WorldWideScience

Sample records for macular dystrophy gene

  1. 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

  2. A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy.

    NARCIS (Netherlands)

    Maugeri, A.; Meire, F.; Hoyng, C.B.; Vink, C.W.; Regemorter, N. van; Karan, G.; Yang, Z.; Cremers, F.P.M.; Zhang, K.

    2004-01-01

    PURPOSE: To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation. METHODS: Ophthalmic examination and mutation screening by direct sequencing of

  3. Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies.

    Science.gov (United States)

    Paloma, E; Martínez-Mir, A; Vilageliu, L; Gonzàlez-Duarte, R; Balcells, S

    2001-06-01

    The ABCA4 gene has been involved in several forms of inherited macular dystrophy. In order to further characterize the complex genotype-phenotype relationships involving this gene, we have performed a mutation analysis of ABCA4 in 14 Spanish patients comprising eight STGD (Stargardt), four FFM (fundus flavimaculatus), and two CRD (Cone-rod dystrophy) patients. SSCP (single-strand conformation polymorphism) analysis and DNA sequencing of the coding and 5' upstream regions of this gene allowed the identification of 16 putatively pathogenic alterations, nine of which are novel. Most of these were missense changes, and no patient was found to carry two null alleles. Overall, the new data agree with a working model relating the different pathogenic phenotypes to the severity of the mutations. When considering the information presented here together with that of previous reports, a picture of the geographic distribution of three particular mutations emerges. The R212C change has been found in French, Italian, Dutch, German, and Spanish but not in British patients. In the Spanish collection, R212C was found in a CRD patient, indicating that it may be a rather severe change. In contrast, c.2588G>C, a very common mild allele in the Dutch population, is rarely found in Southern Europe. Interestingly, the c.2588G>C mutation has been found in a double mutant allele together with the missense R1055W. Finally, the newly described L1940P was found in two unrelated Spanish patients, and may be a moderate to severe allele. Copyright 2001 Wiley-Liss, Inc.

  4. A peculiar autosomal dominant macular dystrophy caused by an asparagine deletion at codon 169 in the peripherin/RDS gene

    NARCIS (Netherlands)

    van Lith-Verhoeven, Janneke J. C.; van den Helm, Bellinda; Deutman, August F.; Bergen, Arthur A. B.; Cremers, Frans P. M.; Hoyng, Carel B.; de Jong, Paulus T. V. M.

    2003-01-01

    Objective: To describe the clinical and genetic findings in a family with a peculiar autosomal dominant macular dystrophy with peripheral deposits. Methods: All family members underwent an ophthalmic examination, and their genomic DNA was screened for mutations in the human retinal degeneration slow

  5. North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene.

    Science.gov (United States)

    Bowne, Sara J; Sullivan, Lori S; Wheaton, Dianna K; Locke, Kirsten G; Jones, Kaylie D; Koboldt, Daniel C; Fulton, Robert S; Wilson, Richard K; Blanton, Susan H; Birch, David G; Daiger, Stephen P

    2016-01-01

    To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13 . The duplication creates a partial copy of CCNC and a complete copy of PRDM13 . The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  7. Clinical and molecular genetic analysis of best vitelliform macular dystrophy.

    NARCIS (Netherlands)

    Boon, C.J.F.; Theelen, T.; Hoefsloot, L.H.; Schooneveld, M.J. van; Keunen, J.E.E.; Cremers, F.P.M.; Klevering, B.J.; Hoyng, C.B.

    2009-01-01

    PURPOSE: To describe the phenotype of Best vitelliform macular dystrophy (BVMD) and to evaluate genotype-phenotype and histopathologic correlations. METHODS: Retrospective analysis of patients with BVMD who underwent an extensive ophthalmic examination, including best-corrected Snellen visual

  8. CLINICAL AND MOLECULAR GENETIC ANALYSIS OF BEST VITELLIFORM MACULAR DYSTROPHY

    NARCIS (Netherlands)

    Boon, Camiel J. F.; Theelen, Thomas; Hoefsloot, Elisabeth H.; van Schooneveld, Mary J.; Keunen, Jan E. E.; Cremers, Frans P. M.; Klevering, B. Jeroen; Hoyng, Carel B.

    2009-01-01

    Purpose: To describe the phenotype of Best vitelliform macular dystrophy (BVMD) and to evaluate genotype-phenotype and histopathologic correlations. Methods: Retrospective analysis of patients with BVMD who underwent an extensive ophthalmic examination, including best-corrected Snellen visual

  9. Fine mapping of Best`s macular dystrophy localises the gene in close proximity to, but distinct from, the D115480/ROM1

    Energy Technology Data Exchange (ETDEWEB)

    Graff, C.; Ahlbom, B.E.; Anneren, G. [University Hospital, Uppsala (Sweden)] [and others

    1994-09-01

    Best`s macular dystrophy (BMD) is an autosomal dominant disease characterized by accumulation of lipofuscin beneath the pigment epithelium of the macula, leading to early-onset impairment of central vision. The gene has previously been mapped to 11q13. Based on DNA from 191 people from a large 12-generation family, the gene now has been mapped to a 1.5 cM interval between the markers Fc{epsilon}RI and D11S480/ROM1. By disequilibrium analysis the gene was estimated to be 0.321 cM centromeric to the marker D11S480. Since this on average corresponds to 300 kb, the gene may be at a distance contained in YAC molecules. To physically characterize this region, YAC clones positive for markers flanking BMD have been identified. Sequence analysis of the candidate gene ROM1 did not reveal any mutation. However, one recombination between intragenic ROM1 polymorphisms and BMD was detected, which make it highly unlikely that mutations in ROM1 are causing BMD.

  10. ERG and OCT findings of a patient with a clinical diagnosis of occult macular dystrophy in a patient of Ashkenazi Jewish descent associated with a novel mutation in the gene encoding RP1L1.

    Science.gov (United States)

    Saffra, Norman; Seidman, Carly Jane; Rakhamimov, Aleksandr; Tsang, Stephen H

    2017-05-04

    A 57-year-old man with a past medical history of diabetes presented for consultation with a several year history of slowly progressive vision loss in both eyes, which continued to deteriorate over 7 years of follow-up. Multimodal imaging was performed and was significant for the following: on spectral domain optical coherence tomography, a gap lesion was present in the ellipsoid layer, beneath the umbo, as well as subtle macular changes on auto fluorescence imaging. Multifocal electroretinography was performed and was abnormal, and a clinical diagnosis of occult macular dystrophy was made. The patient was subsequently evaluated with genetic testing that revealed a novel p.P73S:c 217C>T nonsense mutation within the retinitis pigmentosa 1-like-1 (RP1L1) gene. The clinical significance of the identified variation will require further investigation. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  11. Genetics Home Reference: vitelliform macular dystrophy

    Science.gov (United States)

    ... 30 [updated 2013 Dec 12]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

  12. Dome-shaped macula associated with Best vitelliform macular dystrophy.

    Science.gov (United States)

    Battaglia Parodi, Maurizio; Zucchiatti, Ilaria; Fasce, Francesco; Cascavilla, Maria Lucia; Cicinelli, Maria Vittoria; Bandello, Francesco

    2015-01-01

    Dome-shaped macula (DSM) has been described recently as an inward convexity of the macula typical of myopic eyes detectable on spectral-domain optical coherence tomography (SD-OCT). The authors describe a case of monolateral DSM associated with Best vitelliform macular dystrophy (VMD). Case report. A 60-year-old man already diagnosed with VMD in vitelliruptive stage underwent SD-OCT that revealed the typical vitelliform material accumulation associated in the left eye with a convex elevation of the macula. No change was registered over a 1-year follow-up. This is the first report describing a monolateral DSM associated with VMD. Dome-shaped macula could be considered as a nonspecific scleral alteration, probably due to increased scleral thickness, which can accompany many retinal disorders.

  13. Confirmation of linkage of Best`s macular dystrophy to 11q13, and evidence for genetic heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Mansergh, F.C.; Kenna, P.F.; Farrar, G.J. [Trinity College, Dublin (United Kingdom)] [and others

    1994-09-01

    Best`s macular dystrophy, also known as vitelliform macular degeneration, is an autosomal dominant, early onset form of macular degeneration. The disease is characterized by a roughly circular deposit of lipofuscin beneath the pigment epithelium of the retinal macula. Linkage studies were performed in two families, one Irish and one German, segregating typical Best`s macular dystrophy. In the Irish family (BTMD1), linkage analysis mapped the disease causing gene to chromosome 11q13, in a 10 cM region between the microsatellite markers PYGM and D11S871. Both markers showed different recombinants with the disease phenotype. This is a region that has previously shown linkage in families affected with Best`s macular dystrophy. Lod scores of 9.63, 9.12, 6.92, and 6.83 at zero recombination, were obtained with markers D11S1344, D11S1361, D11S1357 and D11S903, respectively. This data places the disease locus definitvely within the region between PYGM and D11S871. Linkage has been significantly excluded in this region in the German family (FamE), thereby providing evidence for genetic heterogeneity in this disease. The retinal specific gene, rod outer membrane protein 1 (ROM1), which maps to this region, has been screened for mutations in family BTMD1 by SSCPE analysis and by direct sequencing. Some of the promoter region, the three exons, and both introns have been sequenced; however, no mutations were found. It is likely that a gene other than ROM1 within this region may be responsible for causing the disease phenotype.

  14. Analysis of macular cone photoreceptors in a case of occult macular dystrophy

    Directory of Open Access Journals (Sweden)

    Tojo N

    2013-05-01

    Full Text Available Naoki Tojo Tomoko Nakamura Hironori Ozaki Miyako Oka Toshihiko Oiwake Atsushi HayashiDepartment of Ophthalmology, University of Toyama, Toyama, JapanPurpose: To investigate changes in cone photoreceptors with adaptive optics (AO fundus imaging and spectral domain optical coherence tomography (SD-OCT in a case of occult macular dystrophy (OMD.Patient and methods: Both eyes of a 42-year-old woman diagnosed with OMD were examined. We used an AO fundus camera to obtain images of cone photoreceptors in the macula of the OMD subject and five healthy control subjects. Correlations between the AO images and the SD-OCT images were examined. Cone photoreceptors in eight areas in the macula of OMD and healthy control subjects were analyzed and compared.Results: SD-OCT showed a loss of the cone outer-segment tips line outside of the fovea in both eyes of the subject with OMD. The left eye with decreased visual acuity showed a discontinuous photoreceptor inner-segment and outer-segment line and cone outer-segment tips line at the fovea in SD-OCT and loss of cone mosaics as a dark spot in the AO image. In panoramic AO images and cone-density maps, less cone density was observed in a ring-like region outside the fovea than in the peripheral retina. In most of the areas examined, the cone densities were lower in the OMD eyes than in the healthy control eyes.Conclusions: Cone densities in the macula of the OMD patient were greatly decreased. AO images were found to be useful to evaluate morphologic changes in cone photoreceptors in patients with OMD.Keywords: occult macular dystrophy, adaptive optics, cone photoreceptor, cone analysis, optical coherence tomography

  15. Late-onset Stargardt-like macular dystrophy maps to chromosome 1p13

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, J.; Gerber, S.; Rozet, J.M. [Hopital des Enfants Malades, Paris (France)] [and others

    1994-09-01

    Stargardt`s disease (MIM 248200), originally described in 1909, is an autosomal recessive condition of childhood, characterized by a sudden and bilateral loss of central vision. Typically, it has an early onset (7 to 12 years), a rapidly progressive course and a poor final outcome. The central area of the retina (macula) displays pigmentary changes in a ring form with depigmentation and atrophy of the retinal pigmentary epithelium (RPE). Perimacular yellowish spots, termed fundus flavimaculatus, are observed in a high percentage of patients. We have recently reported the genetic mapping of Stargardt`s disease to chromosome 1p13. On the other hand, considering that fundus flavimaculatus (MIM 230100) is another form of fleck fundus disease, with a Stargardt-like retinal aspect but with a late-onset and a more progressive course, we decided to test the hypothesis of allelism between typical Stargardt`s disease and late-onset autosomal recessive fundus flavimaculatus. Significant pairwise lod scores were obtained in each of four multiplex families (11 affected individuals, 12 relatives) with four markers of the 1p13 region (Z = 4.79, 4.64, 3.07, 3.16 at loci D1S435, D1S424, D1S236, and D1S415, respectively at {theta} = 0). Multipoint analysis showed that the best estimate for location of the disease gene is between D1S424 and D1S236 (maximum lod score of 5.20) as also observed in Stargardt`s disease. Our results are consistent with the location of the gene responsible of the late-onset Stargardt-like macular dystrophy in the 1p13 region and raise the hypothesis of either allelic mutational events or contiguous genes in this chromosomal region. The question of possible relationship with some age-related macular dystrophies in now open to debate.

  16. [Novel CHST6 compound heterozygous mutations cause macular corneal dystrophy in a Chinese family].

    Science.gov (United States)

    Qi, Yan-hua; Dang, Xiu-hong; Su, Hong; Zhou, Nan; Liang, Ting; Wang, Zheng; Huang, Shang-zhi

    2010-02-01

    The aim of this study was to identify mutations of CHST6 gene in a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes of MCD. Corneal button of the proband was obtained from penetrating keratoplasty for the treatment of severe corneal dystrophy. The sections and ultrathin sections of this specimen were examined under light microscope and transmission electron microscope (TEM). Genomic DNA was extracted from leukocytes in peripheral blood from the family members. The coding region of CHST6 was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by direct sequencing and restriction enzyme digestion. Histochemical study revealed positive results of colloidal iron stain. TEM revealed enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. Two mutations, Q298X Y358H, were identified in exon 3 of CHST6. Three patients were compound heterozygotes of these two mutations. The C892T transversion occurred at codon 298 turned the codon of glutamine to a stop codon; the T1072C transversion occurred at codon 358 caused a missense mutation, tyrosine to histidine. All six unaffected family members were heterozygotes. These two mutations were not detected in any of the 100 control subjects. The novel compound heterozygous mutation results in loss of CHST6 function and causes the occurrence of MCD. This is the first report of this gene mutation.

  17. 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. 2015 BMJ Publishing Group Ltd.

  18. Simultaneous Presence of Macular Corneal Dystrophy and Retinitis Pigmentosa in Three Members of a Family

    Directory of Open Access Journals (Sweden)

    Farhad Nejat

    2018-03-01

    Full Text Available Macular corneal dystrophy (MCD is an autosomal recessive hereditary disease. In most cases, various mutations in carbohydrate sulfotransferase 6 (CHST6 gene are the main cause of MCD. These mutations lead to a defect in keratan sulfate synthesis. Retinitis pigmentosa (RP is another eye disorder with nyctalopia as its common symptom. It has been shown that more than 65 genes have been implicated in different forms of RP. Herein, we report on a 9-member family with 2 girls and 5 boys. Both parents, one of the girls and one of the boys had normal eye vision and another boy had keratoconus. Other children (1 girl and 2 boys suffered from both MCD and RP. Corneal transplantation and medical supplements were used for MCD and RP during the follow-up period, respectively. Based on the family tree, it seems that the inheritance of both diseases is autosomal recessive. Based on our search of databases, there is no report on the simultaneous presence of MCD and RP. To the best of our knowledge, the present article is the first case report on this topic. Molecular genetic investigation is needed to clarify the mechanism of concurrent MCD and RP.

  19. Atypical vitelliform macular dystrophy misdiagnosed as chronic central serous chorioretinopathy: case reports

    Directory of Open Access Journals (Sweden)

    Lee Young

    2012-07-01

    Full Text Available Abstract Background To report two cases of atypical vitelliform macular dystrophy misdiagnosed as chronic central serous chorioretinopathy. Case presentation Two patients with incidentally discovered abnormalities of the retina without specific symptoms were referred to our hospital for consultation. Bilateral macula atrophic lesions were observed and optical coherence tomography revealed serous retinal detachment in the macula. Fluorescein angiography showed multiple leakages around the central hypofluorescent area and indocyanine green angiography showed partially dilated choroidal vessels. Fundus autofluorescence (FAF showed a decreasing pattern of autofluorescence in the subretinal fluid area, and increasing autofluorescence at the border of the serous retinal detachment. Both patients were diagnosed with chronic central serous chorioretinopathy. Photodynamic therapy and intravitreal bevacizumab injection were administered for engorged choroidal vessels during follow-up, but neither patient showed improvement in symptoms or ophthalmologic findings. Based on re-evaluation by fundus photography, optical coherence tomography, fluorescein angiography, and comparison of the results of FAF with the first visit, vitelliform macular dystrophy was suspected and a definite diagnosis was made by electrooculography and genetic testing. Conclusion In patients with continuous serous retinal detachment without response to photodynamic therapy or intravitreal bevacizumab injection, careful fundus exam and FAF can be used to diagnose atypical vitelliform macular dystrophy.

  20. Novel Presenting Phenotype in a Child With Autosomal Dominant Best's Vitelliform Macular Dystrophy.

    Science.gov (United States)

    Abdalla, Yasmine F; De Salvo, Gabriella; Elsahn, Ahmad; Self, James E

    2017-07-01

    Best's macular dystrophy (BMD) usually manifests with visual failure in the first or second decade of life; however, there is a large variability in expressivity of the disease, and some patients have no manifestation other than a pathological electro-oculogram (EOG). Autosomal dominant Best's vitelliform macular dystrophy (AD-BVMD) has a very specific phenotype that varies with the stage of the disease. In recent years, the authors have seen description of another clinical entity known as autosomal recessive BMD. Herein, the authors describe a 5-year-old girl referred from a peripheral hospital for investigation with a positive family history of BMD. Clinical findings included best-corrected visual acuity of 0.325 and 0.300 in the right and left eyes, respectively, by Sonksen logMar test, full color vision, normal orthoptic examination, and a small degree of hyperopia consistent with age. Macular optical coherence tomography (OCT) showed intraretinal fluid cysts and EOG showed reduced Arden ratio. Genetic testing was done for the proband and her father, who were found to be heterozygous for c.37C>T p. (Arg13Cys). The proband's younger sister will be reviewed and followed up once of age. The authors identified a new phenotype of AD-BVMD; although this is a single patient, more young children with BMD can now be scanned with the availability of hand-held OCT with better knowledge of the phenotype. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:580-585.]. Copyright 2017, SLACK Incorporated.

  1. Optical coherence tomography of the photoreceptor layer in the healthy eye and in eyes with hereditary macular dystrophy

    International Nuclear Information System (INIS)

    Stur, M.; Hermann, B.; Drexler, W.; Unterhuber, A.; Sattmann, H.; Ergun, E.; Wirtitsch, M.

    2007-01-01

    Optical coherence tomography is primarily used for the evaluation of pronounced alterations of the retinal architecture, such as in macular holes, epiretinal gliosis, intra- and subretinal fluid accumulation as well as retinal atrophy. Ultrahigh resolution OCT devices also allow the assessment of discrete alterations of the photoreceptor layer and the retinal pigment epithelium. On the basis of cases from two different macular dystrophies, the importance of the evaluation of the photoreceptor layer and its correlation with visual acuity is demonstrated.(author) [de

  2. Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophies

    Directory of Open Access Journals (Sweden)

    Erdem Yuksel

    2016-04-01

    Full Text Available ABSTRACT Purpose: To evaluate the visual outcomes, recurrence patterns, safety, and efficacy of excimer laser phototherapeutic keratectomy (PTK in conjunction with mitomycin C (MMC for corneal macular and granular diystrophies. Methods: The patients were divided into two groups. Group 1 included patients with macular corneal dystrophy (MCD that caused superficial corneal plaque opacities, and Group 2 included patients with granular corneal dystrophy (GCD. Patients in both groups were pre-, peri-, and postoperatively evaluated. The groups were compared in terms of uncorrected visual acuity (VA, best spectacle-corrected VA, presence of mild or significant recurrence, and time of recurrence. Results: Eighteen eyes (nine with MCD and nine with GCD of 18 patients (10 men and eight women were included. PTK was performed for each eye that was included in this study. The mean ablation amount was 117.8 ± 24.4 µm and 83.5 ± 45.7 µm in MCD and GCD, respectively, (p=0.18. The postoperative improvement of the mean VA was similar between the two groups before recurrences (p>0.43 and after recurrences (p>0.71. There were no statistically significant differences in the recurrence rate and the recurrence-free period for any recurrence type. Conclusion: PTK was an effective, safe, and minimally invasive procedure for patients with MCD and GCD. PTK in conjunction with MMC was similarly effective for both groups in terms of recurrence and visual outcomes.

  3. Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophies.

    Science.gov (United States)

    Yuksel, Erdem; Cubuk, Mehmet Ozgur; Eroglu, Hulya Yazıcı; Bilgihan, Kamil

    2016-04-01

    To evaluate the visual outcomes, recurrence patterns, safety, and efficacy of excimer laser phototherapeutic keratectomy (PTK) in conjunction with mitomycin C (MMC) for corneal macular and granular diystrophies. The patients were divided into two groups. Group 1 included patients with macular corneal dystrophy (MCD) that caused superficial corneal plaque opacities, and Group 2 included patients with granular corneal dystrophy (GCD). Patients in both groups were pre-, peri-, and postoperatively evaluated. The groups were compared in terms of uncorrected visual acuity (VA), best spectacle-corrected VA, presence of mild or significant recurrence, and time of recurrence. Eighteen eyes (nine with MCD and nine with GCD) of 18 patients (10 men and eight women) were included. PTK was performed for each eye that was included in this study. The mean ablation amount was 117.8 ± 24.4 µm and 83.5 ± 45.7 µm in MCD and GCD, respectively, (p=0.18). The postoperative improvement of the mean VA was similar between the two groups before recurrences (p>0.43) and after recurrences (p>0.71). There were no statistically significant differences in the recurrence rate and the recurrence-free period for any recurrence type. PTK was an effective, safe, and minimally invasive procedure for patients with MCD and GCD. PTK in conjunction with MMC was similarly effective for both groups in terms of recurrence and visual outcomes.

  4. Presentación de tres casos de distrofia macular de North Carolina Presentation of three cases with North Carolina macular dystrophy

    Directory of Open Access Journals (Sweden)

    Mavys Soto García

    2012-06-01

    Full Text Available Se presentan las características oftalmológicas de tres pacientes, dos hermanos varones y su padre con diagnóstico de distrofia macular de North Carolina. Este es un trastorno genético que produce degeneración macular congénita o de inicio precoz. Se caracteriza por una herencia autosómica dominante, con penetrancia completa, genéticamente mapeados en el cromosoma 6q16. Las lesiones son principalmente estacionarias. Las manifestaciones fundoscópicas varían. En estos pacientes predomina la lesión disciforme en área macular, disminución del grosor macular correspondiente con el coloboma macular, con idénticas particulares en los tres pacientes. La agudeza visual varía en rango de 0,6 a 0,2 en estos pacientes.The ophthalmological characteristics of three patients, two male siblings and their father, with diagnosis of North Carolina macular dystrophy were presented. This is a genetic dysfunction that causes congenital or early onset macular degeneration. It is characterized by a dominant autosomal heredity, with complete penetrance, genetically mapped in the chromosome 6q16. The lesions are mainly stationary. The funduscopic manifestations vary. The type of lesion is mainly stationary whereas funduscopic manifestations are varied. The dysciform lesion in the macular area and decrease of the macular thicness according to the macular coloboma prevailed, with identical particularities in the three patients. The visual acuity varied from 0.6 to 0.2.

  5. Macular hole-associated retinal detachment in Best vitelliform dystrophy: Series of two cases and literature review

    Science.gov (United States)

    Tewari, Ruchir; Kumar, Vinod; Ravani, Raghav; Dubey, Devashish; Chandra, Parijat; Kumar, Atul

    2018-01-01

    Two eyes of 2 patients with macular hole-associated retinal detachment in clinically diagnosed vitelliruptive stage of Best vitelliform dystrophy were surgically managed by 25-gauge sutureless pars plana vitrectomy, internal limiting membrane (ILM) peeling with inverted ILM flap, and short-acting (SF6) gas tamponade. The patients were assessed with respect to best-corrected visual acuity, color fundus photographs, shortwave fundus autofluorescence, and swept source optical coherence tomography. Surgical intervention led to Type 1 closure of macular hole, resolution of retinal detachment, and improvement in vision in both patients. PMID:29676326

  6. Macular hole-associated retinal detachment in Best vitelliform dystrophy: Series of two cases and literature review

    Directory of Open Access Journals (Sweden)

    Ruchir Tewari

    2018-01-01

    Full Text Available Two eyes of 2 patients with macular hole-associated retinal detachment in clinically diagnosed vitelliruptive stage of Best vitelliform dystrophy were surgically managed by 25-gauge sutureless pars plana vitrectomy, internal limiting membrane (ILM peeling with inverted ILM flap, and short-acting (SF6 gas tamponade. The patients were assessed with respect to best-corrected visual acuity, color fundus photographs, shortwave fundus autofluorescence, and swept source optical coherence tomography. Surgical intervention led to Type 1 closure of macular hole, resolution of retinal detachment, and improvement in vision in both patients.

  7. 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.

  8. Emerging strategies for cell and gene therapy of the muscular dystrophies

    OpenAIRE

    Muir, Lindsey A.; Chamberlain, Jeffrey S.

    2009-01-01

    The muscular dystrophies are a heterogeneous group of over 40 disorders that are characterised by muscle weakness and wasting. The most common are Duchenne muscular dystrophy and Becker muscular dystrophy, which result from mutations within the gene encoding dystrophin; myotonic dystrophy type 1, which results from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase gene; and facioscapulohumeral dystrophy, which is associated with contractions in the subtelomeric region ...

  9. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    Science.gov (United States)

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  10. Quantitative Fundus Autofluorescence in Best Vitelliform Macular Dystrophy: RPE Lipofuscin is not Increased in Non-Lesion Areas of Retina.

    Science.gov (United States)

    Sparrow, Janet R; Duncker, Tobias; Woods, Russell; Delori, François C

    2016-01-01

    Since the lipofuscin of retinal pigment epithelial (RPE) cells has been implicated in the pathogenesis of Best vitelliform macular dystrophy, we quantified fundus autofluorescence (quantitative fundus autofluorescence, qAF) as an indirect measure of RPE lipofuscin levels. Mean non-lesion qAF was found to be within normal limits for age. By spectral domain optical coherence tomography (SD-OCT) vitelliform lesions presented as fluid-filled subretinal detachments containing reflective material. We discuss photoreceptor outer segment debris as the source of the intense fluorescence of these lesions and loss of anion channel functioning as an explanation for the bullous photoreceptor-RPE detachment. Unexplained is the propensity of the disease for central retina.

  11. 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....... in delivering a gene to all muscle groups. Cell replacement therapy has also been difficult to realize. Will it even be possible to design specific therapy protocols for all MDs? Or is a more realistic goal to treat some of the secondary manifestations that are common to several forms of MD, such as membrane...

  12. An experimental study of BIGH3 gene mutations in the patients with corneal dystrophies

    International Nuclear Information System (INIS)

    Jin Tao; Zou Liuhe; Yang Ling

    2004-01-01

    Objective: To evaluate BIGH3 gene mutations in Chinese patents with corneal dystrophies. Methods: 2ml peripheral venous blood was collected from 15 patients with granular corneal dystrophies and 5 normal subjects. Leucocytes DNA was extracted with standard method. With two pairs of oligonucleotide primers, exon 4 and exon 12 of the BIGH3 gene were amplified using the polymerase chain reaction. Amplified DNA fragments were purified and sequenced directly. Results: Mutations in BIGH3 gene were detected in all the patients with corneal dystrophies. BIGH3 gene mutations were not found in normal subjects. 12 patients with Avellino corneal dystrophy had the missense mutation R124H in the BIGH3 gene. 3 patients with granular corneal dystrophy had the missense mutation R555W in the BIGH3 gene. Conclusion: R124H and R555W mutations in BIGH3 gene were also found in the Chinese patients with Avellino and granular corneal dystrophies. In China, Avellino corneal dystrophy associated with the R124H mutation is the most common form in the corneal dystrophies resulted by BIGH3 gene mutions. Condon 124 and 555 are also the hot spots for the mutations in the BIGH3 gene in the Chinese patients with corneal dystrophies. Molecular genetic analysis may be repuired for proper diagnosis and subclassification of corneal dystrophies. (authors)

  13. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene.

    Science.gov (United States)

    Fishman, G A; Stone, E M; Grover, S; Derlacki, D J; Haines, H L; Hockey, R R

    1999-04-01

    To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene. Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene. Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene. Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change. A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of

  14. Three Studies Point to Same Risk Gene for Age-Related Macular Degeneration

    Science.gov (United States)

    ... point to same risk gene for age-related macular degeneration NIH-funded research helps unravel the biology of ... rare, but powerful risk factor for age-related macular degeneration (AMD), a common cause of vision loss in ...

  15. 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.

  16. Macular xanthophylls, lipoprotein-related genes, and age-related macular degeneration.

    Science.gov (United States)

    Koo, Euna; Neuringer, Martha; SanGiovanni, John Paul

    2014-07-01

    Plant-based macular xanthophylls (MXs; lutein and zeaxanthin) and the lutein metabolite meso-zeaxanthin are the major constituents of macular pigment, a compound concentrated in retinal areas that are responsible for fine-feature visual sensation. There is an unmet need to examine the genetics of factors influencing regulatory mechanisms and metabolic fates of these 3 MXs because they are linked to processes implicated in the pathogenesis of age-related macular degeneration (AMD). In this work we provide an overview of evidence supporting a molecular basis for AMD-MX associations as they may relate to DNA sequence variation in AMD- and lipoprotein-related genes. We recognize a number of emerging research opportunities, barriers, knowledge gaps, and tools offering promise for meaningful investigation and inference in the field. Overviews on AMD- and high-density lipoprotein (HDL)-related genes encoding receptors, transporters, and enzymes affecting or affected by MXs are followed with information on localization of products from these genes to retinal cell types manifesting AMD-related pathophysiology. Evidence on the relation of each gene or gene product with retinal MX response to nutrient intake is discussed. This information is followed by a review of results from mechanistic studies testing gene-disease relations. We then present findings on relations of AMD with DNA sequence variants in MX-associated genes. Our conclusion is that AMD-associated DNA variants that influence the actions and metabolic fates of HDL system constituents should be examined further for concomitant influence on MX absorption, retinal tissue responses to MX intake, and the capacity to modify MX-associated factors and processes implicated in AMD pathogenesis. © 2014 American Society for Nutrition.

  17. Macular xanthophylls, lipoprotein-related genes, and age-related macular degeneration1234

    Science.gov (United States)

    Koo, Euna; Neuringer, Martha; SanGiovanni, John Paul

    2014-01-01

    Plant-based macular xanthophylls (MXs; lutein and zeaxanthin) and the lutein metabolite meso-zeaxanthin are the major constituents of macular pigment, a compound concentrated in retinal areas that are responsible for fine-feature visual sensation. There is an unmet need to examine the genetics of factors influencing regulatory mechanisms and metabolic fates of these 3 MXs because they are linked to processes implicated in the pathogenesis of age-related macular degeneration (AMD). In this work we provide an overview of evidence supporting a molecular basis for AMD-MX associations as they may relate to DNA sequence variation in AMD- and lipoprotein-related genes. We recognize a number of emerging research opportunities, barriers, knowledge gaps, and tools offering promise for meaningful investigation and inference in the field. Overviews on AMD- and high-density lipoprotein (HDL)–related genes encoding receptors, transporters, and enzymes affecting or affected by MXs are followed with information on localization of products from these genes to retinal cell types manifesting AMD-related pathophysiology. Evidence on the relation of each gene or gene product with retinal MX response to nutrient intake is discussed. This information is followed by a review of results from mechanistic studies testing gene-disease relations. We then present findings on relations of AMD with DNA sequence variants in MX-associated genes. Our conclusion is that AMD-associated DNA variants that influence the actions and metabolic fates of HDL system constituents should be examined further for concomitant influence on MX absorption, retinal tissue responses to MX intake, and the capacity to modify MX-associated factors and processes implicated in AMD pathogenesis. PMID:24829491

  18. Progress toward Gene Therapy for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Chamberlain, Joel R; Chamberlain, Jeffrey S

    2017-05-03

    Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  19. 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.

  20. Recent Advancements in Gene Therapy for Hereditary Retinal Dystrophies

    Directory of Open Access Journals (Sweden)

    Ayşe Öner

    2017-12-01

    Full Text Available Hereditary retinal dystrophies (HRDs are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision, and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family, highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been proposed as potentially efficacious therapies. Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Dozens of promising proofs of concept have been obtained in animal models of HRDs and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. This review summarizes the clinical development of retinal gene therapy.

  1. Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

    Science.gov (United States)

    2015-01-01

    Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

  2. Age-Related Macular Degeneration: Insights into Inflammatory Genes

    Directory of Open Access Journals (Sweden)

    Raffaella Cascella

    2014-01-01

    Full Text Available Age-related macular degeneration (AMD is a progressive neurodegenerative disease that affects approximately 8.7% of elderly people worldwide (>55 years old. AMD is characterized by a multifactorial aetiology that involves several genetic and environmental risk factors (genes, ageing, smoking, family history, dietary habits, oxidative stress, and hypertension. In particular, ageing and cigarette smoking (including oxidative compounds and reactive oxygen species have been shown to significantly increase susceptibility to the disease. Furthermore, different genes (CFH, CFI, C2, C3, IL-6, IL-8, and ARMS2 that play a crucial role in the inflammatory pathway have been associated with AMD risk. Several genetic and molecular studies have indicated the participation of inflammatory molecules (cytokines and chemokines, immune cells (macrophages, and complement proteins in the development and progression of the disease. Taking into consideration the genetic and molecular background, this review highlights the genetic role of inflammatory genes involved in AMD pathogenesis and progression.

  3. Lipids, lipid genes, and incident age-related macular degeneration: the three continent age-related macular degeneration consortium

    NARCIS (Netherlands)

    Klein, Ronald; Myers, Chelsea E.; Buitendijk, Gabriëlle H. S.; Rochtchina, Elena; Gao, Xiaoyi; de Jong, Paulus T. V. M.; Sivakumaran, Theru A.; Burlutsky, George; McKean-Cowdin, Roberta; Hofman, Albert; Iyengar, Sudha K.; Lee, Kristine E.; Stricker, Bruno H.; Vingerling, Johannes R.; Mitchell, Paul; Klein, Barbara E. K.; Klaver, Caroline C. W.; Wang, Jie Jin

    2014-01-01

    To describe associations of serum lipid levels and lipid pathway genes to the incidence of age-related macular degeneration (AMD). Meta-analysis. setting: Three population-based cohorts. population: A total of 6950 participants from the Beaver Dam Eye Study (BDES), Blue Mountains Eye Study (BMES),

  4. Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy.

    Science.gov (United States)

    Al-Zaidy, Samiah A; Sahenk, Zarife; Rodino-Klapac, Louise R; Kaspar, Brian; Mendell, Jerry R

    2015-09-02

    Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin.

  5. Descrição de nova distrofia macular associada à síndrome dos cabelos anágenos frouxos New macular dystrophy associated with loose anagen hair syndrome

    Directory of Open Access Journals (Sweden)

    Mário Teruo Sato

    2002-03-01

    Full Text Available Objetivos: Descrever os achados oftalmológicos, dermatológicos e de microscopia óptica (MO e microscopia eletrônica de varredura (MEV de nova distrofia macular associada à síndrome dos cabelos anágenos frouxos (SCAF. Métodos: Uma família de sete pacientes, quatro deles afetados, foi examinada. Os pacientes foram submetidos ao exame oftalmológico completo, teste de cores (Ishihara e Farnsworth D-15, ecografia, angiografia, exames laboratoriais e dermatológico, teste do suor, microscopia óptica e microscopia eletrônica de varredura dos fios de cabelo. Resultados: Em duas irmãs afetadas encontramos no fundo de olho dispersões pigmentares em pólo posterior da retina, com estafiloma da mácula. Em dois irmãos foram encontradas as mesmas dispersões pigmentares em pólo posterior, com maior pigmentação e coloração amarelada em área macular e sem estafiloma. A avaliação na microscopia óptica e microscopia eletrônica de varredura dos indivíduos afetados confirmou a SCAF. Em uma mulher e em um homem não afetados todos os exames foram normais, exceto que na MO e MEV encontramos algumas semelhanças com os indivíduos afetados. Quanto ao modo de herança, o heredograma é compatível com herança autossômica recessiva com expressão parcial no heterozigoto. Conclusões: Há somente um relato na literatura internacional da associação de SCAF e coloboma ocular. Neste trabalho descrevemos os achados de nova distrofia macular associada à síndrome dos cabelos anágenos frouxos, distrofia cujos achados fundoscópicos são diferentes entre homens e mulheres. Por se tratar do primeiro relato na literatura, os achados descritos sugerem fortemente que esta associação pode ser parte de uma nova entidade nosológica.Purpose: To describe the ophthalmological, dermatological, light microscopy (LM and scanning electron microscopy (SEM findings of a new macular dystrophy associated with the loose anagen hair syndrome (LAHS. Methods: A

  6. Advances in gene therapy for muscular dystrophies [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Hayder Abdul-Razak

    2016-08-01

    Full Text Available 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.

  7. DGGE based whole-gene mutation scanning of the dystrophlin gene in Duchenne and Becker muscular dystrophy patients

    NARCIS (Netherlands)

    Hofstra, RMW; Mulder, IM; Vossen, R; de Koning-Gans, PAM; Kraak, M; Ginjaar, IB; van der Hout, AH; Bakker, E; Buys, CHCM; van Essen, AJ; den Dunnen, JT

    2004-01-01

    Duchenne and Becker muscular dystrophy (DMD and BMD) are caused by mutations in the dystrophin gene. Large rearrangements in the gene are found in about two,thirds of DMD patients, with similar to60% carrying deletions and 5-10% carrying duplications. Most of the remaining 30-35% of patients are

  8. Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle

    Science.gov (United States)

    Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.

    1988-03-01

    A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.

  9. Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene

    DEFF Research Database (Denmark)

    Xu, H; Wu, X R; Wewer, U M

    1994-01-01

    The classic murine muscular dystrophy strain, dy, was first described almost 40 years ago. We have identified the molecular basis of an allele of dy, called dy2J, by detecting a mutation in the laminin alpha 2 chain gene--the first identified mutation in laminin-2. The G to A mutation in a splice...

  10. Cone rod dystrophies

    Science.gov (United States)

    Hamel, Christian P

    2007-01-01

    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 always advised. Currently

  11. 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

  12. Gene-diet interactions in age-related macular degeneration

    Science.gov (United States)

    Age-related macular degeneration (AMD) is a prevalent blinding disease, accounting for roughly 50% of blindness in developed nations. Very significant advances have been made in terms of discovering genetic susceptibilities to AMD as well as dietary risk factors. To date, nutritional supplementation...

  13. [From gene to disease: from the ABCA4 gene to Stargardt disease, cone-rod dystrophy and retinitis pigmentosa

    NARCIS (Netherlands)

    Cremers, F.P.M.; Maugeri, A.; Klevering, B.J.; Hoefsloot, L.H.; Hoyng, C.B.

    2002-01-01

    Autosomal recessive Stargardt disease is caused by mutations in the ABCA4 gene. Mutations in ABCA4 are also found in two-thirds of cases with autosomal recessive cone-rod dystrophy, and a small fraction of patients with autosomal recessive retinitis pigmentosa. Patients with autosomal recessive

  14. Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

    Energy Technology Data Exchange (ETDEWEB)

    Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y. [Tel Aviv Univ. (Israel)

    1994-02-15

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.

  15. Gene Ontology and KEGG Enrichment Analyses of Genes Related to Age-Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Jian Zhang

    2014-01-01

    Full Text Available Identifying disease genes is one of the most important topics in biomedicine and may facilitate studies on the mechanisms underlying disease. Age-related macular degeneration (AMD is a serious eye disease; it typically affects older adults and results in a loss of vision due to retina damage. In this study, we attempt to develop an effective method for distinguishing AMD-related genes. Gene ontology and KEGG enrichment analyses of known AMD-related genes were performed, and a classification system was established. In detail, each gene was encoded into a vector by extracting enrichment scores of the gene set, including it and its direct neighbors in STRING, and gene ontology terms or KEGG pathways. Then certain feature-selection methods, including minimum redundancy maximum relevance and incremental feature selection, were adopted to extract key features for the classification system. As a result, 720 GO terms and 11 KEGG pathways were deemed the most important factors for predicting AMD-related genes.

