choroidal changes in patients with cone dystrophy (CD and to correlate these findings with clinical and electroretinography (ERG findings. Methods: This case-control study included 40 eyes of 20 patients with CD and 40 eyes of 40 age- and refraction-matched healthy individuals. Choroidal thickness (CT measurements were obtained under the foveal center and at 500 and 1,500 μm from the nasal and temporal regions to the center of the fovea, respectively. EDI-OCT and ERG data were analyzed, and the correlations of CT with the best-corrected visual acuity (BCVA and the central foveal thickness (CFT were evaluated. Results: The mean subfoveal CTs in the CD and control groups were 240.70 ± 70.78 and 356.18 ± 48.55 μm, respectively. The subfoveal CT was significantly thinner in patients with CD than in the controls (p<0.001. The patients with CD also had significantly thinner choroids than the controls at each measurement location relative to the fovea (p<0.001. The subfoveal CT in the CD group correlated with CFT (p=0.012, but no significant correlation was found between the subfoveal CT and BCVA or photopic ERG responses. Conclusions: The present study demonstrated a significant thinning of the choroid in patients with CD. EDI-OCT is a useful technique for describing the choroidal changes occurring in CD. Future studies investigating the association between choroidal changes and outer retinal destruction or the disease stage may provide a better understanding of the pathophysiology of CD.

  3. Early-onset facioscapulohumeral muscular dystrophy - significance of pelvic extensors in sagittal spinal imbalance.

    Science.gov (United States)

    Lee, Choon Sung; Kang, Suk Jung; Hwang, Chang Ju; Lee, Sung-Woo; Ahn, Young-Joon; Kim, Yung-Tae; Lee, Dong-Ho; Lee, Mi Young

    2009-11-01

    Although facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited myopathy, cases of infantile or early-childhood onset have rarely been reported. The purpose of this study was to describe a case of early-onset FSHD with lumbar hyperlordosis, which shows the significance of the dynamic component of sagittal spinal imbalance. An 11-year-old girl presented with progressive gait disturbance and lumbar hyperlordosis. The motor power of her pelvic extensor muscles was grade 3. Pelvic tilt and hip flexion were markedly increased as determined by gait analysis. The most important factor in the development of hyperlordosis is the weakness of the pelvic extensor muscles, and the results of gait analysis exquisitely explain the pathophysiology. The patient stands with her spine hyperextended to maintain upright posture by a compensatory mechanism of relatively strong back extensor muscles. Corrective surgery for lumbar hyperlordosis was not considered because it could have eliminated the compensatory lumbar hyperextension, thus making the spine of the patient stoop forward through her hip joint during walking by the weakness of her pelvic extensor muscles. This FSHD case is an impressive example of a patient showing the concept that weak pelvic extensor muscles cannot keep the spine upright and balanced.

  4. Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations

    Directory of Open Access Journals (Sweden)

    Babu Lal Kumawat

    2016-01-01

    Full Text Available Background: Congenital hereditary endothelial dystrophy (CHED is an autosomal recessive disorder characterized by bilateral, symmetrical, noninflammatory corneal clouding (edema present at birth or shortly thereafter. This study reports on an unusual delayed presentation of CHED with compound heterozygous SLC4A11 mutations. Materials and Methods: A 45-year-old female, presenting with bilateral decreased vision since childhood that deteriorated in the last 5 years, was evaluated to rule out trauma, viral illness, chemical injury, glaucoma, and corneal endothelial dystrophies. Tear sample was sent for herpes simplex viral (HSV antigen testing. Genomic DNA from peripheral blood was screened for mutations in all exons of SLC4A11 by direct sequencing. Full-thickness penetrating keratoplasty was done and corneal button was sent for histopathological examination. Results: Slit-lamp findings revealed bilateral diffuse corneal edema and left eye spheroidal degeneration with scarring. Increased corneal thickness (762 μm and 854 μm in the right and left eyes, respectively, normal intraocular pressure (12 mmHg and 16 mmHg in the right and left eyes, respectively, inconclusive confocal scan, and specular microscopy, near normal tear film parameters, were the other clinical features. HSV-polymerase chain reaction was negative. Histopathological examination revealed markedly thickened Descemet′s membrane with subepithelial spheroidal degeneration. SLC4A11 screening showed a novel variant p.Ser415Asn, reported mutation p.Cys386Arg and two polymorphisms, all in the heterozygous state and not identified in 100 controls. Conclusions: The study shows, for the first time, compound heterozygous SLC4A11 mutations impair protein function leading to delayed onset of the disease.

  5. A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype

    NARCIS (Netherlands)

    Littink, Karin W.; Pott, Jan-Willem R.; Collin, Rob W. J.; Kroes, Hester Y.; Verheij, Joke B. G. M.; Blokland, Ellen A. W.; Miro, Marta de Castro; Hoyng, Carel B.; Klaver, Caroline C. W.; Koenekoop, Robert K.; Rohrschneider, Klaus; Cremers, Frans P. M.; van den Born, L. Ingeborgh; den Hollander, Anneke I.

    2010-01-01

    PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP)

  6. Age of onset of RNA toxicity influences phenotypic severity: evidence from an inducible mouse model of myotonic dystrophy (DM1).

    Science.gov (United States)

    Gladman, Jordan T; Mandal, Mahua; Srinivasan, Varadamurthy; Mahadevan, Mani S

    2013-01-01

    Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by an expanded (CTG)n tract in the 3' UTR of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1)). More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3' UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.

  7. Age of onset of RNA toxicity influences phenotypic severity: evidence from an inducible mouse model of myotonic dystrophy (DM1.

    Directory of Open Access Journals (Sweden)

    Jordan T Gladman

    Full Text Available Myotonic dystrophy type 1 (DM1 is the most common muscular dystrophy in adults. It is caused by an expanded (CTGn tract in the 3' UTR of the Dystrophia Myotonica Protein Kinase (DMPK gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1. More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3' UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.

  8. Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES: Benefits and Limitations.

    Directory of Open Access Journals (Sweden)

    Amit Tiwari

    Full Text Available Inherited retinal dystrophies (IRDs are Mendelian diseases with tremendous genetic and phenotypic heterogeneity. Identification of the underlying genetic basis of these dystrophies is therefore challenging. In this study we employed whole exome sequencing (WES in 11 families with IRDs and identified disease-causing variants in 8 of them. Sequence analysis of about 250 IRD-associated genes revealed 3 previously reported disease-associated variants in RHO, BEST1 and RP1. We further identified 5 novel pathogenic variants in RPGRIP1 (p.Ser964Profs*37, PRPF8 (p.Tyr2334Leufs*51, CDHR1 (p.Pro133Arg and c.439-17G>A and PRPF31 (p.Glu183_Met193dup. In addition to confirming the power of WES in genetic diagnosis of IRDs, we document challenges in data analysis and show cases where the underlying genetic causes of IRDs were missed by WES and required additional techniques. For example, the mutation c.439-17G>A in CDHR1 would be rated unlikely applying the standard WES analysis. Only transcript analysis in patient fibroblasts confirmed the pathogenic nature of this variant that affected splicing of CDHR1 by activating a cryptic splice-acceptor site. In another example, a 33-base pair duplication in PRPF31 missed by WES could be identified only via targeted analysis by Sanger sequencing. We discuss the advantages and challenges of using WES to identify mutations in heterogeneous diseases like IRDs.

  9. Infrared imaging enhances retinal crystals in Bietti’s crystalline dystrophy

    Directory of Open Access Journals (Sweden)

    Brar VS

    2015-04-01

    Full Text Available Vikram S Brar, William H Benson Department of Ophthalmology, Medical College of Virginia Campus, Virginia Commonwealth University School of Medicine, Richmond, VA, USA Abstract: Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. Keywords: Bietti’s crystalline dystrophy, infrared imaging, spectral domain optical coherence tomography

  10. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation

    NARCIS (Netherlands)

    Laat, P. de; Smeitink, J.A.M.; Janssen, M.C.H.; Keunen, J.E.E.; Boon, C.J.F.

    2013-01-01

    OBJECTIVE: To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. DESIGN: Observati

  11. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation

    NARCIS (Netherlands)

    Laat, P. de; Smeitink, J.A.M.; Janssen, M.C.H.; Keunen, J.E.E.; Boon, C.J.F.

    2013-01-01

    OBJECTIVE: To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. DESIGN:

  12. Infrared imaging enhances retinal crystals in Bietti’s crystalline dystrophy

    Science.gov (United States)

    Brar, Vikram S; Benson, William H

    2015-01-01

    Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. PMID:25931805

  13. Terapia gênica em distrofias hereditárias de retina Gene therapy for inherited retinal dystrophies

    Directory of Open Access Journals (Sweden)

    Monique Côco

    2009-08-01

    Full Text Available As distrofias hereditárias de retina abrangem um amplo número de doenças caracterizadas por lenta e progressiva degeneração da retina. São o resultado de mutações em genes expressos em fotorreceptores e no epitélio pigmentado da retina. A herança pode ser autossômica dominante, autossômica recessiva, ligada ao X recessiva, digênica ou herança mitocondrial. Atualmente não há tratamento para essas doenças e os pacientes convivem com a perda progressiva da visão. O aconselhamento genético e o suporte para reabilitação têm indicação nestes casos. Pesquisas envolvendo a base molecular e genética dessas doenças está continuamente em expansão e ampliam as perspectivas para novas formas de tratamento. Dessa forma, a terapia gênica, que consiste na inserção de material genético exógeno em células de um indivíduo com finalidade terapêutica, tem sido a principal forma de tratamento para as distrofias hereditárias de retina. O olho é um órgão peculiar para a terapia gênica, pois é anatomicamente dividido em compartimentos, imunologicamente privilegiado e com meios transparentes. A maioria das doenças oculares tem defeitos em genes conhecidos. Além disso, há modelo animal bem caracterizado para algumas condições. Propostas para pesquisa clínica em terapia gênica nas degenerações retinianas hereditárias com defeito no gene RPE65, recentemente tiveram aprovação ética e os resultados preliminares obtidos trouxeram grandes expectativas na melhora da qualidade de vida dos pacientes.The inherited retinal dystrophies comprise a large number of disorders characterized by a slow and progressive retinal degeneration. They are the result of mutations in genes that express in either the photoreceptor cells or the retinal pigment epithelium. The mode of inheritance can be autosomal dominant, autosomal recessive, X linked recessive, digenic or mitochondrial DNA inherited. At the moment, there is no treatment for these

  14. Inherited Retinal Degenerative Disease Registry

    Science.gov (United States)

    2016-03-21

    Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

  15. Photobiomodulation reduces photoreceptor death and regulates cytoprotection in early states of P23H retinal dystrophy

    Science.gov (United States)

    Kirk, Diana K.; Gopalakrishnan, Sandeep; Schmitt, Heather; Abroe, Betsy; Stoehr, Michele; Dubis, Adam; Carroll, Joseph; Stone, Jonathan; Valter, Krisztina; Eells, Janis

    2013-03-01

    Irradiation by light in the far-red to near-infrared (NIR) region of the spectrum (photobiomodulation, PBM) has been demonstrated to attenuate the severity of neurodegenerative disease in experimental and clinical studies. The purpose of this study was to test the hypothesis that 670 nm PBM would protect against the loss of retinal function and improve photoreceptor survival in a rodent model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated once per day with a 670 nm LED array (180 sec treatments at 50 mW/cm2; fluence 9 joules/cm2) (Quantum Devices Inc., Barneveld WI) from postnatal day (p) 16-20 or from p10-20. Sham-treated rats were restrained, but not exposed to NIR light. The status of the retina was determined at p22 by assessment of mitochondrial function, oxidative stress and cell death. In a second series of studies, retinal status was assessed at p30 by measuring photoreceptor function by ERG and retinal morphology by Spectral Domain Optical Coherence Tomography (SD-OCT). 670 nm PBM increased retinal mitochondrial cytochrome oxidase activity and upregulated the retina's production of the key mitochondrial antioxidant enzyme, MnSOD. PBM also attenuated photoreceptor cell loss and improved photoreceptor function. PBM protects photoreceptors in the developing P23H retina, by augmenting mitochondrial function and stimulating antioxidant protective pathways. Photobiomodulation may have therapeutic potential, where mitochondrial damage is a step in the death of photoreceptors.

  16. Retinal ectopias and mechanically weakened basement membrane in a mouse model of muscle-eye-brain (MEB) disease congenital muscular dystrophy.

    Science.gov (United States)

    Hu, Huaiyu; Candiello, Joseph; Zhang, Peng; Ball, Sherry L; Cameron, David A; Halfter, Willi

    2010-07-28

    Some forms of congenital muscular dystrophy are associated with cortical and retinal dysplasias. Protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice, one of the mouse models of muscular dystrophy, exhibit a thinner retina with reduced density of retinal ganglion cells. This study is aimed to further characterize the knockout retina, with special emphasis on the inner limiting membrane, the basement membrane of the retina. Immunofluorescence staining and transmission electron microscopy were used to analyze the retinas. Atomic force microscopy was performed on the inner limiting membrane preparations to examine their mechanical properties. The inner limiting membrane of the knockout mice exhibited frequent breaks with protrusions of the Müller glial processes and ectopic placement of retinal ganglion cells into the vitreous humor. Disruptions in inner limiting membrane integrity developmentally precede the cellular abnormalities. Regions of disrupted inner limiting membrane were also associated with molecular abnormalities of Müller glia that included diminished presence of the integral membrane proteins Kir4.1 (an inwardly rectifying potassium channel) and aquaporin-4. When measured with atomic force microscopy, the POMGnT1 knockout mouse inner limiting membrane (ILM) exhibited significantly reduced Young's modulus and is therefore mechanically weaker than the ILM from controls. Deficiency of POMGnT1-mediated glycosylation of dystroglycan is implicated in reduced stiffness of the ILM. The weakened ILM results in the disruption of the membrane and subsequent reduction in retinal integrity.

  17. A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, AJ; de Visser, M; van Meegen, M; Ginjaar, HB; van Essen, AJ; Jennekens, FGI; Jongen, PJH; Leschot, NJ; Bolhuis, PA

    1998-01-01

    Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family

  18. A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, AJ; de Visser, Marianne; van Meegen, M; Ginjaar, HB; van Essen, AJ; Jennekens, FGI; Jongen, PJH; Leschot, NJ; Bolhuis, PA

    Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family

  19. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders.

    Science.gov (United States)

    Al-Maawali, Almundher; Dupuis, Lucie; Blaser, Susan; Heon, Elise; Tarnopolsky, Mark; Al-Murshedi, Fathiya; Marshall, Christian R; Paton, Tara; Scherer, Stephen W; Roelofsen, Jeroen; van Kuilenburg, André B P; Mendoza-Londono, Roberto

    2015-03-01

    PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.

  20. Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel

    Science.gov (United States)

    Bravo-Gil, Nereida; Méndez-Vidal, Cristina; Romero-Pérez, Laura; González-del Pozo, María; Rodríguez-de la Rúa, Enrique; Dopazo, Joaquín; Borrego, Salud; Antiñolo, Guillermo

    2016-01-01

    Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management. PMID:27032803

  1. Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats

    Science.gov (United States)

    Ofri, Ron; Reilly, Christopher M.; Maggs, David J.; Fitzgerald, Paul G.; Shilo-Benjamini, Yael; Good, Kathryn L.; Grahn, Robert A.; Splawski, Danielle D.; Lyons, Leslie A.

    2015-01-01

    Purpose A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Methods Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Results Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. Conclusions A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness. PMID:26258614

  2. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    Science.gov (United States)

    2016-08-26

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  3. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Preisler, Nicolai; Lukacs, Zoltan; Vinge, Lotte

    2013-01-01

    Late-onset Pompe disease is a rare, but potentially treatable metabolic myopathy, and therefore should not be overlooked. However, it is not unusual that patients go undiagnosed for many years. We hypothesized that patients with late-onset Pompe disease may have been overlooked in a population...

  4. Animals deficient in C2Orf71, an autosomal recessive retinitis pigmentosa-associated locus, develop severe early-onset retinal degeneration.

    Science.gov (United States)

    Kevany, Brian M; Zhang, Ning; Jastrzebska, Beata; Palczewski, Krzysztof

    2015-05-01

    Genetic mapping was recently used to identify the underlying cause for a previously uncharacterized cohort of autosomal recessive retinitis pigmentosa cases. Genetic mapping of affected individuals resulted in the identification of an uncharacterized gene, C2Orf71, as the causative locus. However, initial homology searches failed to reveal similarities to any previously characterized protein or domain. To address this issue, we characterized the mouse homolog, BC027072. Immunohistochemistry with a custom polyclonal antibody showed staining localized to the inner segments (IS) of photoreceptor cells, as well as the outer segments (OS) of cone cells. A knockout mouse line (BC(-/-)) was generated and demonstrated that loss of this gene results in a severe, early-onset retinal degeneration. Histology and electron microscopy (EM) revealed disorganized OS as early as 3 weeks with complete loss by 24 weeks of age. EM micrographs displayed packets of cellular material containing OS discs or IS organelles in the OS region and abnormal retinal pigmented epithelium cells. Analyses of retinoids and rhodopsin levels showed retinal degenerations. Although its function remains unknown, this protein appears essential for normal OS development/maintenance and vision in humans and mice. RNAseq data are available in the GEO database under accession: GSE63810.

  5. Distrofias retinianas da infância: análise retrospectiva Retinal dystrophies in childhood: retrospective analysis

    Directory of Open Access Journals (Sweden)

    Heloisa Andrade Maestrini

    2004-12-01

    distrofias retinianas da infância são um grupo heterogêneo de doenças que se manifestam por meio de sintomas inespecíficos. Uma análise cuidadosa dos sintomas, o exame oftalmológico completo e os exames complementares, principalmente ERG, testes de visão de cores e campo visual, podem ser úteis em seu diagnóstico.PURPOSE: To describe the clinical features and the results of diagnostic methods in all patients with diagnosis of one of the following retinal dystrophies: Leber congenital amaurosis (LCA, achromatopsia, cone distrophy or cone-rod distrophy, examined at the Low Vision Department of the Federal University of Minas Gerais, in the period of 1992 to 2003. METHODS: Retrospective analysis of charts of 40 patients. Ten had LCA, 17 had achromatopsia, 6 had cone distrophy and 7 had cone-rod distrophy. RESULTS: Visual acuity was extremely low in patients with LCA, ranging from 20/710 to light perception. The mean value for achromatopsia was 20/200, 20/280 for cone distrophy and 20/260 for cone-rod distrophy. High hyperopia was the most common refractional error in LCA patients. Hyperopia was more frequent in cases of achromatopsia and cone distrophy, while in cone-rod distrophy myopia predominated. Fundoscopy was altered in most cases of LCA, cone distrophy and rod-cone distrophy, and normal in most cases of achromatopsia. Oculodigital sign and enophtalmus were found only in LCA patients while photofobia and color vision defects prevailed in other groups. Nistagmus and strabismus were frequent findings in all groups. There was a high incidence of delayed neuro-psycho-motor development in LCA patients. Two of them had also associated genetic syndromes. Patients presented symptoms very early in life in LCA and achromatopsia, while in cone and cone-rod distrophies symptoms appeared later, but never after the age of 10. Consanguinity and positive familial history were strongly associated in all groups. The ERG was extinct in LCA, showed reduced photopic response in

  6. Three intravitreal bevacizumab versus two intravitreal triamcinolone injections in recent onset central retinal vein occlusion.

    Science.gov (United States)

    Ramezani, Alireza; Esfandiari, Hamed; Entezari, Morteza; Moradian, Siamak; Soheilian, Masoud; Dehsarvi, Babak; Yaseri, Mehdi

    2014-11-01

    To evaluate the effects of repeated intravitreal injections of bevacizumab (IVB) versus triamcinolone acetonide (IVT) in the treatment of acute central retinal vein occlusion (CRVO). In this randomized clinical trial, 86 eyes with recent onset (central macular thickness (CMT), and intraocular pressure (IOP) changes. Mean BCVA improved significantly at 6 months in both groups; from 0.87 ± 0.49 to 0.41 ± 0.35 logMAR in IVB group, and from 0.81 ± 0.45 to 0.62 ± 0.48 logMAR in IVT group (p < 0.001). However, between-group differences reach a significant level at months 4 (p = 0.003) and 6 (p < 0.001) in favour of the IVB group. In terms of CMT reduction, the difference between the groups was statistically significant (p = 0.002) at month 6. Significant differences were noted more in the ischaemic cases in favour of the IVB group. Mean IOP rise was significantly higher in the IVT group at all visits. Both 3-times monthly IVB injections and 2-times IVT injections could be effective in cases with recent onset CRVO up to 6 months. However, considering the better outcomes after IVB injections and the potential complications of IVT injections, we would recommend prescheduled repeated IVB injections for such cases. The observed favourable responses were more pronounced in the ischaemic types; nevertheless, this should be confirmed in larger studies. © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  7. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies

    Science.gov (United States)

    Glöckle, Nicola; Kohl, Susanne; Mohr, Julia; Scheurenbrand, Tim; Sprecher, Andrea; Weisschuh, Nicole; Bernd, Antje; Rudolph, Günther; Schubach, Max; Poloschek, Charlotte; Zrenner, Eberhart; Biskup, Saskia; Berger, Wolfgang; Wissinger, Bernd; Neidhardt, John

    2014-01-01

    Hereditary retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different forms of RD can be caused by mutations in >100 genes, including >1600 exons. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. So far, NGS is not routinely used in gene diagnostics. We developed a diagnostic NGS pipeline to identify mutations in 170 genetically and clinically unselected RD patients. NGS was applied to 105 RD-associated genes. Underrepresented regions were examined by Sanger sequencing. The NGS approach was successfully established using cases with known sequence alterations. Depending on the initial clinical diagnosis, we identified likely causative mutations in 55% of retinitis pigmentosa and 80% of Bardet–Biedl or Usher syndrome cases. Seventy-one novel mutations in 40 genes were newly associated with RD. The genes USH2A, EYS, ABCA4, and RHO were more frequently affected than others. Occasionally, cases carried mutations in more than one RD-associated gene. In addition, we found possible dominant de-novo mutations in cases with sporadic RD, which implies consequences for counseling of patients and families. NGS-based mutation analyses are reliable and cost-efficient approaches in gene diagnostics of genetically heterogeneous diseases like RD. PMID:23591405

  8. Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa.

    Directory of Open Access Journals (Sweden)

    Giulia Venturini

    Full Text Available Retinitis pigmentosa (RP is a hereditary disease that leads to the progressive degeneration of retinal photoreceptor cells and to blindness. It is caused by mutations in several distinct genes, including the ciliary gene FAM161A, which is associated with a recessive form of this disorder. Recent investigations have revealed that defects in FAM161A represent a rather prevalent cause of hereditary blindness in Israel and the Palestinian territories, whereas they seem to be rarely present within patients from Germany. Genetic or clinical data are currently not available for other countries. In this work, we screened a cohort of patients with recessive RP from North America to determine the frequency of FAM161A mutations in this ethnically-mixed population and to assess the phenotype of positive cases. Out of 273 unrelated patients, only 3 subjects had defects in FAM161A. A fourth positive patient, the sister of one of these index cases, was also identified following pedigree analysis. They were all homozygous for the p.T452Sfx3 mutation, which was previously reported as a founder DNA variant in the Israeli and Palestinian populations. Analysis of cultured lymphoblasts from patients revealed that mutant FAM161A transcripts were actively degraded by nonsense-mediated mRNA decay. Electroretinographic testing showed 30 Hz cone flicker responses in the range of 0.10 to 0.60 microvolts in all cases at their first visit (age 12 to 23 (lower norm  =  50 μV and of 0.06 to 0.32 microvolts at their most recent examination (age 27 to 43, revealing an early-onset of this progressive disease. Our data indicate that mutations in FAM161A are responsible for 1% of recessive RP cases in North America, similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. We also show that, at the molecular level, the disease is likely caused by FAM161A protein deficiency.

  9. Retinal structure in young patients aged 10 years or less with Best vitelliform macular dystrophy

    DEFF Research Database (Denmark)

    Schatz, Patrik; Sharon, Dror; Al-Hamdani, Sermed

    2016-01-01

    ranged from subtle thickening at the level of the retinal pigment epithelium-photoreceptor interdigitation line, to subretinal fluid and precipitate-like changes at the level of the photoreceptor outer segments, and further to choroidal neovascularization. The photoreceptor inner segment ellipsoid layer...... of the retinal pigment epithelium-photoreceptor interdigitation line. The photoreceptor inner segment seems to be unaffected unless choroidal neovascularization develops, which seems promising regarding future gene therapy....

  10. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-03-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function.

  11. Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease.

    Science.gov (United States)

    Palmio, Johanna; Jonson, Per Harald; Evilä, Anni; Auranen, Mari; Straub, Volker; Bushby, Kate; Sarkozy, Anna; Kiuru-Enari, Sari; Sandell, Satu; Pihko, Helena; Hackman, Peter; Udd, Bjarne

    2015-11-01

    DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation.

  12. Identification of CNGA3 mutations in 46 families: common cause of achromatopsia and cone-rod dystrophies in Chinese patients.

    Science.gov (United States)

    Li, Shiqiang; Huang, Li; Xiao, Xueshan; Jia, Xiaoyun; Guo, Xiangming; Zhang, Qingjiong

    2014-09-01

    Mutations in CNGA3 are the most common cause of achromatopsia and cone-rod dystrophies. To identify CNGA3 mutations in patients with cone dystrophies or Leber congenital amaurosis. Clinical data and genomic DNA in 267 Chinese probands from 138 families with cone dystrophies and 129 families with Leber congenital amaurosis collected at the Zhongshan Ophthalmic Center, Guangzhou, China. Variants in CNGA3 and associated phenotypes, assessed by Sanger sequencing of CNGA3, bioinformatics of variants, and segregation analysis. Homozygous or compound heterozygous mutations in CNGA3, including 26 novel and 13 known mutations, were identified in 46 probands from 138 families with cone dystrophies, but none were found in any of the probands from 129 families with Leber congenital amaurosis. The 46 probands with CNGA3 mutations could be further classified as likely having achromatopsia (18 probands) and cone-rod dystrophies (28 probands) based on electroretinographic recordings. Analysis of family members in 17 of 46 families demonstrated good segregation of the disease with the CNGA3 mutations. To our knowledge, this study is the first systemic analysis of CNGA3 in Chinese patients and expands the mutational spectrum and associated phenotypes. Our results suggest that CNGA3 mutations are a common cause of cone-rod dystrophies and achromatopsia in the Chinese population. These data indicate that CNGA3-associated cone dystrophies may be a common form of early-onset severe retinal dystrophies. Therapeutic potential such as gene therapy targeting this gene may benefit some children with early-onset severe retinal dystrophies.

  13. Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

    Science.gov (United States)

    de Castro-Miró, Marta; Tonda, Raul; Escudero-Ferruz, Paula; Andrés, Rosa; Mayor-Lorenzo, Andrés; Castro, Joaquín; Ciccioli, Marcela; Hidalgo, Daniel A.; Rodríguez-Ezcurra, Juan José; Farrando, Jorge; Pérez-Santonja, Juan J.; Cormand, Bru; Marfany, Gemma

    2016-01-01

    Background NGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD). Methods A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken. Results Genetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation. Conclusion The diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes. PMID:28005958

  14. IROme, a new high-throughput molecular tool for the diagnosis of inherited retinal dystrophies-a price comparison with Sanger sequencing.

    Science.gov (United States)

    Schorderet, Daniel F; Bernasconi, Maude; Tiab, Leila; Favez, Tatiana; Escher, Pascal

    2014-01-01

    The molecular diagnosis of retinal dystrophies (RD) is difficult because of genetic and clinical heterogeneity. Previously, the molecular screening of genes was done one by one, sometimes in a scheme based on the frequency of sequence variants and the number of exons/length of the candidate genes. Payment for these procedures was complicated and the sequential billing of several genes created endless paperwork. We therefore evaluated the costs of generating and sequencing a hybridization-based DNA library enriched for the 64 most frequently mutated genes in RD, called IROme, and compared them to the costs of amplifying and sequencing these genes by the Sanger method. The production cost generated by the high-throughput (HT) sequencing of IROme was established at CHF 2,875.75 per case. Sanger sequencing of the same exons cost CHF 69,399.02. Turnaround time of the analysis was 3 days for IROme. For Sanger sequencing, it could only be estimated, as we never sequenced all 64 genes in one single patient. Sale cost for IROme calculated on the basis of the sale cost of one exon by Sanger sequencing is CHF 8,445.88, which corresponds to the sale price of 40 exons. In conclusion, IROme is cheaper and faster than Sanger sequencing and therefore represents a sound approach for the diagnosis of RD, both scientifically and economically. As a drop in the costs of HT sequencing is anticipated, target resequencing might become the new gold standard in the molecular diagnosis of RD.

  15. Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy.

    Science.gov (United States)

    Tzameret, Adi; Sher, Ifat; Belkin, Michael; Treves, Avraham J; Meir, Amilia; Nagler, Arnon; Levkovitch-Verbin, Hani; Barshack, Iris; Rosner, Mordechai; Rotenstreich, Ygal

    2014-01-01

    Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.5 × 10(6) cells in 5 μl was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2 h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six

  16. Ullrich Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Goknur Haliloglu

    2011-09-01

    Full Text Available ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenitalmuscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in theWestern world mostly seen with de novo dominant mutations in the collagenVI genes. Milder form of the condition is the Bethlem myopathy. There may beoverlap forms in the clinic resembling the Ehler-Danlos syndrome. There hasbeen some radical efforts for cure especially through the apoptosis cascades.Key words: Ullrich congenital muscular dystrophy, collgen VI genes, Bethlemmyopathy, autophagy.

  17. Ullrich Congenital Muscular Dystrophy

    OpenAIRE

    2011-01-01

    ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenitalmuscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in theWestern world mostly seen with de novo dominant mutations in the collagenVI genes. Milder form of the condition is the Bethlem myopathy. There may beoverlap forms in the clinic resembling the Ehler-Danlos syndrome. There hasbeen some radical efforts for cure espe...

  18. Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

    Science.gov (United States)

    Oh, Annie; Pearce, Jacqueline W.; Gandolfi, Barbara; Creighton, Erica K.; Suedmeyer, William K.; Selig, Michael; Bosiack, Ann P.; Castaner, Leilani J.; Whiting, Rebecca E. H.; Belknap, Ellen B.; Lyons, Leslie A.; Aderdein, Danielle; Alves, Paulo C.; Barsh, Gregory S.; Beale, Holly C.; Boyko, Adam R.; Castelhano, Marta G.; Chan, Patricia; Ellinwood, N. Matthew; Garrick, Dorian J.; Helps, Christopher R.; Kaelin, Christopher B.; Leeb, Tosso; Lohi, Hannes; Longeri, Maria; Malik, Richard; Montague, Michael J.; Munday, John S.; Murphy, William J.; Pedersen, Niels C.; Rothschild, Max F.; Swanson, William F.; Terio, Karen A.; Todhunter, Rory J.; Warren, Wesley C.

    2017-01-01

    African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management. PMID:28322220

  19. Evolution of Cellular Inclusions in Bietti’s Crystalline Dystrophy

    Directory of Open Access Journals (Sweden)

    Emiko Furusato

    2010-03-01

    Full Text Available Bietti’s crystalline dystrophy (BCD consists of small, yellow-white, glistening intraretinal crystals in the posterior pole, tapetoretinal degeneration with atrophy of the retinal pigment epithelium (RPE and “sclerosis” of the choroid; in addition, sparking yellow crystals in the superficial marginal cornea are also found in many patients. BCD is inherited as an autosomal-recessive trait (4q35-tel and usually has its onset in the third decade of life. This review focuses on the ultrastructure of cellular crystals and lipid inclusions of BCD.

  20. Bietti crystalline dystrophy and choroidal neovascularisation.

    Science.gov (United States)

    Gupta, B; Parvizi, S; Mohamed, M D

    2011-02-01

    Bietti crystalline dystrophy is a rare autosomal recessive condition characterised by the presence of crystals in the retina and is followed by retinal and choroidal degeneration. We present a novel finding of juxtafoveal choroidal neovascularisation in Bietti crystalline dystrophy and demonstrate a spectral domain optical coherence tomography image of this disorder.

  1. An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

    Science.gov (United States)

    Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

    2016-09-01

    Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable.

  2. Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X.

    Science.gov (United States)

    Orosz, Orsolya; Rajta, István; Vajas, Attila; Takács, Lili; Csutak, Adrienne; Fodor, Mariann; Kolozsvári, Bence; Resch, Miklós; Sényi, Katalin; Lesch, Balázs; Szabó, Viktória; Berta, András; Balogh, István; Losonczy, Gergely

    2017-03-01

    Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, we describe a new genotype-phenotype correlation attributed to rare exon 3 interchange haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes (L- and M-opsin genes). A multigenerational family with X-linked high myopia and cone dystrophy was investigated. Affected male patients had infantile onset myopia with normal visual acuity and color vision until their forties. Visual acuity decreased thereafter, along with the development of severe protan and deutan color vision defects. A mild decrease in electroretinography response of cone photoreceptors was detected in childhood, which further deteriorated in middle-aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively. Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone-rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X.

  3. Muscle diseases: the muscular dystrophies.

    Science.gov (United States)

    McNally, Elizabeth M; Pytel, Peter

    2007-01-01

    Dystrophic muscle disease can occur at any age. Early- or childhood-onset muscular dystrophies may be associated with profound loss of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups.

  4. Muscular Dystrophy

    Science.gov (United States)

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a genetic ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most ...

  5. Muscular Dystrophy

    Science.gov (United States)

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the ...

  6. Bietti's Crystalline Dystrophy

    Science.gov (United States)

    ... Dystrophy > Facts About Bietti's Crystalline Dystrophy Facts About Bietti's Crystalline Dystrophy This information was developed by the ... is the best person to answer specific questions. Bietti’s Crystalline Dystrophy Defined What is Bietti’s Crystalline Dystrophy? ...

  7. Ullrich Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Goknur Haliloglu

    2011-06-01

    Full Text Available ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenital muscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in the Western world mostly seen with de novo dominant mutations in the collagen VI genes. Milder form of the condition is the Bethlem myopathy. There may be overlap forms in the clinic resembling the Ehler-Danlos syndrome. There has been some radical efforts for cure especially through the apoptosis cascades.

  8. Late-onset persistent retinal microvascular changes after bone marrow transplantation: 3-year follow-up

    Directory of Open Access Journals (Sweden)

    Muccioli Cristina

    2002-01-01

    Full Text Available Purpose: To describe a case of persistent retinopathy after bone marrow transplantation in the absence of radiation therapy. Methods: Case Report. Results: A 42 year-old man developed bilateral visual loss 15 months after receiving a bone marrow transplant for acute leukemia. The patient was treated with a high dose of cyclosporin A and oral corticosteroids. No radiation therapy was given. Late-onset, multiple, bilateral cotton-wool spots developed 15 months after the bone marrow transplantation and still persist. After three years other cotton-wool spots arose in the absence of any immunosuppressive therapy. Conclusions: Bone marrow transplantation microvasculopathy of the retina may be related to certain combinations of chemotherapy drugs or immunosuppression itself and may persist in the absence of these immunosuppressive drugs.

  9. Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion.

    Science.gov (United States)

    Kuppermann, Baruch D; Haller, Julia A; Bandello, Francesco; Loewenstein, Anat; Jiao, Jenny; Li, Xiao-Yan; Whitcup, Scott M

    2014-09-01

    To evaluate the onset and duration of improvement in best-corrected visual acuity (BCVA) in eyes treated with dexamethasone intravitreal implant 0.7 mg (DEX implant) for macular edema after branch or central retinal vein occlusion. Post hoc analysis of data from 2 previously reported multicenter, 6-month, randomized sham-controlled clinical trials. Patients received a single DEX implant (n = 427) or sham procedure (n = 426) in the study eye. The primary endpoint was the percentage of eyes with ≥ 15-letter improvement in BCVA from baseline at postimplant Day 7. The baseline mean BCVA was 20/80. At Day 7, 10.3% of DEX implant-treated eyes versus 4.0% of sham-treated eyes (P retinal vein occlusion, 5.1; and central retinal vein occlusion, 5.8) with DEX implant and 1.6 letters (branch retinal vein occlusion, 2.3; and central retinal vein occlusion, 0.1) with sham (P < 0.001). The mean time from initial observation of ≥ 15-letter BCVA gain to the last observation of ≥ 15-letter BCVA gain was 70 days. Dexamethasone intravitreal implant treatment led to improvement in BCVA compared with sham procedure as early as postimplant Day 7. The duration of ≥ 3-line improvement was typically 2 to 3 months.

  10. Retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Hamel Christian

    2006-10-01

    Full Text Available Abstract Retinitis pigmentosa (RP is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms. Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema, and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis.