  16. Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain

    Science.gov (United States)

    Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas

    1988-03-01

    Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

  17. Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Andrea Farini

    2014-01-01

    Full Text Available Muscular dystrophies (MDs are a heterogeneous group of diseases, caused by mutations in different components of sarcolemma, extracellular matrix, or enzymes. Inflammation and innate or adaptive immune response activation are prominent features of MDs. Various therapies under development are directed toward rescuing the dystrophic muscle damage using gene transfer or cell therapy. Here we discussed current knowledge about involvement of immune system responses to experimental therapies in MDs.

  18. The muscular dystrophies associated with central nervous system lesions: a brief review from a standpoint of the localization and function of causative genes.

    Science.gov (United States)

    Yamamoto, Tomoko; Hiroi, Atsuko; Osawa, Makiko; Shibata, Noriyuki

    2014-01-01

    The muscular dystrophies have been traditionally classified based mainly on clinical manifestation and mode of inheritance. Owing to the discoveries of causative genes, new terminologies derived from each gene, such as dystrophinopathy, α-dystroglycanopathy, sarcoglycanopathy and fukutinopathy, have also become common. Mutations of each gene may cause several clinical phenotypes. Some muscular dystrophies accompany central nervous system (CNS) lesions, especially in the congenital muscular dystrophies. Cobblestone lissencephaly (type II lissencephaly) is a well-known CNS malformation observed in severe forms of α-dystroglycanopathy. Moreover, CNS involvement has been reported in other muscular dystrophies, such as Duchenne muscular dystrophy. In this review, genes related to the muscular dystrophies associated with CNS lesions are briefly described along with the molecular characteristics of each gene and the pathomechanism of the CNS lesions. Understanding of both the clinicopathological characteristics of these CNS lesions and their molecular mechanisms is important for the diagnosis, care of patients, and development of new therapeutic strategies.

  19. Immunological identification of a high molecular weight protein as a condidate for the product of the Duchenne muscular dystrophy gene

    Energy Technology Data Exchange (ETDEWEB)

    Kao, L.; Krstenansky, J.; Mendell, J.; Rammohan, K.W.; Gruenstein, E. (Univ. of Cincinnati College of Medicine, OH (USA))

    1988-06-01

    An oligopeptide was synthesized based on translation of the nucleotide sequence of the putative exon region of clone pERT87-25 from the gene for Duchenne muscular dystrophy. Immunization of rabbits with this oligopeptide induced the formation of antibodies directed against a protein present in human, rat, and rabbit skeletal muscle. This protein, which is missing in the skeletal muscle of two patients with Duchenne muscular dystrophy, has a molecular mass of {approx}320-420 kDa and is clearly different from the putative Duchenne muscular dystrophy-related protein nebulin. The data suggest that this 320-420-kDa protein is produced by the Duchenne muscular dystrophy gene.

  20. Immunological identification of a high molecular weight protein as a condidate for the product of the Duchenne muscular dystrophy gene

    International Nuclear Information System (INIS)

    Kao, L.; Krstenansky, J.; Mendell, J.; Rammohan, K.W.; Gruenstein, E.

    1988-01-01

    An oligopeptide was synthesized based on translation of the nucleotide sequence of the putative exon region of clone pERT87-25 from the gene for Duchenne muscular dystrophy. Immunization of rabbits with this oligopeptide induced the formation of antibodies directed against a protein present in human, rat, and rabbit skeletal muscle. This protein, which is missing in the skeletal muscle of two patients with Duchenne muscular dystrophy, has a molecular mass of ∼320-420 kDa and is clearly different from the putative Duchenne muscular dystrophy-related protein nebulin. The data suggest that this 320-420-kDa protein is produced by the Duchenne muscular dystrophy gene

  1. From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Barresi Rita

    2011-06-01

    Full Text Available Abstract Muscular dystrophies are a large heterogeneous group of inherited diseases that cause progressive muscle weakness and permanent muscle damage. Very few muscular dystrophies show sufficient specific clinical features to allow a definite diagnosis. Because of the currently limited capacity to screen for numerous genes simultaneously, muscle biopsy is a time and cost-effective test for many of these disorders. Protein analysis interpreted in correlation with the clinical phenotype is a useful way of directing genetic testing in many types of muscular dystrophies. Immunohistochemistry and western blot are complementary techniques used to gather quantitative and qualitative information on the expression of proteins involved in this group of diseases. Immunoanalysis has a major diagnostic application mostly in recessive conditions where the absence of labelling for a particular protein is likely to indicate a defect in that gene. However, abnormalities in protein expression can vary from absence to very subtle reduction. It is good practice to test muscle biopsies with antibodies for several proteins simultaneously and to interpret the results in context. Indeed, there is a degree of direct or functional association between many of these proteins that is reflected by the presence of specific secondary abnormalities that are of value, especially when the diagnosis is not straightforward.

  2. Deletion Analysis Of The Duchenne/Becker Muscular Dystrophy Gene Using Multiplex Polymerase Chain Reaction

    Directory of Open Access Journals (Sweden)

    Dastur R

    2003-01-01

    Full Text Available The diagnosis of Duchenne Muscular Dystrophy (DMD and Becker Muscular Dystrophy (BMD is mainly based on clinical profile, serum CPK values, muscle biopsy and immunostaining for dystrophin. Most recent and accurate method for diagnosing DMD/BMD is by detection of mutations in the DMD gene. This was done in 100 unrelated patients using 19 exons including the promoter region in two sets of multiplex polymerase chain reaction (PCR. These primers amplify most of the exons in the deletion prone ′hotspot′ regions allowing determination of deletion end point. Intragenic deletions were detected in 74 patients indicating that the use of PCR-based assays will allow deletion detection help in prenatal diagnosis for most of the DMD/BMD patients. The frequency of deletions observed in the present study was 74%.

  3. Conservation of the Duchenne muscular dystrophy gene in mice and humans

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, E.P.; Monaco, A.P.; Feener, C.C.; Kunkel, L.M.

    1987-10-16

    A portion of the Duchenne muscular dystrophy (DMD) gene transcript from human fetal skeletal muscle and mouse adult heart was sequence, representing approximately 25 percent of the total, 14-kb DMD transcript. The nucleic acid and predicted amino acid sequences from the two species are nearly 90 percent homologous. The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggest that the DMD protein is not nebulin.

  4. System Biology Approach: Gene Network Analysis for Muscular Dystrophy.

    Science.gov (United States)

    Censi, Federica; Calcagnini, Giovanni; Mattei, Eugenio; Giuliani, Alessandro

    2018-01-01

    Phenotypic changes at different organization levels from cell to entire organism are associated to changes in the pattern of gene expression. These changes involve the entire genome expression pattern and heavily rely upon correlation patterns among genes. The classical approach used to analyze gene expression data builds upon the application of supervised statistical techniques to detect genes differentially expressed among two or more phenotypes (e.g., normal vs. disease). The use of an a posteriori, unsupervised approach based on principal component analysis (PCA) and the subsequent construction of gene correlation networks can shed a light on unexpected behaviour of gene regulation system while maintaining a more naturalistic view on the studied system.In this chapter we applied an unsupervised method to discriminate DMD patient and controls. The genes having the highest absolute scores in the discrimination between the groups were then analyzed in terms of gene expression networks, on the basis of their mutual correlation in the two groups. The correlation network structures suggest two different modes of gene regulation in the two groups, reminiscent of important aspects of DMD pathogenesis.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Screening of Dystrophin Gene Deletions in Egyptian Patients with DMD/BMD Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Laila K. Effat

    2000-01-01

    Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are allelic disorders caused by mutations within the dystrophin gene. Our study has identified 100 Egyptian families collected from the Human Genetics Clinic, National Research Center, Cairo. All cases were subjected to complete clinical evaluation pedigree analysis, electromyography studies, estimation of serum creatine phosphokinase enzyme (CPK levels and DNA analysis. Multiplex PCR using 18 pairs of specific primers were used for screening of deletion mutations within the dystrophin gene. A frequency of 55% among the families. Sixty per cent of detected deletions involved multiple exons spanning the major or the minor hot spot of the dystrophin gene. The remainder 40% which mainly involved exon 45. Comparing these findings with frequencies of other countries it was found that our figures fall within the reported range of 40%– for deletions. The distribution of deletions in our study and other different studies was variable and specific ethnic differences do not apparently account for specific deletions. In addition this study concluded that employment of the 18 exon analysis is a cost effective and a highly accurate (97% to launch a nationwide program.

  7. Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy

    Science.gov (United States)

    Wehling-Henricks, Michelle; Li, Zhenzhi; Lindsey, Catherine; Wang, Ying; Welc, Steven S.; Ramos, Julian N.; Khanlou, Négar; Kuro-o, Makoto; Tidball, James G.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a lethal muscle disease involving progressive loss of muscle regenerative capacity and increased fibrosis. We tested whether epigenetic silencing of the klotho gene occurs in the mdx mouse model of DMD and whether klotho silencing is an important feature of the disease. Our findings show that klotho undergoes muscle-specific silencing at the acute onset of mdx pathology. Klotho experiences increased methylation of CpG sites in its promoter region, which is associated with gene silencing, and increases in a repressive histone mark, H3K9me2. Expression of a klotho transgene in mdx mice restored their longevity, reduced muscle wasting, improved function and greatly increased the pool of muscle-resident stem cells required for regeneration. Reductions of fibrosis in late, progressive stages of the mdx pathology achieved by transgene expression were paralleled by reduced expression of Wnt target genes (axin-2), transforming growth factor-beta (TGF-β1) and collagens types 1 and 3, indicating that Klotho inhibition of the profibrotic Wnt/TGFβ axis underlies its anti-fibrotic effect in aging, dystrophic muscle. Thus, epigenetic silencing of klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease. PMID:27154199

  8. Gene expression profiling in limb-girdle muscular dystrophy 2A.

    Directory of Open Access Journals (Sweden)

    Amets Sáenz

    Full Text Available Limb-girdle muscular dystrophy type 2A (LGMD2A is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3. Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens, cell adhesion (fibronectin, muscle development (myosins and melusin and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB is upregulated in LGMD2A muscle samples, it could be hypothesized that beta-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1. Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies.

  9. Clinical study of DMD gene point mutation causing Becker muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Ji-qing CAO

    2015-07-01

    Full Text Available Background  DMD gene point mutation, mainly nonsense mutation, always cause the most severe Duchenne muscular dystrophy (DMD. However, we also observed some cases of Becker muscular dystrophy (BMD carrying DMD point mutation. This paper aims to explore the mechanism of DMD point mutation causing BMD, in order to enhance the understanding of mutation types of BMD.  Methods  Sequence analysis was performed in 11 cases of BMD confirmed by typical clinical manifestations and muscle biopsy. The exon of DMD gene was detected non-deletion or duplication by multiplex ligation-dependent probe amplification (MLPA.  Results  Eleven patients carried 10 mutation types without mutational hotspot. Six patients carried nonsense mutations [c.5002G>T, p.(Glu1668X; c.1615C > T, p.(Arg539X; c.7105G > T, p.(Glu2369X; c.5287C > T, p.(Arg1763X; c.9284T > G, p.(Leu3095X]. One patient carried missense mutation [c.5234G > A, p.(Arg1745His]. Two patients carried frameshift mutations (c.10231dupT, c.10491delC. Two patients carried splicing site mutations (c.4518 + 3A > T, c.649 + 2T > C.  Conclusions  DMD gene point mutation may result in BMD with mild clinical symptoms. When clinical manifestations suggest the possibility of BMD and MLPA reveals non?deletion or duplication mutation of DMD gene, BMD should be considered. Study on the mechanism of DMD point mutation causing BMD is very important for gene therapy of DMD. DOI: 10.3969/j.issn.1672-6731.2015.06.005

  10. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk.

    Science.gov (United States)

    Vollrath, D; Feng, W; Duncan, J L; Yasumura, D; D'Cruz, P M; Chappelow, A; Matthes, M T; Kay, M A; LaVail, M M

    2001-10-23

    The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy (rdy) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.

  11. Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.

    Science.gov (United States)

    Nance, Michael E; Duan, Dongsheng

    2015-12-01

    Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.

  12. Progress on gene therapy, cell therapy, and pharmacological strategies toward the treatment of oculopharyngeal muscular dystrophy.

    Science.gov (United States)

    Harish, Pradeep; Malerba, Alberto; Dickson, George; Bachtarzi, Houria

    2015-05-01

    Oculopharyngeal muscular dystrophy (OPMD) is a muscle-specific, late-onset degenerative disorder whereby muscles of the eyes (causing ptosis), throat (leading to dysphagia), and limbs (causing proximal limb weakness) are mostly affected. The disease is characterized by a mutation in the poly(A)-binding protein nuclear-1 (PABPN1) gene, resulting in a short GCG expansion in the polyalanine tract of PABPN1 protein. Accumulation of filamentous intranuclear inclusions in affected skeletal muscle cells constitutes the pathological hallmark of OPMD. This review highlights the current translational research advances in the treatment of OPMD. In vitro and in vivo disease models are described. Conventional and experimental therapeutic approaches are discussed with emphasis on novel molecular therapies including the use of intrabodies, gene therapy, and myoblast transfer therapy.

  13. Immunological identification of a high molecular weight protein as a candidate for the product of the Duchenne muscular dystrophy gene.

    OpenAIRE

    Kao, L; Krstenansky, J; Mendell, J; Rammohan, K W; Gruenstein, E

    1988-01-01

    An oligopeptide was synthesized based on translation of the nucleotide sequence of the putative exon region of clone pERT87-25 from the gene for Duchenne muscular dystrophy. Immunization of rabbits with this oligopeptide induced the formation of antibodies directed against a protein present in human, rat, and rabbit skeletal muscle. This protein, which is missing in the skeletal muscle of two patients with Duchenne muscular dystrophy, has a molecular mass of approximately equal to 320-420 kDa...

  14. Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.

    NARCIS (Netherlands)

    Jaakson, K.; Zernant, J.; Kulm, M.; Hutchinson, A.; Tonisson, N.; Glavac, D.; Ravnik-Glavac, M.; Hawlina, M.; Meltzer, M.R.; Caruso, R.C.; Testa, F.; Maugeri, A.; Hoyng, C.B.; Gouras, P.; Simonelli, F.; Lewis, R.A.; Lupski, J.R.; Cremers, F.P.M.; Allikmets, R.

    2003-01-01

    Genetic variation in the ABCR (ABCA4) gene has been associated with five distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), and age-related macular degeneration (AMD). Comparative genetic analyses of ABCR variation and diagnostics

  15. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....

  16. Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

    Directory of Open Access Journals (Sweden)

    Rasic Milic V.

    2014-12-01

    Full Text Available Duchenne muscular dystrophy (DMD is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation- dependent probe amplification (MLPA, polymerase chain reaction (PCR] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale. In 37 patients with an estimated full scale intelligence quotient (FSIQ, six (16.22% had borderline intelligence (70

  17. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

    Science.gov (United States)

    McGreevy, Joe W.; Hakim, Chady H.; McIntosh, Mark A.; Duan, Dongsheng

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs. PMID:25740330

  18. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy.

    Science.gov (United States)

    McGreevy, Joe W; Hakim, Chady H; McIntosh, Mark A; Duan, Dongsheng

    2015-03-01

    Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs. © 2015. Published by The Company of Biologists Ltd.

  19. Duchenne muscular dystrophy diagnosed by dystrophin gene deletion test: A case report

    Directory of Open Access Journals (Sweden)

    Rathod Kishor G, Dawre Rahul M, Kamble Milind B,Tambe Saleem H

    2014-04-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disease affecting 1 in 3600—6000 live male births. A muscle biopsy is not necessary if a genetic diagnosis is secured first, particularly as some families might view the procedure as traumatic. DMD occurs as a result of mutations (mainly deletions in the dystrophin gene (DMD; locus Xp21.2. Mutations lead to an absence of or defect in the protein dystrophin, which results in progressive muscle degeneration leading to loss of independent ambulation. Ninety percent of out frame mutations result in DMD, while 90% of in-frame mutations result in BMD. Electron microscopy is not required to confirm DMD. Genetic testing is mandatory irrespective of biopsy results. But the muscle biopsy is not required if the diagnosis is secured first by genetic testing.

  20. Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: Deletion detection and familial diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Patino, A.; Garcia-Delgado, M.; Narbona, J. [Univ. of Navarra, Pamplona (Spain)

    1995-11-06

    Deletion studies were performed in 26 Duchenne muscular dystrophy (DMD) patients through amplification of nine different exons by multiplex polymerase chain reaction (PCR). DNA from paraffin-embedded muscle biopsies was analyzed in 12 of the 26 patients studied. Optimization of this technique is of great utility because it enables analysis of material stored in pathology archives. PCR deletion detection, useful in DMD-affected boys, is problematic in determining the carrier state in female relatives. For this reason, to perform familial linkage diagnosis, we made use of a dinucleotide repeat polymorphism (STRP, or short tandem repeat polymorphism) located in intron 49 of the gene. We designed a new pair of primers that enabled the detection of 22 different alleles in relatives in the 14 DMD families studied. The use of this marker allowed familial diagnosis in 11 of the 14 DMD families and detection of de novo deletions in 3 of the probands. 8 refs., 5 figs., 2 tabs.

  1. 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...... 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....

  2. Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy

    Science.gov (United States)

    Robinson-Hamm, Jacqueline N.; Gersbach, Charles A.

    2016-01-01

    Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength. Exon skipping with oligonucleotides has been successful in several animal models and evaluated in multiple clinical trials. Next-generation oligonucleotide formulations offer significant promise to build on these results. All these approaches to restoring dystrophin expression are encouraging, but many hurdles remain. This review summarizes the current state of these technologies and summarizes considerations for their future development. PMID:27542949

  3. Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds

    NARCIS (Netherlands)

    Wasmann, Rosemarie A.; Wassink-Ruiter, Jolien S. Klein; Sundin, Olof H.; Morales, Elisa; Verheij, Joke B. G. M.; Pott, Jan Willem R.

    Abstract. Purpose: We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds. Methods: Ophthalmological examination, general paediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings.

  4. Associations between genetic polymorphisms of insulin-like growth factor axis genes and risk for age-related macular degeneration

    Science.gov (United States)

    Purpose: Our objective was to investigate if insulin-like growth factor (IGF) axis genes affect the risk for age-related macular degeneration (AMD). Methods: 864 Caucasian non-diabetic participants from the Age-Related Eye Disease Study (AREDS) Genetic Repository were used in this case control st...

  5. A case report: Becker muscular dystrophy presenting with epilepsy and dysgnosia induced by duplication mutation of Dystrophin gene.

    Science.gov (United States)

    Miao, Jing; Feng, Jia-Chun; Zhu, Dan; Yu, Xue-Fan

    2016-12-12

    Becker muscular dystrophy (BMD), a genetic disorder of X-linked recessive inheritance, typically presents with gradually progressive muscle weakness. The condition is caused by mutations of Dystrophin gene located at Xp21.2. Epilepsy is an infrequent manifestation of BMD, while cases of BMD with dysgnosia are extremely rare. We describe a 9-year-old boy with BMD, who presented with epilepsy and dysgnosia. Serum creatine kinase level was markedly elevated (3665 U/L). Wechsler intelligence tests showed a low intelligence quotient (IQ = 65). Electromyogram showed slight myogenic changes and skeletal muscle biopsy revealed muscular dystrophy. Immunohistochemical staining showed partial positivity of sarcolemma for dystrophin-N. Multiplex ligation-dependent probe amplification revealed a duplication mutation in exons 37-44 in the Dystrophin gene. The present case report helps to better understand the clinical and genetic features of BMD.

  6. Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.

    Science.gov (United States)

    Simonelli, Francesca; Testa, Francesco; Zernant, Jana; Nesti, Anna; Rossi, Settimio; Rinaldi, Ernesto; Allikmets, Rando

    2004-01-01

    Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology. Copyright 2004 S. Karger AG, Basel

  7. Community Structure Analysis of Gene Interaction Networks in Duchenne Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Tejaswini Narayanan

    Full Text Available Duchenne Muscular Dystrophy (DMD is an important pathology associated with the human skeletal muscle and has been studied extensively. Gene expression measurements on skeletal muscle of patients afflicted with DMD provides the opportunity to understand the underlying mechanisms that lead to the pathology. Community structure analysis is a useful computational technique for understanding and modeling genetic interaction networks. In this paper, we leverage this technique in combination with gene expression measurements from normal and DMD patient skeletal muscle tissue to study the structure of genetic interactions in the context of DMD. We define a novel framework for transforming a raw dataset of gene expression measurements into an interaction network, and subsequently apply algorithms for community structure analysis for the extraction of topological communities. The emergent communities are analyzed from a biological standpoint in terms of their constituent biological pathways, and an interpretation that draws correlations between functional and structural organization of the genetic interactions is presented. We also compare these communities and associated functions in pathology against those in normal human skeletal muscle. In particular, differential enhancements are observed in the following pathways between pathological and normal cases: Metabolic, Focal adhesion, Regulation of actin cytoskeleton and Cell adhesion, and implication of these mechanisms are supported by prior work. Furthermore, our study also includes a gene-level analysis to identify genes that are involved in the coupling between the pathways of interest. We believe that our results serve to highlight important distinguishing features in the structural/functional organization of constituent biological pathways, as it relates to normal and DMD cases, and provide the mechanistic basis for further biological investigations into specific pathways differently regulated

  8. Identification of pathogenic genes and upstream regulators in age-related macular degeneration.

    Science.gov (United States)

    Zhao, Bin; Wang, Mengya; Xu, Jing; Li, Min; Yu, Yuhui

    2017-06-26

    Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in older individuals. Our study aims to identify the key genes and upstream regulators in AMD. To screen pathogenic genes of AMD, an integrated analysis was performed by using the microarray datasets in AMD derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were further discovered by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We constructed the AMD-specific transcriptional regulatory network to find the crucial transcriptional factors (TFs) which target the DEGs in AMD. Quantitative real time polymerase chain reaction (qRT-PCR) was performed to verify the DEGs and TFs obtained by integrated analysis. From two GEO datasets obtained, we identified 1280 DEGs (730 up-regulated and 550 down-regulated genes) between AMD and normal control (NC). After KEGG analysis, steroid biosynthesis is a significantly enriched pathway for DEGs. The expression of 8 genes (TNC, GRP, TRAF6, ADAMTS5, GPX3, FAP, DHCR7 and FDFT1) was detected. Except for TNC and GPX3, the other 6 genes in qRT-PCR played the same pattern with that in our integrated analysis. The dysregulation of these eight genes may involve with the process of AMD. Two crucial transcription factors (c-rel and myogenin) were concluded to play a role in AMD. Especially, myogenin was associated with AMD by regulating TNC, GRP and FAP. Our finding can contribute to developing new potential biomarkers, revealing the underlying pathogenesis, and further raising new therapeutic targets for AMD.

  9. Dual AAV Gene Therapy for Duchenne Muscular Dystrophy with a 7-kb Mini-Dystrophin Gene in the Canine Model.

    Science.gov (United States)

    Kodippili, Kasun; Hakim, Chady H; Pan, Xiufang; Yang, Hsiao T; Yue, Yongping; Zhang, Yadong; Shin, Jin-Hong; Yang, N Nora; Duan, Dongsheng

    2018-03-01

    Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof of principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ΔH2-R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ΔH2-R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy. We packaged minigene dual vectors in Y731F tyrosine-modified AAV-9 and delivered to the extensor carpi ulnaris muscle of a 12-month-old affected dog at the dose of 2 × 10 13 viral genome particles/vector/muscle. Widespread mini-dystrophin expression was observed 2 months after gene transfer. The missing dystrophin-associated glycoprotein complex was restored. Treatment also reduced muscle degeneration and fibrosis and improved myofiber size distribution. Importantly, dual AAV therapy greatly protected the muscle from eccentric contraction-induced force loss. Our data provide the first clear evidence that dual AAV therapy can be translated to a diseased large mammal. Further development of dual AAV technology may lead to effective therapies for DMD and many other diseases in human patients.

  10. The effect of BCMO1 gene variants on macular pigment optical density in young healthy Caucasians

    Directory of Open Access Journals (Sweden)

    Zachary eKyle-Little

    2014-12-01

    Full Text Available Background: Serum lutein (L and zeaxanthin (Z positively correlate with macular pigment optical density (MPOD, hence the latter is a valuable indirect tool for measuring L and Z content in the macula. L and Z have been attributed antioxidant capacity and protection from certain retinal diseases but their uptake within the eye is thought to depend on genetic, age and environmental factors. In particular gene variants within beta-carotene monooxygenase (BCMO1 are thought to modulate MPOD in the macula.Objectives: To determine the effect of BCMO1 single nucleotide polymorphisms (SNPs rs11645428, rs6420424 and rs6464851 on macular pigment optical density (MPOD in a cohort of young healthy participants of Caucasian origin with normal ocular health.Design: In this cohort study, MPOD was assessed in 46 healthy participants (22 male and 24 female with a mean age of 24 ± 4.0 years (range 19-33. The three SNPs, rs11645428, rs6420424, rs6564851 that have established associations with MPOD were determined using MassEXTEND (hME Sequenom assay. One-way analysis of variance (ANOVA was performed on groups segregated into homozygous and heterozygous BCMO1 genotypes. Correlations between body mass index (BMI, iris colour, gender, central retinal thickness (CRT, diet and MPOD were investigated.Results: MPOD did not significantly vary with BCMO1 rs11645428 (F2,41 = 0.700, p = 0.503, rs6420424 (F2,41 = 0.210, p = 0.801 nor rs6464851 homozygous or heterozygous genotypes (F2,41 = 0,13, p = 0.88, in this young healthy cohort. The combination of these three SNPs into triple genotypes based on plasma conversion efficiency did not affect MPOD (F2,41 = 0.07, p = 0.9. There was a significant negative correlation with MPOD and central retinal thickness (r = - 0.39, p = 0.01 but no significant correlation between BMI, iris colour, gender and MPOD. Conclusion: Our results indicate that macular pigment deposition within the central retina is not dependent on BCMO1 gene variant

  11. Functions of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in neuromuscular system and other somatic organs.

    Science.gov (United States)

    Yamamoto, Tomoko; Shibata, Noriyuki; Saito, Yoshiaki; Osawa, Makiko; Kobayashi, Makio

    2010-06-01

    Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disease, exhibiting muscular dystrophy, and central nervous system (CNS) and ocular malformations. It is included in alpha-dystroglycanopathy, a group of muscular dystrophy showing reduced glycosylation of alpha-dystroglycan. alpha-Dystroglycan is one of the components of dystrophin-glycoprotein complex linking extracellular and intracellular proteins. The sugar chains of alpha-dystroglycan are receptors for extracellular matrix proteins such as laminin. Fukutin, a gene responsible for FCMD, is presumably related to the glycosylation of alpha-dystroglycan like other causative genes of alpha-dystroglycanopathy. The CNS lesion of FCMD is characterized by cobblestone lissencephaly, associated with decreased glycosylation of alpha-dystroglycan in the glia limitans where the basement membrane is formed. Astrocytes whose endfeet form the glia limitans seem to be greatly involved in the genesis of the CNS lesion. Fukutin is probably necessary for astrocytic function. Other components of the CNS may also need fukutin, such as migration and synaptic function in neurons. However, roles of fukutin in oligodendroglia, microglia, leptomeninges and capillaries are unknown at present. Fukutin is expressed in various somatic organs as well, and appears to work differently between epithelial cells and astrocytes. In the molecular level, since the dystrophin-glycoprotein complex is linked to cell signaling pathways involving c-src and c-jun, fukutin may be able to affect cell proliferation/survival. Fukutin was localized in the nucleus on cancer cell lines. With the consideration that mutations of fukutin give rise to wide spectrum of the clinical phenotype, more unknown functions of fukutin besides the glycosylation of alpha-dystroglycan can be suggested. Trials for novel treatments including gene therapy are in progress in muscular dystrophies. Toward effective therapies with minimal side effects, precise

  12. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....... associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy...

  13. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

    Science.gov (United States)

    Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod; Gomez, Ana M; Flanigan, Kevin M; Lowes, Linda P; Alfano, Lindsay N; Berry, Katherine; Meadows, Eric; Lewis, Sarah; Braun, Lyndsey; Shontz, Kim; Rouhana, Maria; Clark, Kelly Reed; Rosales, Xiomara Q; Al-Zaidy, Samiah; Govoni, Alessandra; Rodino-Klapac, Louise R; Hogan, Mark J; Kaspar, Brian K

    2015-01-01

    Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

  14. Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

    OpenAIRE

    Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

    2000-01-01

    The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all fro...

  15. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

    2000-10-01

    The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

  16. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration in a Turkish population

    Directory of Open Access Journals (Sweden)

    Yunus Bulgu

    2014-10-01

    Full Text Available AIM:To assess the association between age-related macular degeneration (AMD and three single nucleotide polymorphisms (SNPs related to the vascular endothelial growth factor (VEGF gene.METHODS: The patients who were diagnosed with AMD were included in this prospective study. Three SNPs (rs1413711, rs2146323, and rs3025033 of the VEGF gene were genotyped by real-time polymerase chain reaction in the genomic DNA isolated from peripheral blood samples of the 82 patients and 80 controls.RESULTS: The genotype frequencies of rs1413711 and rs2146323 were not significantly different between the study group and the control group (P=0.072 and P=0.058. However, there was a significant difference in the genotype frequencies of these SNPs between the wet type AMD and dry type AMD (P=0.005 and P=0.010, respectively. One of the SNPs (rs1413711 was also found to be associated with the severity of AMD (P=0.001 with significant genotype distribution between early, intermediate, and advanced stages of the disease. The ancestral alleles were protective for both SNPs while the polymorphic alleles increased the risk for dry AMD.CONCLUSION: VEGF SNPs rs1413711 and rs2146323 polymorphisms are significantly associated with AMD subtypes in our population.

  17. NMNAT1 variants cause cone and cone-rod dystrophy.

    Science.gov (United States)

    Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

    2018-03-01

    Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

  18. An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Eidinger, Osnat; Leibu, Rina; Newman, Hadas; Rizel, Leah; Perlman, Ido; Ben-Yosef, Tamar

    2015-01-01

    To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family. Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing. The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping. A novel

  19. 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.

  20. Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response

    DEFF Research Database (Denmark)

    Wissinger, Bernd; Schaich, Simone; Baumann, Britta

    2011-01-01

    KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack......Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations...... are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel...

  1. Test of critical steps towards a combined cell and gene therapy approach for the treatment of Duchenne muscular dystrophy

    DEFF Research Database (Denmark)

    Kajhøj, Tine Qvistgaard; Duch, Mogens R.; Pedersen, Finn Skou

    2015-01-01

    Background: Therapies for muscular dystrophies remain a major challenge in spite of advanced strategies using either cell or gene therapy. We here propose a combined approach of cell and gene therapy. As gene delivery vehicles with specific homing potential we have chosen mesoangioblasts which...... for myogenic properties in coculture. Survival and in situ myogenic differentiation were studied upon injection into degenerating M. gastrocnemius of athymic mice. In situ participation in muscle regeneration was confirmed on cryo-sections using EGFP fluorescence as marker. The ability of mesoangioblasts...... to serve as retroviral packaging cells was tested using the murine cell line NIH 3T3 fibroblasts as recipients in vitro and evaluation of transduction by fluorescence microscopy. Results: EGFP-MA retained the ability to differentiate into skeletal muscle myotubes upon co-culture with C2C12 cells. In vivo...

  2. Copy number variation in VEGF gene as a biomarker of susceptibility to age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Norshakimah Md Bakri

    2018-07-01

    Full Text Available Background: Several studies in various populations have been conducted to determine candidate genes that could contribute to age-related macular degeneration (AMD pathogenesis. Objective: The present study was undertaken to determine the association of high temperature requirement A-1 (HTRA1, vascular endothelial growth factor (VEGF and very-low-density receptor (VLDR genes with wet AMD subjects in Malaysia. Methods: A total of 125 subjects with wet AMD and 120 subjects without AMD from the Malaysian population were selected for this study. Genomic DNA was extracted and copy number variations (CNVs were determined using quantitative real-time Polymerase Chain Reaction (qPCR and comparison between the two groups was done. The demographic characteristics were also recorded. Statistical analysis was carried out using software where a level of P  0.05. Conclusion: Observations of an association between CNVs of VEGF gene and wet AMD have revealed that the CNVs of VEGF gene appears to be a possible contributor to wet AMD subjects in Malaysia. Keywords: Age-related macular degeneration, Copy number variations, VEGF, HTRA1, VLDR genes and Malaysia

  3. Achondroplasia and Macular Coloboma.

    Science.gov (United States)

    Ahoor, M H; Amizadeh, Y; Sorkhabi, R

    2015-01-01

    Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examination revealed a well-demarcated circular paramacular lesion in both eyes. As macular coloboma and achondroplasia are developmental disorders, the funduscopic examination is required in patients with achondroplasia.

  4. [Clinical features of patients with Becker muscular dystrophy and deletions of the rod domain of dystrophin gene].

    Science.gov (United States)

    Wang, Yanyun; Zhu, Yuling; Yang, Juan; Li, Yaqin; Sun, Jiangwen; Zhan, Yixin; Zhang, Cheng

    2018-02-10

    OBJECTIVE To explore the clinical features of patients carrying deletions of the rod domain of the dystrophin gene. METHODS Clinical data of 12 Chinese patients with Becker muscular dystrophy (BMD) and such deletions was reviewed. RESULTS Most patients complained of muscle weakness of lower limbs. Two patients had muscle cramps, one had increased creatine kinase (CK) level, and one had dilated cardiomyopathy. CONCLUSION Compared with DMD, the clinical features of BMD are much more variable, particularly for those carrying deletions of the rod domain of the dystrophin gene. Muscular weakness may not be the sole complaint of BMD. The diagnosis of BMD cannot be excluded by moderately elevated CK. For male patients with dilated cardiomyopathy, the possibility of BMD should be considered.

  5. Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

    NARCIS (Netherlands)

    Klevering, B.J.; Ijzer, S.; Rohrschneider, K.; Zonneveld-Vrieling, M.N.; Allikmets, R.; Born, L.I. van den; Maugeri, A.; Hoyng, C.B.; Cremers, F.P.M.

    2004-01-01

    Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or

  6. More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-11-06

    This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

  7. Translational Studies of GALGT2 Gene Therapy for Duchenne Muscular Dystrophy

    Science.gov (United States)

    2014-10-01

    myofibers has been demonstrated to protect both wild type and dystrophic muscles from injury and to inhibit the development of muscular dystrophy in...dose for functional muscle correction after rAAVrh74.MCK.GALGT2 treatment in mdx mouse muscle . The second thing we have learned is that the MHCK7...post- treatment showed very low levels of sustained muscle transduction, however, co-injection of rAAVrh74.MHCK7.GALGT2 with an equivalent dose of

  8. Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene.

    Science.gov (United States)

    Ishizaki, Masatoshi; Fujimoto, Akiko; Ueyama, Hidetsugu; Nishida, Yasuto; Imamura, Shigehiro; Uchino, Makoto; Ando, Yukio

    2015-01-01

    We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy.

  9. Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration

    NARCIS (Netherlands)

    Duvvari, M.R.; Saksens, N.T.M.; Ven, J.P.H. van de; Jong-Hesse, Y. de; Schick, T.; Nillesen, W.M.; Fauser, S.; Hoefsloot, L.H.; Hoyng, C.B.; Jong, E.K.; Hollander, A.I. den

    2015-01-01

    PURPOSE: Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition,

  10. Multi-parametric MRI at 14T for muscular dystrophy mice treated with AAV vector-mediated gene therapy.

    Directory of Open Access Journals (Sweden)

    Joshua Park

    Full Text Available The objective of this study was to investigate the efficacy of using quantitative magnetic resonance imaging (MRI as a non-invasive tool for the monitoring of gene therapy for muscular dystrophy. The clinical investigations for this family of diseases often involve surgical biopsy which limits the amount of information that can be obtained due to the invasive nature of the procedure. Thus, other non-invasive tools may provide more opportunities for disease assessment and treatment responses. In order to explore this, dystrophic mdx4cv mice were systemically treated with a recombinant adeno-associated viral (AAV vector containing a codon-optimized micro-dystrophin gene. Multi-parametric MRI of T2, magnetization transfer, and diffusion effects alongside 3-D volume measurements were then utilized to monitor disease/treatment progression. Mice were imaged at 10 weeks of age for pre-treatment, then again post-treatment at 8, 16, and 24 week time points. The efficacy of treatment was assessed by physiological assays for improvements in function and quantification of expression. Tissues from the hindlimbs were collected for histological analysis after the final time point for comparison with MRI results. We found that introduction of the micro-dystrophin gene restored some aspects of normal muscle histology and pathology such as decreased necrosis and resistance to contraction-induced injury. T2 relaxation values showed percentage decreases across all muscle types measured (tibialis anterior, gastrocnemius, and soleus when treated groups were compared to untreated groups. Additionally, the differences between groups were statistically significant for the tibialis anterior as well. The diffusion measurements showed a wider range of percentage changes and less statistical significance while the magnetization transfer effect measurements showed minimal change. MR images displayed hyper-intense regions of muscle that correlated with muscle pathology in

  11. Evaluation of point mutations in dystrophin gene in Iranian Duchenne and Becker muscular dystrophy patients: introducing three novel variants.

    Science.gov (United States)

    Haghshenas, Maryam; Akbari, Mohammad Taghi; Karizi, Shohreh Zare; Deilamani, Faravareh Khordadpoor; Nafissi, Shahriar; Salehi, Zivar

    2016-06-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked neuromuscular diseases characterized by progressive muscular weakness and degeneration of skeletal muscles. Approximately two-thirds of the patients have large deletions or duplications in the dystrophin gene and the remaining one-third have point mutations. This study was performed to evaluate point mutations in Iranian DMD/BMD male patients. A total of 29 DNA samples from patients who did not show any large deletion/duplication mutations following multiplex polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) screening were sequenced for detection of point mutations in exons 50-79. Also exon 44 was sequenced in one sample in which a false positive deletion was detected by MLPA method. Cycle sequencing revealed four nonsense, one frameshift and two splice site mutations as well as two missense variants.

  12. B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I.

    Science.gov (United States)

    Thomas, Paul J; Xu, Rui; Martin, Paul T

    2016-09-01

    Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo(-) muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo(-) muscles did not cause substantial glycosylation of α dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  13. R102G polymorphism of the complement component 3 gene in Malaysian subjects with neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Nur Afiqah Mohamad

    2018-04-01

    Full Text Available Background: Genetic and environmental factors are known to be risk factors in development of neovascular age-related macular degeneration (nAMD. Genetic factors such as polymorphisms in the complement component pathway genes might play a role in pathogenesis of nAMD and has been studied in various populations excluding Malaysia. Aim of the study: To determine the association of the R102G polymorphism of the complement component (C3 gene in nAMD subjects. Patients and methods: A total of 301 Malaysian subjects (149 case and 152 controls were recruited and genotyped for the R102G (rs2230199 variant of the C3 gene. Genotyping was conducted using the PCR-RFLP method and association analysis was conducted using appropriate statistical tests. Results: From our findings, no significant association was observed in the allele distribution of C3 R102G between nAMD and controls (OR = 1.42, 95% CI = 0.77–2.62, P = 0.268. A further analysis that compared three genetic models (dominant, recessive and co-dominant also recorded no significant difference (P > 0.05. These findings could be due to the low frequency of the GG variant in the case (4.7% and control (1.3% groups, compared to the normal variant CC, which is present in 91.3% of case and 92.8% of control alleles. Conclusion: The present study showed no evidence of association between C3 R102G polymorphism and nAMD in Malaysian subjects. Keywords: Age-related macular degeneration, Complement component 3, C3 gene, R102G gene polymorphism

  14. Bestrophin-3 (vitelliform macular dystrophy 2-like 3 protein) is essential for the cGMP-dependent calcium-activated chloride conductance in vascular smooth muscle cells

    DEFF Research Database (Denmark)

    Matchkov, Vladimir; Larsen, Per; Bouzinova, Elena V.