  11. Study on the related factors of occurrence of vulvar dystrophy in women at peak onset age%高峰发病年龄女性外阴营养不良发生的相关因素研究

    Institute of Scientific and Technical Information of China (English)

    吴晓丽; 申艳

    2011-01-01

    Objective: To study the related factors of occurrence of vulvar dystrophy in women at peak onset age. Methods: 87 patients aged 40 ~ 60 years old who were diagnosed as vulvar dystrophy by pathological examination and biopsy were selected as case group, 98 patients without vulvar dystrophy were selected as control group, the relationship between the occurrence of vulvar dystrophy and the factors including working and living circumstances, dietary habits, health habits, diseases, the history of menstruation and childbearing history was analyzed. Results: The risk factors of vulvar dystrophy included allergic constitution, favoring salty, hot and thermal foods, sedentariness, washing underwears by washing powder and vaginitis (OR > 1) , the protective factors of vulvar dystrophy included extravert personality, favoring vegetarian diet and pork liver (OR < 1) . Conclusion: Allergic constitution, incorrect dietary habits and recurrent vaginitis are related to female vulvar dystrophy closely.%目的:研究高峰发病年龄女性外阴营养不良发生的相关危险因素.方法:以40~60岁之间经病理活检确诊的外阴营养不良患者87例作为病例组,以非外阴营养不良患者98例为对照组,分析外阴营养不良的发生与工作生活环境、饮食习惯、卫生习惯、疾病情况、妇女月经史及生育史等因素之间关系.结果:过敏体质、饮食习惯中偏咸辣烫、生活习惯中喜久坐、洗衣粉洗涤内裤及白带色黄等可能是外阴营养不良发生的危险因素(OR>1),而个性开朗、饮食偏素和喜食猪肝等可能是外阴营养不良的保护性因素(OR<1).结论:过敏体质、不合理饮食习惯、卫生生活习惯及反复阴道炎等与女性外阴营养不良的发生关系较大.

  12. Novel mouse models of oculopharyngeal muscular dystrophy (OPMD) reveal early onset mitochondrial defects and suggest loss of PABPN1 may contribute to pathology.

    Science.gov (United States)

    Vest, Katherine E; Phillips, Brittany L; Banerjee, Ayan; Apponi, Luciano H; Dammer, Eric B; Xu, Weiting; Zheng, Dinghai; Yu, Julia; Tian, Bin; Pavlath, Grace K; Corbett, Anita H

    2017-09-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease caused by polyalanine expansion in the poly(A) binding protein nuclear 1 (PABPN1). Several mouse models have been generated to study OPMD; however, most of these models have employed transgenic overexpression of alanine-expanded PABPN1. These models do not recapitulate the OPMD patient genotype and PABPN1 overexpression could confound molecular phenotypes. We have developed a knock-in mouse model of OPMD (Pabpn1+/A17) that contains one alanine-expanded Pabpn1 allele under the control of the native promoter and one wild-type Pabpn1 allele. This mouse is the closest available genocopy of OPMD patients. We show that Pabpn1+/A17 mice have a mild myopathic phenotype in adult and aged animals. We examined early molecular and biochemical phenotypes associated with expressing native levels of A17-PABPN1 and detected shorter poly(A) tails, modest changes in poly(A) signal (PAS) usage, and evidence of mitochondrial damage in these mice. Recent studies have suggested that a loss of PABPN1 function could contribute to muscle pathology in OPMD. To investigate a loss of function model of pathology, we generated a heterozygous Pabpn1 knock-out mouse model (Pabpn1+/Δ). Like the Pabpn1+/A17 mice, Pabpn1+/Δ mice have mild histologic defects, shorter poly(A) tails, and evidence of mitochondrial damage. However, the phenotypes detected in Pabpn1+/Δ mice only partially overlap with those detected in Pabpn1+/A17 mice. These results suggest that loss of PABPN1 function could contribute to but may not completely explain the pathology detected in Pabpn1+/A17 mice. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Impaired fetal muscle development and JAK-STAT activation mark disease onset and progression in a mouse model for merosin-deficient congenital muscular dystrophy.

    Science.gov (United States)

    Nunes, Andreia M; Wuebbles, Ryan D; Sarathy, Apurva; Fontelonga, Tatiana M; Deries, Marianne; Burkin, Dean J; Thorsteinsdóttir, Sólveig

    2017-06-01

    Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a dramatic neuromuscular disease in which crippling muscle weakness is evident from birth. Here, we use the dyW mouse model for human MDC1A to trace the onset of the disease during development in utero. We find that myotomal and primary myogenesis proceed normally in homozygous dyW-/- embryos. Fetal dyW-/- muscles display the same number of myofibers as wildtype (WT) muscles, but by E18.5 dyW-/- muscles are significantly smaller and muscle size is not recovered post-natally. These results suggest that fetal dyW-/- myofibers fail to grow at the same rate as WT myofibers. Consistent with this hypothesis between E17.5 and E18.5 dyW-/- muscles display a dramatic drop in the number of Pax7- and myogenin-positive cells relative to WT muscles, suggesting that dyW-/- muscles fail to generate enough muscle cells to sustain fetal myofiber growth. Gene expression analysis of dyW-/- E17.5 muscles identified a significant increase in the expression of the JAK-STAT target gene Pim1 and muscles from 2-day and 3-week old dyW-/- mice demonstrate a dramatic increase in pSTAT3 relative to WT muscles. Interestingly, myotubes lacking integrin α7β1, a laminin-receptor, also show a significant increase in pSTAT3 levels compared with WT myotubes, indicating that α7β1 can act as a negative regulator of STAT3 activity. Our data reveal for the first time that dyW-/- mice exhibit a myogenesis defect already in utero. We propose that overactivation of JAK-STAT signaling is part of the mechanism underlying disease onset and progression in dyW-/- mice. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Ocular abnormality in myotonic dystrophy.

    Science.gov (United States)

    Ginsberg, J; Hamblet, J; Menefee, M

    1978-08-01

    A 61-year-old white woman with terminal myotonic dystrophy exhibited advanced peripheral and central retinopathy. Retinal lesions were characterized by hyperpigmentation, common, though nonspecific, in myotonic dystrophy. They resemble both heredo (tapetoretinal) and idiopathic involutional degenerations but rarely cause severe visual impairment. Neither the type nor degree of retinopathy appears to correlate with other ocular features or with the stage of the underlying disease. Our histologic observations confirm and extend those previously described. Electron microscopy suggests a primary disorder of mitochondria which may also affect smooth muscle and the myocardium.

  15. Muscular Dystrophy

    Science.gov (United States)

    ... muscular dystrophy. It's important to be vaccinated for pneumonia and to keep up to date with influenza shots. Dietary changes haven't been shown to slow the progression of muscular dystrophy. But proper nutrition is essential because limited mobility can contribute to ...

  16. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    Science.gov (United States)

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-03-12

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome.

  17. Myotonic Dystrophy Family Registry

    Science.gov (United States)

    2016-03-28

    Myotonic Dystrophy; Congenital Myotonic Dystrophy; Myotonic Dystrophy 1; Myotonic Dystrophy 2; Dystrophia Myotonica; Dystrophia Myotonica 1; Dystrophia Myotonica 2; Myotonia Dystrophica; Myotonic Dystrophy, Congenital; Myotonic Myopathy, Proximal; PROMM (Proximal Myotonic Myopathy); Proximal Myotonic Myopathy; Steinert Disease; Steinert Myotonic Dystrophy; Steinert's Disease; Myotonia Atrophica

  18. Cone rod dystrophies

    Directory of Open Access Journals (Sweden)

    Hamel Christian P

    2007-02-01

    Full Text Available Abstract Cone rod dystrophies (CRDs (prevalence 1/40,000 are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP, also called the rod cone dystrophies (RCDs resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7. Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far. The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs, CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs, and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs. It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is

  19. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations

    OpenAIRE

    Mackay, Donna S.; Borman, Arundhati Dev; Sui, Ruifang; van den Born, L. Ingeborgh; Berson, Eliot L.; Ocaka, Louise A.; Davidson, Alice E.; Heckenlively, John R.; Branham, Kari; Ren, Huanan; Lopez, Irma; Maria, Maleeha; Azam, Maleeha; Henkes, Arjen; Blokland, Ellen

    2013-01-01

    To investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORD) and autosomal recessive retinitis pigmentosa (RP), to delineate the ocular phenotypes, and to provide an overview of all published LCA5 variants in an online database._Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autoflu...

  20. The molecular genetics of the corneal dystrophies--current status.

    Science.gov (United States)

    Klintworth, Gordon K

    2003-05-01

    The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the

  1. Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?

    Science.gov (United States)

    Saad, Leonide; Washington, Ilyas

    2016-01-01

    We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway.

  2. RPE65: role in the visual cycle, human retinal disease, and gene therapy.

    Science.gov (United States)

    Cai, Xue; Conley, Shannon M; Naash, Muna I

    2009-06-01

    RPE65 is an isomerohydrolase expressed in retinal pigment epithelium. It is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision. Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness. Several RPE65 animal models including two different mouse models and a naturally occurring canine model have been thoroughly characterized to determine the mechanisms that underlie RPE65 associated retinal dystrophies. More recently, substantial effort has gone into designing gene therapies for these diseases. Based on several encouraging reports from animal models, at least three clinical trials are currently underway for the treatment of LCA using modified AAV vectors carrying the RPE65 cDNA and have reported positive preliminary results.

  3. Muscular Dystrophy

    Science.gov (United States)

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and muscle loss. Some forms of MD appear in infancy ... types can vary in whom they affect, which muscles they affect, and what the symptoms are. All ...

  4. Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

    Directory of Open Access Journals (Sweden)

    Xinhua Shu

    Full Text Available A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

  5. Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models

    NARCIS (Netherlands)

    Pellissier, Lucie P; Quinn, Peter M; Alves, C Henrique; Vos, Rogier M; Klooster, Jan; Flannery, John G; Heimel, J Alexander; Wijnholds, J.

    2015-01-01

    Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encodin

  6. The limb-girdle muscular dystrophies.

    Science.gov (United States)

    Wicklund, Matthew P; Kissel, John T

    2014-08-01

    A collection of more than 30 genetic muscle diseases that share certain key features, limb-girdle muscular dystrophies are characterized by progressive weakness and muscle atrophy of the hips, shoulders, and proximal extremity muscles with postnatal onset. This article discusses clinical, laboratory, and histologic features of the 6 most prevalent limb-girdle dystrophies. In this large group of disorders, certain distinctive features often can guide clinicians to a correct diagnosis.

  7. LAMA2-related myopathy; frequency among congenital and limb-girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Løkken, Nicoline; Born, Alfred Peter; Duno, Morten;

    2015-01-01

    Introduction: Muscular dystrophy caused by LAMA2-gene mutations is an autosomal recessive disease typically presenting as a severe, early-onset congenital muscular dystrophy (CMD). However, milder cases with a limb-girdle type muscular dystrophy (LGMD) have been described. Methods: In this study...

  8. Myotonic dystrophy.

    Science.gov (United States)

    Thornton, Charles A

    2014-08-01

    Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over a century ago. More recently, a second form of the disease, DM type 2 was recognized, which results from repeat expansion in a different gene. Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. This article reviews the clinical presentation and pathophysiology of DM and discusses current management and future potential for developing targeted therapies.

  9. The benign concentric annular macular dystrophy locus maps to 6p12.3-q16.

    NARCIS (Netherlands)

    Lith-Verhoeven, J.J. van; Hoyng, C.B.; Helm, B. van den; Deutman, A.F.; Brink, H.M.A.; Kemperman, M.H.; Jong, W.H. de; Kremer, J.M.J.; Cremers, F.P.M.

    2004-01-01

    PURPOSE: To describe the clinical findings and to identify the genetic locus in a Dutch family with autosomal dominant benign concentric annular macular dystrophy (BCAMD). METHODS: All family members underwent ophthalmic examination. Linkage analysis of candidate retinal dystrophy loci and a whole g

  10. Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons

    Directory of Open Access Journals (Sweden)

    Hyoung-Tai Kim

    2015-11-01

    Full Text Available OTX2 (orthodenticle homeobox 2 haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2+/GFP heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2+/GFP mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2+/GFP mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

  11. Primary cataract as a key to recognition of myotonic dystrophy type 1

    NARCIS (Netherlands)

    Voermans, N.C.; Erasmus, C.E.; Ockeloen, C.W.; Engelen, B.G.M. van; Eggink, C.A.

    2015-01-01

    PURPOSE: Primary cataract is often the initial manifestation of the adult-onset type of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. It is caused by a CTG repeat expansion within the DMPK gene, and anticipation may cause earlier onset and more severe symptoms in

  12. Non-syndromic retinal ciliopathies: translating gene discovery into therapy

    NARCIS (Netherlands)

    Estrada-Cuzcano, A.; Roepman, R.; Cremers, F.P.; Hollander, A.I. den; Mans, D.A.

    2012-01-01

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defect

  13. Genetics Home Reference: myotonic dystrophy

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions myotonic dystrophy myotonic dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Myotonic dystrophy is part of a group of inherited disorders ...

  14. Duration of rhegmatogenous retinal detachment predicts recovery of retinal sensitivity

    Directory of Open Access Journals (Sweden)

    Rose Rose

    2016-02-01

    Full Text Available The decision to treat a disease is often based on the presence or absence of symptoms, one prototype case being rhegmatogenous retinal detachment. Detachment of the neural retina from the pigment epithelium is a major cause of anatomical and functional dysfunction of the retina, where retinal recovery is inversely related to duration of detachment. The purpose of retinal reattachment is to effect recovery of the photoreceptors and pigment epithelium from degeneration. The aim of this study was to determine the critical duration of rhegmatogenous retinal detachment resulting in optimal retinal recovery after reattachment. A prospective study was conducted at a private hospital in Yogyakarta. Thirty five eyes were involved in this study. Three months after reattachment, central retinal recovery was measured by means of a Goldmann manual kinetic perimeter. The results showed that retinal recovery developed three months after surgery if the onset of rhegmatogenous retinal detachment was less than 28 days before surgery. The results were not significant if the onset of rhegmatogenous retinal detachment was more than 35 days. Although the Goldmann manual kinetic perimeter can efficiently detect central retinal sensitivity, it should be supported by more sensitive tools to evaluate the anatomy and function of the retina.

  15. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

    Directory of Open Access Journals (Sweden)

    Oriana del Rocío Cruz Guzmán

    2012-01-01

    Full Text Available Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset.

  16. MR imaging of fukuyama congenital muscular dystrophy; a case report

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Jeong Hyun; Kim, Yoo Kyung; Koo, Hae Soo; Park, Ki Deuk [Ewha Womans Univ. College of Medicine, Seoul (Korea, Republic of)

    2000-11-01

    Fukuyama congenital muscular dystrophy is a genetic disease and common in Japan. The typical clinical features are hypotonia with an early infantile onset and severe developmental delay. The diagnosis is based on pathologic evidence of muscular dystrophy revealed by biopsy or an increased serum creatine kinase levels. Involvement of the brain is characterized by abnormal cerebral cortical dysplasia, cerebellar dysplasia, and white matter changes. We encountered a case of Fukuyama congenital muscular dystrophy in which brain MRI findings were typical, and present this case together with a review of the literature.

  17. Distrofia retiniana com onda rápida escotópica (DRORE associada à síndrome dos cabelos anágenos frouxos (SCAF. Parte I: Achados oftalmológicos Scotopic fast wave retinal dystrophy (SFWRD associated with loose anagen hair syndrome (LAHS. Part I: Ophthalmological findings

    Directory of Open Access Journals (Sweden)

    Mário Teruo Sato

    2004-06-01

    ópica associada à síndrome dos cabelos anágenos frouxos, distrofia cujos achados fundoscópicos são diferentes entre homens e mulheres e com traçado eletrorretinográfico característico.PURPOSE: To describe the ophthalmological findings of a new macular dystrophy associated with loose anagen hair syndrome (LAHS. METHODS: Eleven patients of the same family, four of whom presented ocular abnormalities, were examined. Seven patients were submitted to the following examinations: a complete ophthalmological examination, color test, ultrasonography, angiography, visual field, optic disc topography, electro-oculogram (EOG, electroretinogram (ERG, laboratory and dermatological tests, sweat testing, light microscopy (LM and scanning electron microscopy (SEM of the scalp hair. In four patients, children of affected, examination was restricted to an ophthalmological examination and light microscopy and the scanning electron microscopy of the scalp hair. RESULTS: Of the four affected patients, two affected sisters showed pigmentary dispersions in the posterior pole of the retina with macular coloboma. Two brothers showed pigmentary dispersions in the posterior pole, with greater pigmentation and a yellowish aspect of the macular area without coloboma. The results of the ectro-oculogram and electroretinogram were within normal limits in three patients without ocular abnormalities. Whereas, electro-oculogram was subnormal and electroretinogram was subnormal with short implicit time (fast in the scotopic phase of the patients with the macular dystrophy, suggesting that the site of this dystrophy is at the level of the retinal pigment epithelium. Due to this peculiar behavior of the implicit time of the wave, such finding can be considered as fundamental to make the diagnosis of this dystrophy. The denomination could be scotopic fast wave retinal dystrophy (SFWRD. Light microscopy and scanning electron microscopy of scalp hair confirmed the loose anagen hair syndrome. CONCLUSIONS: We

  18. Genetics of Bietti Crystalline Dystrophy.

    Science.gov (United States)

    Ng, Danny S C; Lai, Timothy Y Y; Ng, Tsz Kin; Pang, Chi Pui

    2016-01-01

    Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy.

  19. Pattern Dystrophy of the Macula in a Case of Steinert Disease

    Directory of Open Access Journals (Sweden)

    Filipe Esteves

    2013-09-01

    Full Text Available Introduction: Myotonic dystrophies are typically associated with ocular complications like ptosis, weakness of the ocular muscle and cataracts, but also with less recognized retinal changes. Case Report: A 41-year-old female with type 1 myotonic dystrophy complained of progressive vision loss. Slit lamp examination revealed the presence of typical bilateral polychromatic cataract with posterior subcapsular component. Dilated fundus examination was remarkable for bilateral macular depigmented changes. Multimodal imaging analysis of the macula suggested the presence of a butterfly-shaped pattern dystrophy. Discussion: In cases of myotonic dystrophies it is of great relevance to analyze the presence of retinal changes that might limit the visual improvement following cataract extraction.

  20. Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene

    NARCIS (Netherlands)

    Huet, R.A.C. van; Estrada-Cuzcano, A.; Banin, E.; Rotenstreich, Y.; Hipp, S.; Kohl, S.; Hoyng, C.B.; Hollander, A.I. den; Collin, R.W.J.; Klevering, B.J.

    2013-01-01

    PURPOSE: To provide the clinical features in patients with retinal disease caused by C8orf37 gene mutations. METHODS: Eight patients--four diagnosed with retinitis pigmentosa (RP) and four with cone-rod dystrophy (CRD), carrying causal C8orf37 mutations--were clinically evaluated, including

  1. Myotonic dystrophy (DM1) and dysphagia: the need for dysphagia management guidelines and an assessment tool

    NARCIS (Netherlands)

    LaDonna, K.A.; Koopman, W.J.H.; Venance, S.L.

    2011-01-01

    Myotonic dystrophy (DM1) is the most prevalent muscular dystrophy occurring in adulthood. DM1 is a multi-systemic disorder resulting in early-onset cataracts, cardiac rhythm problems, muscle weakness, ptosis, and cognitive and psychiatric manifestations. Dysphagia is one of the most problematic

  2. Evaluation of Limb-Girdle Muscular Dystrophy

    Science.gov (United States)

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  3. Non-syndromic retinal ciliopathies: translating gene discovery into therapy.

    Science.gov (United States)

    Estrada-Cuzcano, Alejandro; Roepman, Ronald; Cremers, Frans P M; den Hollander, Anneke I; Mans, Dorus A

    2012-10-15

    Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies.

  4. Learning about Myotonic Dystrophy

    Science.gov (United States)

    ... of Genetic Tests Genomics and Health Disparities Genetic Discrimination Human Subjects Research Informed Consent for Genomics Research ... with myotonic dystrophy may have a characteristic facial appearance of wasting and weakness of the jaw and ...

  5. Muscular Dystrophy Association

    Science.gov (United States)

    ... Families Live Unlimited Read More Deflazacort demonstrates significant muscle strength improvement in DMD Read More NDA Filing ... the Boot to Support Kids and Adults with Muscular Dystrophy, ALS and Related Diseases Read More Visit ...

  6. Late-onset progressive retinal atrophy in the Gordon and Irish Setter breeds is associated with a frameshift mutation in C2orf71.

    Science.gov (United States)

    Downs, L M; Bell, J S; Freeman, J; Hartley, C; Hayward, L J; Mellersh, C S

    2013-04-01

    Progressive retinal atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 14 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome-wide association with 16 Gordon Setter PRA cases and 22 controls, we identified a novel PRA locus, termed rod-cone degeneration 4 (rcd4), on CFA17 (Praw  = 2.22 × 10(-8) , Pgenome  = 2.00 × 10(-5) ), where a 3.2-Mb region was homozygous within cases. A frameshift mutation was identified in C2orf71, a gene located within this region. This variant was homozygous in 19 of 21 PRA cases and was at a frequency of approximately 0.37 in the Gordon Setter population. Approximately 10% of cases in our study (2 of 21) are not associated with this C2orf71 mutation, indicating that PRA in this breed is genetically heterogeneous and caused by at least two mutations. This variant is also present in a number of Irish Setter dogs with PRA and has an estimated allele frequency of 0.26 in the breed. The function of C2orf71 remains unknown, but it is important for retinal development and function and has previously been associated with autosomal recessive retinitis pigmentosa in humans.

  7. Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A

    Energy Technology Data Exchange (ETDEWEB)

    Speer, M.C.; Yamaoka, L.H.; Stajich, J.; Lewis, K. [and others

    1995-08-28

    The Bethlem myopathy, an autosomal-dominant myopathy, shows a distribution of proximal muscle weakness similar to that observed in dominant limb-girdle muscular dystrophy (LGMD). Yet the Bethlem myopathy differs from most limb-girdle dystrophies in two important regards. First, the Bethlem myopathy presents with joint contractures most commonly observed at the elbows, ankles, and neck. Secondly, disease onset in the Bethlem myopathy is in early childhood, while most dominant LGMDs present with adult onset. 6 refs., 1 fig.

  8. A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13

    Energy Technology Data Exchange (ETDEWEB)

    Balciuniene, J.; Holmgren, G.; Forsman, K. [University Hospital, Umea (Sweden)] [and others

    1995-11-20

    Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders. 34 refs., 3 figs., 2 tabs.

  9. Microglia-Müller glia crosstalk in the rd10 mouse model of retinitis pigmentosa.

    Science.gov (United States)

    Arroba, Ana I; Alvarez-Lindo, Noemí; van Rooijen, Nico; de la Rosa, Enrique J

    2014-01-01

    Retinitis pigmentosa refers to a large, genetically heterogeneous group of retinal dystrophies. This condition is characterized by the gradual onset of blindness due to progressive deterioration of the retina, a process that includes photoreceptor and retinal-pigmented-epithelium cell decay and death, microglial recruitment, reactive gliosis, and vascular disorganization and regression. We found that early in the degenerative process, the rd10 mouse retina exhibits high levels of photoreceptor cell death and reactive Müller gliosis. In explant cultures, both degenerative processes were abrogated by IGF-I treatment. Moreover, the beneficial effect of IGF-I was diminished by microglial depletion using clodronate-containing liposomes. Interestingly, in the absence of IGF-I, microglial depletion partially prevented cell death without affecting Müller gliosis. These findings strongly suggest a role for microglia-Müller glia crosstalk in neuroprotection. However, a subpopulation of microglial cells appears to promote neurodegeneration in the dystrophic retina. Our findings indicate that beneficial neuroprotective effects may be achieved through strategies that modulate microglial cell responses.

  10. LONG-TERM OUTCOMES OF RETINAL DEGENERATIVE DISORDER TREATMENT WITH PEPTIDE BIOREGULATORS

    Directory of Open Access Journals (Sweden)

    M. I. Razumovskiy

    2015-01-01

    Full Text Available Aim. To analyze long-term outcomes and efficacy of retinal degeneration treatment with Retinalamin.Patients and methods. Group I included 20 patients (40 eyes with pigmentary retinal dystrophy (15 patients, 30 eyes and retinal abiotrophy (5 patients, 10 eyes who received treatment with Retinalamin for 5‑7 years. Group II included 11 patients (22 eyes with pigmentary retinal dystrophy (9 patients, 18 eyes and retinal abiotrophy (2 patients, 4 eyes who received treatment with Retinalamin for 23‑25 years. Group III (controls included 15 patients (30 eyes with pigmentary retinal dystrophy (11 patients, 22 eyes and retinal abiotrophy (4 patients, 8 eyes who received traditional treatment (vasodilators, angioprotectors, antisclerotic agents, vitamins for 25 years. Standard ophthalmological examination, i.e., visual acuity measurement, visual field test, refractometry, biomicroscopy, ophthalmoscopy, was performed.Results. First course of treatment with Retinalamin improved vision in 58.1 % of retinal degeneration patients. Visual fields improved in 64.5 % of cases. Repeated treatment courses (1‑2 times a year for 23‑25 years preserved residual vision in 55.6 % of patients and object vision in 11.1 % of cases. In retinal abiotrophy patients, residual vision preserved in 100 % of cases.Conclusions. In retinal degenerations, Retinalamin improves vision and visual fields and decreases total area of absolute scotomas even after the first treatment course as well as preserves vision in prolonged use. 

  11. Epiretinal membrane: a treatable cause of visual disability in myotonic dystrophy type 1.

    Science.gov (United States)

    Kersten, Hannah M; Roxburgh, Richard H; Child, Nicholas; Polkinghorne, Philip J; Frampton, Chris; Danesh-Meyer, Helen V

    2014-01-01

    A wide range of ocular abnormalities have been documented to occur in patients with myotonic dystrophy type 1. The objectives of this study were to investigate the macular and optic nerve morphology using optical coherence tomography in patients with myotonic dystrophy type 1. A total of 30 myotonic dystrophy type 1 patients and 28 controls were recruited for participation. All participants underwent a thorough ophthalmologic examination, including spectral-domain optical coherence tomography of the macula and retinal nerve fibre layer. Images were reviewed by a retinal specialist ophthalmologist, masked to the diagnosis of the participants. Average macular thickness was significantly greater in the myotonic dystrophy group compared to controls [327.3 μm vs. 308.5 μm (p myotonic dystrophy patient group (p = 0.0002): 48.2 % of myotonic dystrophy patient eyes had evidence of epiretinal membrane, compared with 12.5 % of control eyes. Examination revealed that 56.7 % of myotonic dystrophy patients had an epiretinal membrane in at least one eye. Visual acuity was reduced due to the presence of epiretinal membrane in six patient eyes and none of the control eyes. The presence of an epiretinal membrane was significantly correlated with increasing age in the patient group. We report an increased prevalence of epiretinal membrane in the myotonic dystrophy type 1 group. This may be a previously under-recognised form of visual impairment in this group. Epiretinal membranes can be treated surgically. We suggest that, in addition to a comprehensive clinical examination, optical coherence tomography examination is implemented as part of an ophthalmological assessment for the myotonic dystrophy type 1 patient with reduced visual acuity.

  12. Advances in gene therapy technologies to treat retinitis pigmentosa

    OpenAIRE

    2013-01-01

    Hilda Petrs-Silva, Rafael LindenInstitute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilAbstract: Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant a...

  13. 11例迟发性视锥细胞营养不良患者的临床特征观察%Clinical features of 11 patients with late-onset cone dystrophy

    Institute of Scientific and Technical Information of China (English)

    王明扬; 王光璐

    2014-01-01

    Objective To observe the clinical features of late-onset cone dystrophy (LOCD).Methods Eleven patients (15 eyes) of LOCD were enrolled in this study.The patients included 7 males and 4 females.The age was ranged from 50 to 79 years,with a mean age of 60.2 years.There was no obvious photophobia and hemeralopia.The visual acuity was less than or equal to 0.05 in 4 eyes,0.06-0.2 in 5 eyes,0.3-1.0 in 6 eyes.Visual acuity,slit lamp microscope,indirect ophthalmoscopy,flash electroretinogram (FERG) and multifocal electroretinograms (mfERG) were examined for all patients,fundus fluorescein angiography (FFA) for 11 eyes,optical coherence tomography (OCT) and chromoptometry for 6 eyes.Results There were 6 eyes with red/green color blindness,2 eyes with color weakness.Normal fundus was found in 11 eyes,while derangement of macular pigment epithelial in 4 eyes.FFA results showed that there were 5 eyes with normal fundus,4 eyes with blocked fluorescent spots,2 eyes with oval macular atrophy.FERG results showed that in cone response,the amplitude was lower in 6 eyes (including mild decrease in 4 eyes,moderate decrease in 1 eye and severe decrease in 1 eye) ; both in cone and rod response,the amplitude were lower in 9 eyes.mfERG results showed that central part of the cone (less than 7 degree from the center) was damaged in 5 eyes,both central and peripheral part (outside of 7 degree) of the cone were damaged in 10 eyes.OCT results showed that pigment derangement in 3 eyes,fovea was normal in 8 eyes,thinned in 5 eyes (foveal thickness was 83-111 μm).Conclusions The fundus manifestations of LOCD patients are variable,from normal fundus to oval macular atrophy.FERG is abnormal,which mainly in cone response at early stage and both in cone and rod response at late stage.Central part and (or) peripheral part of the cone are abnormal by mfERG.%目的 观察迟发性视锥细胞营养不良(LOCD)患者的临床特征.方法 临床检查确诊的LOCD患者11例15

  14. Clinical characteristics and current therapies for inherited retinal degenerations.

    Science.gov (United States)

    Sahel, José-Alain; Marazova, Katia; Audo, Isabelle

    2014-10-16

    Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.

  15. Retinal Vasculitis

    Science.gov (United States)

    Rosenbaum, James T.; Sibley, Cailin H.; Lin, Phoebe

    2016-01-01

    Purpose of review Ophthalmologists and rheumatologists frequently miscommunicate in consulting on patients with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent papers on this diagnosis. Recent findings 1) The genetic basis of some rare forms of retinal vascular disease have recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; 2) Behçet’s disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; 3) retinal imaging including fluorescein angiography and other newer imaging modalities has proven crucial to the identification and characterization of retinal vasculitis and its complications; 4) although monoclonal antibodies to IL-17A or IL-1 beta failed in trials for Behçet’s disease, antibodies to TNF alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. Summary Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behçet’s disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of non-infectious retinal vasculitis may require alternate therapeutic management. PMID:26945335

  16. Occult Macular Dystrophy

    Directory of Open Access Journals (Sweden)

    Işıl Sayman Muslubaş

    2016-04-01

    Full Text Available Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy

  17. Bilateral eccentric vision training on pseudovitelliform dystrophy with microperimetry biofeedback

    Science.gov (United States)

    Morales, Marco Ulises; Saker, Saker; Amoaku, Winfried M

    2015-01-01

    Low vision patients with eccentric viewing (EV) use extrafoveal retinal areas to compensate for the loss of central vision. Such retinal loci are known as the preferred retinal locus (PRL). It is known that EV is accompanied by unstable fixation. Microperimetry systems with biofeedback training have been used as a rehabilitation aid to improve fixation stability in EV patients. Normally, only the best or dominant eye is selected for such rehabilitation. This case report describes the rehabilitation on both eyes by means of PRL relocation with MAIA microperimetry (Centervue, Padova, Italy) with biofeedback training technology of a 74-year-old woman diagnosed with adult pseudovitelliform dystrophy. The patient presented binocularly similar anatomical and functional characteristics with the PRL located over the dystrophic area. At the end of the 3 months rehabilitation period, the PRL was successfully relocated inferiorly from the fovea showing relevant visual acuity improvement. PMID:25576513

  18. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.

    Science.gov (United States)

    Thompson, Debra A; Janecke, Andreas R; Lange, Jessica; Feathers, Kecia L; Hübner, Christian A; McHenry, Christina L; Stockton, David W; Rammesmayer, Gabriele; Lupski, James R; Antinolo, Guillermo; Ayuso, Carmen; Baiget, Montserrat; Gouras, Peter; Heckenlively, John R; den Hollander, Anneke; Jacobson, Samuel G; Lewis, Richard A; Sieving, Paul A; Wissinger, Bernd; Yzer, Suzanne; Zrenner, Eberhart; Utermann, Gerd; Gal, Andreas

    2005-12-15

    Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.

  19. 以晕厥发病的成年Becker型肌营养不良症1例报道%One report of adult onset Becker muscular dystrophy with syncope

    Institute of Scientific and Technical Information of China (English)

    沈沸; 俞羚; 陆钦池; 朱莹; 李焰生

    2009-01-01

    @@ Becker型肌营养不良症(Becker muscular dystrophy, BMD)是由抗肌萎缩蛋白(Dystrophin蛋白)缺陷导致的缓慢进展的肌肉萎缩、无力伴假性肌肥大为特征的遗传性肌肉疾病.传统上,BMD多在5~10岁起病,至20~25岁丧失独立行走能力,存活至40岁左右[1].随着对Dystrophin蛋白基因的研究深入,已发现一些30岁以后发病或早期以心肌损害为主要表现的BMD[2,3].本文报道1例以心肌损害导致晕厥而首发的成年起病的BMD.

  20. Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice.

    Directory of Open Access Journals (Sweden)

    Jian Liu

    Full Text Available Whilst data recognise both myeloid cell accumulation during choroidal neovascularisation (CNV as well as complement activation, none of the data has presented a clear explanation for the angiogenic drive that promotes pathological angiogenesis. One possibility that is a pre-eminent drive is a specific and early conditioning and activation of the myeloid cell infiltrate. Using a laser-induced CNV murine model, we have identified that disruption of retinal pigment epithelium (RPE and Bruch's membrane resulted in an early recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis and contemporaneous with lesional complement activation. Early recruited CD11b(+ cells expressed a definitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression. Accumulating macrophages from retina and peripheral blood were activated at the site of injury, displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, or earliest stages of angiogenesis. All of these initial events, including distinct VEGF (+ Arg-1(+ myeloid cells, subsided when CNV was established and at the time RPE-VEGF expression was maximal. Depletion of inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, as following depletion Arg-1 signal was lost and CNV suppressed. Furthermore, our in vitro data supported a myeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+ Arg-1(+ phenotype in vivo. Our results reveal a potential early driver initiating angiogenesis via myeloid-derived VEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during any of the stages of macular degeneration and can be explored further for therapeutic gain.

  1. Limb girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Vissing, John

    2016-01-01

    PURPOSE OF REVIEW: The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these conditions. RECENT FINDINGS: Close to half of all LGMD subtypes have been...

  2. Dominant cystoid macular dystrophy

    NARCIS (Netherlands)

    Saksens, N.T.M.; Huet, R.A.C. van; Lith-Verhoeven, J.J. van; Hollander, A.I. den; Hoyng, C.B.; Boon, C.J.

    2015-01-01

    OBJECTIVE: To describe the clinical characteristics and long-term follow-up in patients with autosomal dominant cystoid macular dystrophy (DCMD). DESIGN: Retrospective case series. PARTICIPANTS: Ninety-seven patients with DCMD. METHODS: Extensive ophthalmic examination, including visual acuity (VA),

  3. Central areolar choroidal dystrophy.

    NARCIS (Netherlands)

    Boon, C.J.F.; Klevering, B.J.; Cremers, F.P.M.; Zonneveld-Vrieling, M.N.; Theelen, T.; Hollander, A.I. den; Hoyng, C.B.

    2009-01-01

    OBJECTIVE: To describe the clinical characteristics, follow-up data and molecular genetic background in a large group of patients with central areolar choroidal dystrophy (CACD). DESIGN: Retrospective case series study. PARTICIPANTS: One hundred three patients with CACD from the Netherlands. METHODS

  4. A molecular protocol for diagnosing myotonic dystrophy.

    Science.gov (United States)

    Guida, M; Marger, R S; Papp, A C; Snyder, P J; Sedra, M S; Kissel, J T; Mendell, J R; Prior, T W

    1995-01-01

    Myotonic dystrophy (DM) is an autosomal dominant genetic disease caused by an unstable CTG repeat sequence in the 3' untranslated region of the myotonin protein kinase gene. The CTG repeat is present 5-30 times in the normal population, whereas DM patients have CTG expansions of 50 to several thousand repeats. The age of onset of the disorder and the severity of the phenotype is roughly correlated with the size of the CTG expansion. We developed a molecular protocol for the diagnosis of DM based on an initial polymerase chain reaction screen to detect normal-sized alleles and small expansions, followed by an improved Southern protocol to detect larger expansions.

  5. Genetics Home Reference: Bietti crystalline dystrophy

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions Bietti crystalline dystrophy Bietti crystalline dystrophy Enable Javascript to view the expand/ ... boxes. Download PDF Open All Close All Description Bietti crystalline dystrophy is a disorder in which numerous ...

  6. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations.

    Science.gov (United States)

    Sun, X; Pawlyk, B; Xu, X; Liu, X; Bulgakov, O V; Adamian, M; Sandberg, M A; Khani, S C; Tan, M-H; Smith, A J; Ali, R R; Li, T

    2010-01-01

    Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is required for the biosynthesis of photoreceptor phosphodiesterase (PDE). Gene defects in AIPL1 cause a heterogeneous set of conditions ranging from Leber's congenital amaurosis (LCA), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod dystrophy. In mice, null and hypomorphic alleles cause retinal degeneration similar to human LCA and RP, respectively. Thus these mouse models represent two ends of the disease spectrum associated with AIPL1 gene defects in humans. We evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy in these models could restore PDE biosynthesis in rods and cones and thereby improve photoreceptor survival. We validated the efficacy of human AIPL1 (isoform 1) replacement gene controlled by a promoter derived from the human rhodopsin kinase (RK) gene, which is active in both rods and cones. We found substantial and long-term rescue of the disease phenotype as a result of transgene expression. This is the first gene therapy study in which both rods and cones were targeted successfully with a single photoreceptor-specific promoter. We propose that the vector and construct design used in this study could serve as a prototype for a human clinical trial.

  7. Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations

    NARCIS (Netherlands)

    Avila-Fernandez, A.; Perez-Carro, R.; Corton, M.; Lopez-Molina, M.I.; Campello, L.; Garanto, A.; Fernandez-Sanchez, L.; Duijkers, L.; Lopez-Martinez, M.A.; Riveiro-Alvarez, R.; Silva, L.R. Da; Sanchez-Alcudia, R.; Martin-Garrido, E.; Reyes, N.; Garcia-Garcia, F.; Dopazo, J.; Garcia-Sandoval, B.; Collin, R.W.J.; Cuenca, N.; Ayuso, C.

    2015-01-01

    Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with

  8. Urological manifestations of Duchenne muscular dystrophy.

    Science.gov (United States)

    Askeland, Eric J; Arlen, Angela M; Erickson, Bradley A; Mathews, Katherine D; Cooper, Christopher S

    2013-10-01

    Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  9. Multimodal Imaging in Hereditary Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Francesco Pichi

    2013-01-01

    Full Text Available Introduction. In this retrospective study we evaluated the multimodal visualization of retinal genetic diseases to better understand their natural course. Material and Methods. We reviewed the charts of 70 consecutive patients with different genetic retinal pathologies who had previously undergone multimodal imaging analyses. Genomic DNA was extracted from peripheral blood and genotyped at the known locus for the different diseases. Results. The medical records of 3 families of a 4-generation pedigree affected by North Carolina macular dystrophy were reviewed. A total of 8 patients with Stargardt disease were evaluated for their two main defining clinical characteristics, yellow subretinal flecks and central atrophy. Nine male patients with a previous diagnosis of choroideremia and eleven female carriers were evaluated. Fourteen patients with Best vitelliform macular dystrophy and 6 family members with autosomal recessive bestrophinopathy were included. Seven patients with enhanced s-cone syndrome were ascertained. Lastly, we included 3 unrelated patients with fundus albipunctatus. Conclusions. In hereditary retinal diseases, clinical examination is often not sufficient for evaluating the patient’s condition. Retinal imaging then becomes important in making the diagnosis, in monitoring the progression of disease, and as a surrogate outcome measure of the efficacy of an intervention.

  10. Stem cell therapy for retinal diseases

    Institute of Scientific and Technical Information of China (English)

    Jose Mauricio Garcia,; Luisa Mendon?a; Rodrigo Brant; Murilo Abud; Caio Regatieri; Bruno Diniz

    2015-01-01

    In this review, we discuss about current knowledgeabout stem cell (SC) therapy in the treatment of retinaldegeneration. Both human embryonic stem cell andinduced pluripotent stem cell has been growth inculture for a long time, and started to be explored inthe treatment of blinding conditions. The Food andDrug Administration, recently, has granted clinical trialsusing SC retinal therapy to treat complex disorders, asStargardt's dystrophy, and patients with geographicatrophy, providing good outcomes. This study'sintent is to overview the critical regeneration of thesubretinal anatomy through retinal pigment epitheliumtransplantation, with the goal of reestablish importantpathways from the retina to the occipital cortex of thebrain, as well as the differentiation from pluripotentquiescent SC to adult retina, and its relationshipwith a primary retinal injury, different techniques oftransplantation, management of immune rejection andtumorigenicity, its potential application in improvingpatients' vision, and, finally, approaching future directionsand challenges for the treatment of several conditions.

  11. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    OpenAIRE

    2012-01-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age an...

  12. Neovascularization, enhanced inflammatory response, and age-related cone dystrophy in the Nrl-/-Grk1-/- mouse retina.

    Science.gov (United States)

    Yetemian, Rosanne M; Brown, Bruce M; Craft, Cheryl M

    2010-12-01

    The effects of aging and light exposure on cone photoreceptor survival were compared between mouse retinas of neural retina leucine zipper knockout (Nrl(-/-)) mice and double-knockout mice lacking G-protein-coupled receptor kinase 1 (Nrl(-/-)Grk1(-/-)). Mice were reared in total darkness, ambient cyclic light, or constant light, and their retinas were evaluated from 1 to 9 months of age using immunohistochemistry, electroretinography, and fluorescein angiography. Retinal gene expression and statistically significant probe sets were categorized using analysis software. Select gene expression changes were confirmed with quantitative RT-PCR. In contrast to retinas from Nrl(-/-), those from Nrl(-/-)Grk1(-/-) exhibit a progressive loss of the outer nuclear layer, retinal physiology deficits, and a higher rate of degeneration with increasing age that is independent of environmental light exposure. Changes in retinal neovascularization occur in the Nrl(-/-)Grk1(-/-) at 1 month, before the onset of significant cone functional deficits. Microarray analyses demonstrate statistically significant changes in transcript levels of more than 400 genes, of which the oncostatin M signaling pathway and the inflammatory disease response network were identified. These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl(-/-) background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl(-/-)Grk1(-/-) mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis.

  13. Ocular hemodynamics in patients with rhegmatogenous retinal detachment

    Directory of Open Access Journals (Sweden)

    N. H. Zavgorodnya

    2014-10-01

    Full Text Available Aim. In case of retinal detachment atrophic processes lead to irreversible loss of functions within 4–6 days, it happens on underlying low ocular blood flow. In order to evaluate the degree of violation of regional hemodynamics in patients with retinal detachment two groups of patients were examined: the main group (52 patients with rhegmatogenous retinal detachment and the control group (24 myopic patients with lattice form of peripheral chorioretinal dystrophy. Methods and results. Doppler and reography results had been compared, significant decrease of blood flow in patients with retinal detachment was found. No differences between affected and fellow eye in these patients, close negative correlation between the level of ocular blood flow and the degree of myopia in the control group. Conclusion. This demonstrates the feasibility of actions to improve regional blood flow in patients operated on for retinal detachment.

  14. Duchenne muscular dystrophy and epilepsy.

    Science.gov (United States)

    Pane, M; Messina, S; Bruno, C; D'Amico, A; Villanova, M; Brancalion, B; Sivo, S; Bianco, F; Striano, P; Battaglia, D; Lettori, D; Vita, G L; Bertini, E; Gualandi, F; Ricotti, V; Ferlini, A; Mercuri, E

    2013-04-01

    Cognitive and behavioral difficulties occur in approximately a third of patients with Duchenne muscular dystrophy. The aim of our study was to assess the prevalence of epilepsy in a cohort of 222 DMD patients. Epileptic seizures were found in 14 of the 222 DMD patients (6.3%). The age of onset ranged from 3 months to 16 years (mean 7.8). Seizures were more often focal epilepsy (n=6), generalized tonic-clonic seizures (n=4) or absences (n=4). They were present in 12 of the 149 boys with normal IQ (8.1%) and in two of the 73 with mental retardation (2.7%). In two cases the parents did not report any past or present history of seizures but only 'staring episodes' interpreted as a sign of 'poor attention'. In both patients EEG showed the typical pattern observed in childhood absence epilepsy. Our results suggest that the prevalence of epilepsy in our study (6.3%) is higher than in the general pediatric population (0.5-1%). The risk of epilepsy does not appear to increase in patients with mental retardation.

  15. Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis.

    Science.gov (United States)

    Ku, Cristy A; Chiodo, Vince A; Boye, Sanford L; Goldberg, Andrew F X; Li, Tiansen; Hauswirth, William W; Ramamurthy, Visvanathan

    2011-12-01

    Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease with early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects are characterized at the most severe end of the LCA spectrum. The rapid photoreceptor degeneration and vision loss observed in the LCA patient population are mimicked in a mouse model lacking AIPL1. Using this model, we evaluated if gene replacement therapy using recent advancements in adeno-associated viral vectors (AAV) provides advantages in preventing rapid retinal degeneration. Specifically, we demonstrated that the novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) provided greater preservation of photoreceptors and functional vision in Aipl1 null mice compared with single-stranded AAV2/8. The benefits of sc-Y733F-AAV were evident following viral administration during the active phase of retinal degeneration, where only sc-Y733F-AAV treatment achieved functional vision rescue. This result was likely due to higher and earlier onset of Aipl1 expression. Based on our studies, we conclude that the sc-Y733F-AAV2/8 viral vector, to date, achieves the best rescue for rapid retinal degeneration in Aipl1 null mice. Our results provide important considerations for viral vectors to be used in future gene therapy clinical trials targeting a wider severity spectrum of inherited retinal dystrophies.

  16. Successful Gene Therapy in the RPGRIP1-deficient Dog: a Large Model of Cone–Rod Dystrophy

    Science.gov (United States)

    Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2014-01-01

    For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod–cone dystrophies but not in large models of progressive cone–rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone–rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18–72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22–29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone–rod dystrophy provides great promise for human treatment. PMID:24091916

  17. Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

    Science.gov (United States)

    Deik, A; Johannes, B; Rucker, J C; Sánchez, E; Brodie, S E; Deegan, E; Landy, K; Kajiwara, Y; Scelsa, S; Saunders-Pullman, R; Paisán-Ruiz, C

    2014-12-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

  18. Selective disappearance of medial back muscles in a case of myotonic dystrophy type 1.

    Science.gov (United States)

    Morihara, Ryuta; Hishikawa, Nozomi; Yamashita, Toru; Deguchi, Kentaro; Kurata, Tomoko; Abe, Koji

    2015-01-01

    Here, we report a unique case of late-onset myotonic dystrophy type 1 in a 64-year-old woman, with selective disappearance of the medial lower back muscles. We compared the clinical features of this patient with those of a cohort of 29 patients with myotonic dystrophy type 1 to clarify the correlation between clinical features and lower back muscle atrophy. After classification into three subgroups according to muscle atrophy pattern, medial muscle atrophy was present in 17.2% of the patients. Affected patients were older at onset than non-affected patients, and limb muscle power and respiratory function decreased with atrophy progression.

  19. Meretoja's Syndrome: Lattice Corneal Dystrophy, Gelsolin Type

    Science.gov (United States)

    Abreu, C.; Neves, M.; Oliveira, L.; Beirão, M.

    2017-01-01

    Lattice corneal dystrophy gelsolin type was first described in 1969 by Jouko Meretoja, a Finnish ophthalmologist. It is caused by an autosomal dominant mutation in gelsolin gene resulting in unstable protein fragments and amyloid deposition in various organs. The age of onset is usually after the third decade of life and typical diagnostic triad includes progressive bilateral facial paralysis, loose skin, and lattice corneal dystrophy. We report a case of a 53-year-old female patient referred to our Department of Ophthalmology by severe dry eye and incomplete eyelid closure. She had severe bilateral facial paresis, significant orbicularis, and perioral sagging as well as hypoesthesia of extremities and was diagnosed with Meretoja's syndrome at the age of 50, confirmed by the presence of gelsolin mutation. At our observation she had bilateral diminished tear film break-up time and Schirmer test, diffuse keratitis, corneal opacification, and neovascularization in the left eye. She was treated with preservative-free lubricants and topical cyclosporine, associated with nocturnal complete occlusion of both eyes, and underwent placement of lacrimal punctal plugs. Ocular symptoms are the first to appear and our role as ophthalmologists is essential for the diagnosis, treatment, and monitoring of ocular alterations in these patients. PMID:28250773

  20. A Case of Severe Hydroxychloroquine-Induced Retinal Toxicity in a Patient with Recent Onset of Renal Impairment: A Review of the Literature on the Use of Hydroxychloroquine in Renal Impairment

    Directory of Open Access Journals (Sweden)

    Rajen Tailor

    2012-01-01

    Full Text Available We present a case of a 67-year-old female who presented with a twelve-month history of progressive blurred vision in both eyes. The patient was on hydroxychloroquine 200 mg twice a day for eight years for the treatment of scarring alopecia. Two years prior to presenting, the patient was found to have chronic kidney disease stage 3 secondary to hypertension. Examination revealed bilateral reduced visual acuities with attenuated arterioles and pigmentary changes on retinal assessment. Goldmann visual fields showed grossly constricted fields in both eyes. The patient was diagnosed with retinal toxicity secondary to hydroxychloroquine probably potentiated by renal impairment. Risk factors for retinal toxicity secondary to hydroxychloroquine can be broadly divided into dose-related and patient-related factors. Our patient developed severe retinal toxicity despite being on the recommended daily dose (400 mg per day. Although retinal toxicity at this dose has been documented, the development of renal impairment without dose adjustment or close monitoring of visual function is likely to have potentiated retinal toxicity. This case highlights the need to monitor renal function in patients on hydroxychloroquine. Should renal impairment develop, either the drug should be stopped or the dose reduced with close monitoring of visual function by an ophthalmologist.

  1. Modifying muscular dystrophy through transforming growth factor-β.

    Science.gov (United States)

    Ceco, Ermelinda; McNally, Elizabeth M

    2013-09-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle, with replacement by scar or fibrotic tissue, resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through both candidate gene approaches and genome-wide surveys. Multiple lines of experimental evidence have now converged on the transforming growth factor-β (TGF-β) pathway as a modifier for muscular dystrophy. TGF-β signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or an altered extracellular matrix. Given the important biological role of the TGF-β pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGF-β pathway and approaches to modulate TGF-β activity to ameliorate muscle disease.

  2. Retinitis pigmentosa

    NARCIS (Netherlands)

    Hartong, Dyonne T.; Berson, Eliot L.; Dryja, Thaddeus P.

    2006-01-01

    Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and centra

  3. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation

    OpenAIRE

    Min Ji Kang; Hye Bin Yim; Hyung Bin Hwang

    2016-01-01

    We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR) in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure wa...

  4. Modifying muscular dystrophy through TGFβ

    OpenAIRE

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing ef...

  5. [Duchenne muscular dystrophy pathophysiology].

    Science.gov (United States)

    Péréon, Y; Mercier, S; Magot, A

    2015-12-01

    Dystrophin is a large cytoskeletal protein located at the plasma membrane in both muscle and non-muscle tissues, which mediates interactions between the cytoskeleton, cell membrane, and extracellular matrix. Dystrophin is a key component of multiprotein complexes (dystrophin- associated glycoprotein complex, or DGC). It is also involved in many intracellular cascades affecting membrane proteins such as calcium channels, or various signalisation pathways. In Duchenne Muscular Dystrophy, both dystrophin and DGC proteins are missing. This induces excessive membrane fragility and permeability, dysregulation of calcium homeostasis, oxidative damage, which in turn favour muscle cell necrosis. The latter is initially followed by regeneration. With age, the regenerative capacity of the muscles appears to be exhausted and muscle fibres are gradually replaced by connective and adipose tissue. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Adult foveomacular vitelliform dystrophy

    Directory of Open Access Journals (Sweden)

    Valdir Balarin

    2013-06-01

    Full Text Available Adult foveomacular vitelliform dystrophy is a rare pathology. Less than 1% of the reported cases display perifoveal capillary permeability. The three-year follow-up period of the case revealed a rare form, which had not yet been documented. The patient was a 40-year-old female with normal visual acuity, and a minor complaint of metamorphopsia on the left eye. Retinography showed a perifoveal yellowish subretinal area OS.Angiography showed perifoveal leakage OS. Follow up showed that, over 3 years, capillary incompetence disappeared and the yellow area underwent alterations, becoming atrophic OS. Angiography also showed hyperfluorescence (windows defect. Towards the end, it resembled the appearance of late stage of Best's Disease.

  7. Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.

    Directory of Open Access Journals (Sweden)

    Nathalie Caruso

    2013-06-01

    Full Text Available Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD. FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.

  8. Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in the Nrl−/−Grk1−/− Mouse Retina

    Science.gov (United States)

    Yetemian, Rosanne M.; Brown, Bruce M.

    2010-01-01

    Purpose. The effects of aging and light exposure on cone photoreceptor survival were compared between mouse retinas of neural retina leucine zipper knockout (Nrl−/−) mice and double-knockout mice lacking G-protein–coupled receptor kinase 1 (Nrl−/−Grk1−/−). Methods. Mice were reared in total darkness, ambient cyclic light, or constant light, and their retinas were evaluated from 1 to 9 months of age using immunohistochemistry, electroretinography, and fluorescein angiography. Retinal gene expression and statistically significant probe sets were categorized using analysis software. Select gene expression changes were confirmed with quantitative RT-PCR. Results. In contrast to retinas from Nrl−/−, those from Nrl−/−Grk1−/− exhibit a progressive loss of the outer nuclear layer, retinal physiology deficits, and a higher rate of degeneration with increasing age that is independent of environmental light exposure. Changes in retinal neovascularization occur in the Nrl−/−Grk1−/− at 1 month, before the onset of significant cone functional deficits. Microarray analyses demonstrate statistically significant changes in transcript levels of more than 400 genes, of which the oncostatin M signaling pathway and the inflammatory disease response network were identified. Conclusions. These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl−/− background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl−/−Grk1−/− mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis. PMID:20688726

  9. Paternal transmission of congenital myotonic dystrophy.

    OpenAIRE

    Bergoffen, J; Kant, J.; Sladky, J; McDonald-McGinn, D; Zackai, E H; Fischbeck, K H

    1994-01-01

    The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counsell...

  10. [Adult Refsum disease. A retinal dystrophy with therapeutic options].

    Science.gov (United States)

    Rüther, K

    2005-08-01

    Adult Refsum disease is one of the few forms of tapetoretinal degenerations accessible for therapy. The disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety tissues. Beside tapetoretinal degeneration, additional symptoms are chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, skeletal malformations, and cardiac abnormalities. A diet low in phytanic acid leads to an amelioration of polyneuropathy and ataxia and slows or even stops the other manifestations. This beneficial effect of dietary precautions requires the need to get hold of as much patients as possible but better all of them. The ophthalmologist plays a crucial role to this end because of the early manifestation of the tapetoretinal degeneration. A delay of 11 years between the appearance of first symptoms and the diagnosis of Refsum disease, as reported in the literature, is not acceptable.

  11. Electrophysiological studies in American Quarter horses with neuroaxonal dystrophy.

    Science.gov (United States)

    Finno, Carrie J; Aleman, Monica; Ofri, Ron; Hollingsworth, Steven R; Madigan, John E; Winfield, Laramie; Bannasch, Danika L

    2012-09-01

    Neuroaxonal dystrophy (NAD) is a disease characterized by the sudden onset of neurologic signs in horses ranging from 4 to 36 months of age. Equine degenerative myeloencephalopathy (EDM), a disease that has been associated with low vitamin E concentrations, is considered a more advanced form of NAD. The objective of this report is to describe the electrophysiological features of NAD/EDM in American Quarter horses (QHs). HORSES: Six NAD/EDM-affected QHs and six unaffected QHs were evaluated by ophthalmic examination and electroretinography. Five of the NAD/EDM-affected QH and five unaffected QHs were also evaluated by electroencephalography (EEG). Ophthalmic examination, ERGs, and EEGs were unremarkable in NAD/EDM cases. Neuroaxonal dystrophy/EDM does not appear to cause clinical signs of ocular disease or functional ERG/EEG deficits in QHs. © 2012 American College of Veterinary Ophthalmologists.

  12. CERKL knockdown causes retinal degeneration in zebrafish.

    Directory of Open Access Journals (Sweden)

    Marina Riera

    Full Text Available The human CERKL gene is responsible for common and severe forms of retinal dystrophies. Despite intense in vitro studies at the molecular and cellular level and in vivo analyses of the retina of murine knockout models, CERKL function remains unknown. In this study, we aimed to approach the developmental and functional features of cerkl in Danio rerio within an Evo-Devo framework. We show that gene expression increases from early developmental stages until the formation of the retina in the optic cup. Unlike the high mRNA-CERKL isoform multiplicity shown in mammals, the moderate transcriptional complexity in fish facilitates phenotypic studies derived from gene silencing. Moreover, of relevance to pathogenicity, teleost CERKL shares the two main human protein isoforms. Morpholino injection has been used to generate a cerkl knockdown zebrafish model. The morphant phenotype results in abnormal eye development with lamination defects, failure to develop photoreceptor outer segments, increased apoptosis of retinal cells and small eyes. Our data support that zebrafish Cerkl does not interfere with proliferation and neural differentiation during early developmental stages but is relevant for survival and protection of the retinal tissue. Overall, we propose that this zebrafish model is a powerful tool to unveil CERKL contribution to human retinal degeneration.

  13. Extension of the clinical range of facioscapulohumeral dystrophy : report of six cases

    NARCIS (Netherlands)

    van der Kooi, AJ; Visser, MC; Rosenberg, N; van den Berg-Vos, R; Wokke, JHJ; Bakker, E; de Visser, M

    2000-01-01

    Consensual diagnostic criteria for facioscapulohumeral dystrophy (FSHD) include onset of the disease in facial or shoulder girdle muscles, facial weakness in more than 50% of affected family members, autosomal dominant inheritance in familial cases, and evidence of myopathic disease in at least one

  14. Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy

    DEFF Research Database (Denmark)

    Chiu, Yen-Hui; Hornsey, Mark A; Klinge, Lars

    2009-01-01

    Skeletal muscle requires an efficient and active membrane repair system to overcome the rigours of frequent contraction. Dysferlin is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine...

  15. Complementary and alternative medicine for Duchenne and Becker muscular dystrophies: characteristics of users and caregivers.

    Science.gov (United States)

    Zhu, Yong; Romitti, Paul A; Conway, Kristin M; Andrews, Jennifer; Liu, Ke; Meaney, F John; Street, Natalie; Puzhankara, Soman; Druschel, Charlotte M; Matthews, Dennis J

    2014-07-01

    Complementary and alternative medicine is frequently used in the management of chronic pediatric diseases, but little is known about its use by those with Duchenne or Becker muscular dystrophy. Complementary and alternative medicine use by male patients with Duchenne or Becker muscular dystrophy and associations with characteristics of male patients and their caregivers were examined through interviews with 362 primary caregivers identified from the Muscular Dystrophy Surveillance, Tracking, and Research Network. Overall, 272 of the 362 (75.1%) primary caregivers reported that they had used any complementary and alternative medicine for the oldest Muscular Dystrophy Surveillance, Tracking, and Research Network male in their family. The most commonly reported therapies were from the mind-body medicine domain (61.0%) followed by those from the biologically based practice (39.2%), manipulative and body-based practice (29.3%), and whole medical system (6.9%) domains. Aquatherapy, prayer and/or blessing, special diet, and massage were the most frequently used therapies. Compared with nonusers, male patients who used any therapy were more likely to have an early onset of symptoms and use a wheel chair; their caregivers were more likely to be non-Hispanic white. Among domains, associations were observed with caregiver education and family income (mind-body medicines [excluding prayer and/or blessing only] and whole medical systems) and Muscular Dystrophy Surveillance, Tracking, and Research Network site (biologically based practices and mind-body medicines [excluding prayer and/or blessing only]). Complementary and alternative medicine use was common in the management of Duchenne and Becker muscular dystrophies among Muscular Dystrophy Surveillance, Tracking, and Research Network males. This widespread use suggests further study to evaluate the efficacy of integrating complementary and alternative medicine into treatment regimens for Duchenne and Becker muscular

  16. Genetics of corneal endothelial dystrophies

    Indian Academy of Sciences (India)

    Chitra Kannabiran

    2009-12-01

    The corneal endothelium maintains the level of hydration in the cornea. Dysfunction of the endothelium results in excess accumulation of water in the corneal stroma, leading to swelling of the stroma and loss of transparency. There are four different corneal endothelial dystrophies that are hereditary, progressive, non-inflammatory disorders involving dysfunction of the corneal endothelium. Each of the endothelial dystrophies is genetically heterogeneous with different modes of transmission and/or different genes involved in each subtype. Genes responsible for disease have been identified for only a subset of corneal endothelial dystrophies. Knowledge of genes involved and their function in the corneal endothelium can aid understanding the pathogenesis of the disorder as well as reveal pathways that are important for normal functioning of the endothelium.

  17. Bietti crystalline dystrophy: a morpho-functional evaluation.

    Science.gov (United States)

    Parravano, Mariacristina; Sciamanna, Marta; Giorno, Paola; Boninfante, Antonluca; Varano, Monica

    2012-02-01

    We report the clinical findings and macular function of a patient with Bietti crystalline dystrophy. A 39-year-old woman reported visual loss in both eyes and nyctalopia. A complete ophthalmological evaluation, retromode imaging, SD-OCT acquisition, MP1 microperimetry, and multifocal electroretinogram (mfERG) were performed. Microcrystalline deposits in the cornea and the retina with retinal pigment epithelial atrophy were observed. Retromode imaging revealed visualization of normal large choroidal vessels, cystoid macular edema, and small defined glistening lesions. SD-OCT showed changes in the outer retina with numerous microcrystalline deposits. Microperimetry showed an absolute scotoma involving the perimacular area but sparing of the fovea. In both eyes, mfERG analysis suggests a dysfunction of pre-ganglionic retinal elements detectable in the 20 central retinal degrees. The genetic characterization showed an homozygous mutation c.772C > T[p.Leu258Phe] in exon 6. Retromode imaging and SD-OCT were useful tools to determine the extent and the localization of the crystals. Microperimetry should allow evaluation of the progression of the macular changes.

  18. Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

    Science.gov (United States)

    Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

    2017-01-01

    Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a

  19. Corneal stromal dystrophies: a clinical pathologic study

    Directory of Open Access Journals (Sweden)

    Elvira Barbosa Abreu

    2012-12-01

    Full Text Available INTRODUCTION: Corneal dystrophy is defined as bilateral and symmetric primary corneal disease, without previous associated ocular inflammation. Corneal dystrophies are classified according to the involved corneal layer in superficial, stromal, and posterior dystrophy. Incidence of each dystrophy varies according to the geographic region studied. PURPOSE: To evaluate the prevalence of stromal corneal dystrophies among corneal buttons specimens obtained by penetrating keratoplasty (PK in an ocular pathology laboratory and to correlate the diagnosis with patient age and gender. METHODS: Corneal button cases of penetrating keratoplasty from January-1996 to May-2009 were retrieved from the archives of The Henry C. Witelson Ophthalmic Pathology Laboratory and Registry, Montreal, Canada. The cases with histopathological diagnosis of stromal corneal dystrophies were stained with special stains (Peroxid acid Schiff, Masson trichrome, Congo red analyzed under polarized light, and alcian blue for classification and correlated with epidemiological information (age at time of PK and gender from patients' file. RESULTS: 1,300 corneal buttons cases with clinical diagnose of corneal dystrophy were retrieved. Stromal corneal dystrophy was found in 40 (3.1% cases. Lattice corneal dystrophy was the most prevalent with 26 cases (65%. Nineteen were female (73.07% and the PK was performed at average age of 59.3 years old. Combined corneal dystrophy was found in 8 (20% cases, 5 (62.5% of them were female and the average age of the penetrating keratoplasty was 54.8 years old. Granular corneal dystrophy was represented by 5 (12.5% cases, and 2 (40% of them were female. Penetrating keratoplasty was performed at average age of 39.5 years old in granular corneal dystrophy cases. Macular corneal dystrophy was present in only 1 (2.5% case, in a 36 years old female. CONCLUSION: Systematic histopathological approach and evaluation, including special stains in all stromal

  20. A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy.

    Science.gov (United States)

    Hicks, Debbie; Sarkozy, A; Muelas, N; Koehler, K; Huebner, A; Hudson, G; Chinnery, P F; Barresi, R; Eagle, M; Polvikoski, T; Bailey, G; Miller, J; Radunovic, A; Hughes, P J; Roberts, R; Krause, S; Walter, M C; Laval, S H; Straub, V; Lochmüller, H; Bushby, K

    2011-01-01

    The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100,000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular

  1. Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.

    Science.gov (United States)

    Pellissier, Lucie P; Quinn, Peter M; Alves, C Henrique; Vos, Rogier M; Klooster, Jan; Flannery, John G; Heimel, J Alexander; Wijnholds, Jan

    2015-06-01

    Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function.

  2. Fundus changes in central retinal vein occlusion.

    Science.gov (United States)

    Hayreh, Sohan Singh; Zimmerman, M Bridget

    2015-01-01

    To investigate systematically the retinal and optic disk changes in central retinal vein occlusion (CRVO) and their natural history. This study comprised 562 consecutive patients with CRVO (492 nonischemic [NI-CRVO] and 89 ischemic CRVO [I-CRVO] eyes) seen within 3 months of onset. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. Retinal and subinternal limiting membrane hemorrhages and optic disk edema in I-CRVO were initially more marked (P retinal epithelial pigment degeneration, serous macular detachment, and retinal perivenous sheathing developed at a higher rate in I-CRVO than that in NI-CRVO (P retinal venous engorgement than NI-CRVO (P = 0.003). Fluorescein fundus angiography showed significantly more fluorescein leakage, retinal capillary dilatation, capillary obliteration, and broken capillary foveal arcade (P < 0.0001) in I-CRVO than NI-CRVO. Resolution time of CRVO was longer for I-CRVO than NI-CRVO (P < 0.0001). Characteristics and natural history of fundus findings in the two types of CRVO are different.

  3. Advances in gene therapy technologies to treat retinitis pigmentosa.

    Science.gov (United States)

    Petrs-Silva, Hilda; Linden, Rafael

    2014-01-01

    Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant adenoassociated viral vectors, which show a positive safety record and have so far been successful in several clinical trials for congenital retinal disease. Gene therapy for RP is under development in a variety of animal models, and the results raise expectations of future clinical application. Nonetheless, the translation of such strategies to the bedside requires further understanding of the mutations and mechanisms that cause visual defects, as well as thorough examination of potential adverse effects.

  4. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies.

    Science.gov (United States)

    Kitiratschky, Veronique B D; Grau, Tanja; Bernd, Antje; Zrenner, Eberhart; Jägle, Herbert; Renner, Agnes B; Kellner, Ulrich; Rudolph, Günther; Jacobson, Samuel G; Cideciyan, Artur V; Schaich, Simone; Kohl, Susanne; Wissinger, Bernd

    2008-07-01

    The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

  5. Automated measurement of retinal blood vessel tortuosity

    Science.gov (United States)

    Joshi, Vinayak; Reinhardt, Joseph M.; Abramoff, Michael D.

    2010-03-01

    Abnormalities in the vascular pattern of the retina are associated with retinal diseases and are also risk factors for systemic diseases, especially cardiovascular diseases. The three-dimensional retinal vascular pattern is mostly formed congenitally, but is then modified over life, in response to aging, vessel wall dystrophies and long term changes in blood flow and pressure. A characteristic of the vascular pattern that is appreciated by clinicians is vascular tortuosity, i.e. how curved or kinked a blood vessel, either vein or artery, appears along its course. We developed a new quantitative metric for vascular tortuosity, based on the vessel's angle of curvature, length of the curved vessel over its chord length (arc to chord ratio), number of curvature sign changes, and combined these into a unidimensional metric, Tortuosity Index (TI). In comparison to other published methods this method can estimate appropriate TI for vessels with constant curvature sign and vessels with equal arc to chord ratios, as well. We applied this method to a dataset of 15 digital fundus images of 8 patients with Facioscapulohumeral muscular dystrophy (FSHD), and to the other publically available dataset of 60 fundus images of normal cases and patients with hypertensive retinopathy, of which the arterial and venous tortuosities have also been graded by masked experts (ophthalmologists). The method produced exactly the same rank-ordered list of vessel tortuosity (TI) values as obtained by averaging the tortuosity grading given by 3 ophthalmologists for FSHD dataset and a list of TI values with high ranking correlation with the ophthalmologist's grading for the other dataset. Our results show that TI has potential to detect and evaluate abnormal retinal vascular structure in early diagnosis and prognosis of retinopathies.

  6. Wasting mechanisms in muscular dystrophy.

    Science.gov (United States)

    Shin, Jonghyun; Tajrishi, Marjan M; Ogura, Yuji; Kumar, Ashok

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

  7. Benign concentric annular macular dystrophy

    Directory of Open Access Journals (Sweden)

    Luísa Salles de Moura Mendonça

    2015-06-01

    Full Text Available The purpose of the authors is to show clinical findings of a patient with benign concentric annular macular dystrophy, which is an unusual condition, and part of the "bull’s eye" maculopathy differential diagnosis. An ophthalmologic examination with color perception, fluorescein angiography, and ocular electrophysiology was performed.

  8. Prednisone Therapy for Duchenne Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-02-01

    Full Text Available The effects of prednisone on muscle function and the extent of steroid-related adverse effects were studied in 17 ambulant children with Duchenne muscular dystrophy (DMD at University Hospital, Groningen; Rehabilitation Centre, Utrecht; and Leiden University Medical Centre, the Netherlands.

  9. Glucocorticoids for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-07-01

    Full Text Available Investigators at the Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, and other centers in the UK, conducted a prospective longitudinal study across 17 neuromuscular centers in the UK of 360 boys aged 3-15 years with Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off prednisolone for a mean duration of 4 years.

  10. Inherited myopathies and muscular dystrophies

    NARCIS (Netherlands)

    Cardamone, Michael; Darras, Basil T.; Ryan, Monique M.

    The inherited myopathies and muscular dystrophies are a diverse group of muscle diseases presenting with common complaints and physical signs: weakness, motor delay, and respiratory and bulbar dysfunction. The myopathies are caused by genetic defects in the contractile apparatus of muscle, and

  11. AMPUTATION AND REFLEX SYMPATHETIC DYSTROPHY

    NARCIS (Netherlands)

    GEERTZEN, JHB; EISMA, WH

    Reflex sympathetic dystrophy is a chronic pain syndrome characterized by chronic burning pain, restricted range of motion, oedema and vasolability. Patients are difficult to treat and the prognosis is very often poor. This report emphasizes that an amputation in case of a reflex sympathetic

  12. Porcine models of muscular dystrophy

    Science.gov (United States)

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

  13. Cardiac involvement in Duchenne and Becker muscular dystrophy

    Institute of Scientific and Technical Information of China (English)

    Sophie; Mavrogeni; George; Markousis-Mavrogenis; Antigoni; Papavasiliou; Genovefa; Kolovou

    2015-01-01

    Duchenne and Becker muscular dystrophy(DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation,not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction,heart block or malignant arrhythmias. Not only DMD/BMD patients,but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent,due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects,arrhythmias(supraventricular or ventricular),hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction,independently of age of onset or mutation groups. Cardiovascular magnetic resonance(CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies’ patients and carriers that can be observed even if overt muscular disease is absent. Recently,new CMR techniques,such as postcontrast myocardial T1 mapping,have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications.

  14. Animal models in therapeutic drug discovery for oculopharyngeal muscular dystrophy.

    Science.gov (United States)

    Chartier, Aymeric; Simonelig, Martine

    2013-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease which affects specific muscles. No pharmacological treatments are currently available for OPMD. In recent years, genetically tractable models of OPMD – Drosophila and Caenorhabditis elegans – have been generated. Although these models have not yet been used for large-scale primary drug screening, they have been very useful in candidate approaches for the identification of potential therapeutic compounds for OPMD. In this brief review, we summarize the data that validated active molecules for OPMD in animal models including Drosophila, C. elegans and mouse.

  15. Genetics Home Reference: lattice corneal dystrophy type I

    Science.gov (United States)

    ... corneal dystrophy type I lattice corneal dystrophy type I Enable Javascript to view the expand/collapse boxes. ... All Close All Description Lattice corneal dystrophy type I is an eye disorder that affects the clear, ...

  16. Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)

    Science.gov (United States)

    Carter, David A.; Smart, Matthew J. K.; Letton, William V. G.; Ramsden, Conor M.; Nommiste, Britta; Chen, Li Li; Fynes, Kate; Muthiah, Manickam N.; Goh, Pollyanna; Lane, Amelia; Powner, Michael B.; Webster, Andrew R.; da Cruz, Lyndon; Moore, Anthony T.; Coffey, Peter J.; Carr, Amanda-Jayne F.

    2016-01-01

    Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients. PMID:27653836

  17. Dominant cone-rod dystrophy: a mouse model generated by gene targeting of the GCAP1/Guca1a gene.

    Directory of Open Access Journals (Sweden)

    Prateek K Buch

    Full Text Available Cone dystrophy 3 (COD3 is a severe dominantly inherited retinal degeneration caused by missense mutations in GUCA1A, the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1. The role of GCAP1 in controlling cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in COD3 patients. Disease progression in this novel mouse model of cone dystrophy was determined by a variety of techniques including electroretinography (ERG, retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although retinal development was normal up to 3 months of age, there was a subsequent progressive decline in retinal function, with a far greater alteration in cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of cyclic GMP precedes the observed retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions.

  18. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation

    Directory of Open Access Journals (Sweden)

    Min Ji Kang

    2016-01-01

    Full Text Available We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure was low, but within the normal range in both eyes. Because cataracts are characteristic of myotonic dystrophy, we suggested that her 14-year-old daughter, who did not have any systemic complaints, undergo ophthalmic examination. She also had mild ptosis and snowflake cataracts. Both patients underwent genetic evaluation and were diagnosed with myotonic dystrophy caused by unstable expansion of cytosine-thymine-guanine trinucleotide repeats in the dystrophia myotonica-protein kinase gene. Ophthalmologists can diagnose myotonic dystrophy based on clinical and genetic findings, before the manifestation of systemic abnormalities.

  19. Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

    Science.gov (United States)

    2017-07-11

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Disease; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  20. Genetics Home Reference: early-onset myopathy with fatal cardiomyopathy

    Science.gov (United States)

    ... called sarcomeres . Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of this protein's most ... CMD Salih congenital muscular dystrophy Salih myopathy titinopathy & early-onset myopathy with ...