    2008-01-01

    have recently characterized a cGMP-dependent Ca(2+)-activated Cl(-) current with unique characteristics in smooth muscle cells. This novel current has been shown to coexist with a "classic" (cGMP-independent) Ca(2+)-activated Cl(-) current and to have characteristics distinct from those previously...... known for Ca(2+)-activated Cl(-) currents. Here, we suggest that a bestrophin, a product of the Best gene family, is responsible for the cGMP-dependent Ca(2+)-activated Cl(-) current based on similarities between the membrane currents produced by heterologous expressions of bestrophins and the cGMP......-dependent Ca(2+)-activated Cl(-) current. This is supported by similarities in the distribution pattern of the cGMP-dependent Ca(2+)-activated Cl(-) current and bestrophin-3 (the product of Best-3 gene) expression in different smooth muscle. Furthermore, downregulation of Best-3 gene expression with small...

  15. Myotonic Muscular Dystrophy

    Science.gov (United States)

    ... Marie-Tooth Disease (CMT) Congenital Muscular Dystrophy (CMD) Duchenne Muscular Dystrophy (DMD) Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Dystrophy (DM) Spinal-Bulbar ...

  16. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    Science.gov (United States)

    Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

    2002-06-01

    To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

  17. Deletion Analysis Of The Duchenne/Becker Muscular Dystrophy Gene Using Multiplex Polymerase Chain Reaction

    Directory of Open Access Journals (Sweden)

    Dastur P

    2004-01-01

    Full Text Available The diagnosis of Duchenna Muscular Dystrophy (DMD and Becker Muscular Dystorphy (BMD is mainly based on clinical profile, serum CPK values, muscle biopsy and immunostaining for dystrophin. This was done in 100 unrelated patients using 19 exons including the promoter region in two sets of multiplex polymerase chain reaction (PCR. These primers amplify most of the exons in the deletion prone ′hot spot′ regions allowing determinations of deletion end points. Intragenic deletions were detected in 74 patients indicating that the use of PCR- based assays will allow deletion detection help in prenatal diagnosis for most of the DMD/BMD patients. The frequency of deletions observed in the present study was 74%.

  18. Muscular Dystrophy

    Science.gov (United States)

    ... Surveillance Tracking and Research Network , known as MD STAR net . Learn more about CDC’s other muscular dystrophy ... for Disease Control and Prevention Email Recommend Tweet YouTube Instagram Listen Watch RSS ABOUT About CDC Jobs ...

  19. Muscular dystrophy

    Science.gov (United States)

    ... are no known cures for the various muscular dystrophies. The goal of treatment is to control symptoms. Physical therapy may help maintain muscle strength and function. Leg braces and a wheelchair ...

  20. Identification of a gene expression core signature for Duchenne Muscular Dystrophy (DMD) via integrative analysis reveals novel potential compounds for treatment

    KAUST Repository

    Ichim-Moreno, Norú

    2010-05-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy and one of the most prevalent genetic disorders of childhood. DMD is characterized by rapid progression of muscle degeneration, and ultimately death. Currently, glucocorticoids are the only available treatment for DMD, but they have been shown to result in serious side effects. The purpose of this research was to define a core signature of gene expression related to DMD via integrative analysis of mouse and human datasets. This core signature was subsequently used to screen for novel potential compounds that antagonistically affect the expression of signature genes. With this approach we were able to identify compounds that are 1) already used to treat DMD, 2) currently under investigation for treatment, and 3) so far unknown but promising candidates. Our study highlights the potential of meta-analyses through the combination of datasets to unravel previously unrecognized associations and reveal new relationships. © IEEE.

  1. 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

  2. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

    Science.gov (United States)

    Gonçalves, Ana; Oliveira, Jorge; Coelho, Teresa; Taipa, Ricardo; Melo-Pires, Manuel; Sousa, Mário; Santos, Rosário

    2017-10-03

    A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD.

  3. Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

    Science.gov (United States)

    Xu, Huaigeng

    2017-01-01

    In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic. PMID:28607562

  4. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

    Science.gov (United States)

    Gonçalves, Ana; Coelho, Teresa; Melo-Pires, Manuel; Sousa, Mário

    2017-01-01

    A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. PMID:28972564

  5. Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes

    Science.gov (United States)

    Finno, Carrie J.; Bordbari, Matthew H.; Valberg, Stephanie J.; Lee, David; Herron, Josi; Hines, Kelly; Monsour, Tamer; Scott, Erica; Bannasch, Danika L.; Mickelson, James; Xu, Libin

    2016-01-01

    Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDRmedulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration. PMID:27751910

  6. Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Peter Gee

    2017-01-01

    Full Text Available In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic.

  7. [Central aleolar choroidal dystrophy in sibilings coexisting with alopecia].

    Science.gov (United States)

    Brydak-Godowska, Joanna; Dróbecka-Brydak, Ewa; Paćkowska, Maria; Kecik, Dariusz

    2007-01-01

    Central areolar choroidal dystrophy is localized in macular region and is characterized by atrophy of pigment epithelium, photoreceptors and choriocapillaris. This paper presents the history of two sibilings at the age of 23 and 30, with central aleolar choroidal dystrophy coexisting with alopecia. The results of erg, eog and fluorescein angiography are presented. The results of therapy for glaucoma associated with the Sturge-Weber syndrome are often disappointing.

  8. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy

    Directory of Open Access Journals (Sweden)

    Selwyn M. Prea

    2015-01-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet” form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF. However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly, potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

  9. Pigmentos maculares Macular pigments

    Directory of Open Access Journals (Sweden)

    Renata Canovas

    2009-12-01

    Full Text Available A luteína e a zeaxantina são pigmentos amarelos que se localizam na mácula. Devido à sua localização, diminuem e filtram a quantidade de luz principalmente azul que chega aos fotorreceptores, atuam como antioxidantes e podem melhorar a qualidade visual. Esta é uma revisão do seu mecanismo de incorporação, ação, possíveis aplicações e conhecimento científico a respeito.Lutein and Zeaxanthin are yellow pigments located at the macula. Because of your location macular pigments decrease and filter the amount of blue light that reach photoreceptors, protect the outer retina from oxidative stress and may improve the vision quality. This is a review regarding incorporation mechanism, function and knowledge update.

  10. MLPA based detection of mutations in the dystrophin gene of 180 Polish families with Duchenne/Becker muscular dystrophy.

    Science.gov (United States)

    Zimowski, Janusz G; Massalska, Diana; Holding, Mariola; Jadczak, Sylwia; Fidziańska, Elżbieta; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Kamińska, Anna; Zaremba, Jacek

    2014-01-01

    Duchenne/Becker muscular dystrophy (DMD/BMD) is a recessive, X-linked disorder caused by a mutation in the dystrophin gene. Deletions account for approximately 60-65% of mutations, duplications for 5-10%. The remaining cases are mainly point mutations. According to Monaco theory clinical form of the disease depends on maintaining or disrupting the reading frame. The purpose of the study was to determine frequency and location of deletions and duplications in the dystrophin gene, to determine the compliance between maintaining/disrupting the reading frame and clinical form of the disease and to check the effectiveness of MLPA (multiplex ligation-dependent probe amplification) in the detection of these mutations in hemizygous patients and heterozygous female carriers. The material is composed of combined results of molecular diagnosis carried out in years 2009-2012 in 180 unrelated patients referred with the diagnosis of DMD/BMD tested by use of MLPA. We identified 110 deletions, 22 duplication (in one patient two different duplications were detected) and 2 point mutations. Deletions involved mainly exons 45-54 and 3-21, whereas most duplications involved exons 3-18. The compliance with Monaco theory was 95% for deletions and 76% for duplications. Most of mutations in the dystrophin gene were localized in the hot spots - different for deletions and duplications. MLPA enabled their quick identification, exact localization and determination whether or not they maintained or disrupted the reading frame. MLPA was also effective in detection of deletions and duplications in female carriers. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene.

    Science.gov (United States)

    Birch, D G; Peters, A Y; Locke, K L; Spencer, R; Megarity, C F; Travis, G H

    2001-12-01

    Mutations in the ABCA4(ABCR) gene cause autosomal recessive Stargardt disease (STGD). ABCR mutations were identified in patients with cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) by direct sequencing of all 50 exons in 40 patients. Of 10 patients with RP, one contained two ABCR mutations suggesting a compound heterozygote. This patient had a characteristic fundus appearance with attenuated vessels, pale disks and bone-spicule pigmentation. Rod electroretinograms (ERGs) were non-detectable, cone ERGs were greatly reduced in amplitude and delayed in implicit time, and visual fields were constricted to 10 degrees diameter. Eleven of 30 (37%) patients with CRD had mutations in ABCR. In general, these patients showed reduced but detectable rod ERG responses, reduced and delayed cone responses, and poor visual acuity. Rod photoresponses to high intensity flashes were of reduced maximum amplitude but showed normal values for the gain of phototransduction. Most CRD patients with mutations in ABCR showed delayed recovery of sensitivity (dark adaptation) following exposure to bright light. Pupils were also significantly smaller in these patients compared to controls at 30 min following light exposure, consistent with a persistent 'equivalent light' background due to the accumulation of a tentatively identified 'noisy' photoproduct. Copyright 2001 Academic Press.

  12. Allele-specific Gene Silencing of Mutant mRNA Restores Cellular Function in Ullrich Congenital Muscular Dystrophy Fibroblasts

    Directory of Open Access Journals (Sweden)

    Satoru Noguchi

    2014-01-01

    Full Text Available Ullrich congenital muscular dystrophy (UCMD is an inherited muscle disorder characterized clinically by muscle weakness, distal joint hyperlaxity, and proximal joint contractures. Sporadic and recessive mutations in the three collagen VI genes, COL6A1, COL6A2, and COL6A3, are reported to be causative. In the sporadic forms, a heterozygous point mutation causing glycine substitution in the triple helical domain has been identified in higher rate. In this study, we examined the efficacy of siRNAs, which target point mutation site, on specific knockdown toward transcripts from mutant allele and evaluated consequent cellular phenotype of UCMD fibroblasts. We evaluated the effect of siRNAs targeted to silence-specific COL6A1 alleles in UCMD fibroblasts, where simultaneous expression of both wild-type and mutant collagen VI resulted in defective collagen localization. Addition of mutant-specific siRNAs allowed normal extracellular localization of collagen VI surrounding fibroblasts, suggesting selective inhibition of mutant collagen VI. Targeting the single-nucleotide COL6A1 c.850G>A (p.G284R mutation responsible a sporadic autosomal dominant form of UCMD can potently and selectively block expression of mutant collagen VI. These results suggest that allele-specific knockdown of the mutant mRNA can potentially be considered as a therapeutic procedure in UCMD due to COL6A1 point mutations.

  13. Next-generation sequencing analysis of the ARMS2 gene in Turkish exudative age-related macular degeneration patients.

    Science.gov (United States)

    Bardak, H; Gunay, M; Ercalik, Y; Bardak, Y; Ozbas, H; Bagci, O

    2017-01-23

    Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It is a complex disease with both genetic and environmental risk factors. To improve clinical management of this condition, it is important to develop risk assessment and prevention strategies for environmental influences, and establish a more effective treatment approach. The aim of the present study was to investigate age-related maculopathy susceptibility protein 2 (ARMS2) gene sequences among Turkish patients with exudative AMD. In addition to 39 advanced exudative AMD patients, 250 healthy individuals for whom exome sequencing data were available were included as a control group. Patients with a history of known environmental and systemic AMD risk factors were excluded. Genomic DNA was isolated from peripheral blood and analyzed using next-generation sequencing. All coding exons of the ARMS2 gene were assessed. Three different ARMS2 sequence variations (rs10490923, rs2736911, and rs10490924) were identified in both the patient and control group. Within the control group, two further ARMS2 gene variants (rs7088128 and rs36213074) were also detected. Logistic regression analysis revealed a relationship between the rs10490924 polymorphism and AMD in the Turkish population.

  14. Production of the 2400 kb Duchenne muscular dystrophy (DMD) gene transcript; transcription time and cotranscriptional splicing

    Energy Technology Data Exchange (ETDEWEB)

    Tennyson, C.N.; Worton, R.G. [Univ. of Toronto and the Hospital for Sick Children, Ontario (Canada)

    1994-09-01

    The largest known gene in any organism is the human DMD gene which has 79 exons that span 2400 kb. The extreme nature of the DMD gene raises questions concerning the time required for transcription and whether splicing begins before transcription is complete. DMD gene transcription is induced as cultured human myoblasts differentiate to form multinucleated myotubes, providing a system for studying the kinetics of transcription and splicing. Using quantitative RT-PCR, transcript accumulation was monitored from four different regions within the gene following induction of expression. By comparing the accumulation of transcripts from the 5{prime} and 3{prime} ends of the gene we have shown that approximately 12 hours are required to transcribe 1770 kb of the gene, extrapolating to a time of 16 hours for the transcription unit expressed in muscle. Comparison of accumulation profiles for spliced and total transcript demonstrated that transcripts are spliced at the 5{prime} end before transcription is complete, providing strong evidence for cotranscriptional splicing of DMD gene transcripts. Finally, the rate of transcript accumulation was reduced at the 3{prime} end of the gene relative to the 5{prime} end, perhaps due to premature termination of transcription complexes as they traverse this enormous transcription unit. The lag between transcription initiation and the appearance of complete transcripts could be important in limiting transcript production in dividing cells and to the timing of mRNA appearance in differentiating muscle.

  15. What Is Macular Edema?

    Medline Plus

    Full Text Available ... Ophthalmology/Strabismus Ocular Pathology/Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis ... Macular Edema Sections What Is Macular Edema? What Causes Macular Edema? Macular ...

  16. Muscular Dystrophy

    Science.gov (United States)

    ... sets of muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most severe ... can walk independently. Prednisone If a child has Duchenne muscular ... to help slow the rate of muscle deterioration. By doing so, the child may be ...

  17. Investigating the CFH Gene Polymorphisms as a Risk Factor for Age-related Macular Degeneration in an Iranian Population.

    Science.gov (United States)

    Babanejad, Mojgan; Moein, Hamidreza; Akbari, Mohammad R; Badiei, Azadeh; Yaseri, Mehdi; Soheilian, Masoud; Najmabadi, Hossein

    2016-06-01

    Age-related macular degeneration (AMD) is a complex disorder which results in irreversible vision loss and progressive impairment of central vision. Disease susceptibility is influenced by multiple genetic and environmental factors. Single nucleotide polymorphisms (SNP) in the complement factor H gene are the most important genetic risk factors. We conducted a case-control study to investigate the association four SNPs (dbSNP ID: rs800292, rs1061170, rs2274700 and rs3753395) of CFH gene with AMD in the Iranian population. We recruited 100 AMD patients and 100 age- and sex-matched normal controls. Direct sequencing for three SNPs (rs800292, rs2274700 and rs3753395) and restriction fragment length polymorphism utilized for rs1061170. Allele and genotype frequencies of SNPs were calculated and tested for departure from Hardy-Weinberg equilibrium using the Chi-square test. An allelic and genotypic association was compared by logistic regression analysis using the SNPassoc. According to our results, the frequencies of risk allele for all SNPs (G, G, A, and C alleles of rs800292, rs2274700, rs3753395 and rs1061170, respectively) were significantly higher in AMD patients (p value prevention and treatment of AMD.

  18. Macular degeneration

    Science.gov (United States)

    The macula is the part of the retina that distinguishes fine details at the center of the field of vision. Macular degeneration results from a partial breakdown of the insulating layer between the retina and the choroid layer of ...

  19. What Is Macular Edema?

    Science.gov (United States)

    ... Español Eye Health / Eye Health A-Z Macular Edema Sections What Is Macular Edema? What Causes Macular ... Edema Diagnosis Macular Edema Treatment What Is Macular Edema? Leer en Español: ¿Qué es un edema macular? ...

  20. What Is Macular Edema?

    Medline Plus

    Full Text Available ... Español Eye Health / Eye Health A-Z Macular Edema Sections What Is Macular Edema? What Causes Macular ... Edema Diagnosis Macular Edema Treatment What Is Macular Edema? Leer en Español: ¿Qué es un edema macular? ...

  1. [Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

    Science.gov (United States)

    Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

    2017-02-10

    Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

  2. TGC repeat expansion in the TCF4 gene increases the risk of Fuchs' endothelial corneal dystrophy in Australian cases.

    Directory of Open Access Journals (Sweden)

    Abraham Kuot

    Full Text Available Fuchs' endothelial corneal dystrophy (FECD is a progressive, vision impairing disease. Common single nucleotide polymorphisms (SNPs and a trinucleotide repeat polymorphism, thymine-guanine-cytosine (TGC, in the TCF4 gene have been associated with the risk of FECD in some populations. We previously reported association of SNPs in TCF4 with FECD risk in the Australian population. The aim of this study was to determine whether TGC repeat polymorphism in TCF4 is associated with FECD in the Australian population. In 189 unrelated Australian cases with advanced late-onset FECD and 183 matched controls, the TGC repeat polymorphism located in intron 3 of TCF4 was genotyped using a short tandem repeat (STR assay. The repeat length was verified by direct sequencing in selected homozygous carriers. We found significant association between the expanded TGC repeat (≥ 40 repeats in TCF4 and advanced FECD (P = 2.58 × 10-22; OR = 15.66 (95% CI: 7.79-31.49. Genotypic analysis showed that 51% of cases (97 compared to 5% of controls (9 were heterozygous or homozygous for the expanded repeat allele. Furthermore, the repeat expansion showed stronger association than the most significantly associated SNP, rs613872, in TCF4, with the disease in the Australian cohort. This and haplotype analysis of both the polymorphisms suggest that considering both the polymorphisms together rather than either of the two alone would better predict susceptibility to FECD in the Australian population. This is the first study to report association of the TGC trinucleotide repeat expansion in TCF4 with advanced FECD in the Australian population.

  3. Dissecting microRNA dysregulation in age-related macular degeneration: new targets for eye gene therapy.

    Science.gov (United States)

    Askou, Anne Louise; Alsing, Sidsel; Holmgaard, Andreas; Bek, Toke; Corydon, Thomas J

    2018-02-01

    MicroRNAs (miRNAs) are key regulators of gene expression in humans. Overexpression or depletion of individual miRNAs is associated with human disease. Current knowledge suggests that the retina is influenced by miRNAs and that dysregulation of miRNAs as well as alterations in components of the miRNA biogenesis machinery are involved in retinal diseases, including age-related macular degeneration (AMD). Furthermore, recent studies have indicated that the vitreous has a specific panel of circulating miRNAs and that this panel varies according to the specific pathological stress experienced by the retinal cells. MicroRNA (miRNA) profiling indicates subtype-specific miRNA profiles for late-stage AMD highlighting the importance of proper miRNA regulation in AMD. This review will describe the function of important miRNAs involved in inflammation, oxidative stress and pathological neovascularization, the key molecular mechanisms leading to AMD, and focus on dysregulated miRNAs as potential therapeutic targets in AMD. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  4. A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

    Directory of Open Access Journals (Sweden)

    Gemma L Walmsley

    2010-01-01

    Full Text Available Duchenne muscular dystrophy (DMD, which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot".Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD. The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression.Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD.

  5. FFA STUDY OF MACULAR LESIONS

    Directory of Open Access Journals (Sweden)

    K. Vinayagamurthy

    2017-08-01

    Full Text Available BACKGROUND Macula is an important portion of retina that occupies the posterior pole of retina. Any disease that affects macula results in significant loss of central vision, form vision and colour vision to an extent. Macular lesions can be hereditary as well as acquired. Macular lesions occur in both younger and older individuals. Anatomically, a macular lesions can vary from a simple lesion like an RPF defect to a vision-threatening lesions like choroidal neovascular membrane. Many screening tests that are sensitive and specific are available to assess the functioning of macula called as ‘macular function test’. But, the greater understanding of the retinal vascular led to the usage of fluorescein angiogram in the detection and screening of macular, retinovascular and optic disc lesions. Through fundus fluorescein angiogram is a thirty-year-old procedure; it is still in vogue in almost all parts of the world. It has its own merits. The aim of the study is to study the role of fluorescein angiography in the evaluation of macular lesions. MATERIALS AND METHODS A hospital-based prospective randomised study was done, which included 50 patients. Detailed patient history was taken and thorough ocular and systemic examination was done. All patients were examined by ophthalmoscopy (direct and indirect and slit-lamp examination with 90D followed by fluorescein angiography. Ophthalmoscopic and fluorescein angiography findings were analysed and categorised. Patients were advised proper ocular and systemic treatment and follow up. RESULTS 50 cases with macular lesions were analysed and categorised into conditions like ARMD, CSR, macular oedema, CME, degenerations and dystrophies and miscellaneous conditions. FFA altered the diagnosis in 8% cases and categorised the cases in all cases. 16% patients developed adverse reactions like allergy, vomiting and nausea. On statistical analysis, FFA proved to be cheap and superior diagnostic tool in confirming

  6. Effect of Complement Factor B Gene Polymorphisms on Age-Related Macular Degeneration in North-East of Iran Population

    Directory of Open Access Journals (Sweden)

    N. Roshani Pour

    2017-09-01

    Full Text Available Aims: Age-related macular degeneration (AMD is the most prevalent cause of irreversible blindness and debilitating in old stages, in developed and developing countries that engage the central part of the retina or macula. The aim of this study was to evaluate the relationship of the rs4151667 position of the complement factor B gene polymorphism with AMD (dry type with geographic atrophy phenotype in the North East of Iran population. ­Materials & Methods:­ In this descriptive cross-sectional study in 2015-2016, 44 AMD patients (dry type with geographic atrophy phenotype were randomly selected from Gonabad City, Iran, health centers as the patient group. 50 healthy individuals from the same society that have no relative relations with each other or the patients, but were adapted by age and sex to the patient group, were selected as the control group. The ­­polymorphism of rs4151667 (c.26T>A­ position of the complement factor B gene was determined for all samples by Restriction Fragment Length Polymorphism (RFLP. Data was analyzed the Chi-square test in 2x2.Contingency software. Findings: The frequency of TT genotype in AMD patients (95.5% was significantly (p=0.048 more than the control group (88.0%, but the frequency of AT genotype in AMD patients (4.5% was significantly (p=0.025 less than the control group (12.0%. Conclusion: The polymorphism of rs4151667 (c.26T>A position of complement factor B is effective on the development of AMD in North East of Iran population.

  7. X linked progressive cone dystrophy. Localisation of the gene locus to Xp21-p11.1 by linkage analysis

    NARCIS (Netherlands)

    Meire, F. M.; Bergen, A. A.; de Rouck, A.; Leys, M.; Delleman, J. W.

    1994-01-01

    Six affected males, three female carriers, and two possible carriers were evaluated from a three generation pedigree with X linked progressive cone dystrophy. The affected males presented with progressive decrease of visual acuity, impairment of colour vision, and deterioration of electroretinogram,

  8. Consecutive analysis of mutation spectrum in the dystrophin gene of 507 Korean boys with Duchenne/Becker muscular dystrophy in a single center.

    Science.gov (United States)

    Cho, Anna; Seong, Moon-Woo; Lim, Byung Chan; Lee, Hwa Jeen; Byeon, Jung Hye; Kim, Seung Soo; Kim, Soo Yeon; Choi, Sun Ah; Wong, Ai-Lynn; Lee, Jeongho; Kim, Jon Soo; Ryu, Hye Won; Lee, Jin Sook; Kim, Hunmin; Hwang, Hee; Choi, Ji Eun; Kim, Ki Joong; Hwang, Young Seung; Hong, Ki Ho; Park, Seungman; Cho, Sung Im; Lee, Seung Jun; Park, Hyunwoong; Seo, Soo Hyun; Park, Sung Sup; Chae, Jong Hee

    2017-05-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked recessive muscle diseases caused by mutations in the large and complex dystrophin gene. We analyzed the dystrophin gene in 507 Korean DMD/BMD patients by multiple ligation-dependent probe amplification and direct sequencing. Overall, 117 different deletions, 48 duplications, and 90 pathogenic sequence variations, including 30 novel variations, were identified. Deletions and duplications accounted for 65.4% and 13.3% of Korean dystrophinopathy, respectively, suggesting that the incidence of large rearrangements in dystrophin is similar among different ethnic groups. We also detected sequence variations in >100 probands. The small variations were dispersed across the whole gene, and 12.3% were nonsense mutations. Precise genetic characterization in patients with DMD/BMD is timely and important for implementing nationwide registration systems and future molecular therapeutic trials in Korea and globally. Muscle Nerve 55: 727-734, 2017. © 2016 Wiley Periodicals, Inc.

  9. Identification of a gene expression core signature for Duchenne Muscular Dystrophy (DMD) via integrative analysis reveals novel potential compounds for treatment

    KAUST Repository

    Ichim-Moreno, Norú ; Aranda, Manuel; Voolstra, Christian R.

    2010-01-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy and one of the most prevalent genetic disorders of childhood. DMD is characterized by rapid progression of muscle degeneration, and ultimately death. Currently

  10. Effects of intravitreal ranibizumab on the untreated eye and systemic gene expression profile in age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Michalska-Małecka K

    2016-03-01

    Full Text Available Katarzyna Michalska-Małecka,1,2 Adam Kabiesz,2 Malgorzata W Kimsa,3 Barbara Strzałka-Mrozik,3 Maria Formińska-Kapuścik,2,4 Malgorzata Nita,5 Urszula Mazurek31Clinical Department of Ophthalmology, Medical University of Silesia, Katowice, Poland; 2University Center for Ophthalmology and Oncology, Independent Public Clinical Hospital, Medical University of Silesia, Katowice, Poland; 3Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland; 4Clinical Department of Children Ophthalmology, Medical University of Silesia, Katowice, Poland; 5Domestic and Specialized Medicine Centre “Dilmed”, Katowice, PolandAbstract: The purpose of this study was to evaluate the systemic effects of intravitreal ranibizumab (Lucentis treatment in patients with neovascular age-related macular degeneration (AMD. The impact of intravitreal ranibizumab injections on central retinal thickness (CRT of treated and contralateral untreated eyes, and differences in gene expression patterns in the peripheral blood mononuclear cells were analyzed. The study included 29 patients aged 50 years old and over with diagnosed neovascular AMD. The treatment was defined as 0.5 mg of ranibizumab injected intravitreally in the form of one injection every month during the period of 3 months. CRT was measured by optical coherence tomography. The gene expression profile was assigned using oligonucleotide microarrays of Affymetrix HG-U133A. Studies have shown that there was a change of CRT between treated and untreated eyes, and there were differences in CRT at baseline and after 1, 2, and 3 months of ranibizumab treatment. Three months after intravitreal injection, mean CRT was reduced in the treated eyes from 331.97±123.62 to 254.31±58.75 µm, while mean CRT in the untreated fellow eyes reduced from 251.07±40.29 to 235.45±36.21 µm at the same time. Furthermore, the research has shown

  11. Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

    Science.gov (United States)

    Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

    2015-03-01

    We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

  12. A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene.

    Science.gov (United States)

    Zimowski, Janusz G; Pilch, Jacek; Pawelec, Magdalena; Purzycka, Joanna K; Kubalska, Jolanta; Ziora-Jakutowicz, Karolina; Dudzińska, Magdalena; Zaremba, Jacek

    2017-08-01

    In the material of 227 families with Becker muscular dystrophy (BMD), we found nine non-consanguineous families with 17 male individuals carrying a rare mutation-a single exon 48 deletion of the dystrophin gene-who were affected with a very mild or subclinical form of BMD. They were usually detected thanks to accidental findings of elevated serum creatine phosphokinase (sCPK). A thorough clinical analysis of the carriers, both children (12) and adults (5), revealed in some of them muscle hypotonia (10/17) and/or very mild muscle weakness (9/17), as well as decreased tendon reflexes (6/17). Adults, apart from very mild muscle weakness and calf hypertrophy in some, had no significant abnormalities on neurological assessments and had good exercise tolerance. Parents of the children carriers of the exon 48 deletion are usually unaware of their children being affected, and possibly at risk of developing life-threatening cardiomyopathy. The same concerns the adult male carriers. Therefore, the authors postulate undertaking preventive measures such as cascade screening of the relatives of the probands. Newborn screening programmes of Duchenne muscular dystrophy (DMD)/BMD based on sCPK marked increase may be considered.

  13. Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

    Science.gov (United States)

    Klevering, B Jeroen; Yzer, Suzanne; Rohrschneider, Klaus; Zonneveld, Marijke; Allikmets, Rando; van den Born, L Ingeborgh; Maugeri, Alessandra; Hoyng, Carel B; Cremers, Frans P M

    2004-12-01

    Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

  14. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, A.; Gorgels, T.G.M.F.; ten Brink, J.B.; van der Spek, P.J.; Bossers, K.; Heine, V.M.; Bergen, A.A.

    2015-01-01

    Background The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to

  16. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles : Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, Anna; Gorgels, Theo G M F; Ten Brink, Jacoline B; van der Spek, Peter J; Bossers, Koen; Heine, Vivi M; Bergen, Arthur A

    2015-01-01

    BACKGROUND: The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to

  17. Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration

    NARCIS (Netherlands)

    Bennis, Anna; Gorgels, Theo G. M. F.; ten Brink, Jacoline B.; van der Spek, Peter J.; Bossers, Koen; Heine, Vivi M.; Bergen, Arthur A.

    2015-01-01

    The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to develop new

  18. Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

    Science.gov (United States)

    Nagel-Wolfrum, Kerstin; Möller, Fabian; Penner, Inessa; Wolfrum, Uwe

    2014-09-01

    The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the

  19. Linkage disequilibria among (CA){sub n} polymorphisms in the human dystrophin gene and their implications in carrier detection and prenatal diagnosis in Duchenne and Becker musclar dystrophies

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, R.; Zhong, Y.; Andrade, M. de [Univ. of Texas Graduate School of Biomedical Sciences, Houston, TX (United States)] [and others

    1994-06-01

    Four short tandem repeat loci, characterized by length polymorphisms of (CA){sub n} repeats, have been detected within introns 44, 45, 49, and 50 of the human dystrophin gene. The predicted heterozygosites for these loci range from 72 to 93%, and observed allele numbers range from 6 to 19 in 57 normal chromosomes, revealing their high degree of polymorphism. Evidence for significant disequilibria between the loci within introns 49 and 50 is found. These data appear to be consistent with observations of recombination frequencies between these markers and the length of the intron 44 in relation to the entire region. In addition, these four loci are collectively found to be 100% informative in carrier detection/prenatal diagnosis of Becker and Duchenne muscular dystrophies (B/DMD), whereas scoring the (CA){sub n} markers within introns 45 and 49 alone gives a 99.6% success rate. 13 refs., 4 tabs.

  20. Association of age-related macular degeneration and reticular macular disease with cardiovascular disease.

    Science.gov (United States)

    Rastogi, Neelesh; Smith, R Theodore

    2016-01-01

    Age-related macular degeneration is the leading cause of adult blindness in the developed world. Thus, major endeavors to understand the risk factors and pathogenesis of this disease have been undertaken. Reticular macular disease is a proposed subtype of age-related macular degeneration correlating histologically with subretinal drusenoid deposits located between the retinal pigment epithelium and the inner segment ellipsoid zone. Reticular lesions are more prevalent in females and in older age groups and are associated with a higher mortality rate. Risk factors for developing age-related macular degeneration include hypertension, smoking, and angina. Several genes related to increased risk for age-related macular degeneration and reticular macular disease are also associated with cardiovascular disease. Better understanding of the clinical and genetic risk factors for age-related macular degeneration and reticular macular disease has led to the hypothesis that these eye diseases are systemic. A systemic origin may help to explain why reticular disease is diagnosed more frequently in females as males suffer cardiovascular mortality at an earlier age, before the age of diagnosis of reticular macular disease and age-related macular degeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Molecular mechanisms of muscle atrophy in myotonic dystrophies

    OpenAIRE

    Timchenko, Lubov

    2013-01-01

    Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and Zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in p...

  2. What Is Macular Edema?

    Medline Plus

    Full Text Available ... Eye Health A-Z Symptoms Glasses & Contacts Tips & Prevention News Ask an Ophthalmologist Patient Stories Español Eye ... Macular Edema Symptoms Macular Edema Diagnosis Macular Edema Treatment What Is Macular Edema? Leer en Español: ¿Qué ...

  3. What Is Macular Edema?

    Medline Plus

    Full Text Available ... Macular Edema Treatment What Is Macular Edema? Leer en Español: ¿Qué es un edema macular? Dec. 01, 2010 Macular edema is swelling or thickening of the eye's macula, the part of your eye responsible for detailed, central vision. The macula is a very small area ...

  4. Macular Diplopia.

    Science.gov (United States)

    Shippman, Sara; Cohen, Kenneth R; Heiser, Larissa

    2015-01-01

    Maculopathies affect point-to-point foveal correspondence causing diplopia. The effect that the maculopathies have on the interaction of central sensory fusion and peripheral fusion are different than the usual understanding of treatment for diplopia. This paper reviews the pathophysiology of macular diplopia, describes the binocular pathology causing the diplopia, discusses the clinical evaluation, and reviews the present treatments including some newer treatment techniques. © 2015 Board of regents of the University of Wisconsin System, American Orthoptic Journal, Volume 65, 2015, ISSN 0065-955X, E-ISSN 1553-4448.

  5. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.

    Science.gov (United States)

    Rakoczy, Elizabeth P; Lai, Chooi-May; Magno, Aaron L; Wikstrom, Matthew E; French, Martyn A; Pierce, Cora M; Schwartz, Steven D; Blumenkranz, Mark S; Chalberg, Thomas W; Degli-Esposti, Mariapia A; Constable, Ian J

    2015-12-12

    Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 10(10) vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10(11) vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of r

  6. 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.

  7. Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9.

    Science.gov (United States)

    Li, Hongmei Lisa; Fujimoto, Naoko; Sasakawa, Noriko; Shirai, Saya; Ohkame, Tokiko; Sakuma, Tetsushi; Tanaka, Michihiro; Amano, Naoki; Watanabe, Akira; Sakurai, Hidetoshi; Yamamoto, Takashi; Yamanaka, Shinya; Hotta, Akitsu

    2015-01-13

    Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach. We further investigated the genomic integrity by karyotyping, copy number variation array, and exome sequencing to identify clones with a minimal mutation load. Finally, we differentiated the corrected iPSCs toward skeletal muscle cells and successfully detected the expression of full-length dystrophin protein. These results provide an important framework for developing iPSC-based gene therapy for genetic disorders using programmable nucleases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Association of a Chromosomal Rearrangement Event with Mouse Posterior Polymorphous Corneal Dystrophy and Alterations in Csrp2bp, Dzank1, and Ovol2 Gene Expression.

    Directory of Open Access Journals (Sweden)

    Anna L Shen

    Full Text Available We have previously described a mouse model of human posterior polymorphous corneal dystrophy (PPCD and localized the causative mutation to a 6.2 Mbp region of chromosome 2, termed Ppcd1. We now show that the gene rearrangement linked to mouse Ppcd1 is a 3.9 Mbp chromosomal inversion flanked by 81 Kbp and 542 bp deletions. This recombination event leads to deletion of Csrp2bp Exons 8 through 11, Dzank1 Exons 20 and 21, and the pseudogene Znf133. In addition, we identified translocation of novel downstream sequences to positions adjacent to Csrp2bp Exon 7 and Dzank1 Exon 20. Twelve novel fusion transcripts involving Csrp2bp or Dzank1 linked to downstream sequences have been identified. Eight are expressed at detectable levels in PPCD1 but not wildtype eyes. Upregulation of two Csrp2bp fusion transcripts, as well as upregulation of the adjacent gene, Ovol2, was observed. Absence of the PPCD1 phenotype in animals haploinsufficient for Csrp2bp or both Csrp2bp and Dzank1 rules out haploinsufficiency of these genes as a cause of mouse PPCD1. Complementation experiments confirm that PPCD1 embryonic lethality is due to disruption of Csrp2bp expression. The ocular expression pattern of Csrp2bp is consistent with a role for this protein in corneal development and pathogenesis of PPCD1.

  9. Limb girdle muscular dystrophy due to mutations in POMT2

    DEFF Research Database (Denmark)

    Østergaard, Sofie Thurø; Johnson, Katherine; Stojkovic, Tanya

    2018-01-01

    BACKGROUND: Mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four...

  10. 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...... or are registered in other classification systems for muscle disease. On the contrary, diseases that fulfill classical criteria for LGMD have found no place in the LGMD classification system. These shortcomings call for revision/creation of a new classification system for LGMD. The rapidly expanding gene sequencing...... capabilities have helped to speed up new LGMD discoveries, and unveiled pheno-/genotype relations. Parallel to this progress in identifying new LGMD subtypes, emerging therapies for LGMDs are under way, but no disease-specific treatment is yet available for nonexperimental use. SUMMARY: The field of LGMD...

  11. Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

    Science.gov (United States)

    Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

    2016-04-15

    Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Exploiting the full power of temporal gene expression profiling through a new statistical test: Application to the analysis of muscular dystrophy data

    Directory of Open Access Journals (Sweden)

    Turk Rolf

    2006-04-01

    Full Text Available Abstract Background The identification of biologically interesting genes in a temporal expression profiling dataset is challenging and complicated by high levels of experimental noise. Most statistical methods used in the literature do not fully exploit the temporal ordering in the dataset and are not suited to the case where temporal profiles are measured for a number of different biological conditions. We present a statistical test that makes explicit use of the temporal order in the data by fitting polynomial functions to the temporal profile of each gene and for each biological condition. A Hotelling T2-statistic is derived to detect the genes for which the parameters of these polynomials are significantly different from each other. Results We validate the temporal Hotelling T2-test on muscular gene expression data from four mouse strains which were profiled at different ages: dystrophin-, beta-sarcoglycan and gamma-sarcoglycan deficient mice, and wild-type mice. The first three are animal models for different muscular dystrophies. Extensive biological validation shows that the method is capable of finding genes with temporal profiles significantly different across the four strains, as well as identifying potential biomarkers for each form of the disease. The added value of the temporal test compared to an identical test which does not make use of temporal ordering is demonstrated via a simulation study, and through confirmation of the expression profiles from selected genes by quantitative PCR experiments. The proposed method maximises the detection of the biologically interesting genes, whilst minimising false detections. Conclusion The temporal Hotelling T2-test is capable of finding relatively small and robust sets of genes that display different temporal profiles between the conditions of interest. The test is simple, it can be used on gene expression data generated from any experimental design and for any number of conditions, and it

  13. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.

    Science.gov (United States)

    Camerino, Giulia Maria; Cannone, Maria; Giustino, Arcangela; Massari, Ada Maria; Capogrosso, Roberta Francesca; Cozzoli, Anna; De Luca, Annamaria

    2014-11-01

    Weakness and fatigability are typical features of Duchenne muscular dystrophy patients and are aggravated in dystrophic mdx mice by chronic treadmill exercise. Mechanical activity modulates gene expression and muscle plasticity. Here, we investigated the outcome of 4 (T4, 8 weeks of age) and 12 (T12, 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in the gastrocnemius muscle of mdx and wild-type (WT) mice using quantitative real-time PCR. Basal expression of the exercise-sensitive genes peroxisome-proliferator receptor γ coactivator 1α (Pgc-1α) and Sirtuin1 (Sirt1) was higher in mdx versus WT mice at both ages. Exercise increased Pgc-1α expression in WT mice; Pgc-1α was downregulated by T12 exercise in mdx muscles, along with Sirt1, Pparγ and the autophagy marker Bnip3. Sixteen weeks old mdx mice showed a basal overexpression of the slow Mhc1 isoform and Serca2; T12 exercise fully contrasted this basal adaptation as well as the high expression of follistatin and myogenin. Conversely, T12 exercise was ineffective in WT mice. Damage-related genes such as gp91-phox (NADPH-oxidase2), Tgfβ, Tnfα and c-Src tyrosine kinase were overexpressed in mdx muscles and not affected by exercise. Likewise, the anti-inflammatory adiponectin was lower in T12-exercised mdx muscles. Chronic exercise with minor adaptive effects in WT muscles leads to maladaptation in mdx muscles with a disequilibrium between protective and damaging signals. Increased understanding of the pathways involved in the altered mechanical-metabolic coupling may help guide appropriate physical therapies while better addressing pharmacological interventions in translational research. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. What Is Macular Edema?

    Medline Plus

    Full Text Available ... remains. Macular edema is often a complication of diabetic retinopathy , and is the most common form of ... 2016 Study Compares Eylea, Lucentis and Avastin for Diabetic Macular Edema Jul 17, 2015 Top 5 Risk ...