  1. Bietti crystalline corneoretinal dystrophy associated with CYP4V2 gene mutations.

    Science.gov (United States)

    Nakamura, Makoto; Lin, Jian; Nishiguchi, Koji; Kondo, Mineo; Sugita, Jiro; Miyake, Yozo

    2006-01-01

    Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal dystrophy characterized by progressive night blindness, tiny, yellowish, glistening retinal crystals, choroidal sclerosis, and crystalline deposits in the peripheral cornea. Recent studies have demonstrated that the CYP4V2 gene which encodes a CYP450 family protein is the causative gene of the disease. We have identified a homozygous mutation in the CYP4V2 gene in 8 separate Japanese patients with BCD and conclude that mutations in the CYP4V2 gene are the major cause of BCD. The IVS6-8_c.810del/insGC mutation is found at a higher frequency in the Asian populations suggesting a founder effect.

  2. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.

    Science.gov (United States)

    Li, Anren; Jiao, Xiaodong; Munier, Francis L; Schorderet, Daniel F; Yao, Wenliang; Iwata, Fumino; Hayakawa, Mutsuko; Kanai, Atsushi; Shy Chen, Muh; Alan Lewis, Richard; Heckenlively, John; Weleber, Richard G; Traboulsi, Elias I; Zhang, Qingjiong; Xiao, Xueshan; Kaiser-Kupfer, Muriel; Sergeev, Yuri V; Hejtmancik, J Fielding

    2004-05-01

    Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD.

  3. Ocular neovascularization associated with central and hemicentral retinal vein occlusion.

    Science.gov (United States)

    Hayreh, Sohan Singh; Zimmerman, M Bridget

    2012-09-01

    To investigate the incidence of ocular neovascularization (NV) in central and hemicentral retinal vein occlusion. The study comprised consecutive 912 (673 nonischemic and 239 ischemic) central retinal vein occlusion and 190 (147 nonischemic, 43 ischemic) hemicentral retinal vein occlusion eyes. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. In ischemic central retinal vein occlusion, within 6 months from time of onset, the cumulative probability of development of iris NV was 49%, angle NV 37%, NV glaucoma 29%, retinal NV 9%, and disk NV 6%. More severe peripheral retinal hemorrhages were significantly associated with iris NV (P = 0.005), angle NV (P = 0.0004), and NV glaucoma (P = 0.012). Eyes that developed disk NV had more cotton wool spots (P = 0.058) than those without. In ischemic hemicentral retinal vein occlusion, within 12 months of onset, the cumulative probability of development of retinal NV was 29%, disk NV 12%, and iris NV 12%; within 6 months of onset, angle NV was found in 10% and NV glaucoma in 5%. Anterior chamber flare was associated with anterior segment NV and may precede the development of NV. Patients who developed NV were significantly younger, and there was a greater prevalence of NV glaucoma in patients with primary open angle glaucoma. In ischemic central retinal vein occlusion, anterior segment NV is much more common than posterior segment NV, and the cumulative chance of developing anterior segment NV is maximum during the first 6 months. In ischemic hemicentral retinal vein occlusion, posterior segment NV is much more common than anterior segment NV.

  4. Fungal keratitis in Lattice dystrophy

    Directory of Open Access Journals (Sweden)

    Chatterjee Samrat

    2010-01-01

    Full Text Available We report a case of fungal keratitis occurring in a patient with lattice dystrophy. A 57-year-old farmer presented with a corneal ulcer following probable entry of paddy husk in the right eye, of one month duration. Corneal scraping revealed pigmented fungal filaments while culture grew Alternaria alternata. Treatment with 5% natamycin eye drops and 1% atropine healed the infection in four weeks. We would like to draw attention to the fact that the cornea in lattice dystrophy is prone to frequent erosions and is a compromised epithelial barrier to invasion by microorganisms. Patients must be made aware of this fact and should seek attention at the earliest following any trivial trauma. Management of minor corneal abrasions in them should be directed at healing the epithelium with adequate lubricants and preventing infection with topical antibiotic prophylaxis.

  5. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2014-05-01

    by successful treatment of patient mutations. In Aim 3, we have completed generation of a DBA/2J congenic mdx strain that appears to better model the...in-frame deletions that are expected to arise by successful treatment of patient mutations. Our transgenic experiments will model the best-case...macrophage infiltration and necrosis), weight loss after weaning, joint contractures , kyphosis, dystrophy of extraocular muscles, abnormal

  6. [Dystroglycan linkage and muscular dystrophy].

    Science.gov (United States)

    Shimizu, Teruo

    2002-11-01

    Dystroglycan is a key complex between basal lamina laminin, extracellularly and membrano-cytoskeleton, intracellularly. The damage of this linkage is turned out to cause muscular dystrophies. Dystroglycan knockout is lethal. Dystroglycan-associated intracellular proteins such as dystrophin, dystrobrevin, sarcoglycans, plectin and caveolin-3 are responsible for causing severe (Duchenne type) and moderate forms (Becker, LGMDs). Laminin, dystroglycan-binding extracellular protein, is deficient in the most severe form of congenital muscular dystrophy with normal intelligence and eye. Recently, a remarkable progress is made in most severe forms of congenital muscular dystrophy with anomalies of brain and eye such as Fukuyama type (Japan) and muscle-eye-brain disease (Finland). The gene product for Fukuyama type, fukutin, belongs to a family of glycosylation enzymes in bacteria and yeast. Since alpha-dystroglycan contains 14-15 o-glycans, ser/thr-mannose 2-1 GlcNAc 4-1 Gal 3-2 Sial in the middle third mucin-domain and the sial-o-glycan is essential for laminin-binding, and since alpha-dystroglycan is defective in Fukuyama type sarcolemma with anti both sugar moiety- and peptide-antidodies, defective fukutin causes incomplete o-glycosylation of alpha-dystroglycan. In '02, it is clarified that a glycosylation enzyme, POMGnT1 which modifies GlcNAc onto ser/thr-mannose, is defective in 6 MEB patients. The loss of the enzyme activity is turned out to lose alpha-dystroglycan from sarcolemma of MEB. These data strongly suggests that o-glycosylation defect of alpha-dystroglycan causes the most severe congenital muscular dystrophy such as Fukuyama type, MEB and Walker Warburg syndrome.

  7. Clinical features of retinal diseases masquerading as retrobulbar optic neuritis

    Institute of Scientific and Technical Information of China (English)

    JIANG Li-bin; SHEN Ce-ying; CHEN Fei; YAN Wei-yu; Timothy Y.Y.Lai; WANG Ning-li

    2013-01-01

    Background Managements of optic neuritis (ON) included high-dose corticosteroids or combined with systemic immunomodulatory agents.It was important to make a correct diagnosis of ON before initiation of treatment.The purpose of the study was to report and analyze the clinical features of retinal diseases in patients who were misdiagnosed as having retrobulbar ON.Methods Retrospective review of 26 patients (38 eyes) initially diagnosed with retrobulbar ON but were ultimately diagnosed with retinal or macular diseases.Data obtained from fundus examination,fluorescence fundus angiogrephy (FFA),automated static perimetry,full-field electroretinogram (ffERG),multifocal electroretinogram (mfERG),and optical coherence tomography (OCT) were evaluated.Results Thirty-eight eyes of 26 patients were found to have misdiagnosis of retrobulbar ON,based on normal or slight abnormal fundus findings and abnormal visual evoked potentials (VEP).The mean age of the patients was 34 years and the correct diagnosis of the patients included acute zonal occult outer retinopathy (AZOOR,15 eyes,14 patients),occult macular dystrophy (OMD,8 eyes,4 patients),cone or cone-rod dystrophy (10 eyes,5 patients),acute macular neuroretinopathy (AMNR,3 eyes,2 patients),and cancer-associated retinopathy (CAR,2 eyes,1 patient).Conclusion When attempting to diagnose retrobulbar ON in clinical practice,it is crucial to carry out necessary examinations of the retinal function and morphology to decrease misdiagnosis.

  8. The circadian response of intrinsically photosensitive retinal ganglion cells.

    Directory of Open Access Journals (Sweden)

    Andrew J Zele

    Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGC signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central or intrinsic (retinal network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC and outer retina (cone photoreceptors was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux. Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin retinal ganglion cells mediate this circadian variation.

  9. Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J;

    1987-01-01

    The blood-retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured...... the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood-retinal barrier correlated well with changes in retinal morphology as seen...... in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5-10 times the normal value. Onset of diabetes in the decade before and after puberty did not change...

  10. Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

    Directory of Open Access Journals (Sweden)

    Dušanka Savić Pavićević

    2013-01-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

  11. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2.

    Science.gov (United States)

    Kamsteeg, Erik-Jan; Kress, Wolfram; Catalli, Claudio; Hertz, Jens M; Witsch-Baumgartner, Martina; Buckley, Michael F; van Engelen, Baziel G M; Schwartz, Marianne; Scheffer, Hans

    2012-12-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1 of the CNBP (formerly ZNF9) gene, respectively. The length of the (CTG)n repeat expansion in DM1 correlates with disease severity and age of onset. Nevertheless, these repeat sizes have limited predictive values on individual bases. Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.

  12. MR imaging findings of retinal hemorrhage in a case of nonaccidental trauma

    Energy Technology Data Exchange (ETDEWEB)

    Altinok, Deniz; Saleem, Sheena; Smith, Wilbur [Children' s Hospital of Michigan, Department of Pediatric Imaging, Detroit, MI (United States); Zhang, Zaixiang [Wayne State University School of Medicine, Department of Radiology, Detroit, MI (United States); Markman, Lisa [Children' s Hospital of Michigan, Child Protection Team, Detroit, MI (United States)

    2009-03-15

    Retinal hemorrhage is a well-recognized manifestation of child abuse found in many babies with shaken baby syndrome. The presence of retinal hemorrhage is generally associated with more severe neurological damage and a worse clinical outcome. MR imaging findings of retinal hemorrhages are not well described in the pediatric literature. We present a 6-month-old boy with new-onset seizures, subdural hemorrhage and bilateral retinal hemorrhages that were detected by MRI and confirmed by indirect ophthalmoscopy. This case demonstrates the MR imaging findings of retinal hemorrhages and the importance of radiologists being able to recognize these specific imaging features. (orig.)

  13. Choroidal thickness profile in inherited retinal diseases in Indian subjects

    Directory of Open Access Journals (Sweden)

    Jay Chhablani

    2015-01-01

    Full Text Available Purpose: To evaluate changes in choroidal thickness (CT in inherited retinal diseases and its relationship with age, spherical equivalent, visual acuity, and macular thickness. Methods: Retrospective analysis of 51 eyes with features of retinal dystrophy of 26 subjects, who underwent enhanced depth imaging using spectral domain (SD optical coherence tomography (OCT, were included. The CT measurements were made at the fovea and at 5 points with an interval of 500 microns in both directions, nasal and temporal from the fovea and were compared with age-matched healthy subjects. Step-wise regression was used to find the relationship between age, spherical equivalent, best-corrected visual acuity (BCVA, central macular thickness (CMT, and subfoveal CT. Results: Disease distribution was as follows: Stargardt′s disease 18 eyes (9 subjects; Best disease 5 eyes (3 subjects; cone-rod dystrophy 26 eyes (13 subjects; and Bietti′s crystalline dystrophy 2 eyes (1 subject. Mean subfoveal CT was 266.33 ± 76 microns. On regression analysis, no significant correlation was found between subfoveal CT and any other variable such as age (P = 0.9, gender (P = 0.5, CMT (P = 0.1, spherical equivalent (P = 0.3 and BCVA (P = 0.6. While comparing with age-matched healthy subjects, no significant statistical difference was noted (P < 0.05 among all age groups. Conclusion: Our study reports quantitative changes in CT in various common inherited retinal diseases seen in Indian populations. To validate changes in choroid, a longitudinal study with larger sample size is warranted.

  14. Keratoconus in Patients with Macular Stromal Dystrophy.

    Science.gov (United States)

    Kosrirukvongs, Panida; Ngowyutagon, Panotsom; Booranapong, Wipawee

    2016-01-01

    To show the association between keratoconus and macular dystrophy. All patients with macular dystrophy and associated clinical findings leading to a diagnosis of keratoconus by corneal topography were retrospectively reviewed during a 10-year period. Uncorrected and best-corrected visual acuity, automated refraction, manifest refraction, corneal thickness, and corneal curvature by corneal topography were evaluated Three patients with macular dystrophy exhibiting decreased vision, multifocal white dense deposits, and haze surrounding the deposits in the corneal stroma were evaluated. All had a steep corneal curvature of >47 diopters and a thin cornea consistent with keratoconus. Penetrating keratoplasty was performed in one patient with severely decreased vision. Macular dystrophy was diagnosed based on an Alcian blue-stained pathological specimen. Keratoconus may develop as a result of changes associated with macular dystrophy. Therefore, patients with severely decreased vision should be evaluated for keratoconus to ensure proper management.

  15. Spectral Domain Optical Coherence Tomographic Findings of Bietti Crystalline Dystrophy

    Directory of Open Access Journals (Sweden)

    Ali Osman Saatci

    2014-01-01

    Full Text Available We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 μm ± 62.52 for all eyes (170.35 μm ± 56.46 in eyes with intermediate disease and 145.42 μm ± 77.2 in eyes with advanced disease. Mean subfoveal choroidal thickness was 95.37 μm ± 55.93 for the study eyes (116.47 ± 46.92 μm in eyes with intermediate disease and 44.14 μm ± 42.43 in eyes with advanced disease. Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%. SD-OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process.

  16. Spectral domain optical coherence tomographic findings of bietti crystalline dystrophy.

    Science.gov (United States)

    Saatci, Ali Osman; Doruk, Hasan Can; Yaman, Aylin; Oner, Ferit Hakan

    2014-01-01

    We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD) with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 μm ± 62.52 for all eyes (170.35 μm ± 56.46 in eyes with intermediate disease and 145.42 μm ± 77.2 in eyes with advanced disease). Mean subfoveal choroidal thickness was 95.37 μm ± 55.93 for the study eyes (116.47 ± 46.92 μm in eyes with intermediate disease and 44.14 μm ± 42.43 in eyes with advanced disease). Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%). SD-OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process.

  17. [Role of immunological factors in peripheral vitreo-chorioretinal dystrophies and macular ruptures of the retina].

    Science.gov (United States)

    Balashova, L M; Saksonova, E O; Zaĭtseva, N S; Slepova, O S; Teplinskaia, L E; Il'nitskiĭ, V V; Grishin, V L

    1995-01-01

    The authors analyze the results of clinical and immunological examinations of patients with peripheral vitreo-chorioretinal dystrophies (PVCRD) and macular ruptures of the retina. No antibodies to S-AG were detected in the lacrimal fluid in 87.5% of patients with PVCRD without retinal defects. In patients with PVCRD with retinal defects antibodies to S-AG were detected in 70% of cases. These antibodies were absent in the patients with macular ruptures of the retina. In none of the patients were these antibodies detected in the blood serum. The levels of circulating immune complexes were normal in the patients PVCRD and increased in those with macular ruptures of the retina. These data permit a hypothesis on the development of local autoimmune reactions in PVCRD patients in response to the appearance of AG of the injured tissues.

  18. Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease.

    Science.gov (United States)

    Blumen, S C; Brais, B; Korczyn, A D; Medinsky, S; Chapman, J; Asherov, A; Nisipeanu, P; Codère, F; Bouchard, J P; Fardeau, M; Tomé, F M; Rouleau, G A

    1999-07-01

    Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) usually begins with ptosis or dysphagia during the fifth or sixth decade of life. We studied 7 patients with OPMD symptoms starting before the age of 36 years. All were found to be homozygotes for the dominant (GCG)9 OPMD mutation. On average, disease onset was 18 years earlier than in heterozygotes, and patients had a significantly larger number of muscle nuclei containing intranuclear inclusions (INIs) (9.4 vs 4.9%).

  19. [Current studies in myotonic dystrophy].

    Science.gov (United States)

    Zhao, Yimeng; Ishiura, Shoichi

    2014-03-01

    Myotonic dystrophy (DM) is a genetic, progressive, multisystemic disease with muscular disorder as its primary symptom. There are two types of DM (DM1 and DM2) caused by mutations in different genes, and in Japan, DM occurs with an incidence of approximately 1 in 20,000. The pathogenic mechanism underlying the disease is RNA toxicity caused by transcripts of aberrantly elongated CTG or CCTG repeats located in the 3' untranslated region or in the intron. The current treatments for DM is limited to symptomatic care. In this review, we will discuss several new therapeutic strategies based on recent studies of RNA toxicity.

  20. Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Andrea Barp

    Full Text Available Dilated cardiomyopathy (DCM is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD. DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4 also modify DCM onset.A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior; DCM-free patients were censored at the age of last echocardiographic follow-up.Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027.We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.

  1. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations

    Science.gov (United States)

    Sui, Ruifang; van den Born, L. Ingeborgh; Berson, Eliot L.; Ocaka, Louise A.; Davidson, Alice E.; Heckenlively, John R.; Branham, Kari; Ren, Huanan; Lopez, Irma; Maria, Maleeha; Azam, Maleeha; Henkes, Arjen; Blokland, Ellen; Qamar, Raheel; Webster, Andrew R.; Andreasson, Sten; de Baere, Elfride; Bennett, Jean; Chader, Gerald J.; Berger, Wolfgang; Golovleva, Irina; Greenberg, Jacquie; den Hollander, Anneke I.; Klaver, Caroline C.W.; Klevering, B. Jeroen; Lorenz, Birgit; Preising, Markus N.; Ramsear, Raj; Roberts, Lisa; Roepman, Ronald; Rohrschneider, Klaus; Wissinger, Bernd

    2014-01-01

    To investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORD) and autosomal recessive retinitis pigmentosa (RP), to delineate the ocular phenotypes, and to provide an overview of all published LCA5 variants in an online database._Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging was possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of RP were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were pre-screened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of RPE. One of these milder families harbored a homozygous splice site mutation, a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for

  2. Retinal remodeling in human retinitis pigmentosa.

    Science.gov (United States)

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

  3. Mutations in PCYT1A Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy

    Science.gov (United States)

    Yamamoto, Guilherme L.; Baratela, Wagner A.R.; Almeida, Tatiana F.; Lazar, Monize; Afonso, Clara L.; Oyamada, Maria K.; Suzuki, Lisa; Oliveira, Luiz A.N.; Ramos, Ester S.; Kim, Chong A.; Passos-Bueno, Maria Rita; Bertola, Débora R.

    2014-01-01

    Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum. PMID:24387991

  4. Perifoveal function in patients with North Carolina macular dystrophy: the importance of accounting for fixation locus.

    Science.gov (United States)

    Seiple, William; Szlyk, Janet P; Paliga, Jennifer; Rabb, Maurice F

    2006-04-01

    To quantify the extent of visual function losses in patients with North Carolina Macular Dystrophy (NCMD) and to demonstrate the importance of accounting for eccentric fixation when making comparisons with normal data. Five patients with NCMD who were from a single family were examined. Multifocal electroretinograms (mfERGs) and psychophysical assessments of acuity and luminance visual field sensitivities were measured throughout the central retina. Comparisons of responses from equivalent retinal areas were accomplished by shifting normal templates to be centered at the locus of fixation for each patient. Losses of psychophysically measured visual function in patients with NCMD extend to areas adjacent to the locations of visible lesions. The multifocal ERG amplitude was reduced only within the area of visible lesion. Multifocal ERG implicit times were delayed throughout the entire central retinal area assessed. ERG timing is a sensitive assay of retinal function, and our results indicate that NCMD has a widespread effect at the level of the mid and outer retina. The findings also demonstrated that it is necessary to account for fixation locus and to ensure that equivalent retinal areas are compared when testing patients with macular disease who have eccentric fixation.

  5. Meretoja’s Syndrome: Lattice Corneal Dystrophy, Gelsolin Type

    Directory of Open Access Journals (Sweden)

    I. Casal

    2017-01-01

    Full Text Available Lattice corneal dystrophy gelsolin type was first described in 1969 by Jouko Meretoja, a Finnish ophthalmologist. It is caused by an autosomal dominant mutation in gelsolin gene resulting in unstable protein fragments and amyloid deposition in various organs. The age of onset is usually after the third decade of life and typical diagnostic triad includes progressive bilateral facial paralysis, loose skin, and lattice corneal dystrophy. We report a case of a 53-year-old female patient referred to our Department of Ophthalmology by severe dry eye and incomplete eyelid closure. She had severe bilateral facial paresis, significant orbicularis, and perioral sagging as well as hypoesthesia of extremities and was diagnosed with Meretoja’s syndrome at the age of 50, confirmed by the presence of gelsolin mutation. At our observation she had bilateral diminished tear film break-up time and Schirmer test, diffuse keratitis, corneal opacification, and neovascularization in the left eye. She was treated with preservative-free lubricants and topical cyclosporine, associated with nocturnal complete occlusion of both eyes, and underwent placement of lacrimal punctal plugs. Ocular symptoms are the first to appear and our role as ophthalmologists is essential for the diagnosis, treatment, and monitoring of ocular alterations in these patients.

  6. Anesthesia for a Patient with Myotonic Dystrophy

    Directory of Open Access Journals (Sweden)

    Dilek Kalaycı

    2016-09-01

    Full Text Available Myotonic dystrophy is the most common myotonic syndrome causing abnormalities of the skeletal and smooth muscles as well as problems related to the cardiac, gastrointestinal and endocrine systems. In affected people, reduced functional residual capacity, vital capacity, and peak inspiratory pressure are observed within the respiratory system. As would be expected, anesthetic management of these patients is challenging for anesthesiologists. In addition, delayed recovery from anesthesia and cardiac and pulmonary complications may develop in the intraoperative and early postoperative periods due to sensitivity to sedatives, anesthetic agents, and neuromuscular blocking agents. Myotonic dystrophy can be performed with the use of appropriate anesthesia procedures as well as carefully communication between anesthesiologists and surgeons. In conclusion, myotonic dystrophy has variations, which makes it important to preoperatively determine specific surgical and anesthetic management strategies for each patient. In this article, we present a patient with myotonic dystrophy who underwent laparoscopic cholecystectomy surgery for symptomatic cholelithiasis and to discuss the relevant literature.

  7. Duchenne muscular dystrophy - a molecular service

    African Journals Online (AJOL)

    Duchenne muscular dystrophy using molecular technology was instituted at the ..... utilising non-fat dry milk for analysis of proteins and nucleic acids transferred ... acid to high specific activity in vitro by nick translation with DNA polymerase.

  8. Non-Coding RNAs in Muscle Dystrophies

    Directory of Open Access Journals (Sweden)

    Alessandra Ferlini

    2013-09-01

    Full Text Available ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies.

  9. Targeting latent TGFβ release in muscular dystrophy.

    Science.gov (United States)

    Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

    2014-10-22

    Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

  10. Ventilatory support in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Wohlgemuth, M.; Kooi, E.L. van der; Kesteren, R.G. van; Maarel, S.M. van der; Padberg, G.W.A.M.

    2004-01-01

    Respiratory insufficiency due to respiratory muscle weakness is a common complication of many neuromuscular diseases. The prevalence of respiratory failure in facioscapulohumeral muscular dystrophy (FSHD) is unknown. The authors identified 10 FSHD patients on nocturnal ventilatory support at home,

  11. Brain MRI Findings in Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-03-01

    Full Text Available Brain magnetic resonance imaging (MRI findings in 13 patients with congenital muscular dystrophy (MDCIC and Fukutin-related protein (FKRP gene mutations were retrospectively reviewed in a study at Hammersmith Hospital, London, UK, and European centers.

  12. Duchenne muscular dystrophy: the management of scoliosis

    Science.gov (United States)

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

  13. Cardiac involvement in myotonic dystrophy

    DEFF Research Database (Denmark)

    Lund, Marie; Diaz, Lars Jorge; Ranthe, Mattis Flyvholm

    2014-01-01

    disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease......AIMS: To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort. METHODS AND RESULTS: We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone...... genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction...

  14. Posterior polymorphous dystrophy of the cornea. An ultrastructural study.

    Science.gov (United States)

    de Felice, G P; Braidotti, P; Viale, G; Bergamini, F; Vinciguerra, P

    1985-01-01

    A corneal button excised from a 2-month-old infant with congenital posterior polymorphous dystrophy of the cornea, a rare disease affecting Descemet's membrane and endothelium, was examined by electron microscopy. We observed irregularly arranged, sometimes multilayered cells with marked epithelial features, lining the posterior surface of the cornea in place of the endothelium, and Descemet's membrane with focal alterations sometimes involving all of its layers. We interpreted these abnormal cells as epithelial-like cells. As these findings were in a very young patient, which is unusual, we concluded that the onset of the disease may take place in the early period of intrauterine life, corresponding to the beginning of Descemet's membrane production.

  15. Dorzolamide increases retinal oxygen tension after branch retinal vein occlusion

    DEFF Research Database (Denmark)

    Noergaard, Michael Hove; Bach-Holm, Daniella; Scherfig, Erik;

    2008-01-01

    To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs.......To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs....

  16. Porcine models of muscular dystrophy.

    Science.gov (United States)

    Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease.

  17. Cardiac involvement in myotonic dystrophy

    Directory of Open Access Journals (Sweden)

    Koroush Khalighi

    2015-02-01

    Full Text Available Background: Myotonic dystrophy (DM is an inherited progressive muscle disorder caused by defects in muscle proteins. As the incidence of this condition is low, not many are familiar with the multisystem involvement. At times, cardiac disease may even be the predominant manifestation in the form of arrhythmias, conduction defects, and cardiomyopathies. The progression of the disease can lead to sudden, unpredictable death. Thus, it is important to identify this subgroup and treat accordingly. Objective: To identify patients with DM and assess their risk for sudden cardiac death. Methods: Nine patients previously diagnosed with muscular dystrophy were evaluated by cardiologists for various reasons, from a general follow-up to cardiac arrest. All of them had electrocardiograms (EKG and 2-D echocardiograms, and seven of them had further electrophysiological (EP studies. Results: Of the nine patients with DM, eight had EKG evidence of conduction abnormalities ranging from first-degree heart block to complete heart block. Of the seven who had EP studies, five had inducible ventricular tachycardia requiring immediate cardioversion and implantable cardioverter defibrillator (ICD implant. Two of them underwent permanent pacemaker placement due to complete heart block and infra-Hissian block. The remaining two patients opted for a conservative approach with yearly EKG monitoring. Conclusion: Because one-third of the cardiac deaths in patients with DM are sudden, there is a strong need to identify these patients and intervene in those at high risk. Prophylactic pacemaker placement is recommended even in those with minimal conduction system abnormality. However, the common practice is to identify patients at high risk of conduction abnormalities by EP studies and then provide them with prophylactic invasive strategies.

  18. Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy

    OpenAIRE

    2016-01-01

    Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3 ΔE2 ) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin level...

  19. Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Nianting Tong

    Full Text Available BACKGROUND AND PURPOSE: Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. METHODS: Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB extravasation was determined to assess blood-retinal barrier (BRB disruption and the structure of tight junctions (TJ was examined by transmission electron microscopy. RESULTS: Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1 and occludin protein expression and decreased VEGF/PEDF ratio. CONCLUSIONS: Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.

  20. FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy

    Science.gov (United States)

    ... html FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy Exondys 51 seems to fill unmet need ... the first drug for a rare form of muscular dystrophy. Exondys 51 (eteplirsen) was granted accelerated approval ...

  1. Gene Therapy Approaches For The Treatment Of Retinal Disorders

    Science.gov (United States)

    Petit, Lolita; Punzo, Claudio

    2016-01-01

    There is an impelling need to develop effective therapeutic strategies for patients with retinal disorders. Gleaning from the large quantity of information gathered over the past two decades on the mechanisms governing degeneration of the retina, it is now possible to devise innovative therapies based on retinal gene transfer. Different gene-based approaches are under active investigation. They include strategies to correct the specific genetic defect in inherited retinal diseases, strategies to delay the onset of blindness independently of the disease-causing mutations and strategies to reactivate residual cells at late stages of the diseases. In this review, we discuss the status of application of these technologies, outlining the future therapeutic potential for many forms of retinal blinding diseases. PMID:27875674

  2. Retinal and visual system: occupational and environmental toxicology.

    Science.gov (United States)

    Fox, Donald A

    2015-01-01

    Occupational chemical exposure often results in sensory systems alterations that occur without other clinical signs or symptoms. Approximately 3000 chemicals are toxic to the retina and central visual system. Their dysfunction can have immediate, long-term, and delayed effects on mental health, physical health, and performance and lead to increased occupational injuries. The aims of this chapter are fourfold. First, provide references on retinal/visual system structure, function, and assessment techniques. Second, discuss the retinal features that make it especially vulnerable to toxic chemicals. Third, review the clinical and corresponding experimental data regarding retinal/visual system deficits produced by occupational toxicants: organic solvents (carbon disulfide, trichloroethylene, tetrachloroethylene, styrene, toluene, and mixtures) and metals (inorganic lead, methyl mercury, and mercury vapor). Fourth, discuss occupational and environmental toxicants as risk factors for late-onset retinal diseases and degeneration. Overall, the toxicants altered color vision, rod- and/or cone-mediated electroretinograms, visual fields, spatial contrast sensitivity, and/or retinal thickness. The findings elucidate the importance of conducting multimodal noninvasive clinical, electrophysiologic, imaging and vision testing to monitor toxicant-exposed workers for possible retinal/visual system alterations. Finally, since the retina is a window into the brain, an increased awareness and understanding of retinal/visual system dysfunction should provide additional insight into acquired neurodegenerative disorders.

  3. Dynamic eye phantom for retinal oximetry measurements

    Science.gov (United States)

    Lemaillet, Paul; Ramella-Roman, Jessica C.

    2009-11-01

    Measurements of oxygen saturation and flow in the retina can yield information about eye health and the onset of eye pathologies such as diabetic retinopathy. Recently, we developed a multiaperture camera that uses the division of the retinal image into several wavelength-sensitive subimages to compute retinal oxygen saturation. The calibration of such instruments is particularly difficult due to the layered structure of the eye and the lack of alternative measurement techniques. For this purpose, we realize an in vitro model of the human eye composed of a lens, the retina vessel, and three layers: the choroid, the retinal pigmented epithelium, and the sclera. The retinal vessel is modeled with a microtube connected to a micropump and a hemoglobin reservoir in a closed circulatory system. Hemoglobin oxygenation in the vessel could be altered using a reversible fuel cell. The sclera is represented by a Spectralon slab. The optical properties of the other layers are mimicked using titanium dioxide as a scatterer, ink as an absorber, and epoxy as a supporting structure. The optical thickness of each layer of the eye phantom is matched to each respective eye layer.

  4. Muscular Dystrophy: Hope Through Research

    Science.gov (United States)

    ... with DM1 can live a long life, with variable but slowly progressive disability. Typical disease onset is ... feel drowsy and have an excess need to sleep. There is a second form of the disease ...

  5. Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttnmdm) model.

    Science.gov (United States)

    Lopez, Michael A; Pardo, Patricia S; Cox, Gregory A; Boriek, Aladin M

    2008-11-01

    A complex rearrangement mutation in the mouse titin gene leads to an in-frame 83-amino acid deletion in the N2A region of titin. Autosomal recessive inheritance of the titin muscular dystrophy with myositis (Ttn(mdm/mdm)) mutation leads to a severe early-onset muscular dystrophy and premature death. We hypothesized that the N2A deletion would negatively impact the force-generating capacity and passive mechanical properties of the mdm diaphragm. We measured in vitro active isometric contractile and passive length-tension properties to assess muscle function at 2 and 6 wk of age. Micro-CT, myosin heavy chain Western blotting, and histology were used to assess diaphragm structure. Marked chest wall distortions began at 2 wk and progressively worsened until 5 wk. The percentage of myofibers with centrally located nuclei in mdm mice was significantly (P mechanical aberrations of the respiratory pump in mdm mice.

  6. Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Uluç Yis

    2016-01-01

    Full Text Available Megaconial congenital muscular dystrophy (OMIM 602541 is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB gene c.1031G>A (p.R344Q in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.

  7. Progression of foveola-on rhegmatogenous retinal detachment

    DEFF Research Database (Denmark)

    Hajari, Javad Nouri; Kyhnel, Alexander; Bech-Azeddine, Julia

    2014-01-01

    AIMS: Quantitative assessment of the rate of progression of recent onset posterior rhegmatogenous retinal detachment (RRD). METHODS: A prospective observational study on patients presenting with acute symptomatic primary foveola-on RRD over a 32-month period. Patients were evaluated with optical ...

  8. Myocardial Contractile Dysfunction Is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and Is Prevented after Claudin-5 Virotherapy

    Science.gov (United States)

    Milani-Nejad, Nima; Schultz, Eric J.; Slabaugh, Jessica L.; Janssen, Paul M. L.; Rafael-Fortney, Jill A.

    2016-01-01

    Mutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd−/−) of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy withclaudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd−/− mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care. PMID:27999547

  9. Myocardial Contractile Dysfunction is Present Without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and is Prevented after Claudin-5 Virotherapy

    Directory of Open Access Journals (Sweden)

    Nima Milani-Nejad

    2016-12-01

    Full Text Available AbstractMutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd-/- of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy with claudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd-/- mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care.

  10. [Congenital muscular dystrophies in children].

    Science.gov (United States)

    Scavone-Mauro, Cristina; Barros, Graciela

    2013-09-06

    From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

  11. Therapeutics in duchenne muscular dystrophy.

    Science.gov (United States)

    Strober, Jonathan B

    2006-04-01

    Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3,500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child's quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

  12. Rapid glutamate receptor 2 trafficking during retinal degeneration

    Directory of Open Access Journals (Sweden)

    Lin Yanhua

    2012-02-01

    Full Text Available Abstract Background Retinal degenerations, such as age-related macular degeneration (AMD and retinitis pigmentosa (RP, are characterized by photoreceptor loss and anomalous remodeling of the surviving retina that corrupts visual processing and poses a barrier to late-stage therapeutic interventions in particular. However, the molecular events associated with retinal remodeling remain largely unknown. Given our prior evidence of ionotropic glutamate receptor (iGluR reprogramming in retinal degenerations, we hypothesized that the edited glutamate receptor 2 (GluR2 subunit and its trafficking may be modulated in retinal degenerations. Results Adult albino Balb/C mice were exposed to intense light for 24 h to induce light-induced retinal degeneration (LIRD. We found that prior to the onset of photoreceptor loss, protein levels of GluR2 and related trafficking proteins, including glutamate receptor-interacting protein 1 (GRIP1 and postsynaptic density protein 95 (PSD-95, were rapidly increased. LIRD triggered neuritogenesis in photoreceptor survival regions, where GluR2 and its trafficking proteins were expressed in the anomalous dendrites. Immunoprecipitation analysis showed interaction between KIF3A and GRIP1 as well as PSD-95, suggesting that KIF3A may mediate transport of GluR2 and its trafficking proteins to the novel dendrites. However, in areas of photoreceptor loss, GluR2 along with its trafficking proteins nearly vanished in retracted retinal neurites. Conclusions All together, LIRD rapidly triggers GluR2 plasticity, which is a potential mechanism behind functionally phenotypic revisions of retinal neurons and neuritogenesis during retinal degenerations.

  13. Circulating Biomarkers for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-01-01

    Abstract Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. PMID:27858763

  14. Median nail dystrophy involving the thumb nail

    Directory of Open Access Journals (Sweden)

    Rahulkrishna Kota

    2016-01-01

    Full Text Available Median canaliform dystrophy of Heller is a rare entity characterized by a midline or a paramedian ridge or split and canal formation in nail plate of one or both the thumb nails. It is an acquired condition resulting from a temporary defect in the matrix that interferes with nail formation. Habitual picking of the nail base may be responsible for some cases. Histopathology classically shows parakeratosis, accumulation of melanin within and between the nail bed keratinocytes. Treatment of median nail dystrophy includes injectable triamcinalone acetonide, topical 0.1% tacrolimus, and tazarotene 0.05%, which is many a times challenging for a dermatologist. Psychiatric opinion should be taken when associated with the depressive, obsessive-compulsive, or impulse-control disorder. We report a case of 19-year-old male diagnosed as median nail dystrophy.

  15. Weight reduction in boys with muscular dystrophy.

    Science.gov (United States)

    Edwards, R H; Round, J M; Jackson, M J; Griffiths, R D; Lilburn, M F

    1984-06-01

    Many children with muscular dystrophy are overweight, and although weight control is pursued in some centres it is unusual to encourage severe dietary restriction for fear that it might lead to accelerated loss of muscle. In this study, two overweight boys with muscular dystrophy were monitored by whole-body nitrogen balance, total body potassium, strength and functional measurements during calorie restriction. Both patients were found to have a transient loss of nitrogen on commencing the low calorie intake: thereafter, weight loss was not found to have any deleterious effect on muscle bulk or function in either patient. It is suggested that controlled weight-reduction in obese children with muscular dystrophy is a safe and practical way of losing excess fat, which can improve mobility and self-esteem, and may possibly effect longevity.

  16. Non-surgical prevention and management of scoliosis for children with Duchenne muscular dystrophy: what is the evidence?

    Science.gov (United States)

    Harvey, Adrienne; Baker, Louise; Williams, Katrina

    2014-10-01

    A review was performed to examine the evidence for non-surgical interventions for preventing scoliosis and the need for scoliosis surgery in children with Duchenne muscular dystrophy. Medline and Embase databases and reference lists from key articles were searched. After the inclusion and exclusion criteria were applied, 13 studies were critically appraised independently by two reviewers. The included studies examined spinal orthoses and steroid therapy. There were no studies with high levels of evidence (randomised or other controlled trials). The studies with the highest level of evidence were non-randomised experimental trials. There is some evidence that children with Duchenne muscular dystrophy who receive steroid therapy might have delayed onset of scoliosis, but more evidence is required about the long-term risks versus benefits of this intervention. There is weak evidence that spinal orthoses do not prevent and only minimally delay the onset of scoliosis.

  17. Follow-up of a Case of Vitelliform Macular Dystrophy Over an 8-year Period

    Institute of Scientific and Technical Information of China (English)

    Shizhou Huang; Lezheng Wu; Feng Wen; Guangwei Luo; Futian Jiang

    2014-01-01

    Purpose: To show the follow-up of a case of vitelliform mac-ular dystrophy with morphological and visual functional tests over an 8-year period. Methods:.Retrospective review of medical records..The mor-phological examination included color photography,.fluores-cein angiography, and ocular coherence tomography (OCT). The visual functional tests included visual acuity, electro-ocu-logram (EOG) and multifocal electroretinography (mfERG). The patient was observed for 8 years, from 2003 to 2011. Results:.During the follow-up,.the improvement of sensory retinal detachment and reduction of yellow-white deposit were observed with color photography and fluorescein angiography. OCT revealed a decrease in sensory retinal detachment and subretinal hyper-reflective deposits; both of these morphologi-cal changes were correspondent. Visual acuity was maintained throughout the follow-up..The Arden ratio of EOG was de-creased. The amplitudes of mfERG were decreased but slightly increased during the follow-up. Conclusion:.The retinal morphological changes and visual function slightly improved in this case of vitelliform macu-lopathy. The prognosis is good. (Eye Science 2014; 29:165-169)

  18. Oculopharyngeal muscular dystrophy as a paradigm for muscle aging

    Directory of Open Access Journals (Sweden)

    Yotam eRaz

    2014-11-01

    Full Text Available Symptoms in late-onset neuromuscular disorders initiate only from midlife onwards and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD. OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1. The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onwards. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly.Molecular signatures of OPMD muscles are similar to these of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.

  19. Advances in gene therapy for muscular dystrophies.

    Science.gov (United States)

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

  20. Derivation, characterization and retinal differentiation of induced pluripotent stem cells

    Indian Academy of Sciences (India)

    Subba Rao Mekala; Vasundhara Vauhini; Usha Nagarajan; Savitri Maddileti; Subhash Gaddipati; Indumathi Mariappan

    2013-03-01

    Millions of people world over suffer visual disability due to retinal dystrophies which can be age-related or a genetic disorder resulting in gradual degeneration of the retinal pigmented epithelial (RPE) cells and photoreceptors. Therefore, cell replacement therapy offers a great promise in treating such diseases. Since the adult retina does not harbour any stem cells, alternative stem cell sources like the embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer a great promise for generating different cell types of the retina. Here, we report the derivation of four iPSC lines from mouse embryonic fibroblasts (MEFs) using a cocktail of recombinant retroviruses carrying the genes for Oct4, Sox2, Klf4 and cMyc. The iPS clone MEF-4F3 was further characterized for stemness marker expression and stable reprogramming by immunocytochemistry, FACS and RT-PCR analysis. Methylation analysis of the nanog promoter confirmed the reprogrammed epigenetic state. Pluripotency was confirmed by embryoid body (EB) formation and lineage-specific marker expression. Also, upon retinal differentiation, patches of pigmented cells with typical cobble-stone phenotype similar to RPE cells are generated within 6 weeks and they expressed ZO-1 (tight junction protein), RPE65 and bestrophin (mature RPE markers) and showed phagocytic activity by the uptake of fluorescent latex beads.

  1. Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.

    Science.gov (United States)

    Chawla, Rohan; Tripathy, Koushik; Gogia, Varun; Venkatesh, Pradeep

    2016-08-10

    We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids.

  2. Current and emerging treatment strategies for Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Mah JK

    2016-07-01

    Full Text Available Jean K Mah Department of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Abstract: Duchenne muscular dystrophy (DMD is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments

  3. T2 relaxometry of brain in myotonic dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Di Costanzo, A.; Bonavita, V.; Tedeschi, G. [Inst. of Neurological Sciences, 2. Univ. of Naples (Italy); Di Salle, F. [Dept. of Biomorphological and Functional Sciences, Univ. ' ' Federico II' ' , Naples (Italy); Santoro, L. [Dept. of Neurological Sciences, University ' ' Federico II' ' , Naples (Italy)

    2001-03-01

    We investigated the nature and extent of brain involvement in myotonic dystrophy (DM), examining possible T2 relaxation abnormalities in the brain of 20 patients with adult-onset DM and 20 sex- and age-matched normal controls. Brain MRI was performed at 0.5 T, and T2 values were calculated from signal intensity in two echoes. Regions of interest included: frontal, parietal, temporal, occipital and callosal (rostral and splenial) normal-appearing white matter; frontal, occipital, insular and hippocampal cortex; caudate nucleus, putamen, globus pallidus and thalamus. All white-matter and occipital and right frontal cortex regions showed a significantly longer T2 in the patients. Multiple regression analysis, including grey- and white-matter T2 as dependent variables, plus age at onset and at imaging, disease duration, muscular disability, brain atrophy and CTG trinucleotide repeats as independent variables, revealed that only white-matter T2 elongation and disease duration correlated positively. White-matter involvement in DM is more extensive than previously reported by MRI and neuropathological studies and seems to be progressive in the course of disease. (orig.)

  4. Evidence for meiotic drive at the myotonic dystrophy locus

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, A.M.; Barnetson, R.A.; Phillips, M.F. [Institute of Medical Genetics, Wales (United Kingdom)] [and others

    1994-09-01

    Myotonic dystrophy (DM), an autosomal dominant disorder, is the most common form of adult muscular dystrophy, affecting at least 1 in 8000 of the population. It is a multisystemic disorder, primarily characterized by myotonia, muscle wasting and cataract. The molecular basis of DM is an expanded CTG repeat located within the 3{prime} untranslated region of a putative serine-threonine protein kinase on chromosome 19q13.3. DM exhibits anticipation, that is, with successive generations there is increasing disease severity and earlier age of onset. This mechanism and the fact that the origin of the disease has been attributed to one or a small number of founder chromosomes suggests that, in time, DM should die out. Meiotic drive has been described as a way in which certain alleles are transmitted to succeeding generations in preference to others: preferential transmission of large CTG alleles may account for their continued existence in the gene pool. There is evidence that a CTG allele with > 19 repeats may gradually increase in repeat number over many generations until it is sufficiently large to give a DM phenotype. We report a study of 495 transmissions from individuals heterozygous for the CTG repeat and with repeat numbers within the normal range (5-30). Alleles were simply classified as large or small relative to the other allele in an individual. Of 242 male meioses, 126 transmissions from parent to child were of the larger allele to their offspring (57.7%, p=0.014). This shows that there is strong evidence for meiotic drive favoring the transmission of the larger DM allele in unaffected individuals. Contrary to a previous report of meiotic drive in the male, we have shown that females preferentially transmit the larger DM allele. Taken together, the data suggest the occurrence of meiotic drive in both males and females in this locus.

  5. C-terminal truncations in human 3 '-5 ' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schaefer, Ruth; Stam, Anine H.; Haan, Joost; Paulus, T. V. M. de Jong; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease

  6. Retinal Vasculitis in Anti-Synthetase Syndrome.

    Science.gov (United States)

    Donovan, Christopher P; Pecen, Paula E; Baynes, Kimberly; Ehlers, Justis P; Srivastava, Sunil K

    2016-09-01

    A 31-year-old woman with a history of anti-synthetase syndrome-related myositis and interstitial lung disease presented with acute-onset blurry vision and rash on her hands and feet. Visual acuity was hand motion in her right eye and 20/40 in her left eye. Dilated fundus exam showed extensive retinal vasculitis, diffuse intraretinal hemorrhages, and subretinal fluid. Optical coherence tomography revealed significant macular thickening, and fluorescein angiography revealed vascular leakage with peripheral nonperfusion. Aggressive systemic immunosuppression was initiated, with gradual resolution of her disease during 8 months of follow-up. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:874-879.]. Copyright 2016, SLACK Incorporated.

  7. A Drosophila model for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Plas, Mariska Cathelijne van der

    2008-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal

  8. Cardiac manifestations of myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Petri, Helle; Vissing, John; Witting, Nanna

    2012-01-01

    To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conduction abnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involvement and cytosine-thymine-guanine (CTG)-repeat, neuromuscular involvement, age and gende...... in patients with myotonic dystrophy type 1 (MD1)....

  9. Cardiomyopathy in becker muscular dystrophy:Overview

    Institute of Scientific and Technical Information of China (English)

    Rady Ho; My-Le Nguyen; Paul Mather

    2016-01-01

    Becker muscular dystrophy(BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.

  10. Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2010-09-13

    following are key research accomplishments for the Year 1 funding period: Manuscripts in process • DM Escolar, C Tesi -Rocha, E Henricson, J Florence, J...in steroid treated Duchenne Muscular Dystrophy. In revision for journal submission. • A. Zimmerman, C. Tesi -Rocha, P.R. Clemens, A. Connolly, S.T

  11. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD.

  12. Brain Function in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

  13. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  14. INTESTINAL PSEUDOOBSTRUCTION IN MYOTONIC-DYSTROPHY

    NARCIS (Netherlands)

    BRUNNER, HG; HAMEL, BCJ; RIEU, P; HOWELER, CJ; PETERS, FTM

    1992-01-01

    We describe four myotonic dystrophy (DM) patients who developed recurrent intestinal pseudo-obstruction. Some episodes were associated with gastroenteritis, while abdominal crowding may have occurred in one case during the third trimester of pregnancy. In most instances, however, no apparent cause c

  15. Clinical features of facioscapulohumeral muscular dystrophy 2.

    NARCIS (Netherlands)

    Greef, J.C. de; Lemmers, R.J.; Camano, P.; Day, J.W.; Sacconi, S.; Dunand, M.; Engelen, B.G.M. van; Kiuru-Enari, S.; Padberg, G.W.A.M.; Rosa, A.L.; Desnuelle, C.; Spuler, S.; Tarnopolsky, M.; Venance, S.L.; Frants, R.R.; Maarel, S.M. van der; Tawil, R.

    2010-01-01

    OBJECTIVE: In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4

  16. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  17. A novel locus (CORD12 for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1

    Directory of Open Access Journals (Sweden)

    Meunier Isabelle

    2011-04-01

    Full Text Available Abstract Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP, and cone-rod dystrophy (CRD are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad CRD. Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. Results We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. Conclusion A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.

  18. In vivo confocal microscopy in different types of posterior polymorphous dystrophy

    Directory of Open Access Journals (Sweden)

    Babu Kalpana

    2007-01-01

    Full Text Available Posterior polymorphous dystrophy is a rare corneal dystrophy, usually detected by chance. This case series describes the morphologic features in the three different types of posterior polymorphous dystrophy using confocal microscopy.

  19. Retinal Detachment in Preeclampsia

    Directory of Open Access Journals (Sweden)

    Prado Renata Silva do

    2002-01-01

    Full Text Available Preeclampsia is an obstetric disease of unknown cause that affects approximately 5% of pregnant women. The visual system may be affected with variable intensity, being the retinal detachment a rare complication. The retinal detachment in preeclampsia is usually bilateral and serous, and its pathogenesis is related to the choroidal ischemia secondary to an intense arteriolar vasospasm. The majority of patients have complete recovery of vision with clinical management, and surgery is unnecessary. This is a case report of a 27 year old patient who developed the severe form of preeclampsia on her first pregnancy. She had progressive blurred vision, until she could see only shadows. Ophthalmic examination diagnosed spread and bilateral retinal detachment. With blood pressure control at postpartum, the patient had her retina reattached, and recovery of vision.

  20. Probabilistic retinal vessel segmentation

    Science.gov (United States)

    Wu, Chang-Hua; Agam, Gady

    2007-03-01

    Optic fundus assessment is widely used for diagnosing vascular and non-vascular pathology. Inspection of the retinal vasculature may reveal hypertension, diabetes, arteriosclerosis, cardiovascular disease and stroke. Due to various imaging conditions retinal images may be degraded. Consequently, the enhancement of such images and vessels in them is an important task with direct clinical applications. We propose a novel technique for vessel enhancement in retinal images that is capable of enhancing vessel junctions in addition to linear vessel segments. This is an extension of vessel filters we have previously developed for vessel enhancement in thoracic CT scans. The proposed approach is based on probabilistic models which can discern vessels and junctions. Evaluation shows the proposed filter is better than several known techniques and is comparable to the state of the art when evaluated on a standard dataset. A ridge-based vessel tracking process is applied on the enhanced image to demonstrate the effectiveness of the enhancement filter.

  1. Bioelectronic retinal prosthesis

    Science.gov (United States)

    Weiland, James D.

    2016-05-01

    Retinal prosthesis have been translated to clinical use over the past two decades. Currently, two devices have regulatory approval for the treatment of retinitis pigmentosa and one device is in clinical trials for treatment of age-related macular degeneration. These devices provide partial sight restoration and patients use this improved vision in their everyday lives to navigate and to detect large objects. However, significant vision restoration will require both better technology and improved understanding of the interaction between electrical stimulation and the retina. In particular, current retinal prostheses do not provide peripheral visions due to technical and surgical limitations, thus limiting the effectiveness of the treatment. This paper reviews recent results from human implant patients and presents technical approaches for peripheral vision.

  2. The use of SD-OCT in the differential diagnosis of dots, spots and other white retinal lesions

    Directory of Open Access Journals (Sweden)

    Zaharova E

    2011-10-01

    Full Text Available Elena Zaharova1, Jerome Sherman1-31State University of New York's State College of Optometry, University Eye Center, New York, NY, USA; 2SUNY Eye Institute, New York, NY, USA; 3New York Eye Institute and Laser Center, New York, NY, USAPurpose: To demonstrate the utility of a retinal imaging technique using spectral domain optical coherence tomography (SD-OCT for creating a B-scan layer-by-layer analysis to aid in the differential diagnosis of various retinal dots, spots, and other white lesions.Design: Review.Methods: A retrospective review of imaging studies performed with SD-OCT (Topcon, 3DOCT-2000, Oakland, NJ at SUNY State College of Optometry.Results: B-scan layer-by-layer analysis and unique SD-OCT reflectivity patterns of the following retinal white lesions are reviewed in the order of their retinal layer localization: myelinated nerve fiber layer, cotton wool spot, exudates, edema residues, drusen, fundus albipunctatus, Stargardt disease, Bietti crystalline dystrophy, punctate inner choroidopathy (PIC, presumed ocular histoplasmosis syndrome (POHS, post-photocoagulation chorioretinal scarring, and osseous choristoma.Conclusion: The reviewed images demonstrate the utility of SD-OCT in the identification of the unique characteristics of the presented retinal pathologies. SD-OCT is ideal for retinal layer localization of lesions, thus enhancing the differential diagnosis of retinal dots, spots, and other white lesions. Even though true pathognomonic patterns are rare, highly suggestive findings of certain retinal abnormalities often facilitate immediate recognition and diagnosis.Keywords: SD-OCT, photoreceptor integrity line, retinal pigment epithelium, white dot syndrome, retinal pathology, imaging

  3. Retinal flow cytometer.

    Science.gov (United States)

    Alt, C; Veilleux, I; Lee, H; Pitsillides, C M; Côté, D; Lin, C P

    2007-12-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery-vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerve head. We demonstrate that the retinal flow cytometer detects about five times more cells per minute than the original in vivo flow cytometer does in the ear.

  4. [Retinal pneumopexy in the treatment of rhegmatogenous retinal detachment].

    Science.gov (United States)

    Levai, L; Gavriş, Monica; Gábor, Radó; Bagosi, P

    2014-01-01

    To evaluate the efficiency of retinal pneumopexy in patients with rhegmatogenous retinal detachment. This clinical prospective study unrolled between november 2010-june 2012 in the Ophthalmology Department of the Military Hospital in Cluj-Napoca and Satu Mare Emergency Hospital included 20 patients (20 eyes) with rhegmatogenous retinal detachment. Patients were treated with retinal pneumopexy followed by laser photocoagulation. Anatomical and functional results were evaluated 1, 3, 6, 12 and 19 months after treatment. In 17 eyes out of 20, we achieved retinal reattachment and visual recovery. Three cases yelded no success, these being further treated with posterior vitrectomy. Retinal pneumopexy is a minimally invasive treatment method of rhegmatogenous retinal detachment with very good results in well selected cases.

  5. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.

    Science.gov (United States)

    Cirak, Sebahattin; Foley, Aileen Reghan; Herrmann, Ralf; Willer, Tobias; Yau, Shu; Stevens, Elizabeth; Torelli, Silvia; Brodd, Lina; Kamynina, Alisa; Vondracek, Petr; Roper, Helen; Longman, Cheryl; Korinthenberg, Rudolf; Marrosu, Gianni; Nürnberg, Peter; Michele, Daniel E; Plagnol, Vincent; Hurles, Matt; Moore, Steven A; Sewry, Caroline A; Campbell, Kevin P; Voit, Thomas; Muntoni, Francesco

    2013-01-01

    Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.

  6. Exome sequencing identifies compound heterozygous mutations in CYP4V2 in a pedigree with retinitis pigmentosa.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available Retinitis pigmentosa (RP is a heterogeneous group of progressive retinal degenerations characterized by pigmentation and atrophy in the mid-periphery of the retina. Twenty two subjects from a four-generation Chinese family with RP and thin cornea, congenital cataract and high myopia is reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family presented with bone spicule-shaped pigment deposits in retina, retinal vascular attenuation, retinal and choroidal dystrophy, as well as punctate opacity of the lens, reduced cornea thickness and high myopia. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. After mutation analysis in a few known RP candidate genes, exome sequencing was used to analyze the exomes of 3 patients III2, III4, III6 and the unaffected mother II2. A total of 34,693 variations shared by 3 patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in the rest family members by PCR and Sanger sequencing. Compound heterozygous c.802-8_810del17insGC and c.1091-2A>G mutations of the CYP4V2 gene, known as genetic defects for Bietti crystalline corneoretinal dystrophy, were identified as causative mutations for RP of this family.

  7. Cataract extraction in eyes with Fuchs' endothelial dystrophy in China

    Institute of Scientific and Technical Information of China (English)

    XIE Li-xin; HUANG Yu-sen; Ann Mei-Chi Chiu; LIN Ping; YAO Zhan; SUN Jie

    2005-01-01

    @@ It is a common belief that Fuchs' endothelial dystrophy predominantly affects Caucasians but rarely Asians. However, in one Japanese study, primary corneal guttae (first stage of Fuchs' dystrophy) were found in four of 107 cataract patients.1 With the growing popularity of phacoemulsification in China in the past decade, the increased incidence of endothelial decompensation may be due to learning curves among surgeons as well as that the prevalence of Fuchs' dystrophy among Chinese is higher than we thought. Low index of suspicion for Fuchs' dystrophy may result in missing of diagnosis and occurrence of endothelial decompensation, particularly when no extra protection is provided for endothelial cells during phacoemulsification. This study was aimed at improving our knowledge about Fuchs' dystrophy among Chinese population and reminding surgeons of extra endothelial protection during cataract surgery for patients with Fuchs' dystrophy.

  8. Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

    Science.gov (United States)

    2017-05-30

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  9. Retinal locus for scanning text.

    Science.gov (United States)

    Timberlake, George T; Sharma, Manoj K; Grose, Susan A; Maino, Joseph H

    2006-01-01

    A method of mapping the retinal location of text during reading is described in which text position is plotted cumulatively on scanning laser ophthalmoscope retinal images. Retinal locations that contain text most often are the brightest in the cumulative plot, and locations that contain text least often are the darkest. In this way, the retinal area that most often contains text is determined. Text maps were plotted for eight control subjects without vision loss and eight subjects with central scotomas from macular degeneration. Control subjects' text maps showed that the fovea contained text most often. Text maps of five of the subjects with scotomas showed that they used the same peripheral retinal area to scan text and fixate. Text maps of the other three subjects with scotomas showed that they used separate areas to scan text and fixate. Retinal text maps may help evaluate rehabilitative strategies for training individuals with central scotomas to use a particular retinal area to scan text.

  10. [Ventricular Tachycardia as a First Manifestation of Myotonic Dystrophy].

    Science.gov (United States)

    Mironov, N Yu; Mironova, N A; Sokolov, S F; Mareev, Yu V; Shlevkov, N B; Saidova, M A; Stukalova, O V; Golitsyn, S P

    2015-01-01

    We report a case of bundle-branch reentrant ventricular tachycardia as a first and severe manifestation of myotonic dystrophy. Progressive cardiac conduction disturbances and cardiac arrhythmias are well-known features of myotonic dystrophy, although they are commonly found in late stage of disease in patients with established diagnosis. We review clinical manifestations, diagnostics, management, and prognostic value of cardiac involvement in myotonic dystrophy.

  11. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

    OpenAIRE

    Oriana del Rocío Cruz Guzmán; Ana Laura Chávez García; Maricela Rodríguez-Cruz

    2012-01-01

    Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine di...

  12. Corneal Topography Analysis of Stromal Corneal Dystrophies

    OpenAIRE

    Kocluk, Yusuf; Yalniz-Akkaya, Zuleyha; Burcu, Ayse; Ornek, Firdevs

    2015-01-01

    Objective: The aim was to compare the corneal topography and tomography parameters of macular corneal dystrophy (MCD), granular corneal dystrophy (GCD) and lattice corneal dystrophy (LCD) patients obtained by Scheimpflug imaging system. Methods: The charts, photographs and topography images of patients were reviewed retrospectively. This study included 73 eyes of 73 patients (28 MCD, 20 GCG and 25 LCD patients). Topography images were obtained by Pentacam (Oculus Optikgerate, Wetzlar, Germany...

  13. Distinct genetic regions modify specific muscle groups in muscular dystrophy

    OpenAIRE

    2010-01-01

    Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein γ-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quan...

  14. Molecular mechanisms in muscular dystrophy: a gene expression profiling study.

    OpenAIRE

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di¬vergence are largely unknown as well. In this thesis, gene e...

  15. Learning about Retinitis Pigmentosa

    Science.gov (United States)

    ... that detect light). Photoreceptor cells capture and process light helping us to see. As these cells breakdown and die, patients experience progressive vision loss. The most common feature of all forms of RP is a ... cells that detect dim light) and cones (retinal cells that detect light and ...

  16. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  17. Retinal vein occlusion

    Science.gov (United States)

    ... decrease the risk of retinal vein occlusion. These measures include: Eating a low-fat diet Getting regular exercise Maintaining an ideal weight Not smoking Aspirin or other blood thinners may help prevent blockages in the other eye. Controlling diabetes may ...

  18. Retinal imaging with smartphone.

    Science.gov (United States)

    Ademola-Popoola, D S; Olatunji, V A

    2017-03-01

    The use of smartphones for various purposes among health professionals is increasing, especially with the availability of different applications. On account of cost, fundus cameras are not readily available in ophthalmic practice in developing countries. Since smartphones are readily available, easy to use and portable, they may present a cheap alternative in a resource-limited economy. to explore the use of smartphone (Blackberry Z-10) for retinal imaging in a resource-limited economy. A smartphone (Blackberry Z-10) was used to acquire retinal images with the use of +20D lens in patients with dilated pupils by activating the video mode of the camera. Clear retinal images were obtained in different clinical conditions in adults and children including branch retinal vein occlusion with fibrovascular proliferation, chorioretinal scarring from laser photocoagulation, presumed ocular toxoplasmosis, diabetic retinopathy, retinoblastoma, ocular albinism with fundus hypopigmentation. The ability to have low cost fundus imaging from readily available smartphones in an eye clinic in Nigeria presents a major boost to patient care and also offers an innovative role in research, education, and information sharing.

  19. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  20. Retinal Imaging with Smartphone

    African Journals Online (AJOL)

    2017-03-06

    Mar 6, 2017 ... Aim and Objectives: to explore the use of smartphone (Blackberry. Z-10) for retinal imaging in ... Samsung phones with additional apps/software such as the Filmic pro to ... in Nigeria also compared the iPhone with the Android.

  1. Hereditary retinal eye diseases in childhood and youth affecting the central retina

    Directory of Open Access Journals (Sweden)

    Martin M Nentwich

    2013-01-01

    Classic examinations for patients suffering from hereditary retinal dystrophies of the central retina are funduscopy - also using red-free light - visual-field tests, electrophysiologic tests as electro-retinogram [ERG] and multifocal ERG and tests evaluating color vision. Recently, new imaging modalities have been introduced into the clinical practice. The significance of these new methods such as high-resolution spectral-domain optic coherence tomography [SD-OCT] and fundus autofluorescence will be discussed as well as "next generation sequencing" as a new method for the analysis of genetic mutations in a larger number of patients.

  2. Establishing baseline rod electroretinogram values in achromatopsia and cone dystrophy.

    Science.gov (United States)

    Wang, Isaac; Khan, Naheed W; Branham, Kari; Wissinger, B; Kohl, Susanne; Heckenlively, J R

    2012-12-01

    To establish the normal range of values for rod-isolated b-wave amplitudes in achromatopsia and cone dystrophies. We reviewed charts of 112 patients with various types of cone dystrophy, and compared their standardized electroretinographic rod b-wave amplitudes with age-matched normal controls. Twenty-six patients had known mutations in achromatopsia and cone dystrophy genes, while 53 were characterized by their inheritance pattern since they had yet to have their gene identified. Visual acuity information and scotomata were documented. We found that patients with achromatopsia and cone dystrophy had rod b-wave amplitudes that were significantly lower than age-matched controls, but found no evidence of rod amplitude progression nor loss of peripheral visual fields in the study group. We found that cone dystrophy patients of all types had depressed rod-isolated ERGs across the board. If typical diagnostic criteria are used, these patients might be considered to have "abnormal" rod-isolated electroretinographic values, and might be called "cone-rod dystrophy", even though the waveforms are stable for years. Patients with cone-rod dysfunction patterns on ERG can be better understood by also performing kinetic (Goldmann) visual fields, which will help to distinguish cone dystrophies from progressive cone-rod dystrophies by central scotomata size and progression over time in many forms of cone-rod dystrophy.

  3. Protection of retinal function by sulforaphane following retinal ischemic injury.

    Science.gov (United States)

    Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

    2015-09-01

    Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Progressive retinal nonperfusion in ischemic central retinal vein occlusion.

    Science.gov (United States)

    Wykoff, Charles C; Brown, David M; Croft, Daniel E; Major, James C; Wong, Tien P

    2015-01-01

    Serial wide-field fluorescein angiography was performed on eyes with preproliferative (ischemic) central retinal vein occlusion to evaluate retinal perfusion. Serial wide-field fluorescein angiography was performed on 12 preproliferative central retinal vein occlusion eyes in the 3-year Rubeosis Anti-VEGF (RAVE) trial using the Staurenghi lens (Ocular Staurenghi 230SLO Retina Lens) with a scanning laser ophthalmoscope (Heidelberg HRA Spectralis). "Disk area" was defined anatomically for each eye. Mean total field of gradable retina was 290 disk areas (range, 178-452). All eyes demonstrated extensive areas of retinal nonperfusion; at baseline, mean area of retinal perfusion was 106 disk areas (range, 37-129), correlating with a mean of 46.5% perfused retinal area (range, 19.1-56.4%). The area of retinal nonperfusion increased in all eyes with a mean loss of approximately 8.1% of perfused retinal area per year (range, 4.3-12.4%), which corresponded to a mean 15-disk areas (range, 12-35) of retina evolving from perfused to nonperfused annually. The extent of baseline and final nonperfusion was not significantly different between eyes that developed neovascularization and eyes that did not. In this population of severe central retinal vein occlusion eyes, profound retinal nonperfusion was observed with wide-field fluorescein angiography at baseline and the extent of nonperfusion progressed while undergoing anti-vascular endothelial growth factor therapy.

  5. The Finnish lapphund retinal atrophy locus maps to the centromeric region of CFA9

    OpenAIRE

    Sargan David R; Wickström Kaisa; Aguirre-Hernández Jesús

    2007-01-01

    Abstract Background Dogs have the second largest number of genetic diseases, after humans. Among the diseases present in dogs, progressive retinal atrophy has been reported in more than a hundred breeds. In some of them, the mutation has been identified and genetic tests have allowed the identification of carriers, thus enabling a drastic reduction in the incidence of the disease. The Finnish lapphund is a dog breed presenting late-onset progressive retinal atrophy for which the disease locus...

  6. Visual advantage in deaf adults linked to retinal changes.

    Directory of Open Access Journals (Sweden)

    Charlotte Codina

    Full Text Available The altered sensory experience of profound early onset deafness provokes sometimes large scale neural reorganisations. In particular, auditory-visual cross-modal plasticity occurs, wherein redundant auditory cortex becomes recruited to vision. However, the effect of human deafness on neural structures involved in visual processing prior to the visual cortex has never been investigated, either in humans or animals. We investigated neural changes at the retina and optic nerve head in profoundly deaf (N = 14 and hearing (N = 15 adults using Optical Coherence Tomography (OCT, an in-vivo light interference method of quantifying retinal micro-structure. We compared retinal changes with behavioural results from the same deaf and hearing adults, measuring sensitivity in the peripheral visual field using Goldmann perimetry. Deaf adults had significantly larger neural rim areas, within the optic nerve head in comparison to hearing controls suggesting greater retinal ganglion cell number. Deaf adults also demonstrated significantly larger visual field areas (indicating greater peripheral sensitivity than controls. Furthermore, neural rim area was significantly correlated with visual field area in both deaf and hearing adults. Deaf adults also showed a significantly different pattern of retinal nerve fibre layer (RNFL distribution compared to controls. Significant correlations between the depth of the RNFL at the inferior-nasal peripapillary retina and the corresponding far temporal and superior temporal visual field areas (sensitivity were found. Our results show that cross-modal plasticity after early onset deafness may not be limited to the sensory cortices, noting specific retinal adaptations in early onset deaf adults which are significantly correlated with peripheral vision sensitivity.

  7. Facioscapulohumeral dystrophy: case report and discussion.

    Science.gov (United States)

    Castellano, Vincenzo; Feinberg, Joseph; Michaels, Jennifer

    2008-09-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility.

  8. Anoctamin 5 muscular dystrophy in Denmark

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Petri, Helle

    2013-01-01

    Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic...... characteristics, and muscle protein expression. All patients in our neuromuscular unit with genetically unclassified, recessive limb girdle muscular dystrophy (LGMD2), Miyoshi-type distal myopathy (MMD) or persistent asymptomatic hyperCK-emia (PACK) were assessed for mutations in the ANO5 gene. Genetically...... confirmed patients were evaluated with muscular and cardiopulmonary examination. Among 40 unclassified patients (28 LGMD2, 5 MMD, 7 PACK), 20 were homozygous or compound heterozygous for ANO5 mutations, (13 LGMD2, 5 MMD, 2 PACK). Prevalence of ANO5 deficiency in Denmark was estimated at 1:100.000 and ANO5...

  9. Peripapillary retinal thermal coagulation following electrical injury

    Directory of Open Access Journals (Sweden)

    Manjari Tandon

    2013-01-01

    Full Text Available In this study, we have presented the case report of a 20 year old boy who suffered an electric injury shock, following which he showed peripapillary retinal opacification and increased retinal thickening that subsequently progressed to retinal atrophy. The fluorescein angiogram revealed normal retinal circulation, thus indicating thermal damage to retina without any compromise to retinal circulation.

  10. Proof of concept for AAV2/5-mediated gene therapy in iPSC-derived retinal pigment epithelium of a choroideremia patient

    OpenAIRE

    2014-01-01

    Inherited retinal dystrophies (IRDs) comprise a large group of genetically and clinically heterogeneous diseases that lead to progressive vision loss, for which a paucity of disease-mimicking animal models renders preclinical studies difficult. We sought to develop pertinent human cellular IRD models, beginning with choroideremia, caused by mutations in the CHM gene encoding Rab escort protein 1 (REP1). We reprogrammed REP1-deficient fibroblasts from a CHM -/y patient into induced pluripotent...

  11. New Advanced Technology for Muscular Dystrophy

    Science.gov (United States)

    2009-11-01

    References Aristotle. 350 BC. Historia Animalium: Books VII–X. 1991 edition. D.M. Balme, editor. Harvard University Press, Cambridge, MA. 435–437...hematological disease, and have been proposed as a source for cell based therapies of muscular dystrophy. Since the University of Minnesota is a center...Blood and Marrow Transplantation program at the University of Minnesota to assure that we receive appropriate tissues as they become available. Having

  12. Severe dystrophy in DiGeorge syndrome

    Institute of Scientific and Technical Information of China (English)

    Barnabás Rózsai; (A)kos Kiss; Gy(o)rgyi Csábi; Márta Czakó; Tamás Decsi

    2009-01-01

    We present the case history of a 3-year-old girl who was examined because of severe dystrophy. In the background, cow's milk allergy was found, but her body weight was unchanged after eliminating milk from her diet. Other types of malabsorption were excluded. Based on nasal regurgitation and facial dysmorphisms, the possibility of DiGeorge syndrome was suspected and was confirmed by fluorescence in situ hybridization. The authors suggest a new feature associated with DiGeorge syndrome.

  13. Growth hormone evaluation in Duchenne muscular dystrophy.

    Science.gov (United States)

    Merlini, L; Granata, C; Ballestrazzi, A; Cornelio, F; Tassoni, P; Tugnoli, S; Cacciari, E

    1988-10-01

    Growth hormone (GH) release with pharmacological tests and sleep test, somatomedin C and auxological features were studied in 10 patients affected by Duchenne Muscular Dystrophy. GH release in these patients seems to be lower than normal; moreover some of them are of short stature without an evident relationship with GH deficit. The possible significance of the data obtained is discussed, particularly in relation to the clinical course of the disease, and to current therapeutic trials with a GH release inhibitor (mazindol).

  14. The superhealing MRL background improves muscular dystrophy

    OpenAIRE

    2012-01-01

    Abstract Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg), a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dyst...

  15. The New Pretender: A Large UK Case Series of Retinal Injuries in Children Secondary to Handheld Lasers.

    Science.gov (United States)

    Raoof, Naz; Bradley, Patrick; Theodorou, Maria; Moore, Anthony T; Michaelides, Michel

    2016-11-01

    To characterize a large single-center series of retinal injuries in children secondary to handheld laser devices, with emphasis on potential prognostic factors. Retrospective case series. Sixteen children (24 eyes) with retinal injuries secondary to handheld lasers were identified from our electronic patient record system. Case notes, digital fundus photography, and spectral-domain optical coherence tomography images were reviewed. The mean age of affected children was 12.7 years (range 9-16 years), with 12 male and 4 female subjects. Mean follow up was 5.4 months (range 1-23 months). Five children (31%) were referred as suspected retinal dystrophies. The mean logMAR visual acuity at presentation was 0.30 (20/40) (range -0.20 [20/12.5] to 1.6 [20/800]). Eleven children (69%; 15 eyes) had "mild" injuries with focal retinal disruption confined to the photoreceptor and ellipsoid layers; such injuries were associated with a better prognosis, the mean visual acuity at presentation being 0.10 (20/25). "Moderate" injuries were seen in 3 eyes of 2 children, with retinal disruption confined to the outer retinal layer but diffuse rather than focal in nature. Three patients (4 eyes) had "severe" injuries, with subfoveal outer retinal architecture loss and overlying hyperreflective material in inner retinal layers. Retinal injuries secondary to handheld laser devices may be difficult to diagnose and are likely underreported. It is important that such data are in the public domain, so regulatory authorities recognize the importance of laser retinopathy as an avoidable cause of childhood visual impairment and take steps to minimize the incidence and impact of laser injuries. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  16. CONGENITAL MYOTONIC DYSTROPHY – CASE REPORT

    Directory of Open Access Journals (Sweden)

    David Neubauer

    2001-07-01

    Full Text Available Background. Myotonic dystrophy is inherited as an autosomal dominant trait. It is characterized by myotonia, myopathy of voluntary and involuntary muscles, frontal baldness in men, cardiac conduction abnormalities, catharacts, intellectual deterioration and endocrinopathy. Men with this disorder have often gonadal atrophy and infertility. On the other hand women are generally fertile. During pregnancy their myopathy worsens, often causing severe obstetrical complications. Their children may develop congenital form of the disease with signs of myopathy in utero and have great difficulties in maintaining life functions after birth, together with other characteristical signs of this form: bilateral facial weakness, severe hypotonia, feeding difficulties, talipes equinovarus and mental retardation. The authors present a female newborn with such congenital form of myotonic dystrophy.Conclusions. The authors have emphasized the importance of medical history, regular updating of all the cases of neuromuscular diseases in the region and clinical characteristics for the recognition of congenital form of myotonic dystrophy because of possible prenatal diagnostics and better antenatal and postantal care.

  17. [Management of myocardial damage in muscular dystrophy].

    Science.gov (United States)

    Tamura, Takuhisa

    2011-11-01

    Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future.

  18. Pneumothoraces in collagen VI-related dystrophy: a case series and recommendations for management

    Directory of Open Access Journals (Sweden)

    Kristin L. Fraser

    2017-06-01

    Full Text Available Collagen VI-related dystrophy (collagen VI-RD is a rare neuromuscular condition caused by mutations in the COL6A1, COL6A2 or COL6A3 genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the inevitable respiratory decline of these patients. This series focuses on pneumothorax, an important but previously under-recognised disease manifestation of collagen VI-RD. We describe two distinct clinical presentations within collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan evidence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis. Based on this experience, we offer recommendations for early identification of lung disease in collagen VI-RD and definitive intervention.