  15. Macular degeneration (image)

    Science.gov (United States)

    ... macula in the back of the eye. The macula is important for clear central vision, allowing an individual to see fine details. There are two types of macular degeneration, dry and wet. Dry macular degeneration is more ...

  16. What Is Macular Edema?

    Medline Plus

    Full Text Available ... be able to see after vitrectomy surgery for a macular hole? Jan 24, 2016 Can Prolensa drops help a macular hole? Jan 11, 2016 After a person develops ocular histoplasmosis, ...

  17. What Is Macular Edema?

    Medline Plus

    Full Text Available ... Tips & Prevention News Ask an Ophthalmologist Patient Stories Español Eye Health / Eye Health A-Z Macular Edema ... Edema Treatment What Is Macular Edema? Leer en Español: ¿Qué es un edema macular? Dec. 01, 2010 ...

  18. Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ∆45-55

    Directory of Open Access Journals (Sweden)

    Aoife Gowran

    2018-04-01

    Full Text Available Becker muscular dystrophy (BMD is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi-functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Δ45-55.

  19. Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ∆45-55).

    Science.gov (United States)

    Gowran, Aoife; Spaltro, Gabriella; Casalnuovo, Federica; Vigorelli, Vera; Spinelli, Pietro; Castiglioni, Elisa; Rovina, Davide; Paganini, Stefania; Di Segni, Marina; Gervasini, Cristina; Nigro, Patrizia; Pompilio, Giulio

    2018-04-01

    Becker muscular dystrophy (BMD) is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi-functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Δ45-55). Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

  20. [Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

    Science.gov (United States)

    Swarovskaya, M G; Stepanova, S K; Marussin, A V; Sukhomyasova, A L; Maximova, N R; Stepanov, V A

    2015-06-01

    The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed.

  1. Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Isabella Bernardis

    2016-01-01

    Full Text Available To assess the clinical utility of targeted Next-Generation Sequencing (NGS for the diagnosis of Inherited Retinal Dystrophies (IRDs, a total of 109 subjects were enrolled in the study, including 88 IRD affected probands and 21 healthy relatives. Clinical diagnoses included Retinitis Pigmentosa (RP, Leber Congenital Amaurosis (LCA, Stargardt Disease (STGD, Best Macular Dystrophy (BMD, Usher Syndrome (USH, and other IRDs with undefined clinical diagnosis. Participants underwent a complete ophthalmologic examination followed by genetic counseling. A custom AmpliSeq™ panel of 72 IRD-related genes was designed for the analysis and tested using Ion semiconductor Next-Generation Sequencing (NGS. Potential disease-causing mutations were identified in 59.1% of probands, comprising mutations in 16 genes. The highest diagnostic yields were achieved for BMD, LCA, USH, and STGD patients, whereas RP confirmed its high genetic heterogeneity. Causative mutations were identified in 17.6% of probands with undefined diagnosis. Revision of the initial diagnosis was performed for 9.6% of genetically diagnosed patients. This study demonstrates that NGS represents a comprehensive cost-effective approach for IRDs molecular diagnosis. The identification of the genetic alterations underlying the phenotype enabled the clinicians to achieve a more accurate diagnosis. The results emphasize the importance of molecular diagnosis coupled with clinic information to unravel the extensive phenotypic heterogeneity of these diseases.

  2. 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 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.

  3. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    Science.gov (United States)

    ... with mental retardation Muscular dystrophy, congenital, Fukuyama type Muscular dystrophy, congenital, with central nervous system involvement Polymicrogyria with muscular dystrophy Related Information How ...

  4. Mitochondrial DNA Variants Mediate Energy Production and Expression Levels for CFH, C3 and EFEMP1 Genes: Implications for Age-Related Macular Degeneration

    Science.gov (United States)

    Kenney, M. Cristina; Chwa, Marilyn; Atilano, Shari R.; Pavlis, Janelle M.; Falatoonzadeh, Payam; Ramirez, Claudio; Malik, Deepika; Hsu, Tiffany; Woo, Grace; Soe, Kyaw; Nesburn, Anthony B.; Boyer, David S.; Kuppermann, Baruch D.; Jazwinski, S. Michal; Miceli, Michael V.; Wallace, Douglas C.; Udar, Nitin

    2013-01-01

    Background Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD). Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt) DNA haplogroups (as defined by combinations of mtDNA polymorphisms) that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid) model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD) versus J haplogroup (high risk for AMD). Methodology/Principal Findings Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19) that was devoid of mitochondrial DNA (Rho0). In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism. Conclusion/Significance Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD. PMID:23365660

  5. Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    M Cristina Kenney

    Full Text Available Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD. Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt DNA haplogroups (as defined by combinations of mtDNA polymorphisms that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD versus J haplogroup (high risk for AMD.Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19 that was devoid of mitochondrial DNA (Rho0. In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism.Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD.

  6. The Muscular Dystrophy Gene TMEM5 Encodes a Ribitol β1,4-Xylosyltransferase Required for the Functional Glycosylation of Dystroglycan.

    Science.gov (United States)

    Manya, Hiroshi; Yamaguchi, Yoshiki; Kanagawa, Motoi; Kobayashi, Kazuhiro; Tajiri, Michiko; Akasaka-Manya, Keiko; Kawakami, Hiroko; Mizuno, Mamoru; Wada, Yoshinao; Toda, Tatsushi; Endo, Tamao

    2016-11-18

    A defect in O-mannosyl glycan is the cause of α-dystroglycanopathy, a group of congenital muscular dystrophies caused by aberrant α-dystroglycan (α-DG) glycosylation. Recently, the entire structure of O-mannosyl glycan, [3GlcAβ1-3Xylα1] n -3GlcAβ1-4Xyl-Rbo5P-1Rbo5P-3GalNAcβ1-3GlcNAcβ1-4 (phospho-6)Manα1-, which is required for the binding of α-DG to extracellular matrix ligands, has been proposed. However, the linkage of the first Xyl residue to ribitol 5-phosphate (Rbo5P) is not clear. TMEM5 is a gene product responsible for α-dystroglycanopathy and was reported as a potential enzyme involved in this linkage formation, although the experimental evidence is still incomplete. Here, we report that TMEM5 is a xylosyltransferase that forms the Xylβ1-4Rbo5P linkage on O-mannosyl glycan. The anomeric configuration and linkage position of the product (β1,4 linkage) was determined by NMR analysis. The introduction of two missense mutations in TMEM5 found in α-dystroglycanopathy patients impaired xylosyltransferase activity. Furthermore, the disruption of the TMEM5 gene by CRISPR/Cas9 abrogated the elongation of the (-3GlcAβ1-3Xylα1-) unit on O-mannosyl glycan. Based on these results, we concluded that TMEM5 acts as a UDP-d-xylose:ribitol-5-phosphate β1,4-xylosyltransferase in the biosynthetic pathway of O-mannosyl glycan. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Multiplex Ligation-dependent Probe Amplification Identification of Deletions and Duplications of the Duchenne Muscular Dystrophy Gene in Taiwanese Subjects

    Directory of Open Access Journals (Sweden)

    Hsiao-Lin Hwa

    2007-05-01

    Conclusion: MLPA was proven to be a powerful tool for the detection of DMD gene deletions and duplications in male patients and female carriers. There was a relatively lower frequency of deletion and a higher frequency of duplication of DMD gene in this population compared to previous reports.

  8. Cardiomyopathy in becker muscular dystrophy: Overview.

    Science.gov (United States)

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-06-26

    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.

  9. 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

  10. Associations of candidate genes to age-related macular degeneration among racial/ethnic groups in the multi-ethnic study of atherosclerosis.

    Science.gov (United States)

    Klein, Ronald; Li, Xiaohui; Kuo, Jane Z; Klein, Barbara E K; Cotch, Mary Frances; Wong, Tien Y; Taylor, Kent D; Rotter, Jerome I

    2013-11-01

    To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans. Cross-sectional study. setting: Multicenter study. study population: A total of 2456 persons aged 45-84 years with genotype information and fundus photographs. procedures: Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value ethnic groups. Logistic regression models tested for association in case-control samples. main outcome measure: Prevalence of early AMD. Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for 1 to 10.0 for 4 risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend = 4.2×10(-7)). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency's approaching that of whites. The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. 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)

  12. Limb-Girdle Muscular Dystrophy (LGMD)

    Science.gov (United States)

    ... Marie-Tooth Disease (CMT) Congenital Muscular Dystrophy (CMD) Duchenne Muscular Dystrophy (DMD) Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Dystrophy (DM) Spinal-Bulbar ...

  13. 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.

  14. Roles of Fukutin, the Gene Responsible for Fukuyama-Type Congenital Muscular Dystrophy, in Neurons: Possible Involvement in Synaptic Function and Neuronal Migration

    International Nuclear Information System (INIS)

    Hiroi, Atsuko; Yamamoto, Tomoko; Shibata, Noriyuki; Osawa, Makiko; Kobayashi, Makio

    2011-01-01

    Fukutin is a gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), accompanying ocular and brain malformations represented by cobblestone lissencephaly. Fukutin is related to basement membrane formation via the glycosylation of α-dystoglycan (α-DG), and astrocytes play a crucial role in the pathogenesis of the brain lesion. On the other hand, its precise function in neurons is unknown. In this experiment, the roles of fukutin in mature and immature neurons were examined using brains from control subjects and FCMD patients and cultured neuronal cell lines. In quantitative PCR, the expression level of fukutin looked different depending on the region of the brain examined. A similar tendency in DG expression appears to indicate a relation between fukutin and α-DG in mature neurons. An increase of DG mRNA and core α-DG in the FCMD cerebrum also supports the relation. In immunohistochemistry, dot-like positive reactions for VIA4-1, one of the antibodies detecting the glycosylated α-DG, in Purkinje cells suggest that fukutin is related to at least a post-synaptic function via the glycosylation of α-DG. As for immature neurons, VIA4-1 was predominantly positive in cells before and during migration with expression of fukutin, which suggest a participation of fukutin in neuronal migration via the glycosylation of α-DG. Moreover, fukutin may prevent neuronal differentiation, because its expression was significantly lower in the adult cerebrum and in differentiated cultured cells. A knockdown of fukutin was considered to induce differentiation in cultured cells. Fukutin seems to be necessary to keep migrating neurons immature during migration, and also to support migration via α-DG

  15. Association of exudative age-related macular degeneration with matrix metalloproteinases-2 (-1306 C/T rs243865 gene polymorphism

    Directory of Open Access Journals (Sweden)

    Rasa Liutkeviciene

    2018-01-01

    Full Text Available Purpose: Age-related macular degeneration (AMD is a disease of the macula that significantly affects eyesight and leads to irreversible central vision loss. Recent studies have demonstrated that angiogenesis is the most important mechanism of AMD development. It is associated with extracellular remodeling involving different proteolytic systems, among them matrix metalloproteinases (MMPs, which play an essential role in the etiopathogenesis of AMD. The main objective of the present study was to determine the relationship between exudative AMD and MMP-2 (-1306 C/T rs243865 polymorphism. Methods: The study enrolled 267 patients with exudative AMD and 318 controls. DNA was extracted from peripheral venous blood leukocytes by commercial kits. Genotyping of MMP-2 (-1306 C/T rs243865 was carried out using real-time polymerase chain reaction method. Results: The analysis of MMP-2 (-1306 C/T polymorphism did not reveal any differences in the distribution of CC, CT, and TT genotypes between the exudative AMD and control groups: 58.8%, 31.5% and 9.7% vs. 59.75%, 33.96% and 6.29%, respectively, P = 0.287. When the study population was subdivided into age groups, MMP-2 (-1306 C/T rs243865 CT genotype showed 5.7-fold increased the risk of exudative AMD development compared to CC and TT genotypes together in younger (<65 years males group (P = 0.05. Conclusion: MMP-2 (-1306 C/T polymorphism is associated with exudative AMD development in younger males.

  16. Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Daniel Ardeljan

    Full Text Available Age-related macular degeneration (AMD is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.

  17. Mutation in the RPE65 gene causing hereditary retinal dystrophy in the Briard dogs: application of a new detection method

    Czech Academy of Sciences Publication Activity Database

    Bechyňová, Renata; Dostál, Jaromír; Stratil, Antonín; Jílek, F.; Horák, Pavel

    2008-01-01

    Roč. 53, č. 4 (2008), s. 176-179 ISSN 1212-1819 R&D Projects: GA AV ČR 1QS500450578; GA ČR GD523/03/H076 Institutional research plan: CEZ:AV0Z50450515 Keywords : RPE65 gene * CSNB * dog Subject RIV: EG - Zoology Impact factor: 0.735, year: 2008

  18. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    NARCIS (Netherlands)

    Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

    2002-01-01

    PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

  19. Muscular Dystrophy (MD)

    Science.gov (United States)

    ... patients may need assisted ventilation to treat respiratory muscle weakness and a pacemaker for cardiac abnormalities. View Full Treatment Information Definition The muscular dystrophies (MD) are a group of more than 30 ...

  20. Facioscapulohumeral muscular dystrophy

    Science.gov (United States)

    ... There is no known cure for facioscapulohumeral muscular dystrophy. Treatments are given to control symptoms and improve quality of life. Activity is encouraged. Inactivity such as bedrest can make the muscle disease worse. Physical therapy may help maintain muscle ...

  1. Complications of Macular Peeling

    Science.gov (United States)

    Asencio-Duran, Mónica; Manzano-Muñoz, Beatriz; Vallejo-García, José Luis; García-Martínez, Jesús

    2015-01-01

    Macular peeling refers to the surgical technique for the removal of preretinal tissue or the internal limiting membrane (ILM) in the macula for several retinal disorders, ranging from epiretinal membranes (primary or secondary to diabetic retinopathy, retinal detachment…) to full-thickness macular holes, macular edema, foveal retinoschisis, and others. The technique has evolved in the last two decades, and the different instrumentations and adjuncts have progressively advanced turning into a safer, easier, and more useful tool for the vitreoretinal surgeon. Here, we describe the main milestones of macular peeling, drawing attention to its associated complications. PMID:26425351

  2. Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.

    Science.gov (United States)

    Wein, Nicolas; Alfano, Lindsay; Flanigan, Kevin M

    2015-06-01

    Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Rhabdomyolysis featuring muscular dystrophies.

    Science.gov (United States)

    Lahoria, Rajat; Milone, Margherita

    2016-02-15

    Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice. To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature. We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation. Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600). Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.

    Science.gov (United States)

    Rivera, A; White, K; Stöhr, H; Steiner, K; Hemmrich, N; Grimm, T; Jurklies, B; Lorenz, B; Scholl, H P; Apfelstedt-Sylla, E; Weber, B H

    2000-10-01

    Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of approximately 58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.

  5. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    International Nuclear Information System (INIS)

    Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai; Hu, Ji-Wei; Ouyang, Pin

    2014-01-01

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB +/− mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity

  6. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hsu-Pin; Hsu, Shu-Yuan [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Wu, Wen-Ai; Hu, Ji-Wei [Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Ouyang, Pin, E-mail: ouyang@mail.cgu.edu.tw [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Molecular Medicine Research Center, Chang Gung University, Taiwan (China)

    2014-01-03

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.

  7. Learning about Duchenne Muscular Dystrophy

    Science.gov (United States)

    ... protein. Often these boys are classified as having Becker muscular dystrophy. Genetic testing (looking at the body's genetic instructions) ... National Library of Medicine Web site Duchenne and Becker muscular dystrophy [ghr.nlm.nih.gov] From Genetics Home Reference ...

  8. What Is Macular Edema?

    Medline Plus

    Full Text Available ... an Ophthalmologist Answers Would a macular wrinkle cause black streaks in my vision? Oct 05, 2017 When will I be able to see after vitrectomy surgery for a macular hole? Jan 24, 2016 Can Prolensa drops help a ...

  9. The macular xanthophylls.

    Science.gov (United States)

    Ahmed, Shazia S; Lott, McGregor N; Marcus, Dennis M

    2005-01-01

    The macular pigments are predominantly composed of three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. These carotenoids are concentrated and distributed in a selective manner. The properties of these pigments are further explored along with their methods of uptake, stabilization, and storage. The dual nature of these pigments as filters and antioxidants are elaborated upon in relation to their protective effects upon the macula, specifically in age-related macular degeneration. Evidence suggests that increased levels of macular pigment are correlated with a decreased risk of age-related macular degeneration. Many have sought to exploit this therapeutic relation. Studies reveal that oral supplementation with lutein and zeaxanthin can increase the levels of macular pigments in the retina and plasma. The effects of such supplementation on actual ocular function have yet to be fully addressed. New and standardized methods of assessing macular pigment density are discussed and future areas of research to further our understanding of macular xanthophylls as they pertain to age-related macular degeneration are highlighted.

  10. A novel point mutation (G[sup [minus]1] to T) in a 5[prime] splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker Muscular Dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Hagiwara, Yoko; Nishio, Hisahide; Kitoh, Yoshihiko; Takeshima, Yasuhiro; Narita, Naoko; Wada, Hiroko; Yokoyama, Mitsuhiro; Nakamura, Hajime; Matsuo, Masafumi (Kobe Univ. School of Medicine (Japan))

    1994-01-01

    The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. The authors now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5[prime] splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5[prime] splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G[sup [minus]1]-to-T mutation at the 5[prime] splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. 48 refs., 5 figs.

  11. Development of Non-Hormonal Steroids for the Treatment of Duchenne Muscular Dystrophy

    Science.gov (United States)

    2013-02-01

    constructs envisioned in gene therapy, are also expressed in Becker muscular dystrophy (alleles of dystrophinopathy leading to milder disease). In other words...the Treatment of Duchenne Muscular Dystrophy PRINCIPAL INVESTIGATOR: Terence Partridge, PhD CONTRACTING ORGANIZATION: Children’s...Duchenne Muscular Dystrophy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0754 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Terence Partridge

  12. A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Chicoine Louis G

    2007-09-01

    Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1 A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2 an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3 the use of viral doses to accommodate current limitations imposed by vector production methods; 4 and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation. Methods The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a that recognizes the N-terminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL. The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD. Results Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month, 91.3 ± 3.1 (2 months, and 89.6 ± 1.6% (3 months. rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month, 78.9 ± 7.4 (2 months, and 81.2 ± 6.2% (3 months transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month, 2.1 ± 0.8 (2 months, and 2.1 ± 0.7% (3 months] by vascular delivery. Micro

  13. Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nik-Ahd, Farnoosh; Bertoni, Carmen

    2014-07-01

    Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. © 2014 AlphaMed Press.

  14. Omics in Ophthalmology: Advances in Genomics and Precision Medicine for Leber Congenital Amaurosis and Age-Related Macular Degeneration.

    Science.gov (United States)

    den Hollander, Anneke I

    2016-03-01

    The genomic revolution has had a huge impact on our understanding of the genetic defects and disease mechanisms underlying ophthalmic diseases. Two examples are discussed here. The first is Leber congenital amaurosis (LCA), a severe inherited retinal dystrophy leading to severe vision loss in children, and the second is age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. Twenty years ago, the genetic causes of these diseases were unknown. Currently, more than 20 LCA genes have been identified, and genetic testing can now successfully identify the genetic defects in at least 75% of all LCA cases. Gene-specific treatments have entered the clinical trial phase for three LCA genes, and for seven LCA genes gene-specific therapies have been tested in model systems. Age-related macular degeneration is a multifactorial disease caused by a combination of genetic and environmental factors. Currently, more than 40 loci have been identified for AMD, accounting for 15%-65% of the total genetic contribution to AMD. Despite the progress that has been made so far, genetic testing is not yet recommended for AMD, but this may change if we move to clinical trials or treatments that are dependent on an individual's genotype. The identification of serum or plasma biomarkers using other "-omics" technologies may further improve predictive tests and our understanding of the disease mechanisms of AMD. Ultimately, it is anticipated that predictive tests will help to stratify patients for the most suitable therapy, which will enable the development of precision medicine, tailored to individual needs.

  15. Macular function and morphologic features in juvenile stargardt disease: longitudinal study.

    Science.gov (United States)

    Testa, Francesco; Melillo, Paolo; Di Iorio, Valentina; Orrico, Ada; Attanasio, Marcella; Rossi, Settimio; Simonelli, Francesca

    2014-12-01

    detecting morphologic macular changes prove useful in evaluating disease progression over a short-term follow-up and should be taken into account for the design of future clinical trials of gene therapy to treat retinal dystrophy. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  16. Macular function and morphological features in juvenile Stargardt disease: Longitudinal study

    Science.gov (United States)

    Testa, Francesco; Melillo, Paolo; Iorio, Valentina Di; Orrico, Ada; Attanasio, Marcella; Rossi, Settimio; Simonelli, Francesca

    2014-01-01

    decline of visual functionality and detecting morphological macular changes proves useful to evaluate disease progression over a short-term follow-up and should be taken into account for the design of future gene therapy clinical trials to treat retinal dystrophy. PMID:25097154

  17. Cystoid macular edema

    Directory of Open Access Journals (Sweden)

    Tryfon G Rotsos

    2008-10-01

    Full Text Available Tryfon G Rotsos1, Marilita M Moschos21Medical Retina Service, Moorfields Eye Hospital, London, UK; 2Department of Ophthalmology, University of Athens, GreeceAbstract: We review the epidemiology, pathophysiology, and etiology of cystoid macular edema (CME. Inflammatory, diabetic, post-cataract, and macular edema due to age-related macular degeneration is described. The role of chronic inflammation and hypoxia and direct macular traction is evaluated in each case according to different views from the literature. The different diagnostic methods for evaluating the edema are described. Special attention is given to fluoroangiography and the most modern methods of macula examination, such as ocular coherence tomography and multifocal electroretinography. Finally, we discuss the treatment of cystoid macular edema in relation to its etiology. In this chapter we briefly refer to the therapeutic value of laser treatment especially in diabetic maculopathy or vitrectomy in some selected cases. Our paper is focused mainly on recent therapeutic treatment with intravitreal injection of triamcinolone acetonide and anti-VEGF factors like bevacizumab (Avastin, ranibizumab (Lucentis, pegaptamid (Macugen, and others. The goal of this paper is to review the current status of this treatment for macular edema due to diabetic maculopathy, central retinal vein occlusion and post-cataract surgery. For this reason the results of recent multicenter clinical trials are quoted, as also our experience on the use of intravitreal injections of anti-VEGF factors and we discuss its value in clinical practice.Keywords: cystoid macular edema, anti-VEGF, fluoroangiography, OCT, multifocal electroretinography

  18. What Is Macular Edema?

    Medline Plus

    Full Text Available ... a macular hole? Jan 11, 2016 After a person develops ocular histoplasmosis, is it common that years or even decades pass before the person notices the vision changes and the disease is ...

  19. What Is Macular Edema?

    Medline Plus

    Full Text Available ... the most common form of vision loss for people with diabetes—particularly if it is left untreated. ... a macular hole? Jan 11, 2016 After a person develops ocular histoplasmosis, is it common that years ...

  20. What Is Macular Edema?

    Medline Plus

    Full Text Available ... side) vision remains. Macular edema is often a complication of diabetic retinopathy , and is the most common form of vision loss for people with diabetes—particularly if it is left untreated. Next What ...

  1. Evaluation of new and established age-related macular degeneration susceptibility genes in the Women's Health Initiative Sight Exam (WHI-SE) Study

    Science.gov (United States)

    To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study. This is a multice...

  2. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... is very similar to Duchenne, except kids with Becker MD may not have problems until much later, when they're teenagers or adults. It takes a long time for their muscles to become weak. How Does a Kid Get Muscular Dystrophy? MD is not contagious (say: con-TAY-juss), ...

  3. Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, A. J.; Bonne, G.; Eymard, B.; Duboc, D.; Talim, B.; van der Valk, M.; Reiss, P.; Richard, P.; Demay, L.; Merlini, L.; Schwartz, K.; Busch, H. F. M.; de Visser, M.

    2002-01-01

    Mutations in the lamin A/C gene are found in Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy with cardiac conduction disturbances, dilated cardiomyopathy with conduction system disease, and familial partial lipodystrophy. Cases with lamin A/C mutations presenting with lipodystrophy

  4. 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

  5. Macular Amyloidosis and Epstein-Barr Virus

    Directory of Open Access Journals (Sweden)

    Yalda Nahidi

    2016-01-01

    Full Text Available Background. Amyloidosis is extracellular precipitation of eosinophilic hyaline material of self-origin with special staining features and fibrillar ultrastructure. Macular amyloidosis is limited to the skin, and several factors have been proposed for its pathogenesis. Detection of Epstein-Barr virus (EBV DNA in this lesion suggests that this virus can play a role in pathogenesis of this disease. Objective. EBV DNA detection was done on 30 skin samples with a diagnosis of macular amyloidosis and 31 healthy skin samples in the margin of removed melanocytic nevi by using PCR. Results. In patients positive for beta-globin gene in PCR, BLLF1 gene of EBV virus was positive in 23 patients (8 patients in case and 15 patients in the control group. There was no significant difference in presence of EBV DNA between macular amyloidosis (3.8% and control (23.8% groups (P=0.08. Conclusion. The findings of this study showed that EBV is not involved in pathogenesis of macular amyloidosis.

  6. Serous Macular Detachments

    Directory of Open Access Journals (Sweden)

    Hakan Özdemir

    2012-03-01

    Full Text Available Serous macular detachment has only recently been recognized to occur in a significant number of eyes with macular pathology including diabetic retinopathy, retinal vein occlusion, Behçet disease, Irvine-Gass syndrome and pars planitis. These serous retinal detachments associated with retinal vascular leakage are not suspected clinically or angiographically but can be diagnosed with optical coherence tomography (OCT beneath the edematous neurosensory retina. The detection of shallow foveal detachment may be helpful in better understanding the pathogenesis of these disorders. In addition, the detection of serous macular detachment may also help to better guide and assess the results of therapy in the future. (Turk J Oph thal mol 2012; 42: 146-9

  7. Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy.

    Science.gov (United States)

    Bianco, Bianca; Christofolini, Denise Maria; Conceição, Gabriel Seixas; Barbosa, Caio Parente

    2017-01-01

    Duchenne muscular dystrophy is the most common muscle disease found in male children. Currently, there is no effective therapy available for Duchenne muscular dystrophy patients. Therefore, it is essential to make a prenatal diagnosis and provide genetic counseling to reduce the birth of such boys. We report a case of preimplantation genetic diagnosis associated with Duchenne muscular dystrophy. The couple E.P.R., 38-year-old, symptomatic patient heterozygous for a 2 to 47 exon deletion mutation in DMD gene and G.T.S., 39-year-old, sought genetic counseling about preimplantation genetic diagnosis process. They have had a 6-year-old son who died due to Duchenne muscular dystrophy complications. The couple underwent four cycles of intracytoplasmic sperm injection (ICSI) and eight embryos biopsies were analyzed by polymerase chain reaction (PCR) for specific mutation analysis, followed by microarray-based comparative genomic hybridisation (array CGH) for aneuploidy analysis. Preimplantation genetic diagnosis revealed that two embryos had inherited the maternal DMD gene mutation, one embryo had a chromosomal alteration and five embryos were normal. One blastocyst was transferred and resulted in successful pregnancy. The other embryos remain vitrified. We concluded that embryo analysis using associated techniques of PCR and array CGH seems to be safe for embryo selection in cases of X-linked disorders, such as Duchenne muscular dystrophy.

  8. Orocaecal transit time in Duchenne muscular dystrophy.

    OpenAIRE

    Korman, S H; Bar-Oz, B; Granot, E; Meyer, S

    1991-01-01

    Smooth muscle degeneration may occur in Duchenne muscular dystrophy. We measured fasting orocaecal transit time in patients with advanced Duchenne muscular dystrophy and other muscular dystrophies and in healthy controls. No significant differences were found. In contrast to reports of gastric hypomotility in Duchenne muscular dystrophy, we found no evidence of impaired small intestinal motility.

  9. What Is Age-Related Macular Degeneration?

    Science.gov (United States)

    ... Eye Health / Eye Health A-Z Age-Related Macular Degeneration Sections What Is Macular Degeneration? How is AMD ... What Does Macular Degeneration Look Like? What Is Macular Degeneration? Leer en Español: ¿Qué es la degeneración macular ...

  10. What Is Macular Edema?

    Medline Plus

    Full Text Available ... for Diabetic Macular Edema Jul 17, 2015 Top 5 Risk Factors for AMD Jan 29, 2014 Is Your Laser Pointer Dangerous Enough to Cause Eye Injury? Dec 20, 2013 Study Finds Tablets Help People with Low Vision Nov 27, 2013 Follow The ...

  11. What Is Macular Edema?

    Medline Plus

    Full Text Available ... may be mild to severe, but in many cases, your peripheral (side) vision remains. Macular edema is often a complication of diabetic retinopathy , and is the most common form of vision loss for people with diabetes—particularly if it is left ... Studies Show Zika Virus May Cause More Serious Eye ...

  12. What Is Macular Edema?

    Medline Plus

    Full Text Available ... the retina, where they are transmitted to the brain and interpreted as the images you see. It is the macula that is responsible for your pinpoint vision, allowing you to read, sew or recognize a face. Macular edema develops when blood vessels in the retina are leaking ...

  13. Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD)

    DEFF Research Database (Denmark)

    Brolin, Camilla; Shiraishi, Takehiko

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most...

  14. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Conditions Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Printable PDF Open All Close All Enable Javascript ... dystrophy occur almost exclusively in males. Duchenne and Becker muscular dystrophies have similar signs and symptoms and are caused ...

  15. Rebound macular edema following oral acetazolamide therapy for juvenile X-linked retinoschisis in an Italian family

    Directory of Open Access Journals (Sweden)

    Galantuomo MS

    2016-11-01

    Full Text Available Maria Silvana Galantuomo,1,* Maurizio Fossarello,1 Alberto Cuccu,1 Roberta Farci,1 Markus N Preising,2 Birgit Lorenz,2 Pietro Emanuele Napoli1,* 1Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy; 2Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany *These authors contributed equally to this work Background: Juvenile X-linked retinoschisis (RS1, OMIM: 312700 is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments. Purpose: The purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the RS1 gene (OMIM: 300839 in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT. Methods: Eleven individuals, including two brothers with RS1 (patients 1 and 2, underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications. Results: Sequence analysis of the RS1 gene identified a hemizygous c.589C>T (p.Arg197Cys missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for

  16. [Complete atrioventricular block in Duchenne muscular dystrophy].

    Science.gov (United States)

    Kuru, Satoshi; Tanahashi, Tamotsu; Matsumoto, Shinjirou; Kitamura, Tetsuya; Konagaya, Masaaki

    2012-01-01

    We report a case of complete atrioventricular (AV) block in a 40-year-old patient with Duchenne muscular dystrophy (DMD). While he was bed-ridden and required mechanical ventilation, his cardiac involvement was mild. He had the deletion of exon 45-52 in the dystrophin gene. He underwent transient complete AV block and came to require pacemaker implantation due to recurrence of complete AV block ten days after the first attack. Electrophysiological study revealed mild prolonged AH and HV interval. Although DMD patients with AV block have been rarely reported so far, attention should be paid to AV block for patients who prolonged their lives.

  17. Merosin/laminin-2 and muscular dystrophy

    DEFF Research Database (Denmark)

    Wewer, U M; Engvall, E

    1996-01-01

    structural organization of domains, some of which have been assigned biological activities, including self-assembly and interactions with other proteins. The particular importance of laminins for the formation and stability of cell adhesion complexes is highlighted in severe inherited diseases of muscle...... and skin. Merosin is the collective name for laminins that share a common subunit, the laminin alpha 2 chain. Merosin-deficient congenital muscular dystrophy (CMD) is caused by mutations in the laminin alpha 2 chain gene. The skin disease Herlitz junctional epidermolysis bullosa is caused by mutations...

  18. Next Generation Sequencing approach to molecular diagnosis of Duchenne muscular dystrophy; identification of a novel mutation.

    Science.gov (United States)

    Ebrahimzadeh-Vesal, Reza; Teymoori, Atieh; Azimi-Nezhad, Mohsen; Hosseini, Forough Sadat

    2018-02-20

    Duchenne Muscular Dystrophy (DMD; MIM 310200) is one of the most common and severe type of hereditary muscular dystrophies. The disease is caused by mutations in the dystrophin gene. The dystrophin gene is associated with X-linked recessive Duchenne and Becker muscular dystrophy. This disease occurs almost exclusively in males. The clinical symptoms of muscle weakness usually begin at childhood. The main symptoms of this disorder are gradually muscular weakness. The affected patients have inability to standing up and walking. Death is usually due to respiratory infection or cardiomyopathy. In this article, we have reported the discovery of a new nonsense mutation that creates abnormal stop codon in the dystrophin gene. This mutation was detected using Next Generation Sequencing (NGS) technique. The subject was a 17-year-old male with muscular dystrophy that who was suspected of having DMD. He was referred to Hakim medical genetics center of Neyshabur, IRAN. Copyright © 2017. Published by Elsevier B.V.

  19. KMeyeDB: a graphical database of mutations in genes that cause eye diseases.

    Science.gov (United States)

    Kawamura, Takashi; Ohtsubo, Masafumi; Mitsuyama, Susumu; Ohno-Nakamura, Saho; Shimizu, Nobuyoshi; Minoshima, Shinsei

    2010-06-01

    KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

  20. Phenotypic diversity in autosomal-dominant cone-rod dystrophy elucidated by adaptive optics retinal imaging.

    Science.gov (United States)

    Song, Hongxin; Rossi, Ethan A; Stone, Edwin; Latchney, Lisa; Williams, David; Dubra, Alfredo; Chung, Mina

    2018-01-01

    Several genes causing autosomal-dominant cone-rod dystrophy (AD-CRD) have been identified. However, the mechanisms by which genetic mutations lead to cellular loss in human disease remain poorly understood. Here we combine genotyping with high-resolution adaptive optics retinal imaging to elucidate the retinal phenotype at a cellular level in patients with AD-CRD harbouring a defect in the GUCA1A gene. Nine affected members of a four-generation AD-CRD pedigree and three unaffected first-degree relatives underwent clinical examinations including visual acuity, fundus examination, Goldmann perimetry, spectral domain optical coherence tomography and electroretinography. Genome-wide scan followed by bidirectional sequencing was performed on all affected participants. High-resolution imaging using a custom adaptive optics scanning light ophthalmoscope (AOSLO) was performed for selected participants. Clinical evaluations showed a range of disease severity from normal fundus appearance in teenaged patients to pronounced macular atrophy in older patients. Molecular genetic testing showed a mutation in in GUCA1A segregating with disease. AOSLO imaging revealed that of the two teenage patients with mild disease, one had severe disruption of the photoreceptor mosaic while the other had a normal cone mosaic. AOSLO imaging demonstrated variability in the pattern of cone and rod cell loss between two teenage cousins with early AD-CRD, who had similar clinical features and had the identical disease-causing mutation in GUCA1A . This finding suggests that a mutation in GUCA1A does not lead to the same degree of AD-CRD in all patients. Modifying factors may mitigate or augment disease severity, leading to different retinal cellular phenotypes. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. Muscular Dystrophy: Hope Through Research

    Science.gov (United States)

    ... of muscular dystrophy appeared in 1830, when Sir Charles Bell wrote an essay about an illness that ... linked disorder to their sons but their daughters will be carriers of that disorder. Carrier females occasionally ...

  2. Congenital muscular dystrophies--problems of classification.

    Science.gov (United States)

    Lenard, H G

    1991-04-01

    The classification of congenital muscular dystrophies (CMD), based on perceived clinical and morphological similarities or differences, is controversial. CMD without cerebral involvement has sometimes been divided into a mild and a severe form. This distinction is, however, arbitrary and not uncontested. Whether Ullrich's disease, formerly called atonic-sclerotic dystrophy, is a disease entity and if so, whether it is a primary muscle disorder, is uncertain. CMD without cerebral involvement is inherited in an autosomal recessive fashion in the great majority of cases. CMDs with cerebral involvement are usually classified into at least three forms: the Fukuyama type of CMD, occurring almost exclusively in Japanese patients; CMD with hypomyelination, sometimes also called the occidental type of cerebromuscular dystrophy; and Walker-Warburg syndrome. Muscle-eye-brain disease, described in a number of Finnish patients, may or may not belong in this last category. In CMD with cerebral involvement inheritance is also autosomal recessive. It is possible that single sporadic cases are phenocopies due to infectious or other exogenous causes. Reports of clinical and morphological findings from an increasing number of patients show a high degree of variability within and, on the other hand, certain similarities between the forms of CMD with cerebral involvement. In addition, neuroradiological changes are also found with increasing frequency in CMD patients without clinical neuropsychological abnormalities. It is not unreasonable to speculate that molecular genetic techniques will reveal in the near future a variable defect in one gene locus or defects in a few gene loci as the cause of the various clinical forms of CMDs.

  3. Fuchs' dystrophy associated with radial keratotomy: Lamellar or perforating keratoplasty?

    Science.gov (United States)

    Rodriguez-Ausin, P; Antolin-Garcia, D; Santamaria Garcia, L; Blazquez-Fernandez, A-B

    2017-05-01

    A 70 year-old male patient with a history of radial keratotomy suffering from Fuchs' dystrophy and a cataract. The patient received a two-step surgery: lens phacoemulsification and intraocular lens implant, followed by descemet stripping automated endothelial keratoplasty in both eyes, four months later. There were no complications apart from a recurrent cystoid macular oedema in both eyes. The best corrected visual acuity was 20/40 both eyes, and the patient was satisfied. Descemet stripping automated endothelial keratoplasty may be considered as an alternative to penetrating keratoplasty in the case of endothelial dysfunction and radial keratotomy in patients with no corneal ectasia or significant stromal opacity. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Computerized tomography in myotonic dystrophy

    International Nuclear Information System (INIS)

    Gellerich, I.; Mueller, D.; Koch, R.D.

    1986-01-01

    Besides clinical symptoms, progress and electromyography computerized tomography improves the diagnostics of myotonic dystrophy. Even small changes in muscular structure are detectable and especially the musculus soleus exhibits early and pronounced alterations. By means of density distribution pattern an improved characterization of the disease is possible. Additional information is obtained by cerebral computerized tomography. Atrophy of brain tissue is to be expected in all patients with myotonic dystrophy. (author)

  5. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2012-05-01

    muscle dystrophy with abnormal waddling gait at 4 weeks of age. At 10 weeks of age, double mutants exhibit skeletal muscle degeneration, necrosis... dystrophy (MCMD). Homozygous dyW mice are passive, small, and emaciated, and demonstrate partial hindleg weakness and clasping. Their muscles contain...was statistically significant for both single- treatment groups. Figure 4. Effect of GW and AICAR on body mass, muscle mass, and behavioral

  6. Duchenne muscular dystrophy carriers

    International Nuclear Information System (INIS)

    Matsumura, K.; Nakano, I.

    1989-01-01

    By means of magnetic resonance imaging (MRI), the proton spin-lattice relaxation times (T1 values) of the skeletal muscles were measured in Duchenne muscular dystrophy (DMD) carriers and normal controls. The bound water fraction (BWF) was calculated from the T1 values obtained, according to the fast proton diffusion model. In the DMD carriers, T1 values of the gluteus maximus and quadriceps femoris muscles were significantly higher, and BWFs of these muscles were significantly lower than in normal control. Degenerative muscular changes accompanied by interstitial edema were presumed responsible for this abnormality. No correlation was observed between the muscle T1 and serum creatine kinase values. The present study showed that MRI could be a useful method for studying the dynamic state of water in both normal and pathological skeletal muscles. Its possible utility for DMD carrier detection was discussed briefly. (orig.)

  7. Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

    Science.gov (United States)

    Momma, Kazunari; Noguchi, Satoru; Malicdan, May Christine V; Hayashi, Yukiko K; Minami, Narihiro; Kamakura, Keiko; Nonaka, Ikuya; Nishino, Ichizo

    2012-01-01

    Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene.

  8. Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

    Directory of Open Access Journals (Sweden)

    Kazunari Momma

    Full Text Available Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene.

  9. Genetics Home Reference: cone-rod dystrophy

    Science.gov (United States)

    ... common cause of autosomal recessive cone-rod dystrophy , accounting for 30 to 60 percent of cases. At ... dystrophy play essential roles in the structure and function of specialized light receptor cells (photoreceptors) in the ...