  19. Pneumothoraces in collagen VI-related dystrophy: a case series and recommendations for management.

    Science.gov (United States)

    Fraser, Kristin L; Wong, Scott; Foley, A Reghan; Chhibber, Sameer; Bönnemann, Carsten G; Lesser, Daniel J; Grosmann, Carla; Rutkowski, Anne

    2017-04-01

    Collagen VI-related dystrophy (collagen VI-RD) is a rare neuromuscular condition caused by mutations in the COL6A1, COL6A2 or COL6A3 genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the inevitable respiratory decline of these patients. This series focuses on pneumothorax, an important but previously under-recognised disease manifestation of collagen VI-RD. We describe two distinct clinical presentations within collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan evidence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis. Based on this experience, we offer recommendations for early identification of lung disease in collagen VI-RD and definitive intervention.

  20. Novel LMNA Mutation in a Taiwanese Family with Autosomal Dominant Emery-Dreifuss Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Wen-Chen Liang

    2007-01-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMD is characterized by early-onset contractures, slowly progressive weakness, and muscle wasting in humeroperoneal muscles, and adult-onset cardiomyopathy with conduction block. We analyzed blood samples from an EDMD family, including a mother and two daughters, and found a novel mutation in codon 520 in exon 9 of the lamin A/C (LMNA gene, resulting in a substitution of tryptophan (W by glycine (G in all three patients. The mother died after a stroke-like episode at the age of 43. The elder sister received pacemaker implantation, which improved symptoms of exercise intolerance and dizziness. These cases illustrate the necessity of correct diagnosis, evaluation, and follow-up of cardiac problems due to the wide clinical spectrum and high prevalence of cardiac conduction block in patients with autosomal dominant EDMD. [J Formos Med Assoc 2007;106(2 Suppl:S27-S31

  1. Following the ontogeny of retinal waves: pan-retinal recordings of population dynamics in the neonatal mouse

    Science.gov (United States)

    Maccione, Alessandro; Hennig, Matthias H; Gandolfo, Mauro; Muthmann, Oliver; van Coppenhagen, James; Eglen, Stephen J; Berdondini, Luca; Sernagor, Evelyne

    2014-01-01

    The immature retina generates spontaneous waves of spiking activity that sweep across the ganglion cell layer during a limited period of development before the onset of visual experience. The spatiotemporal patterns encoded in the waves are believed to be instructive for the wiring of functional connections throughout the visual system. However, the ontogeny of retinal waves is still poorly documented as a result of the relatively low resolution of conventional recording techniques. Here, we characterize the spatiotemporal features of mouse retinal waves from birth until eye opening in unprecedented detail using a large-scale, dense, 4096-channel multielectrode array that allowed us to record from the entire neonatal retina at near cellular resolution. We found that early cholinergic waves propagate with random trajectories over large areas with low ganglion cell recruitment. They become slower, smaller and denser when GABAA signalling matures, as occurs beyond postnatal day (P) 7. Glutamatergic influences dominate from P10, coinciding with profound changes in activity dynamics. At this time, waves cease to be random and begin to show repetitive trajectories confined to a few localized hotspots. These hotspots gradually tile the retina with time, and disappear after eye opening. Our observations demonstrate that retinal waves undergo major spatiotemporal changes during ontogeny. Our results support the hypotheses that cholinergic waves guide the refinement of retinal targets and that glutamatergic waves may also support the wiring of retinal receptive fields. PMID:24366261

  2. Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

    Directory of Open Access Journals (Sweden)

    Sundaramurthy Srilekha

    Full Text Available Leber congenital amaurosis (LCA and retinitis pigmentosa (RP are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60% mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

  3. Retinal flow cytometer

    OpenAIRE

    Alt, C.; Veilleux, I.; H. Lee; Pitsillides, C. M.; Côté, D.; Lin, C.P.

    2007-01-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery–vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerv...

  4. Gelatinous drop-like corneal dystrophy: a review.

    Science.gov (United States)

    Kaza, Hrishikesh; Barik, Manas R; Reddy, Mamatha M; Mittal, Ruchi; Das, Sujata

    2017-01-01

    Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterised by subepithelial and stromal amyloid deposits. It is relatively common in Japan. It usually presents in the first two decades of life with subepithelial nodular lesions that later coalesce to form mulberry-like opacities. Although various surgical modalities have been attempted, recurrence remains a major challenge.

  5. Dysphagia is present but mild in myotonic dystrophy type 2

    NARCIS (Netherlands)

    R. Ensink; S. Knuijt; Baziel van Engelen; J. van Vliet; A. Tieleman; Bert de Swart

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  6. Molecular mechanisms in muscular dystrophy : a gene expression profiling study.

    NARCIS (Netherlands)

    Turk, Rolf

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are

  7. Dysphagia is present but mild in myotonic dystrophy type 2.

    NARCIS (Netherlands)

    Tieleman, A.A.; Knuijt, S.; Vliet, J. van; Swart, B.J.M. de; Ensink, R.J.H.; Engelen, B.G.M. van

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  8. Dysphagia is present but mild in myotonic dystrophy type 2

    NARCIS (Netherlands)

    Swart, Bert de; Tieleman, A.; Knuijt, S.; Vliet, J. van; Ensink, R.; Engelen, Baziel van

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  9. Resistance training in patients with limb-girdle and becker muscular dystrophies

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Andersen, Søren P; Ingelsrud, Lina H;

    2013-01-01

    In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD).......In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD)....

  10. Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis.

    Directory of Open Access Journals (Sweden)

    Cheryl A Arcinue

    Full Text Available To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula compared with age-matched HIV-negative controls.Cohort of patients with known HIV under CART (combination Antiretroviral Therapy treatment were examined with a flood-illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT to assess retinal layers and retinal thickness.Twenty-four eyes of 12 patients (n = 6 HIV-positive and 6 HIV-negative were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior, the HIV group had significantly less mean cone photoreceptor density compared with age-matched controls (difference range, 4,308-6,872 cones/mm2. A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative was included in the retinal thickness measurements and retinal layer segmentation with the SD-OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea. We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer was also significantly thickened in all the different locations scanned compared with HIV-negative controls.Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age-matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low-grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis.

  11. Skin features in myotonic dystrophy type 1: an observational study.

    Science.gov (United States)

    Campanati, A; Giannoni, M; Buratti, L; Cagnetti, C; Giuliodori, K; Ganzetti, G; Silvestrini, M; Provinciali, L; Offidani, A

    2015-05-01

    Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1.

  12. [Application of retinal oximeter in ophthalmology].

    Science.gov (United States)

    Li, Jing; Ma, Jianmin; Wang, Ningli

    2015-11-01

    Retinal oximeter is a new machine which has been used in the diagnose, treatment and research of several ophthalmic diseases for recent years. It allows ophthalmologists to gain retinal oxygen saturation directly. Therefore, retinal oximeter might be useful for ophthalmologists to understand ophthalmic diseases more deeper and clarify the impact of ischemia on retinal function. It has been reported in the literatures that retinal oximeter has potentially useful diagnostic and therapeutic indications in various eye diseases such as diabetic retinopathy, central retinal vein and artery occlusion, retinitis pigmentosa, glaucomatous optic neuropathy, et al. In this thesis, the application of retinal oximeter in ophthalmology is reviewed.

  13. Granular corneal dystrophy Groenouw type I (GrI) and Reis-Bücklers' corneal dystrophy (R-B). One entity?

    Science.gov (United States)

    Møller, H U

    1989-12-01

    This paper maintains that Reis-Bücklers' corneal dystrophy and granular corneal dystrophy Groenouw type I are one and the same disease. Included are some of the technically best photographs of Reis-Bücklers' dystrophy found in the literature, and these are compared with photographs from patients with granular corneal dystrophy examined by the author. It is argued that most of the histological and ultrastructural findings on Reis Bücklers' dystrophy described in the literature are either congruent with what is found in granular corneal dystrophy or unspecific.

  14. First Identification of a Triple Corneal Dystrophy Association: Keratoconus, Epithelial Basement Membrane Corneal Dystrophy and Fuchs' Endothelial Corneal Dystrophy

    Directory of Open Access Journals (Sweden)

    Cosimo Mazzotta

    2014-09-01

    Full Text Available Purpose: To report the observation of a triple corneal dystrophy association consisting of keratoconus (KC, epithelial basement membrane corneal dystrophy (EBMCD and Fuchs' endothelial corneal dystrophy (FECD. Methods: A 55-year-old male patient was referred to our cornea service for blurred vision and recurrent foreign body sensation. He reported bilateral recurrent corneal erosions with diurnal visual fluctuations. He underwent corneal biomicroscopy, Scheimpflug tomography, in vivo HRT confocal laser scanning microscopy and genetic testing for TGFBI and ZEB1 mutations using direct DNA sequencing. Results: Biomicroscopic examination revealed the presence of subepithelial central and paracentral corneal opacities. The endothelium showed a bilateral flecked appearance, and the posterior corneal curvature suggested a possible concomitant ectatic disorder. Corneal tomography confirmed the presence of a stage II KC in both eyes. In vivo confocal laser scanning microscopy revealed a concomitant bilateral EBMCD with hyperreflective deposits in basal epithelial cells, subbasal Bowman's layer microfolds and ridges with truncated subbasal nerves as pseudodendritic elements. Stromal analysis revealed honeycomb edematous areas, and the endothelium showed a strawberry surface configuration typical of FECD. The genetic analysis resulted negative for TGFBI mutations and positive for a heterozygous mutation in exon 7 of the gene ZEB1. Conclusion: This is the first case reported in the literature in which KC, EBMCD and FECD are present in the same patient and associated with ZEB1 gene mutation. The triple association was previously established by means of morphological analysis of the cornea using corneal Scheimpflug tomography and in vivo HRT II confocal laser scanning microscopy.

  15. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, M

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of definit

  16. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, Marianne

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of

  17. Retinal oximetry in patients with ischaemic retinal diseases

    DEFF Research Database (Denmark)

    Rilvén, Sandra; Torp, Thomas Lee; Grauslund, Jakob

    2017-01-01

    increased retinal arterial oxygen saturation (raSatO2 ) in patients with DR. In patients with central retinal vein occlusion (CRVO), all studies found that rvSatO2 was reduced, but raSatO2 remained unchanged. Branch retinal vein occlusion was not associated with changes in retinal oxygen saturation......, but this was based on a single study. In conclusion, DR is associated with increased rvSatO2 and might also be related to increased raSatO2 . Central retinal vein occlusion (CRVO) is correlated with increased rvSatO2 but unrelated to raSatO2 . Prospective studies are needed to expand these findings. These would tell...... retinopathy (DR) and four about retinal vein occlusion. No studies about retinal artery occlusion were included. In diabetes, all studies found that increases in retinal venous oxygen saturation (rvSatO2 ) were associated with present as well as increasing levels of DR. Four of six studies also found...

  18. Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy

    Science.gov (United States)

    Lu, Zhaojing; Hu, Xuebin; Liu, Fei; Soares, Dinesh C.; Liu, Xiliang; Yu, Shanshan; Gao, Meng; Han, Shanshan; Qin, Yayun; Li, Chang; Jiang, Tao; Luo, Daji; Guo, An-Yuan; Tang, Zhaohui; Liu, Mugen

    2017-01-01

    Mutations in EYS are associated with autosomal recessive retinitis pigmentosa (arRP) and autosomal recessive cone-rod dystrophy (arCRD) however, the function of EYS and the molecular mechanisms of how these mutations cause retinal degeneration are still unclear. Because EYS is absent in mouse and rat, and the structure of the retina differs substantially between humans and Drosophila, we utilised zebrafish as a model organism to study the function of EYS in the retina. We constructed an EYS-knockout zebrafish-line by TALEN technology which showed visual impairment at an early age, while the histological and immunofluorescence assays indicated the presence of progressive retinal degeneration with a cone predominately affected pattern. These phenotypes recapitulate the clinical manifestations of arCRD patients. Furthermore, the EYS−/− zebrafish also showed mislocalisation of certain outer segment proteins (rhodopsin, opn1lw, opn1sw1, GNB3 and PRPH2), and disruption of actin filaments in photoreceptors. Protein mislocalisation may, therefore, disrupt the function of cones and rods in these zebrafish and cause photoreceptor death. Collectively, these results point to a novel role for EYS in maintaining the morphological structure of F-actin and in protein transport, loss of this function might be the trigger for the resultant cellular events that ultimately lead to photoreceptor death. PMID:28378834

  19. Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15.

    Directory of Open Access Journals (Sweden)

    Debra A Thompson

    Full Text Available Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR are the most common cause of X-linked retinitis pigmentosa (XLRP and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9 strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG a- and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy.

  20. Increased vascular density and vitreo-retinal membranes accompany vascularization of the pigment epithelium in the dystrophic rat retina.

    Science.gov (United States)

    Caldwell, R B; Roque, R S; Solomon, S W

    1989-09-01

    Observations of vascularization of the retinal pigment epithelium (RPE) and formation of vitreo-retinal membranes (VRMs) in Royal College of Surgeons (RCS) rats with inherited retinal dystrophy suggest that vascular proliferation occurs in this model. To test this hypothesis, we studied the progression of vascular changes in RCS and age-matched control rats using quantitative light microscope morphometry and electron microscopy. At 2 weeks, prior to photoreceptor degeneration, the dystrophic retina is comparable with the control. By 2 months, extensive degeneration of photoreceptor cells results in significant thinning of the dystrophic retina as compared with the control. Signs of vascular degeneration are evident at the electron microscope level--"ghost" vessels consisting of acellular basal lamina surrounded by amorphous electron-dense material; degenerating endothelial cells and pericytes; and abnormal deposits of extracellular matrix (ECM) material around blood vessels. Vascular degeneration is accompanied by glial changes in the form of necrotic perivascular glial processes and abnormal ECM deposits among the altered Muller cell processes. At 2-4 months in the dystrophic retina, numbers of vessel profiles in dystrophic retinas are decreased as compared with controls. However, vascular degeneration is overshadowed by the formation of numerous capillary tufts within the RPE layer, which together with retinal thinning results in increased vessel density. Between 4-12 months, the retinal thickness diminishes further, vascularization of the RPE increases, vitreo-retinal membranes are formed, and vascular density increases. In summary, following an initial period of vascular degeneration, vascularization of the RPE is accompanied by an increase in retinal vessel density and by the formation of vitreo-retinal membranes.

  1. Macular Pigment and Lutein Supplementation in ABCA4-associated Retinal Degenerations

    Science.gov (United States)

    Aleman, Tomas S.; Cideciyan, Artur V.; Windsor, Elizabeth A. M.; Schwartz, Sharon B.; Swider, Malgorzata; Chico, John D.; Sumaroka, Alexander; Pantelyat, Alexander Y.; Duncan, Keith G.; Gardner, Leigh M.; Emmons, Jessica M.; Steinberg, Janet D.; Stone, Edwin M.; Jacobson, Samuel G.

    2008-01-01

    PURPOSE To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS Stargardt disease or cone-rod dystrophy patients with foveal fixation and with known or suspected disease-causing mutations in the ABCA4 gene were included. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS MPOD in patients ranged from normal to markedly abnormal. As a group, ABCA4-RD patients had reduced foveal MPOD and there was strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein and 63% of the patient eyes showed a significant augmentation in MPOD. The retinal responders tended to be female, and have lower serum lutein and zeaxanthin, lower MPOD and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration compared to non-responding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences on the natural history of this supplement on macular degenerations require further study. PMID:17325179

  2. Retinal detachment surgery without cryotherapy.

    OpenAIRE

    Chignell, A H; Markham, R H

    1981-01-01

    A series of cases of retinal detachment treated without the application of cryotherapy at the time of surgery has been studied. The omission of cryotherapy while not interfering with retinal reattachment, carries the risk of redetachment at a later date. Macular pucker may still occur in spite of the absence of cryotherapy.

  3. Perceptual Fading without Retinal Adaptation

    Science.gov (United States)

    Hsieh, Po-Jang; Colas, Jaron T.

    2012-01-01

    A retinally stabilized object readily undergoes perceptual fading and disappears from consciousness. This startling phenomenon is commonly believed to arise from local bottom-up sensory adaptation to edge information that occurs early in the visual pathway, such as in the lateral geniculate nucleus of the thalamus or retinal ganglion cells. Here…

  4. Noncoding RNAs: Emerging Players in Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Germana Falcone

    2014-01-01

    Full Text Available The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets.

  5. Gene therapy for inherited retinal degenerations.

    Science.gov (United States)

    Dalkara, Deniz; Sahel, José-Alain

    2014-03-01

    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Progress over the past decade has moved proof-of-concept gene therapies from bench to bedside. The remarkable success in safety and efficacy, in the phase I/II clinical trials for the form of the severe childhood-onset blindness, Leber's Congenital Amaurosis (LCA) type II (due to mutations in the RPE65 gene) generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was due to combining the favorable features of both the retina as a target organ and adeno-associated virus (AAV) as a vector. The retina offers several advantages for gene therapy approaches. It is an anatomically defined structure that is readily accessible for therapy and has some degree of immune privilege, making it suitable for application of viral vectors. AAV, on the other hand, is a non-pathogenic helper dependent virus that has little immunogenicity. This viral vector transduces quiescent cells efficiently and thanks to its small size diffuses well in the interneural matrix, making it suitable for applications in neural tissue. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases. This article will discuss what are some of the most imminent targets for such therapies and what are the challenges that we face in moving these therapies to the clinic. Copyright © 2014 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  6. Spectrophotometric retinal oximetry in pigs

    DEFF Research Database (Denmark)

    Traustason, Sindri; Kiilgaard, Jens Folke; Karlsson, Robert

    2013-01-01

    PURPOSE: To assess the validity of spectrophotometric retinal oximetry, by comparison to blood gas analysis and intra-vitreal measurements of partial pressure of oxygen (pO2). METHODS: Female domestic pigs were used for all experiments (n=8). Oxygen fraction in inspired air was changed using...... a mixture of room air, pure oxygen and pure nitrogen, ranging from 5% to 100% oxygen. Femoral arterial blood gas analysis and retinal oximetry was performed at each level of inspiratory oxygen fraction. Retinal oximetry was performed using a commercial instrument, the Oxymap Retinal Oximeter T1 (Oxymap ehf......, Reykjavik, Iceland). The device simultaneously acquires images at two wavelengths (570 nm and 600 nm) and specialized software automatically detects retinal blood vessels. In three pigs, invasive pO2-measurements were performed after the initial non-invasive measurements. RESULTS: Comparison of femoral...

  7. Bilateral retinitis following typhoid fever.

    Science.gov (United States)

    Prabhushanker, M; Topiwalla, Tasneem T; Ganesan, Geetha; Appandaraj, Sripal

    2017-01-01

    Post typhoid fever immune related reactions affecting the eye is a rare finding which can have various presentations in which typhoid retinopathy is not a well recognized sequelae. Here we present a case of 59 year old male who presented with right eye sudden painless loss of vision 4 weeks after typhoid fever which was diagnosed and treated successfully. His BCVA was 2/60 in right eye and 6/6 in left eye. Fundus examination showed retinitis along with macular serous detachment in right eye and retinitis in left eye. Significant improvement in BCVA in right eye was observed after treatment with oral steroid with resolving retinitis lesions. Diagnosis of post typhoid immune mediated retinitis was made with good resolution following treatment. Immune mediated retinitis is a rare sequelae to typhoid infection which can be successfully treated with systemic steroids with good resolution of the lesions.

  8. Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1.

    Science.gov (United States)

    Ekmekci, Ozgul; Karasoy, Hatice; Bademkiran, Fikret; Akkus, Dilek Evyapan; Yuceyar, Nur

    2014-01-01

    We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.

  9. The superhealing MRL background improves muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Heydemann Ahlke

    2012-12-01

    Full Text Available Abstract Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg, a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis. Methods MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains. Results Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis. Conclusions These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease.

  10. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Gerevini, Simonetta; Caliendo, Giandomenico; Falini, Andrea [IRCCS San Raffaele Scientific Institute, Neuroradiology Unit, Head and Neck Department, Milan (Italy); Scarlato, Marina; Previtali, Stefano Carlo [IRCCS San Raffaele Scientific Institute, Department of Neurology, INSPE and Division of Neuroscience, Milan (Italy); Maggi, Lorenzo; Pasanisi, Barbara; Morandi, Lucia [Fondazione IRCCS Istituto Neurologico ' ' Carlo Besta' ' , Neuromuscular Diseases and Neuroimmunology Unit, Milan (Italy); Cava, Mariangela [IRCCS San Raffaele Scientific Institute, Department of Radiology and Center for Experimental Imaging, Milan (Italy)

    2016-03-15

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. (orig.)

  11. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    Directory of Open Access Journals (Sweden)

    Kaumudi Konkay

    2016-01-01

    Full Text Available Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α 2 deficiency on immunohistochemistry (IHC. Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E, enzyme and immunohistochemistry (IHC with laminin α 2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α 2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α 2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α 2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones.

  12. Sleep disordered breathing in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Della Marca, Giacomo; Frusciante, Roberto; Dittoni, Serena; Vollono, Catello; Buccarella, Cristina; Iannaccone, Elisabetta; Rossi, Monica; Scarano, Emanuele; Pirronti, Tommaso; Cianfoni, Alessandro; Mazza, Salvatore; Tonali, Pietro A; Ricci, Enzo

    2009-10-15

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7+/-12.3 years (range: 26-72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD.

  13. Acute retinal necrosis

    Directory of Open Access Journals (Sweden)

    Hugo Hernán Ocampo

    2009-12-01

    Full Text Available Purpose: Clinical features in a case of acute retinal necrosis are described as well as its diagnostic approach and response to early treatment. Methods: This is a descriptive and retrospective study case report of a 26 year old male patient who arrived to the emergency room with a three day history of sudden visual loss in the right eye (RE. At initial evaluation a visual acuity of hand movements in the RE, 20/15 in the left eye (LE and a right relative afferent pupillary defect were found. Fundoscopy revealed profuse soft exudates and hemorrhages involving posterior pole, inferior hemiretina and superotemporal periphery. Infectious workup and fluoresceinic angiography were made and positive serologies for herpes virus types 1 and 2, without HIV, were found. A diagnosis of acute retinal necrosis was made and treatment with intravenous valgancyclovir for two weeks and intra-vitreous triamcinolone for severe vasculitis, was given. Then a 3 months treatment with oral antiviral agents was prescribed. Results: Patient’s evolution showed improvement with treatment and at two and a half months of follow up, visual acuity was 20/50 in the right eye, normal slit lamp examination, tonometry of 12 mm Hg and fundoscopy improved when compared to initial pictures.Conclusions: A high index of suspicion is needed for diagnosing ARN taking into account clinical findings. Prompt intravenous and intra-vitreous treatments are needed to achieve good clinical and functional outcomes and to avoid central nervous system complications.

  14. Retinal Vessel Caliber and Lifelong Neuropsychological Functioning: An Investigative Tool for Cognitive Epidemiology

    Science.gov (United States)

    Shalev, Idan; Moffitt, Terrie E.; Wong, Tien Y.; Meier, Madeline H.; Houts, Renate M.; Ding, Jie; Cheung, Carol YL; Ikram, M. Kamram; Caspi, Avshalom; Poulton, Richie

    2013-01-01

    Why do more intelligent people live healthier and longer lives? One possibility is that intelligence tests assess health of the brain, but psychological science has lacked technology to evaluate this hypothesis. Digital retinal imaging, a new non-invasive method to visualize microcirculation in the eye, may reflect vascular conditions in the brain. We studied the association between retinal vessel caliber and neuropsychological functioning in the representative Dunedin birth cohort. Wider venular caliber was associated with poorer neuropsychological functioning at midlife, independent of potentially confounding factors. This association was not limited to any specific test domain, and extended to informant-reports of cognitive difficulties in everyday life. Moreover, wider venular caliber was associated with lower childhood IQ tested 25 years earlier. The finding indicates that retinal venular caliber may be an indicator of neuropsychological health years before dementing diseases’ onset, and suggests digital retinal imaging as an investigative tool for psychological science. PMID:23678508

  15. In vivo cellular-resolution retinal imaging in infants and children using an ultracompact handheld probe

    Science.gov (United States)

    Larocca, Francesco; Nankivil, Derek; Dubose, Theodore; Toth, Cynthia A.; Farsiu, Sina; Izatt, Joseph A.

    2016-09-01

    Enabled by adaptive optics, retinal photoreceptor cell imaging is changing our understanding of retinal structure and function, as well as the pathogenesis of numerous ocular diseases. To date, use of this technology has been limited to cooperative adult subjects due to the size, weight and inconvenience of the equipment, thus excluding study of retinal maturation during human development. Here, we report the design and operation of a handheld probe that can perform both scanning laser ophthalmoscopy and optical coherence tomography of the parafoveal photoreceptor structure in infants and children without the need for adaptive optics. The probe, featuring a compact optical design weighing only 94 g, was able to quantify packing densities of parafoveal cone photoreceptors and visualize cross-sectional photoreceptor substructure in children with ages ranging from 14 months to 12 years. The probe will benefit paediatric research by improving the understanding of retinal development, maldevelopment and early onset of disease during human growth.

  16. Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Freya M. Mowat

    2017-06-01

    Full Text Available Despite mutations in the rod phosphodiesterase 6-alpha (PDE6A gene being well-recognized as a cause of human retinitis pigmentosa, no definitive treatments have been developed to treat this blinding disease. We performed a trial of retinal gene augmentation in the Pde6a mutant dog using Pde6a delivery by capsid-mutant adeno-associated virus serotype 8, previously shown to have a rapid onset of transgene expression in the canine retina. Subretinal injections were performed in 10 dogs at 29–44 days of age, and electroretinography and vision testing were performed to assess functional outcome. Retinal structure was assessed using color fundus photography, spectral domain optical coherence tomography, and histology. Immunohistochemistry was performed to examine transgene expression and expression of other retinal genes. Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination. Photoreceptor layer thickness in the treated area was preserved compared with the contralateral control vector treated or uninjected eye. Improved rod and cone photoreceptor survival, rhodopsin localization, cyclic GMP levels and bipolar cell dendrite distribution was observed in treated areas. Some adverse effects including foci of retinal separation, foci of retinal degeneration and rosette formation were identified in both AAV-Pde6a and control vector injected regions. This is the first description of successful gene augmentation for Pde6a retinitis pigmentosa in a large animal model. Further studies will be necessary to optimize visual outcomes and minimize complications before translation to human studies.

  17. Summarising the retinal vascular calibres in healthy, diabetic and diabetic retinopathy eyes.

    Science.gov (United States)

    Leontidis, Georgios; Al-Diri, Bashir; Hunter, Andrew

    2016-05-01

    Retinal vessel calibre has been found to be an important biomarker of several retinal diseases, including diabetic retinopathy (DR). Quantifying the retinal vessel calibres is an important step for estimating the central retinal artery and vein equivalents. In this study, an alternative method to the already established branching coefficient (BC) is proposed for summarising the vessel calibres in retinal junctions. This new method combines the mean diameter ratio with an alternative to Murray׳s cube law exponent, derived by the fractal dimension,experimentally, and the branch exponent of cerebral vessels, as has been suggested in previous studies with blood flow modelling. For the above calculations, retinal images from healthy, diabetic and DR subjects were used. In addition, the above method was compared with the BC and was also applied to the evaluation of arteriovenous ratio as a biomarker of progression from diabetes to DR in four consecutive years, i.e. three/two/one years before the onset of DR and the first year of DR. Moreover, the retinal arteries and veins around the optic nerve head were also evaluated. The new approach quantifies the vessels more accurately. The decrease in terms of the mean absolute percentage error was between 0.24% and 0.49%, extending at the same time the quantification beyond healthy subjects.

  18. Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha 2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?

    Science.gov (United States)

    Taniguchi, Mariko; Kurahashi, Hiroki; Noguchi, Satoru; Sese, Jun; Okinaga, Takeshi; Tsukahara, Toshifumi; Guicheney, Pascale; Ozono, Keiichi; Nishino, Ichizo; Morishita, Shinichi; Toda, Tatsushi

    2006-04-07

    Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.

  19. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Thune, Jens Jakob; Køber, Lars;

    2008-01-01

    of dystrophic changes on muscle biopsy. CONCLUSIONS: This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement.......OBJECTIVE: To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD). DESIGN: Prospective screening. SETTING: Neuromuscular Clinic and Department of Cardiology...... at Rigshospitalet. Patients One hundred one patients with LGMD2A-I and BMD and 29 patients with LGMD2 and no molecular diagnosis. MAIN OUTCOME MEASURES: Clinical investigation, echocardiography, and electrocardiographic findings. RESULTS: Cardiac involvement was present in 24 of 100 patients (24%) with LGMD2A...

  20. Treatment of Laser-Induced Retinal Injuries

    Science.gov (United States)

    1989-06-29

    Distribution List (enclosed) bI’TF rruIoN STATEMEN A Approved for publi reljaso Disatbunon Unlimited TREATMENT OF LASER-INDUCED RETINAL INJURIES FINAL...suprathreshold retinal laser lesions II. Subthreshold retinal laser lesions III. Effect of steroid treatment on laser-induced retinal injury Discussion and...In the present study we investigated the effect of corticosteroid treatment of argon laser-induced retinal injury on vitreal accumulation of both

  1. Retinal degeneration slow (rds) in mouse results from simple insertion of a t haplotype-specific element into protein-coding exon II

    Energy Technology Data Exchange (ETDEWEB)

    Ma, J.; Norton, J.C.; Allen, A.C.; Burns, J.L.; Travis, G.H. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)] [and others

    1995-07-20

    Retinal degeneration slow (rds) is a semidominant mutation of mice that causes dysplasia and degeneration of rod and cone photoreceptors. Mutations in RDS, the human ortholog of the rds gene, are responsible for several inherited retinal dystrophies including a subset of retinitis pigmentosa. The normal rds locus encodes rds/peripherin, an integral membrane glycoprotein present in outer segment discs. Genomic libraries form wildtype and rds/rds mice were screened with an rds cDNA, and phage {lambda} clones that span the normal and mutant loci were mapped. We show that in mice, rds is caused by the insertion into exon II of a 9.2-kb repetitive genomic element that is very similar to the t haplotype-specific element in the H-2 complex. The entire element is included in the RNA products of the mutant locus. We present evidence that rds in mice represents a null allele. 40 refs., 4 figs.

  2. Retinal waves coordinate patterned activity throughout the developing visual system.

    Science.gov (United States)

    Ackman, James B; Burbridge, Timothy J; Crair, Michael C

    2012-10-11

    The morphological and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to show in live neonatal mice that waves of spontaneous retinal activity are present and propagate throughout the entire visual system before eye opening. This patterned activity encompassed the visual field, relied on cholinergic neurotransmission, preferentially initiated in the binocular retina and exhibited spatiotemporal correlations between the two hemispheres. Retinal waves were the primary source of activity in the midbrain and primary visual cortex, but only modulated ongoing activity in secondary visual areas. Thus, spontaneous retinal activity is transmitted through the entire visual system and carries patterned information capable of guiding the activity-dependent development of complex intra- and inter-hemispheric circuits before the onset of vision.

  3. Limb-girdle muscular dystrophy type 2I is not rare in Taiwan.

    Science.gov (United States)

    Liang, Wen-Chen; Hayashi, Yukiko K; Ogawa, Megumu; Wang, Chien-Hua; Huang, Wan-Ting; Nishino, Ichizo; Jong, Yuh-Jyh

    2013-08-01

    Alpha-dystroglycanopathy is caused by the glycosylation defects of α-dystroglycan (α-DG). The clinical spectrum ranges from severe congenital muscular dystrophy (CMD) to later-onset limb girdle muscular dystrophy (LGMD). Among all α-dystroglycanopathies, LGMD type 2I caused by FKRP mutations is most commonly seen in Europe but appears to be rare in Asia. We screened uncategorized 40 LGMD and 10 CMD patients by immunohistochemistry for α-DG and found 7 with reduced α-DG immunostaining. Immunoblotting with laminin overlay assay confirmed the impaired glycosylation of α-DG. Among them, five LGMD patients harbored FKRP mutations leading to the diagnosis of LGMD2I. One common mutation, c.948delC, was identified and cardiomyopathy was found to be very common in our cohort. Muscle images showed severe involvement of gluteal muscles and posterior compartment at both thigh and calf levels, which is helpful for the differential diagnosis. Due to the higher frequency of LGMD2I with cardiomyopathy in our series, the early introduction of mutation analysis of FKRP in undiagnosed Taiwanese LGMD patients is highly recommended.

  4. Clinical profile and molecular diagnosis in patients of facioscapulohumeral dystrophy from Indian subcontinent

    Directory of Open Access Journals (Sweden)

    Tamhankar Parag

    2010-01-01

    Full Text Available Facioscapulohumeral dystrophy (FSHD is an autosomal dominant muscular dystrophy. We retrospectively studied three families (two Indian, one Nepalese with 12 affected members (male:female-7:5. Mean age at onset of weakness was 17.63 + 5.48 years. Patients were classified according to muscle groups affected (F-face, S-scapula, H-humeral, PG-pelvic girdle, P-peroneal, A-loss of independent ambulation: FSH-A (2, four FSH (4, SH (3, FSH-PG (2 and one: F (1. Progression of weakness was classified as F>S>P>PG in eight cases, S> F>P in one, static in three. Eleven patients had electromyographic findings suggestive of myopathy and one had features of neurogenic involvement. Molecular diagnosis was done by southern blotting using probe p13E-11 after digestion of genomic DNA with EcoRI and/or EcoRI/BlnI for twelve patients and three unaffected relatives. No EcoRI fragment smaller than 35 Kb was seen in unaffected subjects. Size of EcoRI fragment varied between 17 kb to 27 kb in affected subjects and was constant for affected members of the same family. Molecular diagnosis by southern blotting has helped to provide genetic counseling for the families.

  5. Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

    Science.gov (United States)

    Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

    2013-03-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

  6. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. (Harvard Medical School, Boston, MA (United States)); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya (National Inst. of Neuroscience, Tokyo (Japan))

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  7. Management of acute central retinal artery occlusion: Intravenous thrombolysis is feasible and safe.

    Science.gov (United States)

    Préterre, Cécile; Godeneche, Gaelle; Vandamme, Xavier; Ronzière, Thomas; Lamy, Matthias; Breuilly, Christophe; Urbanczyk, Cédric; Wolff, Valérie; Lebranchu, Pierre; Sevin-Allouet, Mathieu; Guillon, Benoit

    2017-01-01

    Background Although acute central retinal artery occlusion is as a stroke in the carotid territory (retinal artery), its management remains controversial. The aim of this study was to assess the feasibility and safety of intravenous thrombolysis delivered within 6 h of central retinal artery occlusion in French stroke units. Methods We performed a retrospective analysis of patients treated with intravenous alteplase (recombinant tissue-plasminogen activator), based on stroke units thrombolysis registers from June 2005 to June 2015, and we selected those who had acute central retinal artery occlusion. The feasibility was assessed by the ratio of patients that had received intravenous alteplase within 6 h after central retinal artery occlusion onset among those who had been admitted to the same hospital for acute central retinal artery occlusion. All adverse events were documented. Results Thirty patients were included. Visual acuity before treatment was limited to "hand motion", or worse, in 90% of the cases. The mean onset-to-needle time was 273 min. The individuals treated with intravenous alteplase for central retinal artery occlusion represented 10.2% of all of the patients hospitalized for central retinal artery occlusion in 2013 and 2014. We observed one occurrence of major bleeding, a symptomatic intracerebral hemorrhage. Conclusion When applied early on, intravenous thrombolysis appears to be feasible and safe, provided that contraindications are given due consideration. Whether intravenous thrombolysis is more effective than conservative therapy remains to be determined. In order to conduct a well-designed prospective randomized control trial, an organized network should be in place.

  8. High-resolution meiotic and physical mapping of the Best`s vitelliform macular dystrophy (VMD2) locus to pericentromeric chromosome 11

    Energy Technology Data Exchange (ETDEWEB)

    Weber, B.H.F.; Vogt, G. [Institut fuer Humangenetik, Wuerzburg (Germany); Walker, D. [UBC, Vancouver (Canada)] [and others

    1994-09-01

    Vitelliform macular dystrophy, also known as Best`s disease, is a juvenile-onset macular degeneration with autosomal dominant inheritance. It is characterized by well-demarcated accumulation of lipofuscin-like material within and beneath the retinal pigment epithelium (RPE) and classically results in an egg yolk-like appearance of the macula. Typically, carriers of the disease gene show a specific electrophysiological sign which can be detected by electrooculography (EOG). The EOG measures a standing potential between the cornea and the retina which is primarily generated by the RPE. The histopathological findings as well as the EOG abnormalities suggest that Best`s disease is a generalized disorder of the RPE. The basic biochemical defect is still unknown. As a first step in the positional cloning of the defective gene, the Best`s disease locus was mapped to chromosome 11 between markers at D11S871 and INT2. Subsequently, his region was refined to a 3.7 cM interval flanked by loci D11S903 and PYGM. To further narrow the D11S903-PYGM interval and to obtain an estimate of the physical size of the minimal candidate region, we used a combination of high-resolution PCR hybrid mapping and analysis of recombinant Best`s disease chromosomes. We identified six markers from within the D11S903-PYGM interval that show no recombination with the defective gene in three multigeneration Best`s disease pedigrees. Our hybrid panel localizes these markers on either side of the centromere on chromosome 11. The closest markers flanking the disease gene are at D11S986 in band p12-11.22 and at D11S480 in band q13.2-13.3. Our study demonstrates that the physical size of the Best`s disease region is exceedingly larger than was previously estimated from the genetic data due to the proximity of the defective gene to the centromere of chromosome 11.

  9. Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

    Science.gov (United States)

    Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2012-01-01

    Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID:22828504

  10. Valley sign in Becker muscular dystrophy and outliers of Duchenne and Becker muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Pradhan Sunil

    2004-04-01

    Full Text Available Valley sign has been described in patients with Duchenne muscular dystrophy (DMD. As there are genetic and clinical similarities between DMD and Becker muscular dystrophy (BMD, this clinical sign is evaluated in this study in BMD and DMD/BMD outliers. To evaluate the sign, 28 patients with Becker muscular dystrophy (BMD, 8 DMD/BMD outliers and 44 age-matched male controls with other neuromuscular diseases were studied. The sign was examined after asking patients to abduct their arms to about 90ºwith hands directed upwards; the muscle bulk over the back of the shoulders was observed. The sign was considered positive if the infraspinatus and deltoid muscles were enlarged and between these two muscles, the muscles forming the posterior axillary fold were wasted as if there were a valley between the two mounts. Twenty-five BMD patients and 7 DMD/BMD outliers had positive valley sign. However, it was less remarkable in comparison to DMD. It was absent in all the 44 controls. It was concluded that the presence of valley sign may help in differentiating BMD from other progressive neuromuscular disorders of that age group.

  11. Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance

    Directory of Open Access Journals (Sweden)

    Jeffery Glen

    2008-05-01

    contralateral optic tracts at the optic chiasm vary differently with gene dosage. Increasing dosage increases the proportion projecting ipsilaterally regardless of the size of the total projection. Conclusion Pax6 overexpression does not obviously impair the initial formation of the eye and its major cell-types but prevents normal development of the retina from about E14.5, leading eventually to severe retinal degeneration in postnatal life. This sequence is different to that underlying microphthalmia in Pax6+/- heterozygotes, which is due primarily to defects in the initial stages of lens formation. Before the onset of severe retinal dysplasia, Pax6 overexpression causes defects of retinal axons, preventing their normal growth and navigation through the optic chiasm.

  12. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Research Institute National Institute of Neurological Disorders and Stroke Educational Resources (13 links) Centers for Disease Control and Prevention Centre for Genetics Education Cleveland Clinic: Muscular Dystrophy Disease InfoSearch: Becker ...

  13. Strength training and albuterol in facioscapulohumeral muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, EL; Vogels, OJM; van Asseldonk, RJGP; Lindeman, E; Hendriks, JCM; Wohlgemuth, M; van der Maarel, SM; Padberg, GW

    2004-01-01

    Background: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  14. Cardiac assessment of patients with late stage Duchenne muscular dystrophy

    NARCIS (Netherlands)

    van Bockel, E. A. P.; Lind, J. S.; Zijlstra, J. G.; Wijkstra, P. J.; Meijer, P. M.; van den Berg, M. P.; Slart, R. H. J. A.; Aarts, L. P. H. J.; Tulleken, J. E.

    2009-01-01

    Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, b

  15. Immunoglobulins in granular corneal dystrophy Groenouw type I

    DEFF Research Database (Denmark)

    Møller, H U; Bojsen-Møller, M; Schrøder, H D

    1993-01-01

    Three patients with granular corneal dystrophy Groenouw type I underwent corneal grafting, and cryostat sections of the corneal buttons were examined immunohistochemically for immunoglobulins. Positive results were obtained for IgG, Kappa-, and Lambda chains with immunofluorescence technique...

  16. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Science.gov (United States)

    Makino, Shinji; Endoh, Katsuhisa; Tampo, Hironobu

    2013-01-01

    Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1) associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years. PMID:23781366

  17. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Directory of Open Access Journals (Sweden)

    Shinji Makino

    2013-01-01

    Full Text Available Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1 associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years.

  18. Bilateral patching in retinal detachment: fluid mechanics and retinal "settling".

    Science.gov (United States)

    Foster, William J

    2011-07-20

    When a patient suffers a retinal detachment and surgery is delayed, it is known clinically that bilaterally patching the patient may allow the retina to partially reattach or "settle." Although this procedure has been performed since the 1860s, there is still debate as to how such a maneuver facilitates the reattachment of the retina. Finite element calculations using commercially available analysis software are used to elucidate the influence of reduction in eye movement caused by bilateral patching on the flow of subretinal fluid in a physical model of retinal detachment. It was found that by coupling fluid mechanics with structural mechanics, a physically consistent explanation of increased retinal detachment with eye movements can be found in the case of traction on the retinal hole. Large eye movements increase vitreous traction and detachment forces on the edge of the retinal hole, creating a subretinal vacuum and facilitating increased subretinal fluid. Alternative models, in which intraocular fluid flow is redirected into the subretinal space, are not consistent with these simulations. The results of these simulations explain the physical principles behind bilateral patching and provide insight that can be used clinically. In particular, as is known clinically, bilateral patching may facilitate a decrease in the height of a retinal detachment. The results described here provide a description of a physical mechanism underlying this technique. The findings of this study may aid in deciding whether to bilaterally patch patients and in counseling patients on pre- and postoperative care.

  19. Current and emerging treatment strategies for Duchenne muscular dystrophy

    OpenAIRE

    Mah JK

    2016-01-01

    Jean K Mah Department of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Abstract: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the...

  20. The new frontier in muscular dystrophy research: booster genes

    DEFF Research Database (Denmark)

    Engvall, Eva; Wewer, Ulla M

    2003-01-01

    More than 30 different forms of muscular dystrophy (MD) have been molecularly characterized and can be diagnosed, but progress toward treatment has been slow. Gene replacement therapy has met with great difficulty because of the large size of the defective genes and because of difficulties...... of the boosters are better understood, drugs may be developed to provide the boost to muscle. Some of the experiences in models of muscular dystrophy may inspire new approaches in other genetic degenerative diseases as well....

  1. Cardiac function in muscular dystrophy associates with abdominal muscle pathology

    Science.gov (United States)

    Gardner, Brandon B.; Swaggart, Kayleigh A.; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M.

    2015-01-01

    Background The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Methods Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. Findings The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients. PMID:26029630

  2. AUTOMATIC RETINAL VESSEL TORTUOSITY MEASUREMENT

    Directory of Open Access Journals (Sweden)

    Nidhal Khdhair El Abbadi

    2013-01-01

    Full Text Available Retinal vascular vessels have the role to indicate the retinal diseases and for systematic diseases when there are any abnormalities in retinal vascular pattern. A characteristic of the vascular pattern that is appreciated by clinicians is vascular tortuosity, i.e., how curved or kinked a blood vessel, either vein or artery, appears along its course. In this study we suggest a novel mask filter to track the blood vessel along its course and measuring the blood vessels tortuosity over the entire human retinal vessel network in fundus eye image, by using the arc to chord ratio. The suggested algorithm tested with straight and curve hand drawing lines and gives high accurate results.

  3. [Retinal vasculitis in lupic disease].

    Science.gov (United States)

    Brissaud, P; Laroche, L; Krulik, M; Prier, A M; Saraux, H; Canuel, C; Debray, J

    1985-01-01

    Three cases of retinal vasculitis in SLE-type diseases are reported. The first was central retinal vein occlusion occurring during clinical remission of SLE in a 55 year old black female. Prednisone maintenance therapy was unchanged and visual loss rapidly regressed with heparin therapy. The second case was a 33 year old black female in whom SLE was discovered following relapsing bilateral optic neuritis. A progressive visual improvement was obtained with high dose of prednisone (1 mg/kg/day). The third cas was a 17 year old white girl with retinal vasculitis. She had an unclassified connective tissue disease inaugurated by optic neuritis at the age of 10. High dose prednisone (1 mg/kg/day) was effective on the visual loss. Retinal vasculitis lesions in SLE and their therapy are reviewed.

  4. Infantile neuroaxonal dystrophy caused by uniparental disomy.

    Science.gov (United States)

    Solomons, Joyce; Ridgway, Oliver; Hardy, Carol; Kurian, Manju A; Kurian, Manju; Jayawant, Sandeep; Hughes, Sarah; Pretorius, Pieter; Németh, Andrea H

    2014-04-01

    Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the phospholipase A2 group 6 (Pla2G6) gene. Affected individuals usually present between the ages of 6 months and 2 years with rapid cognitive and motor regression and axial hypotonia. Gait disturbance, limb spasticity, cerebellar signs, and optic atrophy are other common features associated with INAD. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. In this case report, we describe the first individual (female) with INAD due to a combination of uniparental heterodisomy and isodisomy; we discuss the possible underlying mechanism and highlight the importance of parental carrier testing in accurately predicting the recurrence risk in these families. We also confirm the recent report of hypertrophy of the clava (also known as the 'gracile tubercle') as a useful MRI sign in INAD.

  5. Natural history of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Qing KE

    2015-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is X-linked recessive hereditary disease. DMD gene mutations result in dystrophin deficiency, which causes not only muscle movement disorders but also scoliosis, cognitive dysfunction, urinary tract diseases, respiratory diseases and heart diseases. Most patients die in early adult for respiratory and circulatory failure. Early multidisciplinary therapies will significantly delay disease progression and improve patients' quality of life. However, DMD diagnosis and treatment exist significantly time delay now. In this study, we review the natural history of DMD, including motor, cognitive, respiratory and heart function, for improving DMD early recognition, diagnosis and treatment, so as to benefit DMD patients. DOI: 10.3969/j.issn.1672-6731.2015.05.004

  6. Cardiac involvement in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Finsterer, Josef; Stöllberger, Claudia; Meng, Gerhard

    2005-01-01

    Cardiac involvement (CI) in form of myocardial thickening in a patient with genetically confirmed facioscapulohumeral muscular dystrophy (FSHMD) has not been reported. The patient is a 50-year-old male with a tandem repeat size of 17 and 14 kb in the D4Z4 locus on chromosome 4q35. The clinical cardiologic investigation was normal. Blood pressure was 150/90 mm Hg. Funduscopy, 24-hour ambulatory ECG, and 24-hour blood pressure monitoring were normal. ECG showed incomplete right bundle branch block, ST elevation in V2-V4, tall T waves in V3-V5, and hypertrophy signs. Echocardiography revealed left ventricular myocardial thickening of the posterior wall (11.7 mm) and the septum (15.5 mm). In conclusion, CI in genetically confirmed FSHMD may manifest not only as ECG abnormalities but also as left ventricular myocardial thickening. Copyright 2005 S. Karger AG, Basel.

  7. Oculopharyngeal muscular dystrophy: a polyalanine myopathy.

    Science.gov (United States)

    Brais, Bernard

    2009-01-01

    It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

  8. Lower limb muscle impairment in myotonic dystrophy type 1: the need for better guidelines.

    Science.gov (United States)

    Petitclerc, Émilie; Hébert, Luc J; Desrosiers, Johanne; Gagnon, Cynthia

    2015-04-01

    In myotonic dystrophy type 1 (DM1), leg muscle weakness is a major impairment. There are challenges to obtaining a clear portrait of muscle strength impairment. A systematic literature review was conducted on lower limb strength impairment in late-onset and adult phenotypes to document variables which affect strength measurement. Thirty-two articles were reviewed using the COSMIN guidelines. Only a third of the studies described a reproducible protocol. Only 2 muscle groups have documented reliability for quantitative muscle testing and only 1 total score for manual muscle testing. Variables affecting muscle strength impairment are not described in most studies. This review illustrates the variability in muscle strength assessment in relation to DM1 characteristics and the questionable validity of the results with regard to undocumented methodological properties. There is therefore a clear need to adopt a consensus on the use of a standardized muscle strength assessment protocol.

  9. Limb-girdle muscular dystrophy type 2A in Brazilian children

    Directory of Open Access Journals (Sweden)

    Marco Antônio Veloso de Albuquerque

    2015-12-01

    Full Text Available ABSTRACT Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years. The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

  10. The Growing Family of Limb-Girdle Muscular Dystrophies: Old and Newly Identified Members.

    Science.gov (United States)

    Bastian, Alexandra; Mageriu, V; Micu, Gianina; Manole, Emilia

    2015-01-01

    Limb-girdle muscular dystrophies (LGMD) are an extremely heterogeneous and rapidly expanding group of diseases characterized by progressive weakness of pelvic, scapular and trunk muscles with sparing of facial and distal musculature in most of the subtypes, onset in childhood or in adults of both sexes, very variable clinical severity ranging from mild to severe phenotypes, some associated with cardio-pulmonary and extraskeletal impairment and high serum creatine-kinase (CK) levels. In the past years, huge advances have been recorded in the various identification methods and new distinct entities were discovered. However, it is not yet clear why some muscle groups are affected and others spared in a specific subtype of LGMD, why similar clinical pictures are associated with different genes and mutations, while the same gene or mutation may present with very various clinical phenotypes. In this review we summarize the main aspects of positive and differential diagnosis in LGMD.

  11. Photoreceptor Differentiation following Transplantation of Allogeneic Retinal Progenitor Cells to the Dystrophic Rhodopsin Pro347Leu Transgenic Pig

    DEFF Research Database (Denmark)

    Klassen, H; Kiilgaard, Jens Folke; Warfvinge, K;

    2012-01-01

    Purpose. Transplantation of stem, progenitor, or precursor cells has resulted in photoreceptor replacement and evidence of functional efficacy in rodent models of retinal degeneration. Ongoing work has been directed toward the replication of these results in a large animal model, namely, the pig....... Methods. Retinal progenitor cells were derived from the neural retina of GFP-transgenic pigs and transplanted to the subretinal space of rhodopsin Pro347Leu-transgenic allorecipients, in the early stage of the degeneration and the absence of immune suppression. Results. Results confirm the survival...... of allogeneic porcine RPCs without immune suppression in the setting of photoreceptor dystrophy. The expression of multiple photoreceptor markers by grafted cells included the rod outer segment-specific marker ROM-1. Further evidence of photoreceptor differentiation included the presence of numerous...

  12. Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    S N Leow

    Full Text Available To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs on retinal structure and function in Royal College of Surgeons (RCS rats.RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8 and placebo control group (n = 8. In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT. Retinal function was assessed by electroretinography (ERG 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies.No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells.Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.

  13. Recent advances in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Perkins KJ

    2012-10-01

    Full Text Available Kelly J Perkins,1,2 Kay E Davies21Sir William Dunn School of Pathology, 2MRC Functional Genomics Unit, University of Oxford, Oxford, UKAbstract: Duchenne muscular dystrophy (DMD, an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and

  14. Retinal prosthesis for the blind.

    Science.gov (United States)

    Margalit, Eyal; Maia, Mauricio; Weiland, James D; Greenberg, Robert J; Fujii, Gildo Y; Torres, Gustavo; Piyathaisere, Duke V; O'Hearn, Thomas M; Liu, Wentai; Lazzi, Gianluca; Dagnelie, Gislin; Scribner, Dean A; de Juan, Eugene; Humayun, Mark S

    2002-01-01

    Most of current concepts for a visual prosthesis are based on neuronal electrical stimulation at different locations along the visual pathways within the central nervous system. The different designs of visual prostheses are named according to their locations (i.e., cortical, optic nerve, subretinal, and epiretinal). Visual loss caused by outer retinal degeneration in diseases such as retinitis pigmentosa or age-related macular degeneration can be reversed by electrical stimulation of the retina or the optic nerve (retinal or optic nerve prostheses, respectively). On the other hand, visual loss caused by inner or whole thickness retinal diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory processes etc.), or diseases of the central nervous system (not including diseases of the primary and secondary visual cortices) can be reversed by a cortical visual prosthesis. The intent of this article is to provide an overview of current and future concepts of retinal and optic nerve prostheses. This article will begin with general considerations that are related to all or most of visual prostheses and then concentrate on the retinal and optic nerve designs. The authors believe that the field has grown beyond the scope of a single article so cortical prostheses will be described only because of their direct effect on the concept and technical development of the other prostheses, and this will be done in a more general and historic perspective.

  15. Retinal implants: a systematic review.

    Science.gov (United States)

    Chuang, Alice T; Margo, Curtis E; Greenberg, Paul B

    2014-07-01

    Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability.

  16. Filling in the retinal image

    Science.gov (United States)

    Larimer, James; Piantanida, Thomas

    1990-01-01

    The optics of the eye form an image on a surface at the back of the eyeball called the retina. The retina contains the photoreceptors that sample the image and convert it into a neural signal. The spacing of the photoreceptors in the retina is not uniform and varies with retinal locus. The central retinal field, called the macula, is densely packed with photoreceptors. The packing density falls off rapidly as a function of retinal eccentricity with respect to the macular region and there are regions in which there are no photoreceptors at all. The retinal regions without photoreceptors are called blind spots or scotomas. The neural transformations which convert retinal image signals into percepts fills in the gaps and regularizes the inhomogeneities of the retinal photoreceptor sampling mosaic. The filling-in mechamism plays an important role in understanding visual performance. The filling-in mechanism is not well understood. A systematic collaborative research program at the Ames Research Center and SRI in Menlo Park, California, was designed to explore this mechanism. It was shown that the perceived fields which are in fact different from the image on the retina due to filling-in, control some aspects of performance and not others. Researchers have linked these mechanisms to putative mechanisms of color coding and color constancy.

  17. The mechanics of retinal detachment

    Science.gov (United States)

    Chou, Tom; Siegel, Michael

    2013-03-01

    We present a model of the mechanical and fluid forces associated with exudative retinal detachments where the retinal photoreceptor cells separate typically from the underlying retinal pigment epithelium (RPE). By computing the total fluid volume flow arising from transretinal, vascular, and retinal pigment epithelium (RPE) pump currents, we determine the conditions under which the subretinal fluid pressure exceeds the maximum yield stress holding the retina and RPE together, giving rise to an irreversible, extended retinal delamination. We also investigate localized, blister-like retinal detachments by balancing mechanical tension in the retina with both the retina-RPE adhesion energy and the hydraulic pressure jump across the retina. For detachments induced by traction forces, we find a critical radius beyond which the blister is unstable to growth. Growth of a detached blister can also be driven by inflamed tissue within which e.g., the hydraulic conductivities of the retina or choroid increase, the RPE pumps fail, or the adhesion properties change. We determine the parameter regimes in which the blister either becomes unstable to growth, remains stable and finite-sized, or shrinks, allowing possible healing. This work supported by the Army Research Office through grant 58386MA

  18. Heritability of Retinal Vascular Fractals

    DEFF Research Database (Denmark)

    Vergmann, Anna Stage; Broe, Rebecca; Kessel, Line

    2017-01-01

    Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. Methods: This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50°, disc-centered fundus photographs, the reti......Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. Methods: This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50°, disc-centered fundus photographs......, the retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficients. Falconer's formula and quantitative genetic models were used to determine the genetic component of variation. Results: The mean......, the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the retinal...

  19. Limb-girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

    Directory of Open Access Journals (Sweden)

    Marco A. Veloso Albuquerque

    2014-06-01

    Full Text Available Limb-girdle muscular dystrophies (LGMD are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Method: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. Results: The initial clinical signs included: frequent falls (22 cases, difficulty in climbing stairs (13 cases, walk on tip toes (2 cases, difficulty in rising from the floor (2 cases and difficulty on walking (1 case. The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5% were classified as sarcoglycanopathies (LGMD2C-F, five (13,5% as dysferlinopathy (LGMD2B, five (13,5% as calpainopathy (LGMD2A. Mutations in LMNA gene (LGMD1B, FKRP gene (LGMDI and caveolin gene (LGMD 1C were identified in two (5,5%, two (5,5% and one patient (2,5%, respectively. In seven of 37 cases (19% it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis

  20. Modifier locus of the skeletal muscle involvement in Emery-Dreifuss muscular dystrophy.

    Science.gov (United States)

    Granger, B; Gueneau, L; Drouin-Garraud, V; Pedergnana, V; Gagnon, F; Ben Yaou, R; Tezenas du Montcel, S; Bonne, G

    2011-02-01

    Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy.

  1. Interactive retinal blood flow analysis of the macular region.

    Science.gov (United States)

    Tian, Jing; Somfai, Gábor Márk; Campagnoli, Thalmon R; Smiddy, William E; Debuc, Delia Cabrera

    2016-03-01

    The study of retinal hemodynamics plays an important role to understand the onset and progression of diabetic retinopathy. In this work, we developed an interactive retinal analysis tool to quantitatively measure the blood flow velocity (BFV) and blood flow rate (BFR) in the macular region using the Retinal Function Imager (RFI). By employing a high definition stroboscopic fundus camera, the RFI device is able to assess retinal blood flow characteristics in vivo. However, the measurements of BFV using a user-guided vessel segmentation tool may induce significant inter-observer differences and BFR is not provided in the built-in software. In this work, we have developed an interactive tool to assess the retinal BFV and BFR in the macular region. Optical coherence tomography data was registered with the RFI image to locate the fovea accurately. The boundaries of the vessels were delineated on a motion contrast enhanced image and BFV was computed by maximizing the cross-correlation of pixel intensities in a ratio video. Furthermore, we were able to calculate the BFR in absolute values (μl/s). Experiments were conducted on 122 vessels from 5 healthy and 5 mild non-proliferative diabetic retinopathy (NPDR) subjects. The Pearson's correlation of the vessel diameter measurements between our method and manual labeling on 40 vessels was 0.984. The intraclass correlation (ICC) of BFV between our proposed method and built-in software was 0.924 and 0.830 for vessels from healthy and NPDR subjects, respectively. The coefficient of variation between repeated sessions was reduced significantly from 22.5% to 15.9% in our proposed method (p<0.001). Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Determination of retinal surface area.

    Science.gov (United States)

    Nagra, Manbir; Gilmartin, Bernard; Thai, Ngoc Jade; Logan, Nicola S

    2017-09-01

    Previous attempts at determining retinal surface area and surface area of the whole eye have been based upon mathematical calculations derived from retinal photographs, schematic eyes and retinal biopsies of donor eyes. 3-dimensional (3-D) ocular magnetic resonance imaging (MRI) allows a more direct measurement, it can be used to image the eye in vivo, and there is no risk of tissue shrinkage. The primary purpose of this study is to compare, using T2-weighted 3D MRI, retinal surface areas for superior-temporal (ST), inferior-temporal (IT), superior-nasal (SN) and inferior-nasal (IN) retinal quadrants. An ancillary aim is to examine whether inter-quadrant variations in area are concordant with reported inter-quadrant patterns of susceptibility to retinal breaks associated with posterior vitreous detachment (PVD). Seventy-three adult participants presenting without retinal pathology (mean age 26.25 ± 6.06 years) were scanned using a Siemens 3-Tesla MRI scanner to provide T2-weighted MR images that demarcate fluid-filled internal structures for the whole eye and provide high-contrast delineation of the vitreous-retina interface. Integrated MRI software generated total internal ocular surface area (TSA). The second nodal point was used to demarcate the origin of the peripheral retina in order to calculate total retinal surface area (RSA) and quadrant retinal surface areas (QRSA) for ST, IT, SN, and IN quadrants. Mean spherical error (MSE) was -2.50 ± 4.03D and mean axial length (AL) 24.51 ± 1.57 mm. Mean TSA and RSA for the RE were 2058 ± 189 and 1363 ± 160 mm(2) , respectively. Repeated measures anova for QRSA data indicated a significant difference within-quadrants (P area/mm increase in AL. Although the differences between QRSAs are relatively small, there was evidence of concordance with reported inter-quadrant patterns of susceptibility to retinal breaks associated with PVD. The data allow AL to be converted to QRSAs, which will assist further

  3. ACUTE RETINAL ARTERIAL OCCLUSIVE DISORDERS

    Science.gov (United States)

    Hayreh, Sohan Singh

    2011-01-01

    The initial section deals with basic sciences; among the various topics briefly discussed are the anatomical features of ophthalmic, central retinal and cilioretinal arteries which may play a role in acute retinal arterial ischemic disorders. Crucial information required in the management of central retinal artery occlusion (CRAO) is the length of time the retina can survive following that. An experimental study shows that CRAO for 97 minutes produces no detectable permanent retinal damage but there is a progressive ischemic damage thereafter, and by 4 hours the retina has suffered irreversible damage. In the clinical section, I discuss at length various controversies on acute retinal arterial ischemic disorders. Classification of acute retinal arterial ischemic disorders These are of 4 types: CRAO, branch retinal artery occlusion (BRAO), cotton wools spots and amaurosis fugax. Both CRAO and BRAO further comprise multiple clinical entities. Contrary to the universal belief, pathogenetically, clinically and for management, CRAO is not one clinical entity but 4 distinct clinical entities – non-arteritic CRAO, non-arteritic CRAO with cilioretinal artery sparing, arteritic CRAO associated with giant cell arteritis (GCA) and transient non-arteritic CRAO. Similarly, BRAO comprises permanent BRAO, transient BRAO and cilioretinal artery occlusion (CLRAO), and the latter further consists of 3 distinct clinical entities - non-arteritic CLRAO alone, non-arteritic CLRAO associated with central retinal vein occlusion and arteritic CLRAO associated with GCA. Understanding these classifications is essential to comprehend fully various aspects of these disorders. Central retinal artery occlusion The pathogeneses, clinical features and management of the various types of CRAO are discussed in detail. Contrary to the prevalent belief, spontaneous improvement in both visual acuity and visual fields does occur, mainly during the first 7 days. The incidence of spontaneous visual

  4. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Science.gov (United States)

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  5. A patient with acute macular neuroretinopathy and central retinal vein occlusion

    Directory of Open Access Journals (Sweden)

    Hirooka K

    2013-07-01

    Full Text Available Kiriko Hirooka,1 Wataru Saito,1,2 Kousuke Noda,1,2 Susumu Ishida1,21Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; 2Department of Ocular Circulation and Metabolism, Hokkaido University Graduate School of Medicine, Sapporo, JapanPurpose: The precise mechanism causing acute macular neuroretinopathy (AMN is still unknown. A recent report suggested that choroidal circulation impairment correlates with its pathogenesis. We report a rare case with simultaneous onset of AMN and central retinal vein occlusion (CRVO, which is a retinal circulation disorder.Methods: Case report.Results: A 44-year-old woman complained of central visual loss of the left eye for the previous 2 weeks. The patient’s visual acuity was 0.5 in the left eye (OS. Fundoscopic examination revealed a wedge-shaped, dark reddish-brown lesion at the macula, and CRVO-like retinal hemorrhages OS. Fluorescein angiography revealed retinal vasculitis and hypofluorescence corresponding to the macular lesion. The patient’s scanning laser ophthalmoscopy infrared imaging result led to a diagnosis of AMN. Two weeks after corticosteroid pulse therapy, her visual acuity improved to 1.2 OS, with improvement of macular findings and Humphrey perimetry. When the dose of oral corticosteroid was decreased, the AMN lesion worsened, with recurrence of retinal hemorrhages. Visual functions improved again after an increased dose of corticosteroid.Conclusion: These results suggest that circulatory disorders almost simultaneously occurred in choroidal and retinal vessels, resulting in the onset of both AMN and CRVO.Keywords: choroidal circulation, optical coherence tomography, retinal circulation, systemic corticosteroid therapy

  6. Post-fever retinitis: a single center experience from south India.

    Science.gov (United States)

    Vishwanath, Srilatha; Badami, Kalpana; Sriprakash, K S; Sujatha, B L; Shashidhar, S D; Shilpa, Y D

    2014-08-01

    Various retinal manifestations can occur following a febrile illness due to viral, bacterial or protozoal etiology. As there are limited data in the literature, we undertook this study to analyse the clinical presentation of post-fever retinitis due to various etiologies, as well as its course and management. This was a retrospective study of 14 consecutive cases who presented to the Vitreo Retina Department of our hospital over a 1-year period between January 2010 and December 2010. All patients underwent detailed ophthalmic examination and relevant investigations including fundus fluorescein angiography and optical coherence tomography (OCT). Basic and specific investigations were performed as necessary. All patients were given systemic steroids which were tapered based on clinical response. Twenty-one eyes of 14 patients (7 bilateral, 7 unilateral) were studied. Onset of ocular symptoms was approximately 3 weeks after fever. Four patients had specific etiology-one each of chikungunya, enteric fever, malaria and abdominal abscess with pneumococcal pneumonia. The presenting visual acuity of the affected eyes averaged 2/60. Six eyes had relative afferent pupillary defect. All patients had solitary or multiple patches of retinitis at the posterior pole and exudation at the macula. OCT through the lesions revealed inner retinal hyperreflectivity and thickening with after-shadowing. All patients showed improvement in vision with unilateral cases improving to an average of 6/12 and bilateral cases improving to an average of 6/24. Patients also showed resolution of retinitis, macular edema and serous detachment. Post-fever retinitis as a condition manifested approximately 3 weeks after onset of fever. Irrespective of the cause of the fever, clinical presentation of cases was similar with inner retinitis at the posterior pole and a favourable response to steroids, suggesting a possible immunological basis for this condition.

  7. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1.

    Directory of Open Access Journals (Sweden)

    Sandra J Feeney

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.

  8. Identification of a Novel Mutation in the Titin Gene in a Chinese Family with Limb-Girdle Muscular Dystrophy 2J.

    Science.gov (United States)

    Zheng, Wen; Chen, Han; Deng, Xiong; Yuan, Lamei; Yang, Yan; Song, Zhi; Yang, Zhijian; Wu, Yuan; Deng, Hao

    2016-10-01

    Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.

  9. Central retinal vessel blood flow after surgical treatment for central retinal vein occlusion.

    NARCIS (Netherlands)

    Crama, N.; Gualino, V.; Restori, M.; Charteris, D.G.

    2010-01-01

    PURPOSE: The purpose of this study was to determine the effect of radial optic neurotomy and retinal endovascular surgery on retinal blood flow velocity in patients with central retinal vein occlusion. METHODS: A prospective interventional case series. RESULTS: Six patients with a central retinal

  10. Central retinal vein occlusion following Sirsasana (headstand posture

    Directory of Open Access Journals (Sweden)

    Shah Nikunj

    2009-01-01

    Full Text Available We report a case of central retinal vein occlusion (CRVO following Sirsasana, a head-down postural yoga. A 55-year-old male patient presented to us, with sudden-onset loss of vision following Sirsasana, in the right eye. The patient had suffered from pulmonary thromboembolism 5 years earlier and was receiving warfarin prophylaxis. Over 6 months of follow-up, the patient developed neovascularization of the iris and was subjected to panretinal laser with no improvement in visual acuity. Sirsasana could be an important risk factor for CRVO especially in predisposed patients.

  11. The Nuss technique for Jeune asphyxiating thoracic dystrophy repair in siblings.

    Science.gov (United States)

    Kikuchi, Noriaki; Kashiwa, Hideo; Ogino, Toshihoko; Kato, Mituhiro; Hayasaka, Kiyoshi

    2010-08-01

    Jeune syndrome, or asphyxiating thoracic dysplasia, is an autosomal recessive osteochondrodysplasia. Four forms of Jeune syndrome have been proposed: lethal, severe, mild, and latent. In the severe form, respiratory failure leads to death in early infancy. We present 2 cases of a mild variant of Jeune syndrome in a 14-year-old girl and her 9-year-old brother, who were referred to us because of characteristic concave deformities of bilateral middle-lower chest walls without cardiopulmonary distress or renal failure. In addition, both showed short statue (-2.1 and -2.5 SD), progressive retinal dystrophy, and metaphyseal dysplasia (cone-shaped metaphysis and metacarpal brachydactyly). The chest wall deformity was treated at the age of 9 years in the sister and at the age of 7 years in the brother. According to the Nuss procedure, 2 bent bars were inserted into the thoracic cavity from each lateral intercostal space at the midaxillary line and pulled out over the lower end of the sternum. The ends of inserted bars were fixed to soft tissue over the sternum with nonabsorbable sutures. Conjoined costal cartilage around the sternum restricts the number of bars that can be positioned. A single bar for deformity of each side could not achieve complete reconstruction, but the patients and their parents were satisfied with the results cosmetically.

  12. High-Resolution Imaging of Patients with Bietti Crystalline Dystrophy with CYP4V2 Mutation

    Directory of Open Access Journals (Sweden)

    Kiyoko Gocho

    2014-01-01

    Full Text Available The purpose of this study was to determine the retinal morphology of eyes with Bietti crystalline dystrophy (BCD associated with a CYP4V2 mutation using high-resolution imaging techniques. Three subjects with BCD underwent detailed ophthalmic examinations. High-resolution fundus images were obtained with an adaptive optics (AO fundus camera. A common homozygous mutation was detected in the three patients. Funduscopic examination of the three patients revealed the presence of crystalline deposits in the retina, and all of the crystalline deposits were also detected in the infrared (IR images. The crystals observed in the IR images were seen as bright reflective plaques located on the RPE layer in the SD-OCT images. The clusters of hyperreflective signals in the AO images corresponded to the crystals in the IR images. High-magnification AO images revealed that the clusters of hyperreflective signals consisted of circular spots that are similar to the signals of cone photoreceptors. Most of these circular spots were detected in healthy areas in the FAF images. There is a possibility that circular spots observed by AO are residual cone photoreceptors located over the crystals.

  13. High-Resolution Imaging of Patients with Bietti Crystalline Dystrophy with CYP4V2 Mutation.

    Science.gov (United States)

    Gocho, Kiyoko; Kameya, Shuhei; Akeo, Keiichiro; Kikuchi, Sachiko; Usui, Ayumi; Yamaki, Kunihiko; Hayashi, Takaaki; Tsuneoka, Hiroshi; Mizota, Atsushi; Takahashi, Hiroshi

    2014-01-01

    The purpose of this study was to determine the retinal morphology of eyes with Bietti crystalline dystrophy (BCD) associated with a CYP4V2 mutation using high-resolution imaging techniques. Three subjects with BCD underwent detailed ophthalmic examinations. High-resolution fundus images were obtained with an adaptive optics (AO) fundus camera. A common homozygous mutation was detected in the three patients. Funduscopic examination of the three patients revealed the presence of crystalline deposits in the retina, and all of the crystalline deposits were also detected in the infrared (IR) images. The crystals observed in the IR images were seen as bright reflective plaques located on the RPE layer in the SD-OCT images. The clusters of hyperreflective signals in the AO images corresponded to the crystals in the IR images. High-magnification AO images revealed that the clusters of hyperreflective signals consisted of circular spots that are similar to the signals of cone photoreceptors. Most of these circular spots were detected in healthy areas in the FAF images. There is a possibility that circular spots observed by AO are residual cone photoreceptors located over the crystals.

  14. Small Molecules that Protect Mitochondrial Function from Metabolic Stress Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models.

    Science.gov (United States)

    Beeson, Craig; Lindsey, Chris; Nasarre, Cecile; Bandyopadhyay, Mausumi; Perron, Nathan; Rohrer, Bärbel

    2016-01-01

    One feature common to many of the pathways implicated in retinal degeneration is increased metabolic stress leading to impaired mitochondrial function. We found that exposure of cells to calcium ionophores or oxidants as metabolic stressors diminish maximal mitochondrial capacity. A library of 50,000 structurally diverse "drug-like" molecules was screened for protection against loss of calcium-induced loss of mitochondrial capacity in 661W rod-derived cells and C6 glioblastomas. Initial protective hits were then tested for protection against IBMX-induced loss of mitochondrial capacity as measured via respirometry. Molecules that protected mitochondria were then evaluated for protection of rod photoreceptor cells in retinal explants from rd1 mice. Two of the molecules attenuated loss of photoreceptor cells in the rd1 model. In the 661W cells, exposure to calcium ionophore or tert-butylhydroperoxide caused mitochondrial fragmentation that was blocked with the both compounds. Our studies have identified molecules that protect mitochondria and attenuate loss of photoreceptors in models of retinal degeneration suggesting that they could be good leads for development of therapeutic drugs for treatment of a wide variety of retinal dystrophies.

  15. Massive Retinal Pigment Epithelial Detachment Following Acute Hypokalemic Quadriparesis in Dengue Fever.

    Science.gov (United States)

    Goel, Neha; Bhambhwani, Vishaal; Jain, Pooja; Ghosh, Basudeb

    2016-01-01

    To describe an unusual retinal manifestation of dengue fever in an endemic region. A 35 year old male presenting with acute onset decreased vision in his right eye, was found to have a massive retinal pigment epithelial detachment (PED) extending up to the vascular arcades. He had been diagnosed with acute hypokalemic quadriparesis in dengue fever in the preceding week, which had resolved following treatment. The patient was managed conservatively. At three months follow up, there was spontaneous flattening of the PEDs with improvement in visual acuity. Dengue fever complicated by acute hypokalemic quadriparesis can be associated with PED, which can be large. The condition resolves spontaneously and bears a good prognosis.

  16. Retinal nerve fiber layer thickness is associated with lesion length in acute optic neuritis

    DEFF Research Database (Denmark)

    Kallenbach, K; Simonsen, Helle Juhl; Sander, B

    2010-01-01

    included 41 patients with unilateral optic neuritis and 19 healthy volunteers. All patients were evaluated and examined within 28 days of onset of symptoms. The peripapillary retinal nerve fiber layer thickness (RNFLT), an objective quantitative measure of optic nerve head edema, was measured by optical...... coherence tomography and the length and location of the inflammatory optic nerve lesion were evaluated using MRI. RESULTS: Ophthalmoscopically, 34% of the patients had papillitis. The retinal nerve fiber layer in affected eyes (mean 123.1 microm) was higher during the acute phase than that of fellow eyes...... (mean 98.1 microm, p eyes (mean 97.1 microm, p

  17. [Congenital retinal folds in different clinical cases].