  10. Respiratory function in facioscapulohumeral muscular dystrophy 1

    NARCIS (Netherlands)

    Wohlgemuth, M.; Horlings, G.C.; Kooi, E.L. van der; Gilhuis, H.J.; Hendriks, J.C.M.; Maarel, S.M. van der; Engelen, B.G.M. van; Heijdra, Y.F.; Padberg, G.W.A.M.

    2017-01-01

    To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory

  11. What Are the Types of Muscular Dystrophy?

    Science.gov (United States)

    ... muscular dystrophy? There are more than 30 forms of muscular dystrophy (MD), with information on the primary types included in the table below. 1 Duchenne (DMD) What It Is Common Symptoms How It ...

  12. The Intriguing Regulators of Muscle Mass in Sarcopenia and Muscular Dystrophy

    OpenAIRE

    Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

    2014-01-01

    Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This revie...

  13. Naturally Protected Muscle Phenotypes: Development of Novel Treatment Strategies for Duchenne Muscular Dystrophy

    OpenAIRE

    Dowling, Paul; Doran, Philip; Lohan, James; Culligan, Kevin; Ohlendieck, Kay

    2004-01-01

    Primary abnormalities in the dystrophin gene underlie x-linked muscular dystrophy. However, the absence of the dystrophin isoform Dp427 does not necessarily result in a severe dystrophic phenotype in all muscle groups. Distal mdx muscles, namely extraocular and toe fibres, appear to represent a protected phenotype in muscular dystrophy. Thus, a comparative analysis of affected versus naturally protected muscle cells should lead to a greater knowledge of the molecular pathogenes...

  14. Analysis of CTG repeat length variation in the DMPK gene in the general population and the molecular diagnosis of myotonic dystrophy type 1 in Malaysia.

    Science.gov (United States)

    Ambrose, Kathlin K; Ishak, Taufik; Lian, Lay-Hoong; Goh, Khean-Jin; Wong, Kum-Thong; Ahmad-Annuar, Azlina; Thong, Meow-Keong

    2017-03-31

    The lack of epidemiological data and molecular diagnostic services in Malaysia has hampered the setting-up of a comprehensive management plan for patients with myotonic dystrophy type 1 (DM1), leading to delayed diagnosis, treatment and support for patients and families. The aim of this study was to estimate the prevalence of DM1 in the 3 major ethnic groups in Malaysia and evaluate the feasibility of a single tube triplet-primed PCR (TP-PCR) method for diagnosis of DM1 in Malaysia. We used PCR to determine the size of CTG repeats in 377 individuals not known to be affected by DM and 11 DM1 suspected patients, recruited from a tertiary hospital in Kuala Lumpur. TP-PCR was performed on selected samples, followed by Southern blot hybridisation of PCR amplified fragments to confirm and estimate the size of CTG expansion. The number of individuals not known to be affected by DM with (CTG) >18 was determined according to ethnic group and as a whole population. The χ 2 test was performed to compare the distribution of (CTG) >18 with 12 other populations. Additionally, the accuracy of TP-PCR in detecting CTG expansion in 11 patients with DM1 was determined by comparing the results with that from Southern blot hybridisation. Of the 754 chromosomes studied, (CTG) >18 frequency of 3.60%, 1.57% and 4.00% in the Malay, Chinese and Indian subpopulations, respectively, was detected, showing similarities to data from Thai, Taiwanese and Kuwaiti populations. We also successfully detected CTG expansions in 9 patients using the TP-PCR method followed by the estimation of CTG expansion size via Southern blot hybridisation. The results show a low DM1 prevalence in Malaysia with the possibility of underdiagnosis and demonstrates the feasibility of using a clinical and TP-PCR-based approach for rapid and cost-effective DM1 diagnosis in developing countries. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): a prospective study of 25 patients

    International Nuclear Information System (INIS)

    Perloff, J.K.; Stevenson, W.G.; Roberts, N.K.; Cabeen, W.; Weiss, J.

    1984-01-01

    The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium

  16. Diabetic Macular Edema.

    Science.gov (United States)

    Gundogan, Fatih C; Yolcu, Umit; Akay, Fahrettin; Ilhan, Abdullah; Ozge, Gokhan; Uzun, Salih

    2016-01-01

    Diabetic macular edema (DME), one the most prevalent causes of visual loss in industrialized countries, may be diagnosed at any stage of diabetic retinopathy. The diagnosis, treatment, and follow up of DME have become straightforward with recent developments in fundus imaging, such as optical coherence tomography. Laser photocoagulation, intravitreal injections, and pars plana vitrectomy surgery are the current treatment modalities; however, the positive effects of currently available intravitreally injected agents are temporary. At this point, further treatment choices are needed for a permanent effect. The articles published between 1985-2015 years on major databases were searched and most appropriate 40 papers were used to write this review article.

  17. Muscular dystrophy in a dog resembling human becker muscular dystrophy.

    Science.gov (United States)

    Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

    2014-05-01

    A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. CT findings of muscular dystrophy

    International Nuclear Information System (INIS)

    Saitoh, Hiroshi

    1991-01-01

    CT scans of muscles in patients with limb girdle type (LG), myotonic type (MYD) and Duchenne type (DMD) dystrophies were obtained at five different body levels: the neck, L3 vertebral body, pelvic girdle, thigh and lower leg. CT numbers, cross sectional areas (CSA) and %CSA of muscle or fat were evaluated in each muscle. The characteristic CT patterns for each type of muscular dystrophy were obtained. Compared with DMD, the gracilis and soleus were more severely damaged in LG and the biceps femoris remained relatively preserved among the hamstrings. In addition, the multifidus of the neck and sternocleidomastoid also were more severely damaged in MYD. This study suggests that CT scan will be useful in the differential diagnosis of these types of muscular dystrophy as well as in planning appropriate rehabilitation and detecting damaged muscles. (author)

  19. Age-related macular degeneration

    DEFF Research Database (Denmark)

    la Cour, Morten; Kiilgaard, Jens Folke; Nissen, Mogens Holst

    2002-01-01

    Age-related macular degeneration (AMD) is a common macular disease affecting elderly people in the Western world. It is characterised by the appearance of drusen in the macula, accompanied by choroidal neovascularisation (CNV) or geographic atrophy. The disease is more common in Caucasian....... Smoking is probably also a risk factor. Preventive strategies using macular laser photocoagulation are under investigation, but their efficacy in preventing visual loss is as yet unproven. There is no treatment with proven efficacy for geographic atrophy. Optimal treatment for exudative AMD requires...

  20. Gene therapy for Stargardt disease associated with ABCA4 gene.

    Science.gov (United States)

    Han, Zongchao; Conley, Shannon M; Naash, Muna I

    2014-01-01

    Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt's disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8 kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4 (-/-) murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt's disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach.

  1. [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

    Science.gov (United States)

    Magot, A; Mercier, S; Péréon, Y

    2015-12-01

    Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

    Directory of Open Access Journals (Sweden)

    Ana Cotta

    2014-09-01

    Full Text Available Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

  3. Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).

    Science.gov (United States)

    Yanagisawa, Suiho; Kondo, Naoshi; Miki, Akiko; Matsumiya, Wataru; Kusuhara, Sentaro; Tsukahara, Yasutomo; Honda, Shigeru; Negi, Akira

    2011-01-01

    To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects parchitecture of this phenotypically heterogeneous disorder.

  4. Preferred retinal locus in macular disease: characteristics and clinical implications.

    Science.gov (United States)

    Greenstein, Vivienne C; Santos, Rodrigo A V; Tsang, Stephen H; Smith, R Theodore; Barile, Gaetano R; Seiple, William

    2008-10-01

    To investigate the location and fixation stability of preferred retinal locations (PRLs) in patients with macular disease, and the relationship among areas of abnormal fundus autofluorescence, the PRL and visual sensitivity. Fifteen patients (15 eyes) were studied. Seven had Stargardt disease, 1 bull's eye maculopathy, 5 age-related macular degeneration, 1 Best disease, and 1 pattern dystrophy. All tested eyes had areas of abnormal fundus autofluorescence. The PRL was evaluated with fundus photography and the Nidek microperimeter. Visual field sensitivity was measured with the Nidek microperimeter. Of the 15 eyes, 4 had foveal and 11 had eccentric fixation. Eccentric PRLs were above the atrophic lesion and their stability did not depend on the degree of eccentricity from the fovea. Visual sensitivity was markedly decreased in locations corresponding to hypofluorescent areas. Sensitivity was not decreased in hyperfluorescent areas corresponding to flecks but was decreased if hyperfluorescence was in the form of dense annuli. Eccentric PRLs were in the superior retina in regions of normal fundus autofluorescence. Fixation stability was not correlated with the degree of eccentricity from the fovea. To assess the outcomes of treatment trials it is important to use methods that relate retinal morphology to visual function.

  5. Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings

    Directory of Open Access Journals (Sweden)

    Ulrike Mütze

    2017-03-01

    Discussion: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.

  6. Macular degeneration - age-related

    Science.gov (United States)

    ... AMD occurs when the blood vessels under the macula become thin and brittle. Small yellow deposits, called drusen, form. Almost all people with macular degeneration start with the dry form. Wet AMD occurs ...

  7. A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration.

    Science.gov (United States)

    Chavali, Venkata R M; Khan, Naheed W; Cukras, Catherine A; Bartsch, Dirk-Uwe; Jablonski, Monica M; Ayyagari, Radha

    2011-05-15

    Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5(+/-)) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruch's membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5(+/-) mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies.

  8. Stem cell transplantation for treating Duchenne muscular dystrophy

    Science.gov (United States)

    Yang, Xiaofeng

    2012-01-01

    OBJECTIVE: To identify global research trends in stem cell transplantation for treating Duchenne muscular dystrophy using a bibliometric analysis of Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of studies on stem cell transplantation for treating Duchenne muscular dystrophy from 2002 to 2011 retrieved from Web of Science. SELECTION CRITERIA: Inclusion criteria: (a) peer-reviewed published articles on stem cell transplantation for treating Duchenne muscular dystrophy indexed in Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and (c) publication between 2002 and 2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) corrected papers. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to subject areas; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) distribution according to institution in China; (7) distribution according to institution that cooperated with Chinese institutions; (8) top-cited articles from 2002 to 2006; (9) top-cited articles from 2007 to 2011. RESULTS: A total of 318 publications on stem cell transplantation for treating Duchenne muscular dystrophy were retrieved from Web of Science from 2002 to 2011, of which almost half derived from American authors and institutes. The number of publications has gradually increased over the past 10 years. Most papers appeared in journals with a focus on gene and molecular research, such as Molecular Therapy, Neuromuscular Disorders, and PLoS One. The 10 most-cited papers from 2002 to 2006 were mostly about different kinds of stem cell transplantation for muscle regeneration, while the 10 most-cited papers from 2007 to 2011 were mostly about new techniques of stem cell transplantation

  9. Dysphagia in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Wohlgemuth, M.; Swart, B.J.M. de; Kalf, J.G.; Joosten, F.B.M.; Vliet, A.M. van der; Padberg, G.W.A.M.

    2006-01-01

    Dysphagia is not considered a symptom of facioscapulohumeral muscular dystrophy (FSHD). In this study, the authors found that dysphagia does occur in patients with advanced FSHD showing mild involvement of the jaw and lingual muscles. Dysphagia is seldom life threatening in these patients. The

  10. 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

  11. 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.

  12. 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.

  13. Faecal incontinence in myotonic dystrophy

    OpenAIRE

    Abercrombie, J; Rogers, J; Swash, M

    1998-01-01

    Two siblings with myotonic dystrophy presented for treatment of faecal incontinence. The pathophysiology of this functional disorder is described with the results of anorectal manometry, EMG, and biopsy of smooth and striated muscle of the anorectal sphincters. Both medical and surgical management of the incontinence was unsatisfactory in the long term. Involvement of gastrointestinal musculature is a characteristic feature the disease.



  14. 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

  15. 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

  16. A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration

    OpenAIRE

    Rivera, Andrea; White, Karen; Stöhr, Heidi; Steiner, Klaus; Hemmrich, Nadine; Grimm, Timo; Jurklies, Bernhard; Lorenz, Birgit; Scholl, Hendrik P. N.; Apfelstedt-Sylla, Eckhart; Weber, Bernhard H. F.

    2000-01-01

    Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in ...

  17. Diagnosis of becker muscular dystrophy: Results of Re-analysis of DNA samples

    NARCIS (Netherlands)

    Straathof, Chiara S. M.; van Heusden, Dave; Ippel, Pieternella F.; Post, Jan G.; Voermans, Nicol C.; de Visser, Marianne; Brusse, Esther; van den Bergen, Janneke C.; van der Kooi, Anneke J.; Verschuuren, Jan J. G. M.; Ginjaar, Hendrika B.

    2016-01-01

    The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995. All requests for DNA analysis of the DMD gene in

  18. Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities.

    Directory of Open Access Journals (Sweden)

    Catherine Cukras

    Full Text Available Retinitis Pigmentosa (RP is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A in the gene encoding retinol binding protein 4 (RBP4. This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5(th decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

  19. Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities.

    Science.gov (United States)

    Cukras, Catherine; Gaasterland, Terry; Lee, Pauline; Gudiseva, Harini V; Chavali, Venkata R M; Pullakhandam, Raghu; Maranhao, Bruno; Edsall, Lee; Soares, Sandra; Reddy, G Bhanuprakash; Sieving, Paul A; Ayyagari, Radha

    2012-01-01

    Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5(th) decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

  20. UTILIZATION OF FUNDUS AUTOFLUORESCENCE, SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY, AND ENHANCED DEPTH IMAGING IN THE CHARACTERIZATION OF BIETTI CRYSTALLINE DYSTROPHY IN DIFFERENT STAGES.

    Science.gov (United States)

    Li, Qian; Li, Yang; Zhang, Xiaohui; Xu, Zhangxing; Zhu, Xiaoqing; Ma, Kai; She, Haicheng; Peng, Xiaoyan

    2015-10-01

    To characterize Bietti crystalline dystrophy (BCD) in different stages using multiple imaging modalities. Sixteen participants clinically diagnosed as BCD were included in the retrospective study and were categorized into 3 stages according to fundus photography. Eleven patients were genetically confirmed. Fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging features of BCD were analyzed. On fundus autofluorescence, the abnormal autofluorescence was shown to enlarge in area and decrease in intensity with stages. Using spectral domain optical coherence tomography, the abnormalities in Stage 1 were observed to localize in outer retinal layers, whereas in Stage 2 and Stage 3, more extensive retinal atrophy was seen. In enhanced depth imaging, the subfoveal choroidal layers were delineated clearly in Stage 1; in Stage 2, destructions were primarily found in the choriocapillaris with associated alterations in the outer vessels; Stage 3 BCD displayed severe choroidal thinning. Choroidal neovascularization and macular edema were exhibited with high incidence. IVS6-8del17bp/inGC of the CYP4V2 gene was the most common mutant allele. Noninvasive fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging may help to characterize the chorioretinal pathology of BCD at different degrees, and therefore, we propose staging of BCD depending on those methods. Physicians should be cautious of the vision-threatening complications of the disease.

  1. Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2010-09-13

    A Zimmerman, T Duong, J Florence and the CINRG Investigators. Pulmonary Function Characteristics of Boys with Duchenne and Becker Muscular Dystrophy ...designated CINRG site staff 1. Has the participant been clinically diagnosed with Limb-Girdle or Becker muscular dystrophy ? LGMD BMD 2. Was...Number: W81XWH-09-1-0592 TITLE: CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy PRINCIPAL INVESTIGATOR: Avital Cnaan, PhD

  2. Delayed healing of corneal epithelium after phototherapeutic keratectomy for lattice dystrophy.

    Science.gov (United States)

    Das, Sujata; Langenbucher, Achim; Seitz, Berthold

    2005-04-01

    To evaluate the time period necessary for complete epithelial healing after phototherapeutic keratectomy (o-PTK) carried out for various superficial corneal opacities. A total of 197 eyes were divided into 9 groups: group 1, Cogan dystrophy including recurrences (n = 15); group 2, Reis Bucklers dystrophy including recurrences (n = 12); group 3, granular dystrophy including recurrences (n = 63); group 4, lattice dystrophy including recurrences (n = 19); group 5, macular dystrophy including recurrences (n = 10); group 6, herpetic scars (n = 5); group 7, corneal scars of nonherpetic origin (including scrofulous, traumatic, central keratoconus, post-pterygium surgery) (n = 31); group 8, Salzmann nodular degeneration (n = 22); and group 9, miscellaneous (such as bullous keratopathy, acute chemical burn, corneal degeneration) (n = 20). After o-PTK, patients were examined daily at the slit lamp using fluorescein and blue light. The time period necessary for complete healing of the epithelial defect was compared among these groups. Delayed healing was considered where the epithelium was not closed after 7 days. One hundred sixty-one eyes (95%) healed within 7 days. Overall, 63%, 80%, and 85% of epithelial defects were closed within 3, 4, and 5 days, respectively. Out of 9 eyes that had delayed healing, 6 eyes (67%) belonged to lattice dystrophy category. Mean time taken for healing in group 4 (8.6 +/- 8.4 days) was significantly longer than those in group 1 (3.0 +/- 1.5 days, P = 0.009), group 2 (3.7 +/- 3.1 days, P = 0.03), group 3 (3.1 +/- 1.5 days, P = 0.001), group 5 (2.7 +/- 0.8 days, P = 0.01), group 7 (3.6 +/- 2.4 days, P = 0.007), group 8 (3.3 +/- 1.3 days, P = 0.009), and group 9 (3.0 +/- 1.9 days, P = 0.011). Eyes with lattice corneal dystrophy suffered from delayed epithelial healing after o-PTK. In addition to adequate counseling, these patients should be followed up closely until complete closure of the epithelium to avoid ulceration, scarring, or even

  3. Altered cross-bridge properties in skeletal muscle dystrophies

    Directory of Open Access Journals (Sweden)

    Aziz eGuellich

    2014-10-01

    Full Text Available Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca2+ through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal muscle dystrophies and discuss their ultimate impacts on striated muscle function.

  4. Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials.

    Science.gov (United States)

    Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S; Verschuuren, Jan J; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E; Muntoni, Francesco

    2011-12-01

    Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both

  5. Dystrophin Immunity in Duchenne’s Muscular Dystrophy

    Science.gov (United States)

    Mendell, Jerry R.; Campbell, Katherine; Rodino-Klapac, Louise; Sahenk, Zarife; Shilling, Chris; Lewis, Sarah; Bowles, Dawn; Gray, Steven; Li, Chengwen; Galloway, Gloria; Malik, Vinod; Coley, Brian; Clark, K. Reed; Li, Juan; Xiao, Xiao; Samulski, Jade; McPhee, Scott W.; Samulski, R. Jude; Walker, Christopher M.

    2010-01-01

    SUMMARY We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne’s muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. (Funded by the Muscular Dystrophy Association and others; ClinicalTrials.gov number, NCT00428935.) PMID:20925545

  6. An Overview of Recent Therapeutics Advances for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Mah, Jean K

    2018-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.

  7. [Encopresis revealing myotonic dystrophy in 2 children].

    Science.gov (United States)

    Avez-Couturier, J; Michaud, L; Cuisset, J-M; Lamblin, M-D; Dolhem, P; Turck, D; Vallée, L; Gottrand, F

    2009-05-01

    Gastrointestinal symptoms are very frequent in myotonic dystrophy but largely unrecognized. They can be the revealing factors of the disease. We report 2 cases of 10 and 17-year-old children with persistent encopresis starting at the age of 3 and 5 years in spite of laxative treatment. Neurological examination and anorectal manometry provided the diagnosis of myotonic dystrophy. Procainamide treatment was introduced and the digestive symptoms improved. Any child with encopresis should have complete evaluation to rule out the diagnosis of myotonic dystrophy and physicians should look for upper and/or lower gastrointestinal symptoms in every patient with myotonic dystrophy.

  8. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran

    OpenAIRE

    BARZEGAR, Mohammad; HABIBI, Parinaz; BONYADY, Mortaza; TOPCHIZADEH, Vahideh; SHIVA, Shadi

    2015-01-01

    How to Cite This Article: Barzegar M, Habibi P, Bonyady M, Topchizadeh V, Shiva Sh. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran. Iran J Child Neurol. 2015 Winter; 9(1): 42-48.AbstractObjectiveDuchene and Becker Muscular Dystrophy (DMD/ BMD) are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different popula...

  9. Duchenne muscular dystrophy

    Science.gov (United States)

    ... and gene therapy may be used in the future. The use of steroids and the lack of ... Selcen D. Muscle diseases. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. Philadelphia, PA: ...

  10. Genetic diagnosis of Duchenne and Becker muscular dystrophy using multiplex ligation-dependent probe amplification in Rwandan patients.

    Science.gov (United States)

    Uwineza, Annette; Hitayezu, Janvier; Murorunkwere, Seraphine; Ndinkabandi, Janvier; Kalala Malu, Celestin Kaputu; Caberg, Jean Hubert; Dideberg, Vinciane; Bours, Vincent; Mutesa, Leon

    2014-04-01

    Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in six Rwandan patients presenting a phenotype of Duchenne and Becker muscular dystrophies and six asymptomatic female carrier relatives using multiplex ligation-dependent probe amplification (MLPA). Our results revealed deletion of the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two brothers and a de novo deletion of the exons 46-50 in the fourth patient. No copy number variation was found in two patients. Only one female carrier presented exon deletion in the DMD gene. This is the first cohort of genetic analysis in Rwandan patients affected by Duchenne and Becker muscular dystrophies. This report confirmed that MLPA assay can be easily implemented in low-income countries.

  11. Association of HTRA1 rs11200638 with age-related macular degeneration (AMD) in Brazilian patients.

    Science.gov (United States)

    Lana, Tamires Prates; da Silva Costa, Sueli Matilde; Ananina, Galina; Hirata, Fábio Endo; Rim, Priscila Hae Hyun; Medina, Flávio MacCord; de Vasconcellos, José Paulo Cabral; de Melo, Mônica Barbosa

    2018-01-01

    Age-related macular degeneration is a multifactorial disease that can lead to vision impairment in older individuals. Although the etiology of age-related macular degeneration remains unknown, risk factors include age, ethnicity, smoking, hypertension, obesity, and genetic factors. Two main loci have been identified through genome-wide association studies, on chromosomes 1 and 10. Among the variants located at the 10q26 region, rs11200638, located at the HTRA1 gene promoter, has been associated with age-related macular degeneration in several populations and is considered the main polymorphism. We conducted a replication case-control study to analyze the frequency and participation of rs11200638 in the etiology of age-related macular degeneration in a sample of patients and controls from the State of São Paulo, Brazil, through polymerase chain reaction and enzymatic digestion. The frequency of the A allele was 57.60% in patients with age-related macular degeneration and 36.45% in controls (p value age-related macular degeneration group compared to the control group (p = 1.21 e-07 and 0.0357, respectively). No statistically significant results were observed after stratification in dry versus wet types or advanced versus non-advanced forms. To our knowledge, this is the first time the association between rs11200638 and overall age-related macular degeneration has been reported in South America.

  12. Duchenne and Becker Muscular Dystrophy: Contribution of a Molecular and Immunohistochemical Analysis in Diagnosis in Morocco

    Directory of Open Access Journals (Sweden)

    Hanane Bellayou

    2009-01-01

    Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are X-linked recessive disorders caused by mutations of the DMD gene located at Xp21. In DMD patients, dystrophin is virtually absent; whereas BMD patients have 10% to 40% of the normal amount. Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. To explain the contribution of immunohistochemical and genetic analysis in the diagnosis of these dystrophies, we present 10 cases of DMD/BMD with particular features. We have analyzed the patients with immunohistochemical staining and PCR multiplex to screen for exons deletions. Determination of the quantity and distribution of dystrophin by immunohistochemical staining can confirm the presence of dystrophinopathy and allows differentiation between DMD and BMD, but dystrophin staining is not always conclusive in BMD. Therefore, only identification involved mutation by genetic analysis can establish a correct diagnosis.

  13. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    Science.gov (United States)

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study)

    DEFF Research Database (Denmark)

    Nguyen, Quan Dong; Schachar, Ronald A; Nduaka, Chudy I

    2012-01-01

    To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation.......To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation....

  15. Becker muscular dystrophy: an unusual presentation.

    OpenAIRE

    Thakker, P B; Sharma, A

    1993-01-01

    A 15 year old boy who presented with passing painless dark urine was found to have myoglobinuria. His creatine phosphokinase was raised, and a muscle biopsy specimen showed non-specific dystrophic changes. Subsequent DNA analysis led to the diagnosis of Becker muscular dystrophy. Myoglobinuria may be a presenting symptom of Becker muscular dystrophy.

  16. Mild and severe muscular dystrophy caused by a single {gamma}-sarcoglycan mutation

    Energy Technology Data Exchange (ETDEWEB)

    McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W. [Brigham and Women`s Hospital, Boston, MA (United States)] [and others

    1996-11-01

    Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein {gamma}-sarcoglycan. The previous mutation analysis of {gamma}-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the {gamma}-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding {gamma}-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the {gamma}-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of {alpha}-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the {gamma}-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from {gamma}-sarcoglycan gene mutations. 19 refs., 5 figs., 3 tabs.

  17. Emerging genetic therapies to treat Duchenne muscular dystrophy

    Science.gov (United States)

    Nelson, Stanley F.; Crosbie, Rachelle H.; Miceli, M. Carrie; Spencer, Melissa J.

    2010-01-01

    Purpose of review Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations. The purpose of this review is to highlight two emerging therapies designed to repair the primary genetic defect, called `exon skipping' and `nonsense codon suppression'. Recent findings A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops. Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo. Both approaches have concluded phase I trials with no serious adverse events. Summary These novel therapies that act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans. Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy. PMID:19745732

  18. 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......PURPOSE: Generalized retinal dystrophy is a frequent cause of visual impairment and blindness in younger individuals and a subject of new clinical intervention trials. Nonetheless, there are few nation-wide population-based epidemiological data of generalized retinal dystrophy. The purpose...... and chorioretinal dystrophies from the 19th century to the present. Among 3076 registered cases, the primary diagnosis of generalized retinal dystrophy was assessed by chart review, including fundus photographs and electroretinograms. Demographic data on the Danish population were retrieved from Statistics Denmark...

  19. Progressive macular hypomelanosis: an overview

    NARCIS (Netherlands)

    Relyveld, Germaine N.; Menke, Henk E.; Westerhof, Wiete

    2007-01-01

    Progressive macular hypomelanosis (PMH) is a common skin disorder that is often misdiagnosed. Various authors have written about similar skin disorders, referring to them by different names, but we believe that all these similar disorders are part of the same entity.PMH is characterized by

  20. Age-Related Macular Degeneration.

    Science.gov (United States)

    Mehta, Sonia

    2015-09-01

    Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. AMD is diagnosed based on characteristic retinal findings in individuals older than 50. Early detection and treatment are critical in increasing the likelihood of retaining good and functional vision. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Comparative proteomic analyses of macular and peripheral retina of cynomolgus monkeys (Macaca fascicularis).

    Science.gov (United States)

    Okamoto, Haru; Umeda, Shinsuke; Nozawa, Takehiro; Suzuki, Michihiro T; Yoshikawa, Yasuhiro; Matsuura, Etsuko T; Iwata, Takeshi

    2010-01-01

    The central region of the primate retina is called the macula. The fovea is located at the center of the macula, where the photoreceptors are concentrated to create a neural network adapted for high visual acuity. Damage to the fovea, e.g., by macular dystrophies and age-related macular degeneration, can reduce central visual acuity. The molecular mechanisms leading to these diseases are most likely dependent on the proteins in the macula which differ from those in the peripheral retina in expression level. To investigate whether the distribution of proteins in the macula is different from the peripheral retina, proteomic analyses of tissues from these two regions of cynomolgus monkeys were compared. Two-dimensional gel electrophoresis and mass spectrometry identified 26 proteins that were present only in the macular gel spots. The expression levels of five proteins, cone photoreceptor specific arrestin-C, gamma-synuclein, epidermal fatty acid binding protein, tropomyosin 1alpha chain, and heterogeneous nuclear ribonucleoproteins A2/B1, were significantly higher in the macula than in the peripheral retina. Immunostaining of macula sections by antibodies to each identified protein revealed unique localization in the retina, retinal pigment epithelial cells and the choroidal layer. Some of these proteins were located in cells with higher densities in the macula. We suggest that it will be important to study these proteins to determine their contribution to the pathogenesis and progression of macula diseases.

  2. Application of OCT in traumatic macular hole

    Directory of Open Access Journals (Sweden)

    Wen-Li Fu

    2017-12-01

    Full Text Available AIM: To observe the application of optical coherence tomography(OCTin the diseases of traumatic macular hole. METHODS: Twenty-five eyes of 23 patients with traumatic macular hole from January 2015 to January 2017 were enrolled in this study, including 9 eyes treated without surgeries, 16 eyes with surgeries. The image features were analyzed using OCT from ZEISS. RESULTS: The OCT characteristics in patients with traumatic macular hole were partial or full-thickness disappearance of the neuro-epithelium. Posterior vitreous detachment was not seen in the traumatic macular hole. OCT examination revealed that 4 eyes had partial detachment of macular hole and 21 eyes had full thickness detachment. Of the twenty-one eyes, 4 eyes had simple macular hole, 10 eyes had macular full-layer division with peripheral nerve epithelium edema, 7 eyes had the macular full-layer hole with the neuro-epithelium localized detachment. In the 25 eyes, 9 eyes did not undergo the surgery, of which 7 eyes were self-healing; 16 eyes were surgically treated. Postoperative OCT showed the macular structure were normal in 12 eyes with the visual acuity improved 3 lines; retinal nerve epithelium were thinning in 4 eyes, visual acuities were not significant improved after surgery. CONCLUSION: OCT examination is necessary for the diagnosis and treatment of traumatic macular hole.

  3. Vertical transmission of macular telangiectasia type 2.

    Science.gov (United States)

    Delaere, Lien; Spielberg, Leigh; Leys, Anita M

    2012-01-01

    The purpose of this study was to report vertical transmission of macular telangiectasia type 2 and type 2 diabetes mellitus in 3 families. In this retrospective interventional case series, the charts of patients with inherited macular telangiectasia type 2 were reviewed. A large spectrum of presentations of macular telangiectasia type 2 was observed and has been studied with different techniques including best-corrected visual acuity, microperimetry, confocal blue reflectance fundus autofluorescence, fluorescein angiography, and time domain and spectral domain optical coherence tomography. Vertical transmission of macular telangiectasia type 2 and associated type 2 diabetes mellitus is described in 3 families. Symptomatic as well as asymptomatic eyes with macular telangiectasia type 2 were identified. In 2 families, a mother and son experienced visual loss and were diagnosed with macular telangiectasia type 2. All 4 patients had type 2 diabetes. Diabetic retinopathy was observed in one mother and her son. In the third family, the index patient was diagnosed macular telangiectasia type 2 after complaints of metamorphopsia. She and her family members had type 2 diabetes mellitus, and further screening of her family revealed familial macular telangiectasia type 2. None of the patients were treated for macular telangiectasia type 2. Macular telangiectasia type 2 may be more common than previously assumed, as vision can remain preserved and patients may go undiagnosed. Screening of family members is indicated, and detection of mild anomalies is possible using fundus autofluorescence and spectral domain optical coherence tomography.

  4. Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy

    NARCIS (Netherlands)

    van den Bergen, J. C.; Schade van Westrum, S. M.; Dekker, L.; van der Kooi, A. J.; de Visser, M.; Wokke, B. H. A.; Straathof, C. S.; Hulsker, M. A.; Aartsma-Rus, A.; Verschuuren, J. J.; Ginjaar, H. B.

    2014-01-01

    Objective Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose

  5. The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy : an updated protocol

    NARCIS (Netherlands)

    vanEssen, AJ; Kneppers, ALJ; vanderHout, AH; Scheffer, H; Ginjaar, IB; tenKate, LP; vanOmmen, GJB; Buys, CHCM; Bakker, E

    1997-01-01

    Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% of patients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a

  6. A De novo Mutation in Dystrophin Causing Muscular Dystrophy in a Female Patient

    Directory of Open Access Journals (Sweden)

    Hao Yu

    2017-01-01

    Conclusions: We identified two novel de novo mutations of DMD gene in two Chinese pedigrees, one of which caused a female patient with muscular dystrophy. The mutational analysis is important for DMD patients and carriers in the absence of a family history. The NGS can help detect the mutations in MLPA-negative patients.

  7. New insights into mitral valve dystrophy : A Filamin-A genotype-phenotype and outcome study

    NARCIS (Netherlands)

    Le Tourneau, Thierry; Le Scouarnec, Solena; Cueff, Caroline; Bernstein, Daniel; Aalberts, Jan J J; Lecointe, Simon; Mérot, Jean; Bernstein, Jonathan A; Oomen, Toon; Dina, Christian; Karakachoff, Matilde; Desal, Hubert; Al Habash, Ousama; Delling, Francesca N; Capoulade, Romain; Suurmeijer, Albert J H; Milan, David; Norris, Russell A; Markwald, Roger; Aikawa, Elena; Slaugenhaupt, Susan A; Jeunemaitre, Xavier; Hagège, Albert; Roussel, Jean-Christian; Trochu, Jean-Noël; Levine, Robert A; Kyndt, Florence; Probst, Vincent; Le Marec, Hervé; Schott, Jean-Jacques

    2018-01-01

    Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring

  8. The influence of low dystrophin levels on disease pathology in mouse models for Duchenne Muscular Dystrophy

    NARCIS (Netherlands)

    Putten, Maaike van

    2013-01-01

    Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive to exercise-induced damage, resulting in progressive muscle wasting, loss of ambulation and premature

  9. Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions.

    NARCIS (Netherlands)

    Koenekoop, R.K.; Lopez, I.; Hollander, A.I. den; Allikmets, R.; Cremers, F.P.M.

    2007-01-01

    Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular

  10. Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

    DEFF Research Database (Denmark)

    Weisschuh, Nicole; Mayer, Anja K; Strom, Tim M

    2016-01-01

    Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing...

  11. Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy

    Science.gov (United States)

    Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.

    2007-01-01

    The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly…

  12. Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

    Science.gov (United States)

    Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

    2004-01-01

    Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the…

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

    NARCIS (Netherlands)

    Saksens, N.T.; Krebs, M.P.; Schoenmaker, F.E.; Hicks, W.; Yu, M.; Shi, L.; Rowe, L.; Collin, G.B.; Charette, J.R.; Letteboer, S.J.; Neveling, K.; Moorsel, T.W. van; Abu-Ltaif, S.; Baere, E. De; Walraedt, S.; Banfi, S.; Simonelli, F.; Cremers, F.P.; Boon, C.J.; Roepman, R.; Leroy, B.P.; Peachey, N.S.; Hoyng, C.B.; Nishina, P.M.; Hollander, A.I. den

    2016-01-01

    Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding alpha-catenin 1) in three families with butterfly-shaped pigment

  14. CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice

    NARCIS (Netherlands)

    Pellissier, L.P.; Lundvig, D.M.S.; Tanimoto, N.; Klooster, J.; Vos, R.M.; Richard, F.; Sothilingam, V.; Garrido, M. Garcia; Bivic, A. le; Seeliger, M.W.; Wijnholds, J.

    2014-01-01

    Mutations in the CRB1 gene lead to retinal dystrophies ranging from Leber congenital amaurosis (LCA) to early-onset retinitis pigmentosa (RP), due to developmental defects or loss of adhesion between photoreceptors and Muller glia cells, respectively. Whereas over 150 mutations have been found, no

  15. CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice

    NARCIS (Netherlands)

    Pellissier, Lucie P; Lundvig, Ditte M S; Tanimoto, Naoyuki; Klooster, J.; Vos, Rogier M; Richard, Fabrice; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Le Bivic, André; Seeliger, Mathias W; Wijnholds, J.

    2014-01-01

    Mutations in the CRB1 gene lead to retinal dystrophies ranging from Leber congenital amaurosis (LCA) to early-onset retinitis pigmentosa (RP), due to developmental defects or loss of adhesion between photoreceptors and Müller glia cells, respectively. Whereas over 150 mutations have been found, no

  16. Molecular and preclinical aspects of antisense oligonucleotide treatment for myotonic dystrophy type 1

    NARCIS (Netherlands)

    Gonzalez Barriga, A.M.M.

    2017-01-01

    Myotonic Dystrophy type 1 (DM1) is a genetic disorder caused by an expansion of a (CTG)n repeat in the DMPK gene, which is carried by all individuals, but normally contains less than 37 triplets. Only when this threshold is exceeded the person carrying it will develop DM1, with an age of onset and

  17. Cell membrane integrity in myotonic dystrophy type 1: implications for therapy

    NARCIS (Netherlands)

    Gonzalez, A.M.M.; Kranzen, J.; Croes, H.J.E.; Bijl, S.; Broek, W.J.A.A. van den; Kessel, I.D.G. van; Engelen, B.G.M. van; Deutekom, J.C. van; Wieringa, B.; Mulders, S.A.; Wansink, D.G.

    2015-01-01

    Myotonic Dystrophy type 1 (DM1) is a multisystemic disease caused by toxic RNA from a DMPK gene carrying an expanded (CTG*CAG)n repeat. Promising strategies for treatment of DM1 patients are currently being tested. These include antisense oligonucleotides and drugs for elimination of expanded RNA or

  18. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    Science.gov (United States)

    ... Boost from Existing Medication Spotlight on Research Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication By Colleen Labbe, M.S. | March 1, 2013 A mouse hanging on a wire during a test of muscle strength. Mice with a mutant dystrophin gene, which ...

  19. Phenotypic variability in Meesmann's dystrophy

    DEFF Research Database (Denmark)

    Ehlers, Niels; Hjortdal, Jesper; Nielsen, Kim

    2008-01-01

    symptoms often include blurred vision and ocular irritation. Typical cases may be entirely free of complaints. Intermittent pain episodes, such as occur in recurrent erosion syndrome, are not the rule. Genetic sequencing indicated a familial relationship with the originally described Meesmann family......'s dystrophy occurs worldwide. The largest family described is the original German one, now supplemented with a Danish branch. Despite the presence of an identical genetic defect, the clinical phenotype varies. This suggests that non-KRT12-related mechanisms are responsible for the variation....

  20. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, M; Vissing, J

    2013-01-01

    Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic......, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest...

  1. Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Speer, M.C.; Stauffer, J. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

    1995-09-01

    Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive Limb Girdle muscular dystrophy (LGMD2C) characterized by late age of onset, proximal muscle weakness leading to disability, high creatine kinase values, normal intelligence and normal dystrophin in muscle biopsy. We have shown previously that three DLMD families from Tunisia are linked to chromosome 13q12. To further localize the LGMD2C gene, we have investigated seven additional families (119 individuals). Both genotyping and two-point linkage analysis were performed as described elsewhere. 7 refs., 1 fig., 1 tab.

  2. Precursors of Age-Related Macular Degeneration

    DEFF Research Database (Denmark)

    Munch, Inger Christine; Linneberg, Allan; Larsen, Michael

    2013-01-01

    PURPOSE: To investigate associations of small, hard macular drusen and larger macular drusen with obesity-related risk factors. METHODS: Cross-sectional study of 888 subjects aged 30-60 years characterized using anthropometric measurements and blood sample analyses. Physical activity was assessed...... by questionnaire. Digital grayscale fundus photographs were recorded in red-free illumination and graded for the presence of macular drusen >63µm in either eye and the presence of 20 or more small, hard macular drusen as a mean of both eyes. RESULTS: Macular drusen >63µm were associated with the level of physical...... activity, the age- and sex adjusted odds ratio being 0.33 (95% confidence interval 0.13-0.82, P=0.016) for participants who were physically active more than 7 h/week compared with participants active 0-2 h/week. In women, macular drusen >63µm were associated with higher serum triglycerides (P=0...