    Science.gov (United States)

    Munteanu, M

    2005-01-01

    We present 12 clinical cases of congenital retinal folds with different etiologies: posterior primitive vitreous persistency and hyperplasia (7 cases),retinocytoma (1 case). retinopathy of prematurity (1 case), astrocytoma of the retina (1 case), retinal vasculitis (1 case), Goldmann-Favre syndrome (1 case). Etiopathogenic and nosological aspects are discussed; the congenital retinal folds are interpreted as a symptom in a context of a congenital or acquired vitreo-retinal pathology.

  18. Morphologic imaging in muscular dystrophies and inflammatory myopathies

    Energy Technology Data Exchange (ETDEWEB)

    Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick [CHU de Lille, Clinique neurologique, Lille (France); Morillon, David; Cotten, Anne [CHRU de Lille, Service de Radiologie Osteoarticulaire, Hopital Roger Salengro, Lille (France); Stojkovic, Tanya [G-H Pitie-Salpetriere, Institut de Myologie, Paris (France)

    2010-12-15

    To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

  19. Assessment of disease activity in muscular dystrophies by noninvasive imaging.

    Science.gov (United States)

    Maguire, Katie K; Lim, Leland; Speedy, Sedona; Rando, Thomas A

    2013-05-01

    Muscular dystrophies are a class of disorders that cause progressive muscle wasting. A major hurdle for discovering treatments for the muscular dystrophies is a lack of reliable assays to monitor disease progression in animal models. We have developed a novel mouse model to assess disease activity noninvasively in mice with muscular dystrophies. These mice express an inducible luciferase reporter gene in muscle stem cells. In dystrophic mice, muscle stem cells activate and proliferate in response to muscle degeneration, resulting in an increase in the level of luciferase expression, which can be monitored by noninvasive, bioluminescence imaging. We applied this noninvasive imaging to assess disease activity in a mouse model of the human disease limb girdle muscular dystrophy 2B (LGMD2B), caused by a mutation in the dysferlin gene. We monitored the natural history and disease progression in these dysferlin-deficient mice up to 18 months of age and were able to detect disease activity prior to the appearance of any overt disease manifestation by histopathological analyses. Disease activity was reflected by changes in luciferase activity over time, and disease burden was reflected by cumulative luciferase activity, which paralleled disease progression as determined by histopathological analysis. The ability to monitor disease activity noninvasively in mouse models of muscular dystrophy will be invaluable for the assessment of disease progression and the effectiveness of therapeutic interventions.

  20. Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy.

    Science.gov (United States)

    Choi, Jongkyu; Dixon, Donald M; Dansithong, Warunee; Abdallah, Walid F; Roos, Kenneth P; Jordan, Maria C; Trac, Brandon; Lee, Han Shin; Comai, Lucio; Reddy, Sita

    2016-08-03

    Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3(ΔE2)) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3(ΔE2) mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3(ΔE2) mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3(ΔE2) mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1.

  1. Distribution, markers and functions of retinal microglia

    NARCIS (Netherlands)

    Chen, L.; Yang, P.Z.; Kijlstra, A.

    2002-01-01

    Retinal microglia originate from hemopoietic cells and invade the retina from the retinal margin and the optic disc, most likely via the blood vessels of the ciliary body and iris, and the retinal vasculature, respectively. The microglial precursors that appear in the retina prior to vascularization

  2. Choroidal melanoma clinically simulating a retinal angioma

    Energy Technology Data Exchange (ETDEWEB)

    Shields, J.A.; Joffe, L.; Guibor, P.

    1978-01-01

    An amelanotic fundus lesion in a 35-year-old man was associated with a dilated retinal vessel, thus suggesting the diagnosis of retinal angioma. Fluorescein angiography and B-scan ultrasonography were not diagnostic, but a radioactive phosphorus uptake test suggested the lesion was malignant. The enucleated globe showed a malignant choroidal melanoma drained by a large retinal vein.

  3. Choroidal melanoma clinically simulating a retinal angioma.

    Science.gov (United States)

    Shields, J A; Joffe, L; Guibor, P

    1978-01-01

    An amelanotic fundus lesion in a 35-year-old man was associated with a dilated retinal vessel, thus suggesting the diagnosis of retinal angioma. Fluorescein angiography and B-scan ultrasonography were not diagnostic, but a radioactive phosphorus uptake test suggested the lesion was malignant. The enucleated globe showed a malignant choroidal melanoma drained by a large retinal vein.

  4. Noninvasive Retinal Markers in Diabetic Retinopathy

    DEFF Research Database (Denmark)

    Blindbæk, Søren Leer; Torp, Thomas Lee; Lundberg, Kristian

    2017-01-01

    The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and ...

  5. Exploring the retinal connectome

    Science.gov (United States)

    Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Shaw, Margaret V.; Yang, Jia-Hui; DeMill, David; Lauritzen, James S.; Lin, Yanhua; Rapp, Kevin D.; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross

    2011-01-01

    Purpose A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. Methods We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Results Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive

  6. Serum Creatinine Level: A Supplemental Index to Distinguish Duchenne Muscular Dystrophy from Becker Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Huili Zhang

    2015-01-01

    Full Text Available Background. To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn level reflects disease severity. Methods. Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy. Results. Serum Crn level had a strong inverse correlation with Vignos score by simple correlation (r=-0.793 and partial correlation analysis after adjustment for age, height, and weight (r=-0.791; both P<0.01. Serum Crn level was significantly higher in patients with in-frame than out-of-frame mutations (Z=-4.716, P<0.01 and in Becker muscular dystrophy (BMD patients than Duchenne muscular dystrophy (DMD patients at ages 4, 5, 7, and 9 yr (all P<0.0125. After adjusting for age, height, and weight, BMD patients still had a significantly higher serum Crn level than DMD patients (β=7.140, t=6.277, P<0.01. Conclusions. Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.

  7. The effects of myotonic dystrophy and Duchenne muscular dystrophy on the orofacial muscles and dentofacial morphology.

    Science.gov (United States)

    Kiliaridis, S; Katsaros, C

    1998-12-01

    This article takes a closer view of two of the less rare myopathies, myotonic dystrophy (MyD) and Duchenne muscular dystrophy (DMD). A high prevalence of malocclusions was found among the patients affected by these diseases. The development of the malocclusions in MyD patients seems to be strongly related to the vertical aberration of their craniofacial growth due to the involvement of the masticator, muscles in association with the possibly less affected suprahyoid musculature. Thus, a new situation is established around the teeth transversely. The lowered tongue is not in a position to counterbalance the forces developed during the lowering of the mandible by the stretched facial musculature. This may affect the teeth transversely, decreasing the width of the palate and causing posterior crossbite. The lowered position of the mandible, in combination with the decreased biting forces, may permit an overeruption of the posterior teeth, with increased palatal vault height and development of anterior open bite. The development of the malocclusions in DMD patients also seems to be strongly related to the involvement of the orofacial muscles by the disease. However, the posterior crossbite is not developed owing to the narrow maxillary arch, as is the case in MyD patients. On the contrary, the posterior crossbite in DMD is due to the transversal expansion of the mandibular arch, possibly because of the decreased tonus of the masseter muscle near the molars, in combination with the enlarged hypotonic tongue and the predominance of the less affected orbicularis oris muscle.

  8. Retinal Optical Coherence Tomography Imaging

    Science.gov (United States)

    Drexler, Wolfgang; Fujimoto, James G.

    The eye is essentially transparent, transmitting light with only minimal optical attenuation and scattering providing easy optical access to the anterior segment as well as the retina. For this reason, ophthalmic and especially retinal imaging has been not only the first but also most successful clinical application for optical coherence tomography (OCT). This chapter focuses on the development of OCT technology for retinal imaging. OCT has significantly improved the potential for early diagnosis, understanding of retinal disease pathogenesis, as well as monitoring disease progression and response to therapy. Development of ultrabroad bandwidth light sources and high-speed detection techniques has enabled significant improvements in ophthalmic OCT imaging performance, demonstrating the potential of three-dimensional, ultrahigh-resolution OCT (UHR OCT) to perform noninvasive optical biopsy of the living human retina, i.e., the in vivo visualization of microstructural, intraretinal morphology in situ approaching the resolution of conventional histopathology. Significant improvements in axial resolution and speed not only enable three-dimensional rendering of retinal volumes but also high-definition, two-dimensional tomograms, topographic thickness maps of all major intraretinal layers, as well as volumetric quantification of pathologic intraretinal changes. These advances in OCT technology have also been successfully applied in several animal models of retinal pathologies. The development of light sources emitting at alternative wavelengths, e.g., around #1,060 nm, not only enabled three-dimensional OCT imaging with enhanced choroidal visualization but also improved OCT performance in cataract patients due to reduced scattering losses in this wavelength region. Adaptive optics using deformable mirror technology, with unique high stroke to correct higher-order ocular aberrations, with specially designed optics to compensate chromatic aberration of the human eye, in

  9. Optimizing Bone Health in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Jason L. Buckner

    2015-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA, as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA.

  10. Wnt7a treatment ameliorates muscular dystrophy.

    Science.gov (United States)

    von Maltzahn, Julia; Renaud, Jean-Marc; Parise, Gianni; Rudnicki, Michael A

    2012-12-11

    Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.

  11. Falls and stumbles in myotonic dystrophy.

    Science.gov (United States)

    Wiles, C M; Busse, M E; Sampson, C M; Rogers, M T; Fenton-May, J; van Deursen, R

    2006-03-01

    To investigate falls and risk factors in patients with myotonic dystrophy type 1 (DM1) compared with healthy volunteers. 13 sequential patients with DM1 from different kindreds were compared with 12 healthy volunteers. All subjects were evaluated using the Rivermead Mobility Index, Performance Oriented Mobility Assessment, and modified Activities Specific Balance Confidence scale. Measures of lower limb muscle strength, gait speed, and 7-day ambulatory activity monitoring were recorded. Subjects returned a weekly card detailing stumbles and falls. 11 of 13 patients (mean age 46.5 years, seven female) had 127 stumbles and 34 falls over the 13 weeks, compared with 10 of 12 healthy subjects (34.4 years, seven female) who had 26 stumbles and three falls. Patients were less active than healthy subjects but had more falls and stumbles per 5000 right steps taken (mean (SD) events, 0.21 (0.29) v 0.02 (0.02), p = 0.007). Patients who fell (n = 6) had on average a lower Rivermead Mobility score, slower self selected gait speed, and higher depression scores than those who did not. DM1 patients stumble or fall about 10 times more often than healthy volunteers. Routine inquiry about falls and stumbles is justified. A study of multidisciplinary intervention to reduce the risk of falls seems warranted.

  12. Electrical impedance myography in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Statland, Jeffrey M; Heatwole, Chad; Eichinger, Katy; Dilek, Nuran; Martens, William B; Tawil, Rabi

    2016-10-01

    In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD). We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared with measures of strength, FSHD disease severity, and functional outcomes. Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics. EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54: 696-701, 2016. © 2016 Wiley Periodicals, Inc.

  13. Autophagy in granular corneal dystrophy type 2.

    Science.gov (United States)

    Choi, Seung-Il; Kim, Eung Kweon

    2016-03-01

    Autophagy is a lysosomal degradative process that is essential for cellular homeostasis and metabolic stress adaptation. Defective autophagy is involved in the pathogenesis of many diseases including granular corneal dystrophy type 2 (GCD2). GCD2 is an autosomal dominant disorder caused by substitution of histidine for arginine at codon 124 (R124H) in the transforming growth factor β-induced gene (TGFBI) on chromosome 5q31. Transforming growth factor β-induced protein (TGFBIp) is degraded by autophagy, but mutant-TGFBIp accumulates in autophagosomes and/or lysosomes, despite significant activation of basal autophagy, in GCD2 corneal fibroblasts. Furthermore, inhibition of autophagy induces cell death of GCD2 corneal fibroblasts through active caspase-3. As there is currently no pharmacological treatment for GCD2, development of novel therapies is required. A potential strategy for preventing cytoplasmic accumulation of mutant-TGFBIp in GCD2 corneal fibroblasts is to enhance mutant-TGFBIp degradation. This could be achieved by activation of the autophagic pathway. Here, we will consider the role and the potential therapeutic benefits of autophagy in GCD2, with focus on TGFBIp degradation, in light of the recently established role of autophagy in protein degradation.

  14. Molecular diagnosis of Duchenne muscular dystrophy.

    Science.gov (United States)

    Nallamilli, Babi Ramesh Reddy; Ankala, Arunkanth; Hegde, Madhuri

    2014-10-01

    Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The mutation spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for sequence variants. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). This unit initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed protocols of current molecular diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing, and NGS-based sequencing assay.

  15. [Study on preferred retinal locus].

    Science.gov (United States)

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  16. Angiographic results of retinal-retinal anastomosis and retinal-choroidal anastomosis after treatments in eyes with retinal angiomatous proliferation

    Directory of Open Access Journals (Sweden)

    Saito M

    2012-08-01

    Full Text Available Masaaki Saito,1 Tomohiro Iida,1,2 Mariko Kano,1 Kanako Itagaki11Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, 2Department of Ophthalmology, Tokyo Women's Medical University School of Medicine, Tokyo, JapanBackground: The purpose of this study was to evaluate the angiographic results of retinal-retinal anastomosis (RRA and retinal-choroidal anastomosis (RCA for eyes with retinal angiomatous proliferation (RAP after treatment with intravitreal bevacizumab injections as monotherapy or intravitreal bevacizumab combined with photodynamic therapy.Methods: In this interventional, consecutive case series, we retrospectively reviewed five naïve eyes from four patients (mean age 80 years treated with three consecutive monthly intravitreal bevacizumab (1.25 mg/0.05 mL injections as initial treatment, and followed up for at least 3 months. In cases with over 3 months of follow-up and having recurrence of RAP or leakage by fluorescein angiography, retreatment was performed with a single intravitreal bevacizumab injection and photodynamic therapy.Results: Indocyanine green angiography showed RRA in three eyes with subretinal neovascularization and RCA in two eyes with choroidal neovascularization at baseline. At 3 months after baseline (month 3, neither the RRA nor RCA was occluded in any eye on indocyanine green angiography. Retreatment with intravitreal bevacizumab plus photodynamic therapy was performed in three eyes at months 3 (persistent leakage on fluorescein angiography, 6, and 7 (recurrence of RAP lesion, which achieved obvious occlusion of the RRA and RCA. Mean best-corrected visual acuity improved from 0.13 to 0.21 at month 3 (P = 0.066. No complications or systemic adverse events were noted.Conclusion: Although intravitreal bevacizumab for RAP was effective in improving visual acuity during short-term follow-up, intravitreal bevacizumab could not achieve complete occlusion of RRA and RCA, which could

  17. In vivo confocal microscopy in recurrent granular dystrophy in corneal graft after penetrating keratoplasty.

    Science.gov (United States)

    Traversi, Claudio; Martone, Gianluca; Malandrini, Alex; Tosi, Gian Marco; Caporossi, Aldo

    2006-11-01

    Two case reports of recurrent granular dystrophy in corneal grafts after penetrating keratoplasty are presented. Slit-lamp examination and confocal microscopy (HRT II) were performed in two patients with recurrent granular dystrophy. All confocal microscopic findings of granular dystrophy were evaluated in the graft. Dystrophic lesions of the donor cornea presented the same confocal microscopic aspects in both eyes, and were similar to granular dystrophy lesions. Confocal microscopy is an imaging method that may provide new information on corneal microanatomy in dystrophies. It may be particularly useful in improving the early diagnosis of dystrophic lesions in corneal grafts.

  18. Central retinal vein occlusion concomitant with dengue fever.

    Science.gov (United States)

    Velaitham, Punithamalar; Vijayasingham, Nandini

    2016-01-01

    Dengue virus infection is on the rise and there is increasing number of ocular complications that are being reported. Most common ocular complications are macular edema, macular hemorrhages, and foveolitis. There are case reports on branch retinal vessel occlusions. Most of the ocular complications are attributed to the bleeding tendency and transudative process in dengue viral infection. This is a case report of ischemic central retinal vein occlusion (CRVO) concomitant with dengue fever. A 41 year old Malay female was admitted to medical ward and diagnosed to have "dengue fever with warning signs". On the day of admission she noted sudden onset of right eye blurring of vision. She presented to our clinic 1 week later. Ocular examination revealed right eye visual acuity of <20/1000 and ischaemic CRVO with macular edema. She had no other risk factors to develop retinal vein occlusion. She progressively developed proliferative retinopathy and received multiple laser therapy. There was no anterior segment neovascularization. However, her vision improved to only 20/400 despite of resolution of macular edema and new vessels elsewhere. Dengue virus infection is known to cause thrombocytopenia which can result in hemorrhagic events. It can also cause procoagulant state which can result in thrombotic events secondary to immune reaction. Awareness among treating physicians of such ocular complication which can result in significant morbidity for patient is necessary.

  19. Effect of maternal transmissions on clinical manifestations of myotonic dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Eguchi, I.; Koike, R.; Onodera, O. [Niigata Univ. (Japan)] [and others

    1994-09-01

    The mutation of myotonic dystrophy (DM) has been identified as unstable expansions of trinucleotide CTG repeat, located on chromosome 19q13-3. Although previous investigations have emphasized the strong association of the sizes of the CTG repeat with ages of onset as well as the clinical manifestations, effects of the paternal or maternal transmissions other than CTG repeats on the clinical manifestations in DM have not been evaluated in detail. To investigate how parental transmission affect the DM phenotype, we analyzed 15 cases of paternal transmission and 25 cases of maternal transmission. We have classified DM patients into 4 clinical grades. As in accordance with previous reports, there is a good correlation on sizes of the CTG repeat with their clinical features. The sizes of the CTG repeat in congenital DM patients (4.13{plus_minus}0.221 kbp) (Mean {plus_minus}SEM), who inherited mutant genes from their mothers, were not significantly larger than those of non-congenital DM patients (3.65 {plus_minus}0.36 kbp). As it has been well established that congenital DM patients are born to affected mothers, we investigated to see if there are any parental bias on the clinical manifestations in non-congenital DM. We classified each case into 4 classes depending on the size ranges of the CTG repeat (0 to 1.5 kbp, 1.5 to 3.0 kbp, 3.0 to 4.5 kbp, 4.5 kbp<). In each group of the size ranges of the CTG repeat, the distribution of cases among grades I to III were compared between paternally and maternally transmitted cases. There were statistically significant differences in the distributions of cases among grades I to III for the size ranges of 3 to 4.5 kbp expansions (p<0.01) and over 4.5 kbp expansions (p<0.05) on {chi}{sup 2} test, respectively. The results revealed that maternally transmitted cases tend to show severe phenotypes compared to paternally transmitted ones even if they have similar sizes of CTG repeat.

  20. Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.

    Science.gov (United States)

    Swaggart, Kayleigh A; Demonbreun, Alexis R; Vo, Andy H; Swanson, Kaitlin E; Kim, Ellis Y; Fahrenbach, John P; Holley-Cuthrell, Jenan; Eskin, Ascia; Chen, Zugen; Squire, Kevin; Heydemann, Ahlke; Palmer, Abraham A; Nelson, Stanley F; McNally, Elizabeth M

    2014-04-22

    Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury.

  1. Idiopathic intracranial hypertension in a child with Duchenne muscular dystrophy.

    Science.gov (United States)

    Weig, Spencer G; Zinn, Matthias M; Howard, James F

    2011-12-01

    Duchenne muscular dystrophy is an X-linked, recessively inherited disorder characterized by progressive weakness attributable to the absence of dystrophin expression in muscle. In multiple studies, the chronic administration of corticosteroids slowed the loss of ambulation that develops in mid to late childhood. Corticosteroids, however, frequently produce unacceptable side effects, including Cushingoid appearance and weight gain. Deflazacort, an oxazoline analogue of prednisolone, produces equivalent benefits on muscle with fewer reported Cushingoid side effects. We present a 9-year-old boy with Duchenne muscular dystrophy who developed morbid obesity and subsequent idiopathic intracranial hypertension after 2 years of receiving deflazacort. Although deflazacort is typically thought to produce less obesity than prednisone, severe Cushingoid side effects may occur in some individuals. To our knowledge, this description is the first of idiopathic intracranial hypertension complicating chronic corticosteroid treatment of Duchenne muscular dystrophy.

  2. Crystalline Subtype of Pre-Descemetic Corneal Dystrophy

    Directory of Open Access Journals (Sweden)

    Rosa Dolz-Marco

    2014-01-01

    Full Text Available Purpose: To report corneal findings in a familial case of the crystalline subtype of pre- Descemetic corneal dystrophy. Case Report: A 19-year-old girl and her 44-year-old mother were found to have asymptomatic, bilateral, punctiform and multi-colored crystalline opacities across the whole posterior layer of the corneas. Endothelial specular microscopy revealed the presence of white round flecks located at different levels anterior to the endothelium. No systemic abnormalities or medications could be related to account for these findings. Conclusion: To the best of our knowledge, this is the third familial report of this rare corneal disorder. Differential diagnosis may include Schnyder corneal dystrophy, cystinosis, Bietti΄s dystrophy and monoclonal gammopathy.

  3. Adult onset tic disorders

    OpenAIRE

    Chouinard, S; Ford, B.

    2000-01-01

    BACKGROUND—Tic disorders presenting during adulthood have infrequently been described in the medical literature. Most reports depict adult onset secondary tic disorders caused by trauma, encephalitis, and other acquired conditions. Only rare reports describe idiopathic adult onset tic disorders, and most of these cases represent recurrent childhood tic disorders.
OBJECTIVE—To describe a large series of patients with tic disorders presenting during adulthood, to compare cl...

  4. High speed coding for velocity by archerfish retinal ganglion cells

    Directory of Open Access Journals (Sweden)

    Kretschmer Viola

    2012-06-01

    Full Text Available Abstract Background Archerfish show very short behavioural latencies in response to falling prey. This raises the question, which response parameters of retinal ganglion cells to moving stimuli are best suited for fast coding of stimulus speed and direction. Results We compared stimulus reconstruction quality based on the ganglion cell response parameters latency, first interspike interval, and rate. For stimulus reconstruction of moving stimuli using latency was superior to using the other stimulus parameters. This was true for absolute latency, with respect to stimulus onset, as well as for relative latency, with respect to population response onset. Iteratively increasing the number of cells used for reconstruction decreased the calculated error close to zero. Conclusions Latency is the fastest response parameter available to the brain. Therefore, latency coding is best suited for high speed coding of moving objects. The quantitative data of this study are in good accordance with previously published behavioural response latencies.

  5. Onset dominance in lateralization.

    Science.gov (United States)

    Freyman, R L; Zurek, P M; Balakrishnan, U; Chiang, Y C

    1997-03-01

    Saberi and Perrott [Acustica 81, 272-275 (1995)] found that the in-head lateralization of a relatively long-duration pulse train could be controlled by the interaural delay of the single pulse pair that occurs at onset. The present study examined this further, using an acoustic pointer measure of lateralization, with stimulus manipulations designed to determine conditions under which lateralization was consistent with the interaural onset delay. The present stimuli were wideband pulse trains, noise-burst trains, and inharmonic complexes, 250 ms in duration, chosen for the ease with which interaural delays and correlations of select temporal segments of the stimulus could be manipulated. The stimulus factors studied were the periodicity of the ongoing part of the signal as well as the multiplicity and ambiguity of interaural delays. The results, in general, showed that the interaural onset delay controlled lateralization when the steady state binaural cues were relatively weak, either because the spectral components were only sparsely distributed across frequency or because the interaural time delays were ambiguous. Onset dominance can be disrupted by sudden stimulus changes within the train, and several examples of such changes are described. Individual subjects showed strong left-right asymmetries in onset effectiveness. The results have implications for understanding how onset and ongoing interaural delay cues contribute to the location estimates formed by the binaural auditory system.

  6. Analysis of human transforming growth factor β-induced gene mutation in corneal dystrophy

    Institute of Scientific and Technical Information of China (English)

    李杨; 孙旭光; 任慧媛; 董冰; 王智群; 孙秀英

    2004-01-01

    Background Corneal dystrophy is a group of inherited blinding diseases of the cornea. This study was to identify the mutations of the keratoepithelin (KE) gene for proper diagnosis of corneal dystrophy. Methods Three families with corneal dystrophy were analysed. Thirteen individuals at risk for corneal dystrophy in family A, the proband and her son in family B, and the proband in family C were examined after their blood samples were obtained. Mutation screening of human transforming growth factor β-induced gene (BIGH3 gene) was performed. Results Five individuals in family A were found by clinical evaluation to be affected with granular corneal dystrophy and carried the BIGH3 mutation W555R. However, both probands in families B and C, also diagnosed with granular corneal dystrophy, harboured the BIGH3 mutation R124H. Conclusion Molecular genetic analysis can improve accurate diagnosis of corneal dystrophy.

  7. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    Science.gov (United States)

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  8. Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Hauerslev, S; Ørngreen, Mette Cathrine; Hertz, Jens Michael;

    2013-01-01

    The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A.......The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A....

  9. [Myotonic dystrophy as a contraindication for electroconvulsive therapy?].

    Science.gov (United States)

    Wynhoven, L M L; Scherders, M J W T; van Suijlekom, J A

    2009-01-01

    A 57-year-old woman with medication-resistant major depression was referred to our clinic for electroconvulsive therapy. After an extensive evaluation of our patient's condition we concluded that in this case the comorbid myotonic dystrophy was a contraindication for the performance of electroconvulsive therapy. However, in the current Dutch Psychiatric Association guidelines this illness is not mentioned as a possible contraindication for electroconvulsive therapy. This raises the question of whether myotonic dystrophy should now be incorporated in these guidelines and makes us wonder to what extent our conclusion could have consequences for the treatment of other neuromuscular illnesses.

  10. The paradox of muscle hypertrophy in muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy.

  11. Structural deterioration of tendon collagen in genetic muscular dystrophy.

    Science.gov (United States)

    Stinson, R H

    1975-08-19

    The structure of gastrocnemius tendons from chickens with genetically induced muscular dystrophy has been studied by low-angle X-ray diffraction. Compared with normal samples there is poor alignment of collagen within the tendons. This difference is quite pronounced at eight weeks when the affected birds are still in comparatively good physical condition. Similar changes have been reported for birds with nutritionally induced muscular dystrophy (Bartlett, M. W., Egelstaff, P. A., Holden, T. M., Stinson, R. H. and Sweeny, P. R. (1973) Biochim. Biophys. Acta 328, 213-220).

  12. [Progress of research in retinal image registration].

    Science.gov (United States)

    Yu, Lun; Wei, Lifang; Pan, Lin

    2011-10-01

    The retinal image registration has important applications in the processes of auxiliary diagnosis and treatment for a variety of diseases. The retinal image registration can be used to measure the disease process and the therapeutic effect. A variety of retinal image registration techniques have been studied extensively in recent years. However, there are still many problems existing and there are numerous research possibilities. Based on extensive investigation of existing literatures, the present paper analyzes the feature of retinal image and current challenges of retinal image registration, and reviews the transformation models of the retinal image registration technology and the main research algorithms in current retinal image registration, and analyzes the advantages and disadvantages of various types of algorithms. Some research challenges and future developing trends are also discussed.

  13. Comparative investigation of stimulus-evoked rod outer segment movement and retinal electrophysiological activity

    Science.gov (United States)

    Lu, Yiming; Wang, Benquan; Yao, Xincheng

    2017-02-01

    Transient retinal phototropism (TRP) has been observed in rod photoreceptors activated by oblique visible light flashes. Time-lapse confocal microscopy and optical coherence tomography (OCT) revealed rod outer segment (ROS) movements as the physical source of TRP. However, the physiological source of TRP is still not well understood. In this study, concurrent TRP and electroretinogram (ERG) measurements disclosed a remarkably earlier onset time of the ROS movements (low sodium treatment reversibly blocked the photoreceptor ERG a-wave, which is known to reflect hyperpolarization of retinal photoreceptors, but preserved the TRP associated rod OS movements well. Our experimental results and theoretical analysis suggested that the physiological source of TRP might be attributed to early stages of phototransduction, before the hyperpolarization of retinal photoreceptors.

  14. Retinal imaging and image analysis

    NARCIS (Netherlands)

    Abramoff, M.D.; Garvin, Mona K.; Sonka, Milan

    2010-01-01

    Many important eye diseases as well as systemic diseases manifest themselves in the retina. While a number of other anatomical structures contribute to the process of vision, this review focuses on retinal imaging and image analysis. Following a brief overview of the most prevalent causes of blindne

  15. [Surgical managment of retinal detachment].

    Science.gov (United States)

    Haritoglou, C; Wolf, A

    2015-05-01

    The detachment of the neurosensory retina from the underlying retinal pigment epithelium can be related to breaks of the retina allowing vitreous fluid to gain access to the subretinal space, to exudative changes of the choroid such as tumours or inflammatory diseases or to excessive tractional forces exerted by interactions of the collagenous vitreous and the retina. Tractional retinal detachment is usually treated by vitrectomy and exudative detachment can be addressed by treatment of the underlying condition in many cases. In rhegmatogenous retinal detachment two different surgical procedures, vitrectomy and scleral buckling, can be applied for functional and anatomic rehabilitation of our patients. The choice of the surgical procedure is not really standardised and often depends on the experience of the surgeon and other more ocular factors including lens status, the number of retinal breaks, the extent of the detachment and the amount of preexisting PVR. Using both techniques, anatomic success rates of over 90 % can be achieved. Especially in young phakic patients scleral buckling offers the true advantage to prevent the progression of cataract formation requiring cataract extraction and intraocular lens implantation. Therefore, scleral buckling should be considered in selected cases as an alternative surgical option in spite of the very important technical refinements in modern vitrectomy techniques. Georg Thieme Verlag KG Stuttgart · New York.

  16. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a Chinese population.

    Science.gov (United States)

    Shan, Jingli; Chen, Bin; Lin, Pengfei; Li, Duoling; Luo, Yuebei; Ji, Kunqian; Zheng, Jinfan; Yuan, Yun; Yan, Chuanzhu

    2014-12-01

    Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate-binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2 years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)11/(GCN)12. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)11 polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype.

  17. Left Ventricular Tonic Contraction as a Novel Biomarker of Cardiomyopathy in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Su, Jennifer A; Ramos-Platt, Leigh; Menteer, JonDavid

    2016-04-01

    Dilated cardiomyopathy (DCM) inevitably afflicts patients with Duchenne muscular dystrophy (DMD) as a consequence of cell death induced by unguarded calcium influx into cardiomyocytes. This mechanism may also inhibit muscle relaxation in early stages of cardiomyopathy. ACE inhibition (ACEi) is known to delay the onset and slow the progression of DCM in DMD. The objective of this study is to use echocardiography to assess for preclinical cardiac changes consistent with intracellular calcium dysregulation before the onset of overt ventricular dysfunction, and to evaluate how prophylactic ACEi may alter these pre-cardiomyopathic changes in the pediatric DMD population. We examined 263 echocardiograms from 70 pediatric patients with DMD. We defined abnormal tonic contraction (TC) as left ventricular internal dimension in diastole (LVIDd) Z-score < -1.5. In our cohort, we found that TC is detectable as early as 8 years of age, and most commonly affects patients between 11 and 15 years. This effect was independent of LV mass and systolic function. Prophylactic ACEi decreased the incidence of TC (p = 0.007) and preserved cardiac function (p < 0.0001). Left ventricular TC often precedes DCM in DMD, most commonly affecting the 11- to 15-year-old age range. TC is not related to ventricular hypertrophy, but rather may be a clinical correlate of the "calcium hypothesis" of DMD pathophysiology. LV TC is thus a promising biomarker for early detection of cardiomyopathy in DMD. ACEi prophylaxis suppresses LV TC and delays the development of DCM in DMD.

  18. The erythrocyte membrane in human muscular dystrophy

    NARCIS (Netherlands)

    W. Ruitenbeek (Willem)

    1979-01-01

    textabstractMore than 250 different forms of human neuromuscular diseases are known. They differ in age of onset, severity of weakness, rate of progression, type of inheritance, groups of muscles affected, frequency of incidence. Sometimes the clinical symptoms are not restricted to nervous and/or m

  19. Myotonic Dystrophy: Increased expression of the normal allele in CDM infants muscle

    Energy Technology Data Exchange (ETDEWEB)

    Radvanyi, H.H.; Gourdon, G.; Junien, C. [Inserm U, Paris (France)]|[Universite Rene Descartes, Paris (France)

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant multisystemic disorder characterized by a highly variable clinical phenotype. The mutation has been identified as an unstable trinucleotide CTG repeat in the 3{prime} untranslated region of the myotonin-protein kinase (MT-PK) gene. Congenital myotonic dystrophy (CDM), which represents the most severe phenotype, is exclusively maternally inherited. Recent studies, analysis by Northern blots and RT-PCR provided apparently conflicting results on the mutated allele expression in samples from congenitally affected children. The level of expression of the mutant allele depends on the extent of the repeat in the adult form and is no longer expressed when over 800-1300 repeats, whether in adult forms or in CDM. Could this decrease account for the late onset forms? However, the differences between the two phenotypes cannot be explained by the same mechanism. Alternatively, these differences could be due to differences in expression of the normal allele. We analyzed by quantitative RT-PCR the expression of the MT-PK gene in muscle samples from four CDM infants and two aged-matched normal controls. In two of these, the mutant allele (3.3 and 8 kb) was undetectable on Northern blots. We observed an increased expression of the MT-PK gene (10- to 20-fold) in tissues of severely affected congenital patients which can be attributed to the normal allele. Since expression of the normal allele is either normal or slightly decreased in the adult form, the dramatic increase in the congenital form could reflect a disturbance in muscle differentiation. Expression studies of MT-PK at different stages of development and, especially after the 20th week, are therefore required.

  20. Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism.

    Science.gov (United States)

    Renjini, R; Gayathri, N; Nalini, A; Srinivas Bharath, M M

    2012-04-01

    Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

  1. Neuropsychological profile of duchenne muscular dystrophy.

    Science.gov (United States)

    Perumal, Anna Roshini; Rajeswaran, Jamuna; Nalini, Atchayaram

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder characterized by progressive muscle wasting. DMD is a fatal X-linked recessive disorder with an estimated prevalence of 1 in 3,500 male live births. This disease has long been associated with intellectual impairment. Research has shown that boys with DMD have variable intellectual performance, indicating the presence of specific cognitive deficits. The aim of the study was to use a battery of intelligence, learning, and memory tests to identify a neuropsychological profile in boys with DMD. A total of 22 boys diagnosed with DMD in the age range of 6 to 10 years old were evaluated using the Wechsler Intelligence Scale for Children-Third Edition, Rey's Auditory Verbal Learning Test, and the Memory for Designs Test. The data were interpreted using means, standard deviations, percentages, and percentiles. Normative data were also used for further interpretation. The results showed that boys with DMD had a significantly lower IQ (88.5). Verbal IQ (86.59) was found to be lower than Performance IQ (92.64). There was evidence of impaired performance on the Processing Speed, Freedom From Distractibility, and Verbal Comprehension Indexes. Specific deficits in information processing, complex attention, immediate verbal memory span, verbal working memory, verbal comprehension, vocabulary, visuoconstruction ability, and verbal learning and encoding were observed. However, perceptional organization, general fund of information, abstract reasoning, visual discrimination and acuity, visual learning and memory, and verbal memory were adequate. The neuropsychological findings support the hypothesis that these children have specific cognitive deficits as opposed to a global intellectual deficit.

  2. Gastrointestinal manifestations in myotonic muscular dystrophy

    Institute of Scientific and Technical Information of China (English)

    Massimo Bellini; Sonia Biagi; Cristina Stasi; Francesco Costa; Maria Gloria Mumolo; Angelo Ricchiuti; Santino Marchi

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness.Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting.A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry,electromyography, functional ultrasonography,scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported.The drugs recommended for treating the gastrointestinal complaints such as prokinetic, antidyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders.Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD.

  3. C-terminal truncations in human 3 '-5 ' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schaefer, Ruth; Stam, Anine H.; Haan, Joost; Paulus, T. V. M. de Jong; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    2007-01-01

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activ

  4. Granular Corneal Dystrophy Manifesting after Radial Keratotomy

    Directory of Open Access Journals (Sweden)

    Sepehr Feizi

    2008-12-01

    Full Text Available

    PURPOSE: To report manifestation of granular corneal dystrophy after radial keratotomy (RK. CASE REPORT: A 32-year-old man presented with white radial lines in both corneas. He had undergone uncomplicated RK in both eyes 8 years ago. Preoperative refraction had been OD: -3.5 -0.75@180 and OS: -3.0 -0.5@175. Uncorrected visual acuity was OD: 8/10 and OS: 7/10; best corrected visual acuity was 9/10 in both eyes with OD: -0.5 -0.5@60 and OS: -0.75 -0.5@80. Slit lamp examination revealed discrete well-demarcated whitish lesions with clear intervening stroma in the central anterior cornea consistent with granular dystrophy. Similar opacities were present within the RK incisions. CONCLUSION: Granular dystrophy deposits may appear within RK incisions besides other previously reported locations.