  3. Co-incidence of Turner syndrome and Duchenne muscular dystrophy - an important problem for the clinician.

    Science.gov (United States)

    Kaczorowska, Ewa; Zimowski, Janusz; Cichoń-Kotek, Monika; Mrozińska, Agnieszka; Purzycka, Joanna; Wierzba, Jolanta; Limon, Janusz; Lipska-Ziętkiewicz, Beata S

    Turner syndrome is a relatively common chromosomal disorder which affects about one in 2000 live born females. Duchenne muscular dystrophy is an X-linked recessive disorder affecting 1:3600 live born males. Considering the above, the coexistence of these two diseases may occur only anecdotally. Here, we report a 4 ½ year-old female with classical 45,X Turner syndrome who also had Duchenne muscular dystrophy caused by a point mutation in the dystrophin gene (c.9055delG). The patient showed the typical phenotype of Turner syndrome including distinctive dysmorphic features (short neck, low posterior hairline, wide position of nipples), aortic coarctation and feet lymphedema. Besides, she presented with an unusually early beginning of muscular dystrophy symptoms with infantile-onset motor developmental delay, intellectual disability and early calf muscular hypertrophy. The coexistence of an X-linked recessive disorder should be considered in women affected by Turner syndrome presenting with additional atypical clinical features.

  4. Functional muscle ischemia in Duchenne and Becker muscular dystrophy

    OpenAIRE

    Thomas, Gail D.

    2013-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSµ) which binds spectrin-like repeats within dystrophin’s rod domain and the adaptor pro...

  5. Methoxsalen-induced macular toxicity

    Directory of Open Access Journals (Sweden)

    Aditya Maitray

    2017-01-01

    Full Text Available Psoralen compounds such as methoxsalen are photosensitizer agents used in conjunction with ultraviolet A (UVA radiation exposure as photochemotherapy (Psoralens and ultraviolet-A therapy [PUVA therapy] for certain epidermal skin disorders such as psoriasis and vitiligo. Methoxsalen has been shown to be associated with premature cataract formation by forming adducts with lens proteins following oral administration and subsequent UVA exposure. Hence, the use of UV-filtering glasses is recommended during PUVA therapy sessions. Ocular tissues can be exposed to its photosensitizing effect with subsequent UV radiation exposure through sunlight if the patient was to be without protective eye glasses, potentially causing macular toxicity. Till date, there have been no reports in the literature of any posterior segment ocular toxicity arising from methoxsalen use. Here, we describe a case of a bilateral macular toxicity in a middle-aged male treated with methoxsalen for vitiligo.

  6. Zebrafish models flex their muscles to shed light on muscular dystrophies.

    Science.gov (United States)

    Berger, Joachim; Currie, Peter D

    2012-11-01

    Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix.

  7. Efficient and fast functional screening of microdystrophin constructs in vivo and in vitro for therapy of duchenne muscular dystrophy

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Larochelle, Nancy; Orlopp, Kristian

    2009-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked, lethal genetic disorder affecting the skeletal muscle compartment, and is caused by mutation(s) in the dystrophin gene. Gene delivery of microdystrophin constructs using adeno-associated virus (AAV) and antisense-mediated exon skipping restoring...

  8. An unusual variant of Becker muscular dystrophy

    NARCIS (Netherlands)

    de Visser, M.; Bakker, E.; Defesche, J. C.; Bolhuis, P. A.; van Ommen, G. J.

    1990-01-01

    We report on 5 brothers with slowly progressive limbgirdle weakness. Calf hypertrophy was absent. The levels of creatine kinase, electromyography, and findings from a muscle biopsy specimen were compatible with muscular dystrophy. The propositus's biopsy specimen also showed numerous rimmed

  9. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    Science.gov (United States)

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., Assistant ... Shree Pandya, P.T., M.S., Assistant Professor, Neurology & Physical Medicine and Rehabilitation A publication of the FSH ...

  10. 3-Methylhistidine excretion in myotonic dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Griggs, R.C.; Moxley, R.T. III; Forbes, G.B.

    1980-12-01

    3-Methylhistidine (3-MH) excretion reflects the rate of muscle protein catabolism, since 3-MH occurs almost exclusively in muscle actin and myosin and is not reutilized or catabolized. We studied 3-MH excretion in 9 patients with myotonic dystrophy, 8 normals, and 10 disease controls with Duchenne dystrophy and other disorders. 3-MH excretion was expressed relative to muscle mass as determined by both urinary creatinine and total body potassium (/sup 40/K method). Absolute 3-MH excretion was decreased in myotonic dystrophy patients but was normal when related to muscle mass. The finding of normal 3-MH excretion in myotonic dystrophy suggests that the muscle wasting in this disorder results from impaired anabolic processes rather than accelerated muscle destruction.

  11. 3-Methylhistidine excretion in myotonic dystrophy

    International Nuclear Information System (INIS)

    Griggs, R.C.; Moxley, R.T. III; Forbes, G.B.

    1980-01-01

    3-Methylhistidine (3-MH) excretion reflects the rate of muscle protein catabolism, since 3-MH occurs almost exclusively in muscle actin and myosin and is not reutilized or catabolized. We studied 3-MH excretion in 9 patients with myotonic dystrophy, 8 normals, and 10 disease controls with Duchenne dystrophy and other disorders. 3-MH excretion was expressed relative to muscle mass as determined by both urinary creatinine and total body potassium ( 40 K method). Absolute 3-MH excretion was decreased in myotonic dystrophy patients but was normal when related to muscle mass. The finding of normal 3-MH excretion in myotonic dystrophy suggests that the muscle wasting in this disorder results from impaired anabolic processes rather than accelerated muscle destruction

  12. How Do People Cope with Muscular Dystrophy?

    Science.gov (United States)

    ... topic are answered in this section. How do people cope with muscular dystrophy (MD)? Although MD presents ... improve health and quality of life. Almost all people with any form of MD experience a worsening ...

  13. Posterior amorphous corneal dystrophy: case report

    OpenAIRE

    Oliveira, Lauro Augusto de [UNIFESP; Vieira, Luiz Antônio [UNIFESP; Freitas, Denise de [UNIFESP; Sousa, Luciene Barbosa de [UNIFESP

    2006-01-01

    O objetivo deste trabalho é alertar o oftalmologista da possibilidade de se deparar com casos raros de distrofias corneanas. Neste caso correlacionamos os achados clínicos da distrofia amorfa posterior com refração, topografia e biomicroscopia ultra-sônica.The purpose of this paper is to warn the ophthalmologist about the possibility of facing rare cases of corneal dystrophies. Clinical findings of a case of posterior amorphous dystrophy were correlated with refraction, topography, and ultras...

  14. Sleep disturbances in myotonic dystrophy type 2

    OpenAIRE

    Shepard, Paul; Lam, Erek M.; St. Louis, Erik K.; Dominik, Jacob

    2012-01-01

    Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep disordered breathing (SDB), hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) ...

  15. 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. PMID:27757431

  16. Radiographic features of Golden Retriever muscular dystrophy.

    Science.gov (United States)

    Brumitt, Jason W; Essman, Stephanie C; Kornegay, Joe N; Graham, John P; Weber, William J; Berry, Clifford R

    2006-01-01

    Golden Retriever muscular dystrophy is an inherited, degenerative myopathy due to the absence of dystrophin and is used as a model of Duchenne muscular dystrophy of young boys. This report describes the radiographic abnormalities of Golden Retriever muscular dystrophy in 26 dogs. The thoracic abnormalities included diaphragmatic asymmetry (18/26), diaphragmatic undulation (18/26), and gastro-esophageal hiatal hernia (6/26). Pelvic abnormalities included narrowing of the body of the ilia (14/19), ventral deviation and curvature of the tuber ischii (14/19), elongation of the obturator foramen with a decrease in opacity of the surrounding bone (12/19), and lateral flaring of the wings of the ilia (12/19). Abdominal abnormalities consisted of hepatomegaly (14/22) and poor serosal detail (12/22). The unique thoracic abnormalities were a consistent finding in affected Golden Retriever muscular dystrophy dogs. The diagnosis of muscular dystrophy should be included in the differential list if the combination of diaphragm undulation and asymmetry, and gastro-esophageal hiatal hernia are identified. These diaphragmatic abnormalities are related to hypertrophy and hyperplasia of the diaphragm. Additionally, the skeletal changes of pelvic tilt, elongation of the pelvis, widening of the obturator foramina and thinning of the ischiatic tables appear to be specific to Golden Retriever muscular dystrophy in dogs. These pelvic abnormalities are most likely secondary to bone remodeling associated with the progressive skeletal myopathy and subsequent contracture/fibrosis.

  17. Macular thickness and macular volume measurements using spectral domain optical coherence tomography in normal Nepalese eyes

    Directory of Open Access Journals (Sweden)

    Pokharel A

    2016-03-01

    Full Text Available Amrit Pokharel,1 Gauri Shankar Shrestha,2 Jyoti Baba Shrestha2 1Department of Ophthalmology, Kathmandu Medical College Teaching Hospital, 2B P Koirala Lions Centre for Ophthalmic Studies, Institute of Medicine, Kathmandu, Nepal Purpose: To record the normative values for macular thickness and macular volume in normal Nepalese eyes. Methods: In all, 126 eyes of 63 emmetropic subjects (mean age: 21.17±6.76 years; range: 10–37 years were assessed for macular thickness and macular volume, using spectral domain-optical coherence tomography over 6×6 mm2 in the posterior pole. A fast macular thickness protocol was employed. Statistics such as the mean, median, standard deviation, percentiles, and range were used, while a P-value was set at 0.05 to test significance. Results: Average macular thickness and total macular volume were larger in males compared to females. With each year of increasing age, these variables decreased by 0.556 µm and 0.0156 mm3 for average macular thickness and total macular volume, respectively. The macular thickness was greatest in the inner superior section and lowest at the center of the fovea. The volume was greatest in the outer nasal section and thinnest in the fovea. The central subfield thickness (r=-0.243, P=0.055 and foveal volume (r=0.216, P=0.09 did not correlate with age. Conclusion: Males and females differ significantly with regard to macular thickness and macular volume measurements. Reports by other studies that the increase in axial length reduced thickness and volume, were negated by this study which found a positive correlation among axial length, thickness, and volume. Keywords: macular thickness, macular volume, optical coherence tomography, Nepal

  18. Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.

    Science.gov (United States)

    Jaakson, K; Zernant, J; Külm, M; Hutchinson, A; Tonisson, N; Glavac, D; Ravnik-Glavac, M; Hawlina, M; Meltzer, M R; Caruso, R C; Testa, F; Maugeri, A; Hoyng, C B; Gouras, P; Simonelli, F; Lewis, R A; Lupski, J R; Cremers, F P M; Allikmets, R

    2003-11-01

    Genetic variation in the ABCR (ABCA4) gene has been associated with five distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), and age-related macular degeneration (AMD). Comparative genetic analyses of ABCR variation and diagnostics have been complicated by substantial allelic heterogeneity and by differences in screening methods. To overcome these limitations, we designed a genotyping microarray (gene chip) for ABCR that includes all approximately 400 disease-associated and other variants currently described, enabling simultaneous detection of all known ABCR variants. The ABCR genotyping microarray (the ABCR400 chip) was constructed by the arrayed primer extension (APEX) technology. Each sequence change in ABCR was included on the chip by synthesis and application of sequence-specific oligonucleotides. We validated the chip by screening 136 confirmed STGD patients and 96 healthy controls, each of whom we had analyzed previously by single strand conformation polymorphism (SSCP) technology and/or heteroduplex analysis. The microarray was >98% effective in determining the existing genetic variation and was comparable to direct sequencing in that it yielded many sequence changes undetected by SSCP. In STGD patient cohorts, the efficiency of the array to detect disease-associated alleles was between 54% and 78%, depending on the ethnic composition and degree of clinical and molecular characterization of a cohort. In addition, chip analysis suggested a high carrier frequency (up to 1:10) of ABCR variants in the general population. The ABCR genotyping microarray is a robust, cost-effective, and comprehensive screening tool for variation in one gene in which mutations are responsible for a substantial fraction of retinal disease. The ABCR chip is a prototype for the next generation of screening and diagnostic tools in ophthalmic genetics, bridging clinical and scientific research. Copyright 2003 Wiley

  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

    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...

  20. The heart in Becker muscular dystrophy, facioscapulohumeral dystrophy, and Bethlem myopathy

    NARCIS (Netherlands)

    de Visser, M.; de Voogt, W. G.; la Rivière, G. V.

    1992-01-01

    We report a study, assessing involvement of the heart in 33 familial cases of Becker muscular dystrophy (BMD), 31 familiar cases of facioscapulohumeral (FSH) dystrophy, and 27 familial cases of Bethlem myopathy. In the patients with BMD, correlations of myocardial involvement with age and extent of

  1. CASE REPORT Moebius syndrome with macular hyperpigmentation ...

    African Journals Online (AJOL)

    Bilateral macular hyperpigmentation was detected in our patient on fundus examination which was not reported previously in Moebius syndrome cases. In addition there is hypoplasia of the right pectoralis major muscle. KEYWORDS Moebius syndrome; Macular hyperpigmentation; Pectoralis major muscle; Cranial nerves; ...

  2. Bilateral Simultaneous Macular Infarction with Spontaneous Visual ...

    African Journals Online (AJOL)

    2018-01-30

    Jan 30, 2018 ... eyes and near acuity was; right eye: N24, left eye: N36. ... Keywords: Macular infarction, macular ischemia, sickle cell, visual loss ... and build upon the work non-commercially, as long as the author is credited and the new.

  3. Correlations Between Macular, Skin, and Serum Carotenoids

    Science.gov (United States)

    Conrady, Christopher D.; Bell, James P.; Besch, Brian M.; Gorusupudi, Aruna; Farnsworth, Kelliann; Ermakov, Igor; Sharifzadeh, Mohsen; Ermakova, Maia; Gellermann, Werner; Bernstein, Paul S.

    2017-01-01

    Purpose Ocular and systemic measurement and imaging of the macular carotenoids lutein and zeaxanthin have been employed extensively as potential biomarkers of AMD risk. In this study, we systematically compare dual wavelength retinal autofluorescence imaging (AFI) of macular pigment with skin resonance Raman spectroscopy (RRS) and serum carotenoid levels in a clinic-based population. Methods Eighty-eight patients were recruited from retina and general ophthalmology practices from a tertiary referral center and excluded only if they did not have all three modalities tested, had a diagnosis of macular telangiectasia (MacTel) or Stargardt disease, or had poor AFI image quality. Skin, macular, and serum carotenoid levels were measured by RRS, AFI, and HPLC, respectively. Results Skin RRS measurements and serum zeaxanthin concentrations correlated most strongly with AFI macular pigment volume under the curve (MPVUC) measurements up to 9° eccentricity relative to MPVUC or rotationally averaged macular pigment optical density (MPOD) measurements at smaller eccentricities. These measurements were reproducible and not significantly affected by cataracts. We also found that these techniques could readily identify subjects taking oral carotenoid-containing supplements. Conclusions Larger macular pigment volume AFI and skin RRS measurements are noninvasive, objective, and reliable methods to assess ocular and systemic carotenoid levels. They are an attractive alternative to psychophysical and optical methods that measure MPOD at a limited number of eccentricities. Consequently, skin RRS and MPVUC at 9° are both reasonable biomarkers of macular carotenoid status that could be readily adapted to research and clinical settings. PMID:28728169

  4. Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ.

    Directory of Open Access Journals (Sweden)

    Kay-Marie Lamar

    2016-05-01

    Full Text Available Latent TGFβ binding proteins (LTBPs regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.

  5. Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ.

    Science.gov (United States)

    Lamar, Kay-Marie; Bogdanovich, Sasha; Gardner, Brandon B; Gao, Quan Q; Miller, Tamari; Earley, Judy U; Hadhazy, Michele; Vo, Andy H; Wren, Lisa; Molkentin, Jeffery D; McNally, Elizabeth M

    2016-05-01

    Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.

  6. [Central Nervous Involvement in Patients with Fukuyama Congenital Muscular Dystrophy].

    Science.gov (United States)

    Ishigaki, Keiko

    2016-02-01

    Fukuyama congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in the Japanese population, is an autosomal recessive disorder caused by mutations in the fukutin (FKTN) gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities and central nervous system involvement with mental retardation and seizures associated with cortical migration defects. The FKTN gene product is thought to be necessary for maintaining migrating neurons in an immature state during migration, and for supporting migration via α-dystroglycan in the central nervous system. Typical magnetic resonance imaging findings in FCMD patients are cobblestone lissencephaly and cerebellar cystic lesions. White matter abnormalities with hyperintensity on T(2)-weighted images are seen especially in younger patients and those with severe phenotypes. Most FCMD patients are mentally retarded and the level is moderate to severe, with IQs ranging from 30 to 50. In our recent study, 62% of patients developed seizures. Among them, 71% had only febrile seizures, 6% had afebrile seizures from the onset, and 22% developed afebrile seizures following febrile seizures. Most patients had seizures that were controllable with just 1 type of antiepileptic drug, but 18% had intractable seizures that must be treated with 3 medications.

  7. Genetics Home Reference: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy Printable PDF Open All Close All ... view the expand/collapse boxes. Description Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy ( APECED ) is an inherited condition that ...

  8. Distrofia em forma-de-borboleta: relato de caso Butterfly-shaped pattern dystrophy: case report

    Directory of Open Access Journals (Sweden)

    David Leonardo Cruvinel Isaac

    2007-02-01

    Full Text Available Os autores apresentam um caso de distrofia macular em forma-de-borboleta, diagnosticado em paciente do sexo masculino, apresentando concomitante atrofia do epitélio pigmentado da retina e perda visual central em um dos olhos. Os achados relatados contrariam conceitos inicialmente disponíveis de curso sempre benigno da doença. A lesão característica e bem delimitada no pólo posterior e a angiofluoresceinografia, permitiram estabelecer o diagnóstico. Descreve-se ainda, pela primeira vez, os achados da distrofia em forma-de-borboleta à tomografia de coerência óptica.The authors present a case of butterfly-shaped pattern dystrophy diagnosed in a male patient, with retinal pigmented epithelium atrophy and central visual acuity decrease in one of the eyes. The evolution of this case was not benign as described in previous reports. A well-defined lesion located in the posterior pole of both eyes associated with fluorescein angiography allowed the diagnosis of this pattern dystrophy. Optical coherence tomography was performed, showing the aspects of the pathology, for the first time.

  9. Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne muscular dystrophy.

    Science.gov (United States)

    Galindo, Cristi L; Soslow, Jonathan H; Brinkmeyer-Langford, Candice L; Gupte, Manisha; Smith, Holly M; Sengsayadeth, Seng; Sawyer, Douglas B; Benson, D Woodrow; Kornegay, Joe N; Markham, Larry W

    2016-04-01

    In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.

  10. Corticosteroid therapy for duchenne muscular dystrophy: improvement of psychomotor function.

    Science.gov (United States)

    Sato, Yuko; Yamauchi, Akemi; Urano, Mari; Kondo, Eri; Saito, Kayoko

    2014-01-01

    Of the numerous clinical trials for Duchenne muscular dystrophy, only the corticosteroid prednisolone has shown potential for temporal improvement in motor ability. In this study, the effects of prednisolone on intellectual ability are examined in 29 cases of Duchenne muscular dystrophy because little information has been reported. And also, motor functions and cardiac functions were evaluated. The treated group was administered prednisolone (0.75 mg/kg) orally on alternate days and the compared with the untreated control group. Gene mutations were investigated. The patients were examined for intelligence quotient adequate for age, brain natriuretic peptide, creatine kinase, and manual muscle testing before treatment and after the period 6 months to 2 years. Intelligence quotient scores of the treated increased to 6.5 ± 11.9 (mean ± standard deviation) were compared with the controls 2.1 ± 4.9 (P = 0.009). Intelligence quotient scores of the patients with nonsense point mutations improved significantly (21.0 ± 7.9) more than those with deletion or duplication (1.9 ± 9.0; P = 0.015). Motor function, such as time to stand up, of those treated improved significantly and brain natriuretic peptide level was reduced to a normal level after treatment in 15 patients (73%). Our results demonstrate the effectiveness of prednisolone in improving intellectual impairment as well as in preserving motor function and brain natriuretic peptide levels. We presume that prednisolone has a read-through effect on the stop codons in the central nervous systems of Duchenne muscular dystrophy because intelligence quotient of point mutation case was improved significantly. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Epigenetic Regulators Modulate Muscle Damage in Duchenne Muscular Dystrophy Model.

    Science.gov (United States)

    Bajanca, Fernanda; Vandel, Laurence

    2017-12-21

    Histone acetyl transferases (HATs) and histone deacetylases (HDAC) control transcription during myogenesis. HDACs promote chromatin condensation, inhibiting gene transcription in muscle progenitor cells until myoblast differentiation is triggered and HDACs are released. HATs, namely CBP/p300, activate myogenic regulatory and elongation factors promoting myogenesis. HDAC inhibitors are known to improve regeneration in dystrophic muscles through follistatin upregulation. However, the potential of directly modulating HATs remains unexplored. We tested this possibility in a well-known zebrafish model of Duchenne muscular dystrophy. Interestingly, CBP/p300 transcripts were found downregulated in the absence of Dystrophin. While investigating CBP rescuing potential we observed that dystrophin-null embryos overexpressing CBP actually never show significant muscle damage, even before a first regeneration cycle could occur. We found that the pan-HDAC inhibitor trichostatin A (TSA) also prevents early muscle damage, however the single HAT CBP is as efficient even in low doses. The HAT domain of CBP is required for its full rescuing ability. Importantly, both CBP and TSA prevent early muscle damage without restoring endogenous CBP/p300 neither increasing follistatin transcripts. This suggests a new mechanism of action of epigenetic regulators protecting dystrophin-null muscle fibres from detaching, independent from the known improvement of regeneration upon damage of HDACs inhibitors. This study builds supporting evidence that epigenetic modulators may play a role in determining the severity of muscle dystrophy, controlling the ability to resist muscle damage. Determining the mode of action leading to muscle protection can potentially lead to new treatment options for muscular dystrophies in the future.

  12. Genetics and molecular pathology of Stargardt-like macular degeneration.

    Science.gov (United States)

    Vasireddy, Vidyullatha; Wong, Paul; Ayyagari, Radha

    2010-05-01

    Stargardt-like macular degeneration (STGD3) is an early onset, autosomal dominant macular degeneration. STGD3 is characterized by a progressive pathology, the loss of central vision, atrophy of the retinal pigment epithelium, and accumulation of lipofuscin, clinical features that are also characteristic of age-related macular degeneration. The onset of clinical symptoms in STGD3, however, is typically observed within the second or third decade of life (i.e., starting in the teenage years). The clinical profile at any given age among STGD3 patients can be variable suggesting that, although STGD3 is a single gene defect, other genetic or environmental factors may play a role in moderating the final disease phenotype. Genetic studies localized the STGD3 disease locus to a small region on the short arm of human chromosome 6, and application of a positional candidate gene approach identified protein truncating mutations in the elongation of very long chain fatty acids-4 gene (ELOVL4) in patients with this disease. The ELOVL4 gene encodes a protein homologous to the ELO group of proteins that participate in fatty acid elongation in yeast. Pathogenic mutations found in the ELOVL4 gene result in altered trafficking of the protein and behave with a dominant negative effect. Mice carrying an Elovl4 mutation developed photoreceptor degeneration and depletion of very long chain fatty acids (VLCFA). ELOVL4 protein participates in the synthesis of fatty acids with chain length longer than 26 carbons. Studies on ELOVL4 indicate that VLCFA may be necessary for normal function of the retina, and the defective protein trafficking and/or altered VLCFA elongation underlies the pathology associated with STGD3. Determining the role of VLCFA in the retina and discerning the implications of abnormal trafficking of mutant ELOVL4 and depleted VLCFA content in the pathology of STGD3 will provide valuable insight in understanding the retinal structure, function, and pathology underlying STGD3

  13. Genetics of Unilateral and Bilateral Age-Related Macular Degeneration Severity Stages

    NARCIS (Netherlands)

    Schick, T.; Altay, L.; Viehweger, E.; Hoyng, C.B.; Hollander, A.I. den; Felsch, M.; Fauser, S.

    2016-01-01

    BACKGROUND: Age-related macular degeneration (AMD) is a common disease causing visual impairment and blindness. Various gene variants are strongly associated with late stage AMD, but little is known about the genetics of early forms of the disease. This study evaluated associations of genetic

  14. Macular thickness after glaucoma filtration surgery.

    Science.gov (United States)

    Sesar, Antonio; Cavar, Ivan; Sesar, Anita Pusić; Geber, Mia Zorić; Sesar, Irena; Laus, Katia Novak; Vatavuk, Zoran; Mandić, Zdravko

    2013-09-01

    The aim of present study was to analyze early postoperative changes in the macular area using optical coherence tomography (OCT) after uncomplicated glaucoma filtration surgery. This prospective study included 32 patients (34 eyes) with open-angle glaucoma, which underwent trabeculectomy with or without use of mitomycin C. Exclusion criteria were macular edema, uveitis, age-related macular degeneration, blurred optical media, secondary glaucoma and angle-closure glaucoma. All standard clinical examinations were made before surgery, at the 2nd day, 1 week and 1 month after surgery. Tomography of the macula was performed during every examination using Cirrus HD OCT for the analysis of central subfield thickness. Results show that thickening of the macula was slightly higher 1 week and 1 month after operation in comparison with baseline end 2nd day postoperativelly. There was no significant difference in the change of macular thickness in patients who have used topical prostaglandins compared with those who have used other topical medications. Also, there was no difference in macular changes between patients treated with or without mitomycin C. In conclusion, we found a slight subclinical increase in macular thickness after uncomplicated trabeculectomy, for which we considered that was the result in reduction of intraocular pressure after glaucoma surgery. Macular thickening after glaucoma filtering surgery could be a physiological reaction to the stress of the retina caused by a sudden reduction of intraocular pressure and it is the consequence of altered relationship between capillary pressure and interstitial fluid pressure.

  15. Yesterday, today and tomorrow of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Cheng ZHANG

    2015-05-01

    Full Text Available The research history of Duchenne muscular dystrophy (DMD may be roughly divided into 3 phases: clinical describing (1836-1985, molecular diagnosis and exploratory therapy (1985-2020, and the pathogenesis illuminating, gene therapy or treatment against the pathogenesis (2020-. During 1836-1985, doctors described the variation of medical history, clinical signs and symptoms, pathology, biochemistry, and genetic regularity of DMD. During 1985-2020, the scientists set up molecular diagnostic methods and exploratory therapy regimens of DMD. After 2020, some gene therapies, for example, the regimens of exon skipping and reading through, may be used in clinical practice. DOI: 10.3969/j.issn.1672-6731.2015.05.002

  16. Visual outcomes of macular hole surgery

    International Nuclear Information System (INIS)

    Khaqan, H.A.; Muhammad, F.J.

    2016-01-01

    To determine the mean visual improvement after internal limiting membrane (ILM) peeling assisted with brilliant blue staining of ILM in macular hole, and stratify the mean visual improvement in different stages of macular hole. Study Design: Quasi-experimental study. Place and Duration of Study: Eye outpatient department (OPD), Lahore General Hospital, Lahore from October 2013 to December 2014. Methodology: Patients with macular hole underwent measurement of best corrected visual acuity (BCVA) and fundus examination with indirect slit lamp biomicroscopy before surgery. The diagnosis of all patients was confirmed on optical coherence tomography. All patients had 23G trans-conjunctival three ports pars plana vitrectomy, ILM peeling, and endotamponade of SF6. The mean visual improvement of different stages of macular hole was noted. Paired t-test was applied. Results: There were 30 patients, 15 males and 15 females (50%). The mean age was 62 ± 10.95 years. They presented with low mean preoperative visual acuity (VA) of 0.96 ± 0.11 logMar. The mean postoperative VA was 0.63 ± 0.24 logMar. The mean visual increase was 0.33 0.22 logMar (p < 0.001). In patients with stage 2 macular hole, mean visual increase was 0.35 ± 0.20 logMar (p < 0.001). In patients with stage 3 macular hole, mean visual increase was 0.44 ± 0.21 logMar (p < 0.001), and in patients with stage 4 macular hole it was 0.13 ± 0.1 logMar (p = 0.004). Conclusion: ILM peeling assisted with brilliant blue is a promising surgery for those patients who have decreased vision due to macular hole, in 2 - 4 stages of macular hole. (author)

  17. Consistency of ocular coherence tomography fast macular thickness mapping in diabetic diffuse macular edema

    International Nuclear Information System (INIS)

    Saraiva, Fabio Petersen; Costa, Patricia Grativol; Inomata, Daniela Lumi; Melo, Carlos Sergio Nascimento; Helal Junior, John; Nakashima, Yoshitaka

    2007-01-01

    Objectives: To investigate optical coherence tomography consistency on foveal thickness, foveal volume, and macular volume measurements in patients with and without diffuse diabetic macular edema. Introduction: Optical coherence tomography represents an objective technique that provides cross-sectional tomographs of retinal structure in vivo. However, it is expected that poor fixation ability, as seen in diabetic macular edema, could alter its results. Several authors have discussed the reproducibility of optical coherence tomography, but only a few have addressed the topic with respect to diabetic maculopathy. Methods: The study recruited diabetic patients without clinically evident retinopathy (control group) and with diffuse macular edema (case group). Only one eye of each patient was evaluated. Five consecutive fast macular scans were taken using Ocular Coherence Tomography 3; the 6 mm macular map was chosen. The consistency in measurements of foveal thickness, foveal volume, and total macular volume for both groups was evaluated using the Pearson's coefficient of variation. The T-test for independent samples was used in order to compare measurements of both groups. Results: Each group consisted of 20 patients. All measurements had a coefficient of variation less than 10%. The most consistent parameter for both groups was the total macular volume. Discussion: Consistency in measurement is a mainstay of any test. A test is unreliable if its measurements can not be correctly repeated. We found a good index of consistency, even considering patients with an unstable gaze. Conclusions: Optical coherence tomography is a consistent method for diabetic subjects with diffuse macular edema. (author)

  18. Consistency of ocular coherence tomography fast macular thickness mapping in diabetic diffuse macular edema

    Energy Technology Data Exchange (ETDEWEB)

    Saraiva, Fabio Petersen; Costa, Patricia Grativol; Inomata, Daniela Lumi; Melo, Carlos Sergio Nascimento; Helal Junior, John; Nakashima, Yoshitaka [Universidade de Sao Paulo (USP), SP (Brazil). Hospital das Clinicas. Dept. de Oftalmologia]. E-mail: fabiopetersen@yahoo.com.br

    2007-07-01

    Objectives: To investigate optical coherence tomography consistency on foveal thickness, foveal volume, and macular volume measurements in patients with and without diffuse diabetic macular edema. Introduction: Optical coherence tomography represents an objective technique that provides cross-sectional tomographs of retinal structure in vivo. However, it is expected that poor fixation ability, as seen in diabetic macular edema, could alter its results. Several authors have discussed the reproducibility of optical coherence tomography, but only a few have addressed the topic with respect to diabetic maculopathy. Methods: The study recruited diabetic patients without clinically evident retinopathy (control group) and with diffuse macular edema (case group). Only one eye of each patient was evaluated. Five consecutive fast macular scans were taken using Ocular Coherence Tomography 3; the 6 mm macular map was chosen. The consistency in measurements of foveal thickness, foveal volume, and total macular volume for both groups was evaluated using the Pearson's coefficient of variation. The T-test for independent samples was used in order to compare measurements of both groups. Results: Each group consisted of 20 patients. All measurements had a coefficient of variation less than 10%. The most consistent parameter for both groups was the total macular volume. Discussion: Consistency in measurement is a mainstay of any test. A test is unreliable if its measurements can not be correctly repeated. We found a good index of consistency, even considering patients with an unstable gaze. Conclusions: Optical coherence tomography is a consistent method for diabetic subjects with diffuse macular edema. (author)

  19. Muscle MRI and functional outcome measures in Becker muscular dystrophy.

    Science.gov (United States)

    Barp, Andrea; Bello, Luca; Caumo, Luca; Campadello, Paola; Semplicini, Claudio; Lazzarotto, Annalisa; Sorarù, Gianni; Calore, Chiara; Rampado, Alessandro; Motta, Raffaella; Stramare, Roberto; Pegoraro, Elena

    2017-11-22

    Becker muscular dystrophy (BMD) is a neuromuscular disorder allelic to Duchenne muscular dystrophy (DMD), caused by in-frame mutations in the dystrophin gene, and characterized by a clinical progression that is both milder and more heterogeneous than DMD. Muscle magnetic resonance imaging (MRI) has been proposed as biomarker of disease progression in dystrophinopathies. Correlation with clinically meaningful outcome measures such as North Star Ambulatory Assessment (NSAA) and 6 minute walk test (6MWT) is paramount for biomarker qualification. In this study, 51 molecularly confirmed BMD patients (aged 7-69 years) underwent muscle MRI and were evaluated with functional measures (NSAA and 6MWT) at the time of the MRI, and subsequently after one year. We confirmed a pattern of fatty substitution involving mainly the hip extensors and most thigh muscles. Severity of muscle fatty substitution was significantly correlated with specific DMD mutations: in particular, patients with an isolated deletion of exon 48, or deletions bordering exon 51, showed milder involvement. Fat infiltration scores correlated with baseline functional measures, and predicted changes after 1 year. We conclude that in BMD, skeletal muscle MRI not only strongly correlates with motor function, but also helps in predicting functional deterioration within a 12-month time frame.

  20. 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.

  1. Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

    Science.gov (United States)

    Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T; Jordan, Maria C; Richardson, Vanitra A; Roos, Kenneth P; Crosbie-Watson, Rachelle H

    2015-12-23

    Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy. SSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix. SSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  2. Muscular dystrophy in a family of Labrador Retrievers with no muscle dystrophin and a mild phenotype.

    Science.gov (United States)

    Vieira, Natassia M; Guo, Ling T; Estrela, Elicia; Kunkel, Louis M; Zatz, Mayana; Shelton, G Diane

    2015-05-01

    Animal models of dystrophin deficient muscular dystrophy, most notably canine X-linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. SIRT1: A Novel Target for the Treatment of Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Atsushi Kuno

    2016-01-01

    Full Text Available Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. Duchenne muscular dystrophy (DMD is the most common and severe form of muscular dystrophy and is caused by mutations in the gene that encodes the cytoskeletal protein dystrophin. The treatment for DMD is limited to glucocorticoids, which are associated with multiple side effects. Thus, the identification of novel therapeutic targets is urgently needed. SIRT1 is an NAD+-dependent histone/protein deacetylase that plays roles in diverse cellular processes, including stress resistance and cell survival. Studies have shown that SIRT1 activation provides beneficial effects in the dystrophin-deficient mdx mouse, a model of DMD. SIRT1 activation leads to the attenuation of oxidative stress and inflammation, a shift from the fast to slow myofiber phenotype, and the suppression of tissue fibrosis. Although further research is needed to clarify the molecular mechanisms underlying the protective role of SIRT1 in mdx mice, we propose SIRT1 as a novel therapeutic target for patients with muscular dystrophies.

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

    Science.gov (United States)

    Rosenberg, T; Haim, M; Hauch, A M; Parving, A

    1997-05-01

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

  5. 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.

  6. Mitochondrial disorders in progressive muscular dystrophies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

    Full Text Available The literature review gives data on the role of mitochondrial disorders in the pathogenesis of different progressive muscular dystrophies. It describes changes in Duchenne, limb-girdle, facial scapulohumeral (Landuzi—Degerina muscular dystrophies. The review is based on both clinical and experimental animal studies. Along with the implication of mitochondria in the pathogenesis of the diseases, it describes muscular dystrophy treatment options compensating for energy disorders and overcoming oxidative stress and mitochondrial dysfunction. Mitochondrial studies in different muscle diseases hand physicians treatment modalities that fail to lead to recovery, but compensate for disorders caused by mutations in the genetic apparatus. 

  7. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures.

    Science.gov (United States)

    Mercuri, Eugenio; Bushby, Kate; Ricci, Enzo; Birchall, Daniel; Pane, Marika; Kinali, Maria; Allsop, Joanna; Nigro, Vincenzo; Sáenz, Amets; Nascimbeni, Annachiara; Fulizio, Luigi; Angelini, Corrado; Muntoni, Francesco

    2005-02-01

    Limb girdle muscular dystrophy 2A is a common variant secondary to mutations in the calpain 3 gene. A proportion of patients has early and severe contractures, which can cause diagnostic difficulties with other conditions. We report clinical and muscle magnetic resonance imaging findings in seven limb girdle muscular dystrophy 2A patients (four sporadic and three familial) who had prominent and early contractures. All patients showed a striking involvement of the posterior thigh muscles. The involvement of the other thigh muscles was variable and was related to clinical severity. Young patients with minimal functional motor impairment showed a predominant involvement of the adductors and semimembranosus muscles while patients with restricted ambulation had a more diffuse involvement of the posterolateral muscles of the thigh and of the vastus intermedius with relative sparing of the vastus lateralis, sartorius and gracilis. At calf level all patients showed involvement of the soleus muscle and of the medial head of the gastrocnemius with relative sparing of the lateral head. MRI findings were correlated to those found in two patients with the phenotype of limb girdle muscular dystrophy 2A without early contractures and the pattern observed was quite similar. However, the pattern observed in limb girdle muscular dystrophy 2A is different from that reported in other muscle diseases such as Emery-Dreifuss muscular dystrophy and Bethlem myopathy which have a significant clinical overlap with limb girdle muscular dystrophy 2A once early contractures are present. Our results suggest that muscle MRI may help in recognising patients with limb girdle muscular dystrophy 2A even when the clinical presentation overlaps with other conditions, and may therefore, be used as an additional investigation to target the appropriate biochemical and genetic tests.

  8. Diabetic macular oedema: under-represented in the genetic analysis of diabetic retinopathy.

    Science.gov (United States)

    Broadgate, Suzanne; Kiire, Christine; Halford, Stephanie; Chong, Victor

    2018-04-01

    Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies. © 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  9. Corneal stromal dystrophies: a clinical pathologic study Distrofia corneana estromal: um estudo clínicopatológico

    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

  10. Intraretinal hemorrhages in cystoid macular edema.

    Science.gov (United States)

    Bovino, J A; Kelly, T J; Marcus, D F

    1984-08-01

    Retinal hemorrhages can be associated with typical cystoid macular edema. We examined the fundus photographs and fluorescein angiograms of 313 eyes of 264 patients with documented cystoid macular edema to establish the incidence and characteristics of associated intraretinal hemorrhages. As we wanted to study only those hemorrhages unique to cystoid macular edema, we excluded 86 eyes because the patients had diseases known to be associated with retinal hemorrhages. These diseases included diabetes mellitus, branch retinal vein occlusion, hypertensive retinopathy, venous stasis retinopathy, and perifoveal telangiectasia. Of the remaining 227 eyes with cystoid macular edema, 56 (24.7%) were identified with retinal hemorrhages not associated with systemic disease. The hemorrhages were characteristically oval, round, or linear and frequently filled or partially filled the intraretinal cystoid space. In many patients, a blood-fluid level was observed.

  11. Genetics Home Reference: Stargardt macular degeneration

    Science.gov (United States)

    ... recognizing faces. In most people with Stargardt macular degeneration , a fatty yellow pigment (lipofuscin) builds up in cells underlying the macula. Over time, the abnormal accumulation of this substance ...

  12. Abnormal sympathetic innervation of the heart in a patient with Emery-Dreifuss muscular dystrophy.

    Science.gov (United States)

    Fujiita, Takashi; Shimizu, Masami; Kaku, Bunji; Kanaya, Hounin; Horita, Yuki; Uno, Yoshihide; Yamazaki, Tsukasa; Ohka, Takio; Sakata, Kenji; Mabuchi, Hiroshi

    2005-07-01

    A 33-year-old man was admitted for general malaise and vomiting. An electrocardiogram showed a complete atrioventricular block and an echocardiogram showed right atrial dilatation and normal wall motion of left ventricle (LV). Gene analysis showed nonsense mutation in the STA gene, which codes for emerin, and Emery-Dreifuss muscular dystrophy was diagnosed. An endomyocardial biopsy of right ventricle showed mild hypertrophy of myocytes. Myocardial scintigraphic studies with Tc-99m methoxyisobutylisonitrile (MIBI) and I-123-betamethyl-p-iodophenylpentadecanoic acid (BMIPP) scintigrams showed no abnormalities. In contrast, I-123 metaiodobenzylguanidine (MIBG) scintigrams showed a diffuse and severe decrease in accumulation of MIBG in the heart. Six months later, his LV wall motion on echocardiograms developed diffuse hypokinesis. These results suggest that the abnormality on I-123 MIBG myocardial scintigrams may predict LV dysfunction in Emery-Dreifuss muscular dystrophy.

  13. Molecular and phenotypic analysis of a family with autosomal recessive cone-rod dystrophy and Stargardt disease.

    NARCIS (Netherlands)

    Ijzer, Suzanne; Born, L.I. van den; Zonneveld, M.N.; Lopez, I.; Ayyagari, R.; Teye-Botchway, L.; Mota-Vieira, L.; Cremers, F.P.M.; Koenekoop, R.K.

    2007-01-01

    PURPOSE: To identify the causative gene mutations in three siblings with severe progressive autosomal recessive cone-rod dystrophy (arCRD) and their fifth paternal cousin with Stargardt disease (STGD1) and to specify the phenotypes. METHODS: We evaluated eight sibs of one family, three family

  14. Current and emerging treatment strategies for Duchenne muscular dystrophy

    Science.gov (United States)

    Mah, Jean K

    2016-01-01

    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 will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying

  15. Macular edema in siliconized eyes

    Directory of Open Access Journals (Sweden)

    Kaya A

    2016-05-01

    Full Text Available Abdullah Kaya,1 Yakup Aksoy,2 Yıldıray Yildirim,3 Murat Sonmez3 1Department of Ophthalmology, Anittepe Military Dispensary, Ankara, Turkey; 2Department of Ophthalmology, Girne Military Hospital, Girne, Cyprus; 3Department of Ophthalmology, GATA Haydarpasa Training Hospital, Istanbul, TurkeyWe read with great interest the article titled “Value of optical coherence tomography in the detection of macular pathology before the removal of silicone oil” by Rashad et al.1 The authors have evaluated the optical coherence tomography (OCT findings before the removal of silicone oil (SiO. We congratulate the authors for this well-organized study and would like to contribute to their findings.View original paper by Rashad and colleagues.

  16. Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?

    OpenAIRE

    Costantini, Antonio; Trevi, Erika; Pala, Maria Immacolata; Fancellu, Roberto

    2016-01-01

    Myotonic dystrophy type 1, also known as Steinert′s disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine (vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell metabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and periphe...

  17. Coverage analysis of lists of genes involved in heterogeneous ...

    Indian Academy of Sciences (India)

    Genes involved in myopathies: 82 genes, based on the disease groups ... 605517 Muscular dystrophy-dystroglycanopathy (congenital with brain and eye ..... Epilepsy, X-linked, with variable learning disabilities and behavior disorders. 300491.

  18. Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.

    Science.gov (United States)

    Meyer, Alain; Lannes, Béatrice; Carapito, Raphaël; Bahram, Seiamak; Echaniz-Laguna, Andoni; Geny, Bernard; Sibilia, Jean; Gottenberg, Jacques Eric

    2015-02-01

    Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8 kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Clinical analysis of intravitreal injection of triamcinolone acetonide combined macular grid photocoagulation treatment for macular edema

    Directory of Open Access Journals (Sweden)

    Xian-Hua Jing

    2014-10-01

    Full Text Available AIM: To investigate the clinical efficacy and safety of intravitreal injection of triamcinolone combined macular grid photocoagulation treatment for macular edema. METHODS: Totally 150 cases(150 eyeswith macular edema in our hospital from July 2009 to November 2013 were selected, which were randomly divided into study group(75 cases, 75 eyesand control group(75 cases, 75 eyes. The cases in control group were treated with macular grid photocoagulation treatment, those in the study group used triamcinolone acetonide combined macular grid photocoagulation treatment. Best corrected visual acuity(BCVA, parallel optical coherence tomography(OCTand fundus fluorescein angiography(FFAwere detected before treatment, after treatment 7d, 1, 3, and 9mo. RESULTS:After the treatment, patients' vision were significantly improved in two groups(PPPP>0.05. Fovea macular neurosensory retinal thickness in the study group was significantly lower than that in control group(PCONCLUSION: Triamcinolone acetonide combined macular grid photocoagulation treatment is accurate, can effectively improve the visual acuity, reduce macular edema, it is safe and reliable, and suitable for clinical application.

  20. A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles.

    Science.gov (United States)

    Caron, Leslie; Kher, Devaki; Lee, Kian Leong; McKernan, Robert; Dumevska, Biljana; Hidalgo, Alejandro; Li, Jia; Yang, Henry; Main, Heather; Ferri, Giulia; Petek, Lisa M; Poellinger, Lorenz; Miller, Daniel G; Gabellini, Davide; Schmidt, Uli

    2016-09-01

    : Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. ©AlphaMed Press.

  1. Respiratory muscle training in Duchenne muscular dystrophy.

    OpenAIRE

    Rodillo, E; Noble-Jamieson, C M; Aber, V; Heckmatt, J Z; Muntoni, F; Dubowitz, V

    1989-01-01

    Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.

  2. Duchenne muscular dystrophy models show their age

    OpenAIRE

    Chamberlain, Jeffrey S.

    2010-01-01

    The lack of appropriate animal models has hampered efforts to develop therapies for Duchenne muscular dystrophy (DMD). A new mouse model lacking both dystrophin and telomerase (Sacco et al., 2010) closely mimics the pathological progression of human DMD and shows that muscle stem cell activity is a key determinant of disease severity.

  3. What Are the Treatments for Muscular Dystrophy?

    Science.gov (United States)

    ... Child Neurology Society. (2005). Practice parameter: Corticosteroid treatment of Duchenne dystrophy. Neurology, 64 , 13-20. Retrieved June 22, 2012, ... Statement. (2004). Respiratory care of the patient with Duchenne muscular ... American Journal of Respiratory and Critical Care Medicine, 170, 456-465. ...

  4. 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…

  5. 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.

  6. Duchenne muscular dystrophy - a molecular service

    African Journals Online (AJOL)

    In 1987 a carrier detection and prenatal diagnostic service for. Duchenne muscular dystrophy using molecular technology was instituted at the Department of Human Genetics, Uni- versity of Cape Town, to serve affe.cted families in southern. Africa. DNA samples from 100 affected male subjects and. 350 of their relatives ...

  7. Aberrant Myokine Signaling in Congenital Myotonic Dystrophy

    Directory of Open Access Journals (Sweden)

    Masayuki Nakamori

    2017-10-01

    Full Text Available Summary: Myotonic dystrophy types 1 (DM1 and 2 (DM2 are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM, a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6 myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling. : Congenital myotonic dystrophy (CDM manifests characteristic genetic (very large CTG repeat expansions, epigenetic (CpG hypermethylation upstream of the repeat, and phenotypic (muscle immaturity features not seen in adult DM. Nakamori et al. find phenotype-genotype and epigenotype correlation in CDM muscle and reveal involvement of the IL-6 myokine signaling pathway in the disease process. Keywords: CTCF, ER stress, IL-6, muscular dystrophy, NF-κB, trinucleotide, cytokine, splicing

  8. Hereditary muscular dystrophies and the heart

    NARCIS (Netherlands)

    Hermans, M. C. E.; Pinto, Y. M.; Merkies, I. S. J.; de Die-Smulders, C. E. M.; Crijns, H. J. G. M.; Faber, C. G.

    2010-01-01

    Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different

  9. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy

    Directory of Open Access Journals (Sweden)

    Agnieszka Madej-Pilarczyk

    2016-03-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMD, a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1 kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2, with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.

  10. Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Yacine Kharraz

    2014-01-01

    Full Text Available Fibrosis is the aberrant deposition of extracellular matrix (ECM components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD, caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression.

  11. The Frequency of Serous Macular Detachment in Diabetic Macular Edema

    Directory of Open Access Journals (Sweden)

    Onur Yaya

    2015-05-01

    Full Text Available Objectives: To investigate the epidemiology and frequency of serous macular detachment (SMD in patients diagnosed with diabetic macular edema (DME. Materials and Methods: Hundred and forty-three eyes of 104 patients with DME were examined retrospectively. According to the results of OCT, the patients were separated into two groups; patients diagnosed with SMD and DME (group 1 and patients diagnosed with DME (group 2. They were assessed based on demographic characteristics, average age, duration of diabetes mellitus (DM, hypertension (HT history, best-corrected visual acuity, and diabetic retinopathy stages. Results: The average age of the patients was 61±8.7 years. Forty-three patients (41.3% were female and 61 patients (58.7% were male. Fifty-four of 104 patients (51.9% had DME with SMD. 21 (38.8% patients had bilateral SMD. In group 1, 31 patients were male (57.4% and 23 patients were female (42.6%. In group 2, 30 (60% patients were male and 20 (40% patients were female. In group 1, average age was 60.2±9.6 and the average duration of DM was 12.2±7.0 years, whereas the average age was 61.9±7.6 and the average duration of DM was 14.06±6.8 years in group 2. Forty-two patients in group 1 (77.8% and 30 patients (60% in group 2 had history of HT. Before the treatment, the average best-corrected visual acuity was found to be 0.30±0.24 in group 1 and 0.32±0.25 in group 2. Conclusion: Today, it is thought that diabetic maculopathy is the leading cause of SMD and it is a determining factor of treatment applications. In our study, we aimed at investigating the frequency of SMD in DME and the risk factors for the development of SMD. Although there were some differences between the factors, only the history of HT was found statistically higher in patients with SMD (p=0.04. (Turk J Ophthalmol 2015; 45: 92-96

  12. A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy

    Science.gov (United States)

    2018-04-17

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

  13. SCARB1 rs5888 is associated with the risk of age-related macular degeneration susceptibility and an impaired macular area.

    Science.gov (United States)

    Stanislovaitiene, Daiva; Zaliuniene, Dalia; Krisciukaitis, Algimantas; Petrolis, Robertas; Smalinskiene, Alina; Lesauskaite, Vita; Tamosiunas, Abdonas; Lesauskaite, Vaiva

    2017-01-01

    Age-related macular degeneration (ARMD), a progressive retinal disease, is responsible for an impaired central vision in about 180 million people worldwide. Current options for ARMD prevention and treatment are limited due to an incomplete understanding of disease etiopathogenesis. We aimed to test the hypothesis that the single nucleotide polymorphism rs5888 of SCARB1 gene reflecting lipid and antioxidant micronutrient metabolism pathways is associated with ARMD susceptibility and to evaluate if there is any relation between SCARB1 rs5888 and the macular lesion area. The prospective case-control study included patients with ARMD (n = 215) and the reference group (n = 238) drawn from a random sample of the Lithuanian population (n = 1436). The genotyping test of SCARB1 rs5888 was carried out using the real-time polymerase chain reaction method. Regression analysis adjusted by gender and age demonstrated that SCARB1 rs5888 TT genotype significantly decreased the odds for ARMD development (OR: 0.61, 95%; CI: 0.380-0.981, p = 0.04). A smoking habit and leading an outdoor life are associated with larger macular lesion areas in ARMD patients (0.54 (0.00-39.06) vs. 3.09 (0.02-19.30) and 0.27 (0.00-34.57) vs. 0.75 (0.00-39.06), respectively). In late stage ARMD subjects with CT genotype, the macular lesion area was larger than in TT carriers (7.64 (0.49-39.06) mm 2 vs. 5.02 (0.03-37.06) mm 2 , p = 0.006). SCARB1 rs5888 and environmental oxidative stress have a prominent role in ARMD susceptibility, early ARMD progression to advanced stage disease and even in the outcome of the disease-an area of macular lesion.

  14. Macular edema in uveitis with emphasis on ocular sarcoidosis

    NARCIS (Netherlands)

    Norel, J. van

    2015-01-01

    This thesis investigates the accumulation of fluid in the yellow spot (macular edema) in ocular inflammation (uveitis). Macular edema may result in definitive loss of vision.Two methods of imaging of macular edema are fluorescein angiography (FA) and optical coherence tomography (OCT). The first

  15. Management of macular epiretinal membrane by vitrectomy and intravitreal triamcinolone.

    Science.gov (United States)

    Shukla, Dhananjay

    2014-04-01

    A patient underwent successful vitrectomy for macular epiretinal membrane with anatomical and functional improvement. 10 weeks later, there was a recurrence of macular edema with corresponding visual decline. An intravitreal injection of triamcinolone acetonide not only restored the macular anatomy but also improved the visual outcome beyond that achieved after surgery.

  16. Intravitreal triamcinolone for diffuse diabetic macular oedema.

    LENUS (Irish Health Repository)

    Gibran, S K

    2012-02-03

    AIM: To evaluate the efficacy of intravitreal triamcinolone (IVTA) for the treatment of diffuse diabetic macular oedema (DME) refractory to conventional argon macular laser therapy. METHODS: A prospective, consecutive, and noncomparative case series was undertaken involving 38 eyes of 38 patients with refractory DME. Triamcinolone acetonide (4 mg) in 0.1 ml was injected intravitreally. LogMar visual acuity (VA) and macular thickness measured by ocular coherence tomography (OCT) were assessed preoperatively and postoperatively at 1, 3, and 6 months. RESULTS: All patients completed 6 months of follow up. VA (mean+\\/-SD) improved from 0.905+\\/-0.23 to 0.605+\\/-0.28, 0.555+\\/-0.29, and 0.730+\\/-0.30 at 1, 3, and 6 months, respectively. Macular thickness baseline (mean+\\/-SD) on OCT was 418.7+\\/-104.2 microm and this decreased to 276.9+\\/-72.6 microm, 250.6+\\/-53.1 microm, and 308.8+\\/-87.3 microm at 1, 3, and 6 months, respectively. CONCLUSIONS: IVTA may be a potential temporary treatment for refractory DME. It is effective in decreasing macular thickness and improving VA but the effect lasts approximately for 6 months in the majority of patients. Further investigations are required to establish the safety of IVTA for the treatment of DME.

  17. Corticosteroid Treatment in Diabetic Macular Edema

    Directory of Open Access Journals (Sweden)

    Burcu Nurözler Tabakcı

    2017-06-01

    Full Text Available Diabetic macular edema is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of macular edema is complex and multifactorial. For many years, laser photocoagulation has been considered the standard therapy for the treatment of diabetic macular edema; however, few patients achieve significant improvements in visual acuity. Today the intravitreal administration of anti-inflammatory or anti-angiogenic agents together with the use of laser photocoagulation represents the standard of care for the treatment of this complication. The intravitreal route of administration minimizes the systemic side effects of corticosteroids. Steroid-related ocular side effects are elevated intraocular pressure and cataract, while injection-related complications include endophthalmitis, vitreous hemorrhage, and retinal detachment. In order to reduce the risks and complications, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated injections for the management of diabetic macular edema. In this review, the efficacy, safety, and therapeutic potential of intravitreal corticosteroids in diabetic macular edema are discussed with a review of recent literature.

  18. Spontaneously resolving macular cyst in an infant

    Directory of Open Access Journals (Sweden)

    Anuradha Ganesh

    2013-01-01

    Full Text Available The purpose of this study is to describe transient macular cysts in an infant and correlate their occurrence with normal development events. A newborn Caucasian girl presented with a protruding corneal mass in her left eye at birth. She underwent a complete ophthalmic examination. A keratinized staphylomatous malformation involving the entire cornea and precluding further visualization of the anterior and posterior segment was observed in the left eye. Spectral domain optical coherence tomography (SD-OCT of the right eye performed when the child was approximately 6-week-old had revealed an unexpected finding of macular cysts involving the inner nuclear and outer retinal layers. Corneal transplant in the left eye was performed a month later. Ocular examination under anesthesia just prior to surgery revealed normal intraocular pressure, anterior segment and retina in the right eye. SD-OCT was normal in both eyes and showed complete resolution of the cysts in the right eye. The patient had not been on any medications at that time. Although clinical retinal examination might be unremarkable, SD-OCT may reveal cystic spaces in the macula. In the absence of conditions known to be associated with macular edema, transient macular cysts may arise due to a developmental incompetence of the blood-retinal barrier or may represent transient spaces created during normal migration of retinal cells. Further study is warranted to delineate the entity of transient macular cysts in infancy.

  19. CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2013-09-01

    monitoring visit to monitor this study, the PITT0908 clinical trial, a study on facioscapulohumeral muscular dystrophy (FSHD), and PITT0112 Becker natural...height findings manuscript are currently in working stage and circulating among co-authors for editing. 2.3.6 Becker Muscular Dystrophy – A Natural...participants with Becker muscular dystrophy . The study period is 36 months per patient. This project is primarily funded by the National Institutes of

  20. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of Duchenne muscular dystrophy. © The Author(s) 2015.

  1. Efficacy of Diacetate Esters of Macular Carotenoids: Effect of Supplementation on Macular Pigment

    Directory of Open Access Journals (Sweden)

    Richard A. Bone

    2018-01-01

    Full Text Available The accumulation of the carotenoids lutein, zeaxanthin, and mesozeaxanthin in the center of the human retina, and known as the macula lutea or macular pigment, is believed to protect the retina from age-related macular degeneration. Since the macular pigment is of dietary origin, supplements containing the relevant carotenoids are readily available. In this study, we compared the changes in macular pigment over a 24-week supplementation period for two groups of 24 subjects each assigned to either of two supplement formulations, 20 mg/day of lutein or 20 mg equivalent free carotenoids of a combination of diacetate esters of the macular carotenoids. The latter group responded with a larger increase (0.0666 ± 0.0481 in macular pigment optical density than the former group (0.0398 ± 0.0430, driven largely by the older subjects. The difference was statistically significant (p=0.0287. There was a general trend towards smaller increases in macular pigment for those subjects whose baseline value was high. However, the trend was only significant (p<0.05 for subjects in the diacetate group. No differences in response could be attributed to the gender of the subjects. We also observed no indication that the use of statin drugs by a few of the older subjects influenced their responses.

  2. MACULAR CHOROIDAL VOLUME CHANGES AFTER INTRAVITREAL BEVACIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

    Science.gov (United States)

    Palkovits, Stefan; Seidel, Gerald; Pertl, Laura; Malle, Eva M; Hausberger, Silke; Makk, Johanna; Singer, Christoph; Osterholt, Julia; Herzog, Sereina A; Haas, Anton; Weger, Martin

    2017-12-01

    To evaluate the effect of intravitreal bevacizumab on the macular choroidal volume and the subfoveal choroidal thickness in treatment naïve eyes with exudative age-related macular degeneration. The macular choroidal volume and the subfoveal choroidal thickness were measured using enhanced depth imaging optical coherence tomography. After a screening examination, each patient received 3 monthly intravitreal injections of 1.25 mg bevacizumab. One month after the third injection was a final assessment. Forty-seven patients with a mean age of 80 ± 6.4 years were included. The macular choroidal volume decreased significantly from median 4.1 mm (interquartile range 3.4-5.9) to median 3.9 mm (interquartile range 3.1-5.6) between the baseline and final examination (difference -0.46 mm, 95% confidence interval: -0.57 to 0.35, P macular choroidal volume at baseline and subfoveal choroidal thickness at baseline were not associated with the response to treatment. The macular choroidal volume and the subfoveal choroidal thickness decreased significantly after 3 monthly bevacizumab injections for exudative age-related macular degeneration.

  3. 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.

  4. Effect of cellular therapy in progression of Becker’s muscular dystrophy: a case study

    Directory of Open Access Journals (Sweden)

    Alok Sharma

    2016-03-01

    Full Text Available Becker muscular dystrophy (BMD is an inherited disorder due to deletions of the dystrophin gene that leads to muscle weakness. Effects of bone marrow mononuclear cell (BMMNC transplantation in Muscular Dystrophy have shown to be safe and beneficial. We treated a 20-year-old male suffering from BMD with autologous BMMNC transplantation followed by multidisciplinary rehabilitation. He presented with muscle weakness and had difficulty in performing his activities. The BMMNCs were transplanted via intrathecal and intramuscular routes. The effects were measured on clinical and functional changes. Over 9 months, gradual improvement was noticed in muscle strength, respiratory functions and North Star Ambulatory Assessment Scale. Functional Independence Measure, Berg Balance Score, Brooke and Vignos Scale remained stable indicating halting of the progression. The case report suggests that cellular therapy combined with rehabilitation may have possibility of repairing and regenerating muscle fibers and decreasing the rate of progression of BMD.

  5. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

    Science.gov (United States)

    Witting, N; Duno, M; Vissing, J

    2013-01-01

    Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. Copyright © 2012 Elsevier B.V. All rights reserved.

  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. [Two cases of Duchenne muscular dystrophy over 40 years after onset].

    Science.gov (United States)

    Ishizaki, Masatoshi; Ueyama, Hidetsugu; Masuda, Teruaki; Nishida, Yasuto; Imamura, Shigehiro; Ando, Yukio

    2013-01-01

    We report two 45 year old men with Duchenne muscular dystrophy. Case 1 showed a deleted exon 50 of the dystrophin gene by MLPA analysis, and Case 2 showed deleted exons 46-52. Both patients presented with severe weakness of the skeletal muscles and respiratory dysfunction, while cardiac involvement was mild and cognitive function was almost normal. The patients are able to shop at a mall, participate in activities, and attend hobbies, although they are bedridden with artificial respiration through tracheotomy. With the progress of the respiratory care and cardiac protective therapy, the prognosis of Duchenne muscular dystrophy has improved remarkably. At present, it is possible to survive over 40 years with maintenance of quality of life, if cardiac damage is not severe.

  8. CT finding and cerebrospinal fluid proteins in muscular dystrophy patients

    International Nuclear Information System (INIS)

    Hirase, Tsutomu; Ide, Masami; Araki, Shukuro; Okamoto, Hiroshi; Kawasaki, Shoichiro; Imamura, Shigehiro.

    1983-01-01

    We analyzed the microcomponents of protein fractions in the cerebrospinal fluid of patients with various types of muscular dystrophy. The degenerative pattern is characterized by an increase in the prealbumin and a decrease in the γ-globulin fraction is shown in the Duchenne and congenital muscular dystrophy. The increase in CSF IgG, γ-globulin fraction is shown in the myotonic dystrophy. In addition to the abnormality of IQ, EEG, and brain CT, abnormal CSF proteins obviously suggest the presence of CNS involvement in muscular dystrophy. (author)

  9. CT finding and cerebrospinal fluid proteins in muscular dystrophy patients

    Energy Technology Data Exchange (ETDEWEB)

    Hirase, Tsutomu; Ide, Masami; Araki, Shukuro; Okamoto, Hiroshi (Kumamoto Univ. (Japan). School of Medicine); Kawasaki, Shoichiro; Imamura, Shigehiro

    1983-06-01

    We analyzed the microcomponents of protein fractions in the cerebrospinal fluid of patients with various types of muscular dystrophy. The degenerative pattern is characterized by an increase in the prealbumin and a decrease in the ..gamma..-globulin fraction is shown in the Duchenne and congenital muscular dystrophy. The increase in CSF IgG, ..gamma..-globulin fraction is shown in the myotonic dystrophy. In addition to the abnormality of IQ, EEG, and brain CT, abnormal CSF proteins obviously suggest the presence of CNS involvement in muscular dystrophy.

  10. Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies

    OpenAIRE

    Meola, G.

    2013-01-01

    Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP....

  11. Genetics Home Reference: myotonic dystrophy

    Science.gov (United States)

    ... 17 [updated 2015 Oct 22]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

  12. Quantitative analysis of macular retinal thickness and macular volume in diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Ying Zhao

    2017-12-01

    Full Text Available AIM: To evaluate and characterize the macular thickness and macular volume in patients of different stages of diabetic retinopathy with special-domain optical coherence tomography(SD-OCT. METHODS: Totally 40 patients(78 eyeswith diabetic retinopathy were recruited in the study from January 2016 to January 2017 in our hospital. According to the international clinical classification of diabetic retinopathy, 20 cases(40 eyeswere categorized as non-proliferative diabetic retinopathy(NPDRgroup and 20 cases proliferative diabetic retinopathy(PDRgroup(38 eyes. All subjects were examined and analyzed with Early Treatment Diabetic Retinopathy Study(ETDRSsubfields, which were embedded in HS(Haag-Streitwith diameter of 1, 3 and 6mm.The changes of retinal thickness and volume of the macular center were measured. RESULTS: The thickness of macular foveolar in NPDR group and PDR group were 252.57±31.36μm, 362.47±20.81μm. The retinal thickness of inner superior subfield(ISMand inner nasal subfield(INMwere the thickest; that of inner inferior subfield(IIMwas next to ISM and INM, and that of inner temporal subfield was the thinnest. Of the outer subfields, the retinal thickness of outer superior subfield(OSMwas the thickest; that of outer nasal subfield(ONMwas next to OSM, and that of outer temporal subfield(OTMand outer inferior subfield(OIMwas the thinnest. The value of macular central concave thickness and retinal thickness in each quadrant of the NPDR group were less than those of the PDR group, the difference was statistically significant(P3, 0.28±0.16mm3, the upper and nasal sides of the middle part of the partition were the largest, the inferior and the temporal side were the smallest. The nasal side of the outer loop was the largest, the upper was the second, the temporal side and the inferior were the smallest. The volume of macular central fovea and the retinal volume in each quadrant of the NPDR group were smaller than those of the PDR group, the

  13. A splice site mutation in laminin-α2 results in a severe muscular dystrophy and growth abnormalities in zebrafish.

    Directory of Open Access Journals (Sweden)

    Vandana A Gupta

    Full Text Available Congenital muscular dystrophy (CMD is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2. Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.

  14. Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions.

    Science.gov (United States)

    Koenekoop, Robert K; Lopez, Irma; den Hollander, Anneke I; Allikmets, Rando; Cremers, Frans P M

    2007-07-01

    Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently approximately 70% (Stargardt), approximately 60-70% (LCA) and approximately 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As approximately 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation.

  15. Long-term changes of macular retinal thickness after idiopathic macular hole surgery

    Directory of Open Access Journals (Sweden)

    Yan Yang

    2014-12-01

    Full Text Available AIM:To determine the changes of regional macular retinal thickness(RTwith spectral domain optical coherence tomography(SD-OCTafter successful pars plana vitrectomy(PPVsurgery with inner limiting membrane(ILMpeeling in patients with idiopathic macular hole.METHODS:A non-randomized retrospective case study on 17 patients(17 eyeswho were hospitalized between March 1, 2011 and June 30, 2013. All 17 eyes had been diagnosed with idiopathic macular hole and thereafter underwent 25G-PPV surgeries performed by the same surgeon with ILM peeling and short-term gas tamponade. In the 6mo-plus follow-up after surgery, these eyes were found to have successful closure in the macular hole. The macular RT of the nine areas in the Early Treatment Diabetic Retinopathy Study was measured by SD-OCT. All patients were applied by SD-OCT with linear scan of the macular. At least four examinations on the operated eye were conducted in contrast to the other normal eye: before the surgery, 3~5wk after the surgery(stage A, 2~3mo after the surgery(stage B, and >6mo after the surgery(stage C.RESULTS:In stage A, the macular RT of operated eyes in the areas of C, IS, II, IN, OS, OI, ON(263.00±39.48, 313.92±18.35, 311.00±18.02, 335.67±19.91, 280.83±33.74, 269.92±23.32, 307.00±28.40were significantly thicker than the corresponding areas of the normal fellow eyes(220.51±23.94, 292.08±21.93, 282.50±20.30, 288.33±20.76, 251.25±17.60, 247.75±21.48, 265.17±24.76μm(PP>0.01. In Stage B, the macular RT in the areas of II, IN, OS(335.67±19.20,319.75±19.20, 273.50±16.89μmwere significantly thicker than the corresponding areas of the normal fellow eyes(286.33±20.46, 293.42±17.64, 252.50±16.32μm(PP> 0.01. In Stage C, the macular RT of operated eyes with the areas of IN(321.17±19.71μmwere significantly thicker than the corresponding areas of the normal fellow eyes(296.25±19.57μm(PP>0.01. Moreover, the macular RT of operated eyes in the areas of ON, IT(307.00±28

  16. [Human myopathy and animal muscular dystrophy].

    Science.gov (United States)

    Schapira, G; Dreyfus, J C; Schapira, F

    1977-08-01

    Two hereditary muscular dystrophies similar to human progressive muscular dystrophy (P.M.D. Duchenne type) have been isolated in animals, one in mouse, the other in chicken. The decrease in the activity of glycogenolytic enzymes is similar to that observed in denervated muscle. Isozymic fetal types for several muscular enzymes have been observed as well in chicken as in man, but this fetal type may also be found in neurogenic atrophy. The release in circulation of muscle enzymes seems more specific. But the origin of the genetic lesion is still unknown. We describe here the three different theories about this problem: i.e. neurogenic, vascular, or myogenic. This last theory implies a trouble of membrane permeability.

  17. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy

    Science.gov (United States)

    Martin, Elizabeth A.; Barresi, Rita; Byrne, Barry J.; Tsimerinov, Evgeny I.; Scott, Bryan L.; Walker, Ashley E.; Gurudevan, Swaminatha V.; Anene, Francine; Elashoff, Robert M.; Thomas, Gail D.; Victor, Ronald G.

    2013-01-01

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates local α-adrenergic vasoconstriction thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. Here, we report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled cross-over trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation fully restored in the muscles of men with BMD by boosting NO-cGMP signaling with a single dose of the drug tadalafil, a phosphodiesterase (PDE5A) inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD. PMID:23197572

  18. Glycomic analyses of mouse models of congenital muscular dystrophy.

    Science.gov (United States)

    Stalnaker, Stephanie H; Aoki, Kazuhiro; Lim, Jae-Min; Porterfield, Mindy; Liu, Mian; Satz, Jakob S; Buskirk, Sean; Xiong, Yufang; Zhang, Peng; Campbell, Kevin P; Hu, Huaiyu; Live, David; Tiemeyer, Michael; Wells, Lance

    2011-06-17

    Dystroglycanopathies are a subset of congenital muscular dystrophies wherein α-dystroglycan (α-DG) is hypoglycosylated. α-DG is an extensively O-glycosylated extracellular matrix-binding protein and a key component of the dystrophin-glycoprotein complex. Previous studies have shown α-DG to be post-translationally modified by both O-GalNAc- and O-mannose-initiated glycan structures. Mutations in defined or putative glycosyltransferase genes involved in O-mannosylation are associated with a loss of ligand-binding activity of α-DG and are causal for various forms of congenital muscular dystrophy. In this study, we sought to perform glycomic analysis on brain O-linked glycan structures released from proteins of three different knock-out mouse models associated with O-mannosylation (POMGnT1, LARGE (Myd), and DAG1(-/-)). Using mass spectrometry approaches, we were able to identify nine O-mannose-initiated and 25 O-GalNAc-initiated glycan structures in wild-type littermate control mouse brains. Through our analysis, we were able to confirm that POMGnT1 is essential for the extension of all observed O-mannose glycan structures with β1,2-linked GlcNAc. Loss of LARGE expression in the Myd mouse had no observable effect on the O-mannose-initiated glycan structures characterized here. Interestingly, we also determined that similar amounts of O-mannose-initiated glycan structures are present on brain proteins from α-DG-lacking mice (DAG1) compared with wild-type mice, indicating that there must be additional proteins that are O-mannosylated in the mammalian brain. Our findings illustrate that classical β1,2-elongation and β1,6-GlcNAc branching of O-mannose glycan structures are dependent upon the POMGnT1 enzyme and that O-mannosylation is not limited solely to α-DG in the brain.

  19. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.

    Science.gov (United States)

    Martin, Elizabeth A; Barresi, Rita; Byrne, Barry J; Tsimerinov, Evgeny I; Scott, Bryan L; Walker, Ashley E; Gurudevan, Swaminatha V; Anene, Francine; Elashoff, Robert M; Thomas, Gail D; Victor, Ronald G

    2012-11-28

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

  20. Defective myoblasts identified in Duchenne muscular dystrophy.

    OpenAIRE

    Blau, H M; Webster, C; Pavlath, G K

    1983-01-01

    A defect in the proliferative capacity of satellite cells, mononucleated precursors of mature muscle fibers, was found in clonal analyses of cells cultured from Duchenne muscular dystrophy (DMD) patients. The total yield of myoblasts per gram of muscle biopsy was decreased to 5% of normal. Of the DMD myoblast clones obtained, a large proportion contained a morphological class of flat distended cells that had an increased generation time and ceased to proliferate beyond 100-1,000 cells but cou...

  1. 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.

  2. Corneal elastosis within lattice dystrophy lesions.

    Science.gov (United States)

    Pe'er, J; Fine, B S; Dixon, A; Rothberg, D S

    1988-01-01

    Corneal buttons of two patients with lattice corneal dystrophy were studied by light and electron microscopy. They showed elastotic degeneration within the amyloid deposits. The amyloid deposits displayed characteristic staining; the elastotic material (elastin) within the deposits stained positive with Verhoeff-van Gieson and Movat pentachrome stains and showed autofluorescence. The characteristic ultrastructural findings of amyloid and elastotic material were also demonstrated. The possibility of the associations of these two materials in the cornea is discussed. Images PMID:3258531

  3. Disability and Survival in Duchenne Muscular Dystrophy

    OpenAIRE

    Kohler, M; Clarenbach, C F; Bahler, C; Brack, T; Russi, E W; Bloch, K E

    2009-01-01

    BACKGROUND: Duchenne muscular dystrophy (DMD) leads to progressive impairment of muscle function, respiratory failure and premature death. Longitudinal data on the course of physical disability and respiratory function are sparse. OBJECTIVES: To prospectively assess physical impairment and disability, respiratory function and survival in DMD patients over several years in order to describe the course of the disease with current care. METHODS: In 43 patients with DMD, aged 5-35 years, yearly a...

  4. 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.

  5. Management of myocardial damage in muscular dystrophy

    International Nuclear Information System (INIS)

    Tamura, Takuhisa

    2011-01-01

    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. (author)

  6. Macular morphology and visual acuity after macular hole surgery with or without internal limiting membrane peeling

    DEFF Research Database (Denmark)

    Christensen, U.C.; Kroyer, K.; Sander, B.

    2010-01-01

    Aim: To examine postoperative macular morphology and visual outcome after 12 months in relation to internal limiting membrane (ILM) peeling versus no peeling, indocyanine green (ICG) staining and re-operation in eyes that achieved macular hole closure after surgery. Methods: Seventy-four eyes...... with closed stage 2 or 3 macular holes were recruited from a randomised clinical trial comparing: (1) vitrectomy without ILM peeling; (2) vitrectomy with 0.05% isotonic ICG-assisted ILM peeling; and (3) vitrectomy with 0.15% trypan blue-assisted ILM peeling. Contrast-enhanced Stratus optical coherence...... between subgroups. Conclusions: Poor vision after 12 months despite macular hole closure was associated with attenuation and disruption of the foveolar photoreceptor matrix. The extent of attenuation and disruption was independent of peeling and staining....

  7. Age-related macular degeneration.

    Science.gov (United States)

    Cheung, Lily K; Eaton, Angie

    2013-08-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the prevalence of the disease increases exponentially with every decade after age 50 years. It is a multifactorial disease involving a complex interplay of genetic, environmental, metabolic, and functional factors. Besides smoking, hypertension, obesity, and certain dietary habits, a growing body of evidence indicates that inflammation and the immune system may play a key role in the development of the disease. AMD may progress from the early form to the intermediate form and then to the advanced form, where two subtypes exist: the nonneovascular (dry) type and the neovascular (wet) type. The results from the Age-Related Eye Disease Study have shown that for the nonneovascular type of AMD, supplementation with high-dose antioxidants (vitamin C, vitamin E, and β-carotene) and zinc is recommended for those with the intermediate form of AMD in one or both eyes or with advanced AMD or vision loss due to AMD in one eye. As for the neovascular type of the advanced AMD, the current standard of therapy is intravitreal injections of vascular endothelial growth factor inhibitors. In addition, lifestyle and dietary modifications including improved physical activity, reduced daily sodium intake, and reduced intake of solid fats, added sugars, cholesterol, and refined grain foods are recommended. To date, no study has demonstrated that AMD can be cured or effectively prevented. Clearly, more research is needed to fully understand the pathophysiology as well as to develop prevention and treatment strategies for this devastating disease. © 2013 Pharmacotherapy Publications, Inc.

  8. CLOSING MACULAR HOLES WITH "MACULAR PLUG" WITHOUT GAS TAMPONADE AND POSTOPERATIVE POSTURING.

    Science.gov (United States)

    Chakrabarti, Meena; Benjamin, Preethi; Chakrabarti, Keya; Chakrabarti, Arup

    2017-03-01

    To investigate the surgical results of macular hole surgery without gas tamponade or postoperative posturing in patients with Stage 3 and Stage 4 macular holes with ≥500 μm mean base diameter. Retrospective interventional case series. Twenty-six patients with Stage 3 and Stage 4 macular holes. Twenty-six eyes of 26 patients with Stage 3 and Stage 4 macular holes and a mean base diameter of 892.8 ± 349 μm underwent pars plana 23-gauge vitrectomy with broad internal limiting membrane peel (ILM peel), inverted ILM flap repositioning (ILMR), and use of autologous gluconated blood clumps as a macular plug to close the macular hole. No fluid-air exchange, endotamponade, or postoperative posturing was used. The subjects were followed up for 12 months. The anatomical outcome of the procedure was evaluated by fundus examination and optical coherence tomography. Spectral domain optical coherence tomography was used to study the restoration of the outer retinal layer integrity in the postoperative period. The preoperative and postoperative best-corrected visual acuities in logMAR units were compared to evaluate functional outcome. Macular hole closure and best-corrected visual acuity before and after surgery. Twenty-six patients with mean age 62.8 ± 7.3 years, preoperative median best-corrected visual acuity 6/60 (1.0 logMAR units), and a mean base diameter of 892.8 ± 349 μm underwent surgery to close macular holes without gas tamponade or postoperative posturing. Twenty patients (76.9%) were phakic. Twenty eyes (76.92%) had Stage 3 macular holes and 6 eyes (23.10%) had Stage 4 macular holes. After a single surgery, hole closure was achieved in 100% of eyes. The median best-corrected visual acuity improved from 6/60 (1.0 logMAR units) to 6/18 (0.50 logMAR units) (P hole closure with statically significant functional improvement for large Stage 3 and Stage 4 macular holes.

  9. Familial trends in a population with macular holes.

    Science.gov (United States)

    Kay, Christine Nichols; Pavan, Peter Reed; Small, Laurie Buccina; Zhang, Tao; Zamba, Gideon K D; Cohen, Steven Myles

    2012-04-01

    To determine if patients with macular hole report an increased family history of macular hole compared with control patients and compare the report of family history between patients with unilateral and bilateral macular holes. This was a multicenter case-control study. Charts of patients coded with diagnosis of macular hole were reviewed, and the diagnosis of idiopathic full-thickness macular hole was ascertained in 166 patients. The control group comprised 136 patients without macular hole or trauma who presented with senile cataract. Family history was obtained from all patients through a telephone interview. Six of 166 (3.6%) macular hole patients surveyed reported a history of macular hole in a primary relative compared with none of 136 (0.0%) control patients (odds ratio is infinity, with 95% confidence interval 1.295 to infinity); however, this finding may be explained by confounders such as age and number of family members. Two of the 142 (1.4%) patients with unilateral holes versus 4 of the 24 (16.7%) patients with bilateral holes reported a family history (odds ratio is 0.0714, with 95% confidence interval 0.0063 to 0.5537), and this finding remains significant when logistic regression is performed to evaluate variables of age and number of family members as potential confounders. There is an increased report of familial occurrence of macular hole in patients with macular holes compared with control patients; however, logistic regression relates this finding to variables of age and number of family members. Patients with bilateral macular holes are more likely to report a family history of macular hole than patients with unilateral macular holes, and this finding remains significant in the presence of age and number of family members. These findings may suggest a familial component to macular hole.

  10. Internal limiting membrane flap transposition for surgical repair of macular holes in primary surgery and in persistent macular holes.

    Science.gov (United States)

    Leisser, Christoph; Hirnschall, Nino; Döller, Birgit; Varsits, Ralph; Ullrich, Marlies; Kefer, Katharina; Findl, Oliver

    2018-03-01

    Classical or temporal internal limiting membrane (ILM) flap transposition with air or gas tamponade are current trends with the potential to improve surgical results, especially in cases with large macular holes. A prospective case series included patients with idiopathic macular holes or persistent macular holes after 23-G pars plana vitrectomy (PPV) and ILM peeling with gas tamponade. In all patients, 23-G PPV and ILM peeling with ILM flap transposition with gas tamponade and postoperative face-down position was performed. In 7 of 9 eyes, temporal ILM flap transposition combined with pedicle ILM flap could be successfully performed and macular holes were closed in all eyes after surgery. The remaining 2 eyes were converted to pedicle ILM flap transposition with macular hole closure after surgery. Three eyes were scheduled as pedicle ILM flap transposition due to previous ILM peeling. In 2 of these eyes, the macular hole could be closed with pedicle ILM flap transposition. In 3 eyes, free ILM flap transposition was performed and in 2 of these eyes macular hole could be closed after surgery, whereas in 1 eye a second surgery, performed as pedicle ILM flap transposition, was performed and led to successful macular hole closure. Use of ILM flaps in surgical repair of macular hole surgery is a new option of treatment with excellent results independent of the diameter of macular holes. For patients with persistent macular holes, pedicle ILM flap transposition or free ILM flap transposition are surgical options.

  11. Assessment of Macular Function during Vitrectomy: New Approach Using Intraoperative Focal Macular Electroretinograms.

    Directory of Open Access Journals (Sweden)

    Celso Soiti Matsumoto

    Full Text Available To describe a new technique to record focal macular electroretinograms (FMERGs during vitrectomy to assess macular function.Intraoperative FMERGs (iFMERGs were recorded in ten patients (10 eyes who undergo vitrectomy. iFMERGs were elicited by focal macular stimulation. The stimulus light was directed to the macular area through a 25 gauge (25G glass fiber optic bundle. Background light was delivered through a dual chandelier-type light fiber probe. Focal macular responses elicited with combinations of stimulus and background luminances were analyzed.A stimulus luminance that was approximately 1.75 log units brighter than the background light was able to elicit focal macular responses that were not contaminated by stray light responses. Thus, a stimulus luminance of 160 cd/m2 delivered on a background of 3 cd/m2 elicited iFMEGs from only the stimulated area. This combination of stimulus and background luminances did not elicit a response when the stimulus was projected onto the optic nerve head. The iFMERGs elicited by a 10° stimulus with a duration of 100 ms and an interstimulus interval of 150 ms consisted of an a-, b-, and d-waves, the oscillatory potentials, and the photopic negative response (PhNR.Focal ERGs with all components can be recorded from the macula and other retinal areas during vitreous surgery. This new technique will allow surgeons to assess the function of focal areas of the retina intraoperatively.

  12. 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.

  13. Upper limb function in adults with Duchenne muscular dystrophy

    NARCIS (Netherlands)

    B. Bartels (Bart); R.F. Pangalila (Robert); M.P. Bergen (Michael); N.A.M. Cobben (Nicolle); H.J. Stam (Henk); M.E. Roebroeck (Marij)

    2011-01-01

    textabstractTo determine upper limb function and associated factors in adults with Duchenne muscular dystrophy. Design: Cross-sectional study. Subjects: A sample of 70 men with Duchenne muscular dystrophy (age range 20-43 years). Methods: General motor function and, in particular, upper limb distal

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

    NARCIS (Netherlands)

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

    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

  15. Further delineation of spondylometaphyseal dysplasia with cone-rod dystrophy

    NARCIS (Netherlands)

    Sousa, Sérgio B.; Russell-Eggitt, Isabelle; Hall, Christine; Hall, Bryan D.; Hennekam, Raoul C. M.

    2008-01-01

    There are several entities that combine a skeletal dysplasia with a retinal dystrophy. Recently, another possibly autosomal recessive entity was added to this group characterized by a specific spondylometaphyseal dysplasia and a cone-rod dystrophy, without other significant impairments. The entity

  16. [Ocular findings in patients with Steinert myotonic dystrophy].

    Science.gov (United States)

    Markowska, Elzbieta; Zalewska, Renata; Mariak, Zofia; Wojnar, Małgorzata

    2006-01-01

    The authors present one of many myotonic dystrophies: Steinert myotonic dystrophy (Steinert disease), which is a disease occuring seldom, and causing a lot of problems during the diagnostic and treatment process. Genetic factors, results of the histopathology tests, main clinical symptoms, particularly ophtalmic manifestation are described in this article.

  17. Central areolar choroidal dystrophy with associated dominant drusen

    Directory of Open Access Journals (Sweden)

    Julie Rodman

    2013-04-01

    Conclusion: Central areolar choroidal dystrophy normally presents without drusen. However, in patients manifesting a specific mutation, central areolar choridal dystrophy may present in conjunction with drusen. It appears that the Arg142Trp mutation is one of the factors predisposing to drusen formation.

  18. 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)....

  19. Bilateral Simultaneous Macular Infarction with Spontaneous Visual ...

    African Journals Online (AJOL)

    To report the rare and dramatic event of bilateral macular infarction in a sickle cell hemoglobinopathy (SS genotype) patient, resulting in bilateral severe reduction in visual acuity. Without any intervention, the patient's vision gradually improved over the follow‑up period. Central visual field defects however persisted.

  20. Driving and Age-Related Macular Degeneration

    OpenAIRE

    Owsley, Cynthia; McGwin, Gerald

    2008-01-01

    This article reviews the research literature on driving and age-related macular degeneration, which is motivated by the link between driving and the quality of life of older adults and their increased collision rate. It addresses the risk of crashes, driving performance, driving difficulty, self-regulation, and interventions to enhance, safety, and considers directions for future research.

  1. Current status in diabetic macular edema treatments

    Institute of Scientific and Technical Information of China (English)

    Pedro; Romero-Aroca

    2013-01-01

    Diabetes is a serious chronic condition,which increase the risk of cardiovascular diseases,kidney failure and nerve damage leading to amputation.Furthermore the ocular complications include diabetic macular edema,is the leading cause of blindness among adults in the industrialized countries.Today,blindness from diabetic macular edema is largely preventable with timely detection and appropriate interventional therapy.The treatment should include an optimized control of glycemia,arterial tension,lipids and renal status.The photocoagulation laser is currently restricted to focal macular edema in some countries,but due the high cost of intravitreal drugs,the use of laser treatment for focal and diffuse diabetic macular edema(DME),can be valid as gold standard in many countries.The intravitreal anti vascular endothelial growth factor drugs(ranibizumab and bevacizumab),are indicated in the treatment of all types of DME,but the correct protocol for administration should be defined for the different Retina Scientific Societies.The corticosteroids for diffuse DME,has a place in pseudophakic patients,but its complications restricted the use of these drugs for some patients.Finally the intravitreal interface plays an important role and its exploration is mandatory in all DME patients.

  2. Macular thickness and volume in the elderly

    DEFF Research Database (Denmark)

    Subhi, Yousif; Forshaw, Thomas; Sørensen, Torben Lykke

    2016-01-01

    manifests in the macula of the elderly focusing on clinical relevant measures that are thicknesses and volumes of different macular areas. Ageing seems to increase center point foveal thickness. Ageing does not seem to change the center subfield thickness significantly. Ageing decreases the inner and outer...

  3. Correlation between choroidal thickness and macular hole

    Directory of Open Access Journals (Sweden)

    Li-Li Wang

    2018-01-01

    Full Text Available AIM:To explore the correlation between choroidal thickness and macular hole, and to provide a theoretical basis for diagnosis and treatment of macular hole. METHODS: This study included 40 cases of monocular idiopathic macular hole patients who were treated in ophthalmology of our hospital from June 2015 to June 2016 and 40 cases of healthy people. Sicked eyes of idiopathic macular hole patients(40 eyeswere set as the Group A, uninjured side eyes(40 eyeswere set as the Group B, eyes of 40 cases of healthy people(40 normal eyeswere set as the Group C. Choroidal thickness of macular fovea, macular fovea 1mm, 3mm at 9 points, 4 directions in the upper, lower, nasal and temporal regions were measured through coherent optical tomography of enhanced deep imaging(enhanced depth image optical coherence tomography, EDI-OCT. They were recorded as SFCT, SCT1mm, SCT3mm, ICT1mm, ICT3mm, NCT1mm, NCT3mm, TCT1mm, TCT3mm, and correlation analysis between SFCT and age was analyzed. RESULTS: Average SFCT of Group A, B had no significant difference, data of the Group C was significantly higher than those of the Group A, B, there was statistical significance(P1mm, SCT3mm, ICT1mm, ICT3mm, NCT1mm, NCT3mm, TCT1mm, TCT3mm of the Group A, B had no significant difference(P>0.05, and choroidal thickness at each point of the Group C was significantly higher than that of Group A and B, there was statistical significance(Pr=-0.065, P=0.148; r=-0.057, P=0.658, SFCT of the Group C was negatively correlated with age(r=-0.343, P=0.041. CONCLUSION: The pathogenesis of idiopathic macular hole may be related to the sharp decrease of choroidal thickness, choroidal thickness of uninjured side eyes reduces more sharply than normal population and choroidal vascular metabolism reduces may be pathogenic.

  4. Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

    Science.gov (United States)

    Hightower, Rylie M; Alexander, Matthew S

    2018-01-01

    Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. © 2017 Wiley Periodicals, Inc.

  5. The Intravitreal Autologous Platelet Concentrate Injection as an Adjunct of Vitrectomy for the Treatment of Refractory Macular Holes

    Science.gov (United States)

    2014-03-06

    Macular Hole With High Myopia (Spherical Equivalent ≤ -6.0 Diopters) or,; Large Size Macular Hole (Diameter > 600 Microns) or; Recurred or Failed Macular Hole From Previous Surgery; or Chronic Macular Hole (Symptom Duration > 6 Months)

  6. 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.

  7. A comparison of swallowing dysfunction in Becker muscular dystrophy and Duchenne muscular dystrophy.

    Science.gov (United States)

    Yamada, Yuka; Kawakami, Michiyuki; Wada, Ayako; Otsuka, Tomoyoshi; Muraoka, Kaori; Liu, Meigen

    2018-06-01

    Swallowing dysfunction has been reported in Duchenne muscular dystrophy (DMD), but has not been studied in Becker muscular dystrophy (BMD). The aims of this study were to report the characteristics of swallowing dysfunction in BMD compared with DMD. The study participants were 18 patients with BMD and 18 patients with DMD. All the patients were examined using videofluorography during swallowing of 5 mL of fluid. The penetration-aspiration scale (P-A scale) and the videofluorographic dysphagia scale (VDS) were used to evaluate dysphagia. Swinyard functional ability stage was not significantly different between the BMD and DMD groups. Rate of aspiration, P-A scale score, and total VDS score did not differ across groups, but the VDS item score for laryngeal elevation was lower in the BMD group than in the DMD group (median scores 4.5 and 9, respectively; p Becker muscular dystrophy (BMD) was not well known. Eighteen patients with BMD and 18 patients with Duchenne muscular dystrophy were examined with videofluorography. Patients with BMD have swallowing problems similar to those observed in patients with DMD.

  8. 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

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

    NARCIS (Netherlands)

    Hoogerwaard, E. M.; Bakker, E.; Ippel, P. F.; Oosterwijk, J. C.; Majoor-Krakauer, D. F.; Leschot, N. J.; van Essen, A. J.; Brunner, H. G.; van der Wouw, P. A.; Wilde, A. A.; 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

  10. Psychiatric disorders appear equally in patients with myotonic dystrophy, facioscapulohumeral dystrophy, and hereditary motor and sensory neuropathy type I.

    NARCIS (Netherlands)

    Kalkman, J.S.; Schillings, M.L.; Zwarts, M.J.; Engelen, B.G.M. van; Bleijenberg, G.

    2007-01-01

    OBJECTIVES: To study the presence of psychiatric comorbidity assessed by the use of a structured clinical interview and self-reported questionnaires in a large sample of patients with adult-onset myotonic dystrophy (DM), facioscapulohumeral muscular dystrophy (FSHD), and hereditary motor and sensory

  11. Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy

    Directory of Open Access Journals (Sweden)

    Hong-Hao Yu

    2016-10-01

    Full Text Available Dystrophinopathy, including Duchenne muscle dystrophy (DMD and Becker muscle dystrophy (BMD is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD. Two piglets were obtained after embryo transfer, one of piglets was identified as DMD-modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD-modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD-modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig.

  12. Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation

    NARCIS (Netherlands)

    Koss-Harnes, D; Hoyheim, B; Jonkman, MF; De Groot, WP; De Weerdt, CJ; Nikolic, B; Wiche, G; Gedde-Dahl, T

    Plectin is one of the largest and most versatile cytolinker proteins known. Cloned and sequenced in 1991, it was later shown to have nonsense mutations in recessive epidermolysis bullosa with muscular dystrophy. A dominant mutation in the gene was found to cause epidermolysis bullosa simplex Ogna

  13. A neonate with congenital myotonic dystrophy

    International Nuclear Information System (INIS)

    Itani, Yasufumi; Anbo, Kazutoshi; Kashiwagi, Sigeru; Yokoya, Susumu; Kato, Kazuo

    1984-01-01

    A boy's neonate with congenital myotonic dystrophy who had difficulty in breathing immediately after birth was reported. A long-term management for artificial breathing was required because of a marked decrease of muscular tone, equinus and the difficulty in sucking milk. Myogenic pattern was seen on EMG and atrophied type I fibers and increased number of type 2 C fibers suggesting the prolongation of differentiation of muscle fibers were seen by muscle biopsy. Cranial CT revealed a marked atrophy of the cerebral cortex and low density area in the white matter, although the latter disappeared 4 months later. (Namekawa, K.)

  14. The golden retriever model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N

    2017-05-19

    Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about

  15. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment......ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment...

  16. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment......ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment...

  17. Survey of Canadian Myotonic Dystrophy Patients' Access to Computer Technology.

    Science.gov (United States)

    Climans, Seth A; Piechowicz, Christine; Koopman, Wilma J; Venance, Shannon L

    2017-09-01

    Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.

  18. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Tai-Chi Lin

    2015-11-01

    Full Text Available Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

  19. Recent advances in treatment of wet age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Ming Li

    2015-02-01

    Full Text Available Age-related macular degeneration(AMDis one of the important eye diseases of the WHO present three big blindness, is one of the main blinding eye disease in people over the age of 50, people over the age of 65, about 2% of the disease caused by monocular blindness, as the population ages, AMD prevalence is increasing in our country. AMD with respect to its clinical manifestations can be divided into dry AMD and wet AMD, wet AMD is the most harmful for the vision of patients, at present there are many treatments for AMD(mainly for wet age-related macular degeneration, mainly including laser treatment, drug therapy, surgical treatment, gene therapy,etc. The treatments of AMD would be illuminated in this article.

  20. Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice

    DEFF Research Database (Denmark)

    Guo, L T; Zhang, X U; Kuang, W

    2003-01-01

    2, lacking domain VI. Interestingly, all mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter......Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal...

  1. Cytogenetic analysis and response to ionizing radiations in a girl with severe muscular dystrophy

    International Nuclear Information System (INIS)

    Meola, G.; Barsi, L.; Velicogna, M.; Scarlato, G.; Fuhrman-Conti, A.M.

    1988-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked condition characterized by a progressive degeneration of skeletal muscle. Mild clinical symptoms have been reported in female carriers of the DMD gene with normal karyotypes, this occurs in about 8% of DMD carriers. The degree of manifestation ranges from pseudohypertrophy of the calf muscles to moderate myopathy with proximal muscle wasting and weakness. Such manifestations can be explained on the basis of preferential inactivation of the X chromosome bearing the normal allele. The authors describe the cytogenetic analysis and the response to ionizing radiations in a severely affected girl exhibiting clinical, neurophysiological, biochemical, and histological findings of DMD

  2. Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

    LENUS (Irish Health Repository)

    Walsh, Richard

    2012-02-01

    Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.

  3. 100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Yongping Yue

    2016-01-01

    Full Text Available Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity.

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

    International Nuclear Information System (INIS)

    Yoo, Jeong Hyun; Kim, Yoo Kyung; Koo, Hae Soo; Park, Ki Deuk

    2000-01-01

    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

  5. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    Science.gov (United States)

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  6. Clinical and tomographic aspects of macular microholes

    International Nuclear Information System (INIS)

    Novelli, Fernando Jose de; Maia Junior, Otacilio de Oliveira; Garrido Neto, Theodomiro; Takahashi, Walter Yukihiko

    2009-01-01

    Purpose: To describe the clinical aspects and evaluate optical coherence tomography of macular microholes. Methods: Seven patients were assessed (8 eyes) with microholes of the macula. All patients underwent complete eye examination, fundus photography, fluorescent angiography and OCT-3 imaging. Results: Ages ranged from 26 to 69 years. Six patients were female (85.7%) and five of them had microhole in the right eye. The presenting symptom was decrease in visual acuity (71.3%) and central scotoma in (14.3%). Five eyes (71.4%) had no defects shown by fluorescent angiography. A defect in the outer retina was demonstrated in all eyes on optical coherence tomography. The lesions were nonprogressive. Conclusion: Macular microholes are small lamellar defects in the outer retina. The condition is nonprogressive, generally unilateral and compatible with good visual acuity. Fundus biomicroscopy associated with an optical coherence tomography are the main elements in the diagnosis and study of this pathology. (author)

  7. Sleep disturbances in myotonic dystrophy type 2.

    Science.gov (United States)

    Shepard, Paul; Lam, Erek M; St Louis, Erik K; Dominik, Jacob

    2012-01-01

    Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep-disordered breathing, hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (5 women, 3 men) with DM2 were identified. Excessive daytime sleepiness was seen in 6 patients (75%), insomnia in 5 (62.5%), and excessive fatigue in 4 (50%). Obstructive sleep apnea was diagnosed in 3 of 5 patients (60%) studied with PSG. Respiratory muscle weakness was present in all 6 patients (100%) who received pulmonary function testing. Four of 8 (50%) met criteria for diagnosis of restless legs syndrome. The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2. Copyright © 2012 S. Karger AG, Basel.

  8. 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.)

  9. Myotonic Dystrophy Type 1 Management and Therapeutics.

    Science.gov (United States)

    Smith, Cheryl A; Gutmann, Laurie

    2016-12-01

    Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy. It is a multisystem disorder with a complex pathophysiology. Although inheritance is autosomal dominant, disease variability is attributed to anticipation, a maternal expansion bias, variable penetrance, somatic mosaicism, and a multitude of aberrant pre-mRNA splicing events. Patient presentations range from asymptomatic or mild late onset adult to severe congenital forms. Multiple organ systems may be affected. Patients may experience early cataracts, myotonia, muscle weakness/atrophy, fatigue, excessive daytime sleepiness, central/obstructive apnea, respiratory failure, cardiac arrhythmia, insulin resistance, dysphagia, GI dysmotility, cognitive impairment, Cluster C personality traits, and/or mood disorders. At present, there is no curative or disease-modifying treatment, although clinical treatment trials have become more promising. Management focuses on genetic counseling, preserving function and independence, preventing cardiopulmonary complications, and symptomatic treatment (e.g., pain, myotonia, hypersomnolence, etc.). Currently, there is an increasing international consensus on monitoring and treatment options for these patients which necessitates a multidisciplinary team to provide comprehensive, coordinated clinical care.

  10. Genetic diagnosis of Duchenne and Becker muscular dystrophy using next-generation sequencing technology: comprehensive mutational search in a single platform.

    Science.gov (United States)

    Lim, Byung Chan; Lee, Seungbok; Shin, Jong-Yeon; Kim, Jong-Il; Hwang, Hee; Kim, Ki Joong; Hwang, Yong Seung; Seo, Jeong-Sun; Chae, Jong Hee

    2011-11-01

    Duchenne muscular dystrophy or Becker muscular dystrophy might be a suitable candidate disease for application of next-generation sequencing in the genetic diagnosis because the complex mutational spectrum and the large size of the dystrophin gene require two or more analytical methods and have a high cost. The authors tested whether large deletions/duplications or small mutations, such as point mutations or short insertions/deletions of the dystrophin gene, could be predicted accurately in a single platform using next-generation sequencing technology. A custom solution-based target enrichment kit was designed to capture whole genomic regions of the dystrophin gene and other muscular-dystrophy-related genes. A multiplexing strategy, wherein four differently bar-coded samples were captured and sequenced together in a single lane of the Illumina Genome Analyser, was applied. The study subjects were 25 16 with deficient dystrophin expression without a large deletion/duplication and 9 with a known large deletion/duplication. Nearly 100% of the exonic region of the dystrophin gene was covered by at least eight reads with a mean read depth of 107. Pathogenic small mutations were identified in 15 of the 16 patients without a large deletion/duplication. Using these 16 patients as the standard, the authors' method accurately predicted the deleted or duplicated exons in the 9 patients with known mutations. Inclusion of non-coding regions and paired-end sequence analysis enabled accurate identification by increasing the read depth and providing information about the breakpoint junction. The current method has an advantage for the genetic diagnosis of Duchenne muscular dystrophy and Becker muscular dystrophy wherein a comprehensive mutational search may be feasible using a single platform.

  11. Primary treatment of diabetic macular edema

    OpenAIRE

    Ranchod, Tushar; Fine,Stuart

    2009-01-01

    Tushar M Ranchod, Stuart L FineScheie Eye Institute, Department, of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USAAbstract: Diabetic macular edema (DME) is a leading cause of vision loss in older Americans. Thermal laser treatment remains the mainstay of treatment for DME. Recently, alternative primary treatments for DME have been evaluated. These treatments include intravitreal injections of steroids as well as pharmaceuticals containing antibodies against vascular endothel...

  12. Immunology of age-related macular degeneration

    Science.gov (United States)

    Ambati, Jayakrishna; Atkinson, John P.; Gelfand, Bradley D.

    2014-01-01

    Age-related macular degeneration (AMD) is a leading cause of blindness in aged individuals. Recent advances have highlighted the essential role of immune processes in the development, progression and treatment of AMD. In this Review we discuss recent discoveries related to the immunological aspects of AMD pathogenesis. We outline the diverse immune cell types, inflammatory activators and pathways that are involved. Finally, we discuss the future of inflammation-directed therapeutics to treat AMD in the growing aged population. PMID:23702979

  13. LONG-TERM EVOLUTION OF DOME-SHAPED MACULA: Increased Macular Bulge is Associated With Extended Macular Atrophy.

    Science.gov (United States)

    Soudier, Guillaume; Gaudric, Alain; Gualino, Vincent; Massin, Pascale; Nardin, Mathieu; Tadayoni, Ramin; Speeg-Schatz, Claude; Gaucher, David

    2016-05-01

    Dome-shaped macula (DSM) may cause impaired vision. This study analyzed the long-term evolution of DSM, most particularly macular changes: serous retinal detachment, retinal pigment epithelium atrophy, and DSM bulge increase. Twenty-nine eyes presenting with DSM were retrospectively studied. Clinical data, color photographs, fluorescein angiographs, and optical coherence tomography examinations were reviewed. Patients were followed up from 6 months to 111 months (mean, 37.89 months). The height of the macular bulge, the size of retinal pigment epithelium macular atrophy, and serous retinal detachment progression were studied. Other macular changes were noted. Mean vision remained stable. Dome-shaped macula height increased significantly from 338.9 μm to 364.3 μm (P = 0.007). Serous retinal detachment was present initially in 15 of 29 eyes; it increased in 4 cases and resolved spontaneously in 7. Macular retinal pigment epithelium atrophy correlated with the bulge height (P = 0.015), and it enlarged during follow-up (1.12 vs. 1.34, P = 0.04). Other macular anomalies were present initially or appeared during follow-up: macular pucker, choroidal neovascularization (CNV), subretinal pigmentary clumps, and flat irregular pigmented epithelium detachment. A few treatments were proven in serous retinal detachment cases but were ineffective in restoring vision. In DSM, vision may be stable for years while macular changes progress: the macular bulge increases as does retinal pigment epithelium atrophy.

  14. INDUCTION OF MACULAR DETACHMENT FOR THE TREATMENT OF PERSISTENT OR RECURRENT IDIOPATHIC MACULAR HOLES.

    Science.gov (United States)

    Szigiato, Andrei-Alexandru; Gilani, Fatimah; Walsh, Mark K; Mandelcorn, Efrem D; Muni, Rajeev H

    2016-09-01

    To analyze the efficacy of induced macular detachment for the treatment of persistent or recurrent idiopathic macular holes after treatment with one or more standard pars plana vitrectomies (PPVs) with internal limiting membrane peeling. This study is a retrospective consecutive case series of 10 patients who underwent a PPV with subretinal balanced salt solution injection from 2011 to 2014 to treat persistent or recurrent idiopathic macular holes. All patients had previously undergone PPV with internal limiting membrane peeling. Visual acuity, ocular examination findings, and optical coherence tomographic images were reviewed preoperatively and postoperatively to assess the anatomical and visual outcomes of this procedure. Nine of the 10 patients who underwent the procedure had closure of their macular holes postoperatively (90%) and remained closed 6 months postoperatively. Most patients reported a subjective visual improvement. A mean objective visual improvement of 16 letters (Early Treatment Diabetic Retinopathy Study, 0.324 logMAR) was seen between preoperative and 6-month postoperative assessments of all patients (pre = 1.490, post = 1.166; P = 0.022). Subgroup analysis of patients with successful closure revealed 20 letters of improvement (0.398 logMAR) in visual acuity (pre = 1.491, post = 1.093; P = 0.004). There were no intraoperative or postoperative complications. In eyes with persistent or recurrent idiopathic macular holes after standard PPV with internal limiting membrane peeling, repeat PPV with subretinal balanced salt solution injection to create a macular detachment may be a viable surgical treatment option. Our results show improved anatomical and visual outcomes postoperatively that compare favorably to other case series describing various surgical treatments for these challenging cases.

  15. Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.

    Science.gov (United States)

    Takeshita, Eri; Minami, Narihiro; Minami, Kumiko; Suzuki, Mikiya; Awashima, Takeya; Ishiyama, Akihiko; Komaki, Hirofumi; Nishino, Ichizo; Sasaki, Masayuki

    2017-06-01

    Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Serum creatinine level: a supplemental index to distinguish Duchenne muscular dystrophy from Becker muscular dystrophy.

    Science.gov (United States)

    Zhang, Huili; Zhu, Yuling; Sun, Yiming; Liang, Yingyin; Li, Yaqin; Zhang, Yu; Deng, Langhui; Wen, Xingxuan; Zhang, Cheng

    2015-01-01

    To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn) level reflects disease severity. Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy. 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 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). Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.

  17. Guidelines for the Perianesthesia Care of the Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Patient.

    Science.gov (United States)

    Alliod, Barbara A; Ash, Rebecca A

    2016-12-01

    More patients suffering with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are presenting to perianesthesia settings for emergent and nonemergent treatment and care. A group of collaborative health care providers at Rush University Medical Center in Chicago developed a multidisciplinary DMD/BMD Task Force to study this disorder and create a set of guidelines to aid those engaging in the planning, execution of care, and recovery of this unique population in the perianesthesia setting. Attention to detail, well-executed preplanning, meticulous awareness of the patient, and prearranged implementation and intervention has proven to offset potential problems and complications and is the key to a successful perianesthesia period. Copyright © 2016 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

  18. Red-Green Color Vision Impairment in Duchenne Muscular Dystrophy

    Science.gov (United States)

    Costa, Marcelo Fernandes ; Oliveira, Andre Gustavo Fernandes ; Feitosa-Santana, Claudia ; Zatz, Mayana ; Ventura, Dora Fix 

    2007-01-01

    The present study evaluated the color vision of 44 patients with Duchenne muscular dystrophy (DMD) (mean age 14.8 years; SD 4.9) who were submitted to a battery of four different color tests: Cambridge Colour Test (CCT), Neitz Anomaloscope, Ishihara, and American Optical Hardy-Rand-Rittler (AO H-R-R). Patients were divided into two groups according to the region of deletion in the dystrophin gene: upstream of exon 30 (n=12) and downstream of exon 30 (n=32). The control group was composed of 70 age-matched healthy male subjects with no ophthalmological complaints. Of the patients with DMD, 47% (21/44) had a red-green color vision defect in the CCT, confirmed by the Neitz Anomaloscope with statistical agreement (P.05). Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with a red-green defect was significantly higher than the expected <10% for the normal male population (P<.001). In contrast, patients with DMD with deletion upstream of exon 30 had normal color vision. This color defect might be partially explained by a retina impairment related to dystrophin isoform Dp260. PMID:17503325

  19. Vascular-targeted therapies for Duchenne muscular dystrophy

    Science.gov (United States)

    2013-01-01

    Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy

  20. Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy

    NARCIS (Netherlands)

    Hoogerwaard, Edo M.; Ginjaar, Ieke B.; Bakker, Egbert; de Visser, Marianne

    2005-01-01

    Associations between clinical phenotype (muscle weakness, dilated cardiomyopathy) and dystrophin abnormalities in muscle tissue among definite carriers of Duchenne (DMD) and Becker muscular dystrophy (BMD) were investigated. No associations between dystrophin abnormalities and clinical variables in

  1. A new chart for weight control in Duchenne muscular dystrophy.

    OpenAIRE

    Griffiths, R D; Edwards, R H

    1988-01-01

    Weight control is desirable in the muscle wasting conditions. A new chart is presented to allow the prediction of an ideal weight, free of excess fat, specifically for boys with Duchenne muscular dystrophy.

  2. Nonmuscular involvement in merosin-negative congenital muscular dystrophy.

    NARCIS (Netherlands)

    Gilhuis, H.J.; Donkelaar, H.J. ten; Tanke, R.B.; Vingerhoets, D.M.; Zwarts, M.J.; Verrips, A.; Gabreëls, F.J.M.

    2002-01-01

    The spectrum of nonmuscular involvement in six children with merosin-negative congenital muscular dystrophy is described. In all children, biochemical, neuroradiologic, cardiac, and neurophysiologic studies were performed. Cerebral structures that were myelinated at gestation, including internal

  3. How Physicians Support Mothers of Children with Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Fujino, Haruo; Saito, Toshio; Matsumura, Tsuyoshi; Shibata, Saki; Iwata, Yuko; Fujimura, Harutoshi; Shinno, Susumu; Imura, Osamu

    2015-09-01

    Communicating about Duchenne muscular dystrophy and its prognosis can be difficult for affected children and their family. We focused on how physicians provide support to the mothers of children with Duchenne muscular dystrophy who have difficulty communicating about the condition with their child. The eligible participants were certified child neurologists of the Japanese Society of Child Neurology. Participants responded to questionnaires consisting of free descriptions of a vignette of a child with Duchenne muscular dystrophy and a mother. We analyzed 263 responses of the participants. We found 4 themes on advising mothers, involving encouraging communication, family autonomy, supporting family, and considering the child's concerns. These results provide a better understanding of the communication between physicians and family members who need help sharing information with a child with Duchenne muscular dystrophy. These findings will assist clinical practitioners in supporting families and the affected children throughout the course of their illness. © The Author(s) 2015.

  4. Predictive factors for masticatory performance in Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Bruggen, H.W. van; Engel-Hoek, L. van den; Steenks, M.H.; Bronkhorst, E.M.; Creugers, N.H.; Groot, I.J.M. de; Kalaykova, S.

    2014-01-01

    Patients with Duchenne muscular dystrophy (DMD) report masticatory and swallowing problems. Such problems may cause complications such as choking, and feeling of food sticking in the throat. We investigated whether masticatory performance in DMD is objectively impaired, and explored predictive

  5. 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

  6. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.

    Science.gov (United States)

    Vulin, Adeline; Barthélémy, Inès; Goyenvalle, Aurélie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maëva; Unterfinger, Yves; Lorain, Stéphanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stéphane; Garcia, Luis

    2012-11-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.

  7. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

    Science.gov (United States)

    Finder, Jonathan; Mayer, Oscar Henry; Sheehan, Daniel; Sawnani, Hemant; Abresch, R Ted; Benditt, Joshua; Birnkrant, David J; Duong, Tina; Henricson, Erik; Kinnett, Kathi; McDonald, Craig M; Connolly, Anne M

    2017-08-15

    Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  8. Prevalence and correlates of apathy in myotonic dystrophy type 1

    OpenAIRE

    Gallais, Benjamin; Montreuil, Mich?le; Gargiulo, Marcela; Eymard, Bruno; Gagnon, Cynthia; Laberge, Luc

    2015-01-01

    Background Apathy in DM1 has long been acknowledged in clinical practice. However, a major drawback is that the concept has been only sparsely explored in previous specific studies. This study aimed to determine the prevalence of apathy in myotonic dystrophy (DM1), to compare it with facioscapulohumeral dystrophy (FSHD) patients and normal healthy controls, and explore its relationship to psychopathological features and cognitive function. Methods Levels of apathy in 38 DM1 patients with adul...

  9. Concurrence of myotonic dystrophy and epilepsy: a case report

    OpenAIRE

    Worku, Dawit Kibru

    2014-01-01

    Introduction Myotonic dystrophy is a clinically and genetically heterogeneous multisystem disorder with a prevalence of 1 in 8000 in the general population. Case presentation A 25-year-old Ethiopian man presented with symptoms of myotonia, muscle wasting, gait problems, frontal baldness, and family history characterizing the hereditary disorder myotonic dystrophy. He had been on treatment for idiopathic generalized epilepsy for over 15 years. A needle electromyography showed insertional class...

  10. Effect of acute postural variation on diabetic macular oedema

    DEFF Research Database (Denmark)

    Vinten, Martin; la Cour, Morten; Lund-Andersen, Henrik

    2010-01-01

    This study aimed to study the pathophysiology of diabetic macular oedema (DMO) by analysis of concomitant changes in macular volume (MV), mean arterial blood pressure (MABP), intraocular pressure (IOP), and retinal artery and vein diameters in response to acute postural changes in patients with DMO...

  11. Very early disease manifestations of macular telangiectasia type 2

    NARCIS (Netherlands)

    Issa, P.C.; Heeren, T.F.C.; Kupitz, E.H.; Holz, F.G.; Berendschot, T.T.J.M.

    Background: To report very early morphologic and functional alterations in patients with macular telangiectasia type 2. Methods: Patients with asymmetric disease manifestations, in whom retinal alterations characteristic for macular telangiectasia type 2 were present in one but not in the apparently

  12. Prognostic significance of delayed structural recovery after macular hole surgery

    DEFF Research Database (Denmark)

    Christensen, Ulrik C; Krøyer, Kristian; Sander, Birgit

    2009-01-01

    was used; however, secondary macular hole surgery had a significant influence on diameter of photoreceptor layer discontinuity at 3 months. CONCLUSIONS: Structural recovery in the form of photoreceptor layer discontinuity with a diameter of more than approximately 1500 microm 3 months after macular hole...

  13. Interocular agreement in melanin and macular pigment optical density.

    NARCIS (Netherlands)

    Kanis, M.J.; Berendschot, T.T.J.M.; van Norren, D.

    2007-01-01

    Macular pigment (MP) and melanin possibly protect the macular area by absorbing blue light and acting as antioxidants. Because little is known about the interocular correlation of melanin, we determined its optical density (MOD) in both eyes of healthy subjects using fundus reflectometry. The

  14. ILM peeling in nontractional diabetic macular edema: review and metanalysis.

    Science.gov (United States)

    Rinaldi, M; dell'Omo, R; Morescalchi, F; Semeraro, F; Gambicorti, E; Cacciatore, F; Chiosi, F; Costagliola, C

    2017-10-31

    To evaluate the effect of internal limiting membrane (ILM) peeling during vitrectomy for nontractional diabetic macular edema. PUBMED, MEDLINE and CENTRAL were reviewed using the following terms (or combination of terms): diabetic macular edema, nontractional diabetic macular edema, internal limiting membrane peeling, vitrectomy, Müller cells. Randomized and nonrandomized studies were included. The eligible studies compared anatomical and functional outcomes of vitrectomy with or without ILM peeling for tractional and nontractional diabetic macular edema. Postoperative best-corrected visual acuity and central macular thickness were considered, respectively, the primary and secondary outcomes. Meta-analysis on mean differences between vitrectomy with and without ILM peeling was performed using inverse variance method in random effects. Four studies with 672 patients were eligible for analysis. No significant difference was found between postoperative best-corrected visual acuity or best-corrected visual acuity change of ILM peeling group compared with nonpeeling group. There was no significant difference in postoperative central macular thickness and central macular thickness reduction between the two groups. The visual acuity outcomes in patients affected by nontractional diabetic macular edema using pars plana vitrectomy with ILM peeling versus no ILM peeling were not significantly different. A larger prospective and randomized study would be necessary.

  15. Prevalence of age-related macular degeneration in elderly Caucasians

    DEFF Research Database (Denmark)

    Erke, Maja G; Bertelsen, Geir; Peto, Tunde

    2012-01-01

    To describe the sex- and age-specific prevalence of drusen, geographic atrophy, and neovascular age-related macular degeneration (AMD).......To describe the sex- and age-specific prevalence of drusen, geographic atrophy, and neovascular age-related macular degeneration (AMD)....

  16. Acute effect of pure oxygen breathing on diabetic macular edema

    DEFF Research Database (Denmark)

    Vinten, Carl Martin; La Cour, Morten; Lund-Andersen, Henrik

    2012-01-01

    Purpose. A small-scale pilot study of the pathophysiology of diabetic macular edema (DME) was made by assessing concomitant changes in macular volume (MV), mean arterial blood pressure (MABP), intraocular pressure (IOP), retinal artery diameter (RAD), and retinal vein diameter (RVD) in response...

  17. Diagnosis of becker muscular dystrophy: Results of Re-analysis of DNA samples.

    Science.gov (United States)

    Straathof, Chiara S M; Van Heusden, Dave; Ippel, Pieternella F; Post, Jan G; Voermans, Nicol C; De Visser, Marianne; Brusse, Esther; Van Den Bergen, Janneke C; Van Der Kooi, Anneke J; Verschuuren, Jan J G M; Ginjaar, Hendrika B

    2016-01-01

    The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995. All requests for DNA analysis of the DMD gene in probands with suspected BMD were re-evaluated. If the phenotype was compatible with BMD, and no deletions or duplications were detected, DNA samples were screened for small mutations. In 79 of 185 referrals, no mutation was found. Analysis could be performed on 31 DNA samples. Seven different mutations, including 3 novel ones, were found. Long-term clinical follow-up is described. Refining DNA analysis in previously undiagnosed cases can identify mutations in the DMD gene and provide genetic diagnosis of BMD. A delayed diagnosis can still be valuable for the proband or the relatives of BMD patients. © 2015 Wiley Periodicals, Inc.

  18. Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family

    Energy Technology Data Exchange (ETDEWEB)

    Frydman, M.; Straussberg, R.; Shomrat, R.; Legum, C. [Tel Aviv Univ. (Israel)] [and others

    1995-09-11

    A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. {open_quotes}Idiopathic{close_quotes} hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia. 13 refs., 3 figs., 1 tab.

  19. Emery–Dreifuss muscular dystrophy: a test case for precision medicine

    Directory of Open Access Journals (Sweden)

    Pillers DAM

    2016-02-01

    Full Text Available De-Ann M Pillers,1 Nicholas H Von Bergen21Division of Neonatology and Newborn Medicine, 2Division of Cardiology, Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USAAbstract: Emery–Dreifuss muscular dystrophy (EDMD is characterized by the clinical triad of scapulohumeroperoneal muscle weakness, joint contractures, and cardiac defects that include arrhythmias and dilated cardiomyopathy. Although there is a defining group of clinical findings, the proteins responsible and their underlying gene defects leading to EDMD are varied. A common aspect of the gene defects is their involvement in, or with, the nuclear envelope. Treatment approaches are largely based on clinical symptoms. The genetic diversity of EDMD predicts that a cure will ultimately depend upon the individual's defect at the gene level, making this an ideal candidate for a precision medicine approach.Keywords: emerin, FHL1, lamins A/C, nuclear envelope

  20. Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

    Energy Technology Data Exchange (ETDEWEB)

    Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Russo, L.S. [Univ. of Florida, Jacksonville, FL (United States); Riconda, D.L. [Orlando Regional Medical Center, Orlando, FL (United States)

    1994-02-01

    Two male cousins with Duchenne muscular dystrophy were found to have different maternal dystrophin gene haplotypes and different deletion mutations. One propositus showed two noncontiguous deletions-one in the 5{prime}, proximal deletional hotspot region, and the other in the 3{prime}, more distal deletional hotspot region. The second propositus showed only the 5{prime} deletion. Using multiple fluorescent exon dosage and fluorescent multiplex CA repeat linkage analyses, the authors show that the mother of each propositus carries both deletions on the same grandmaternal X chromosome. This paradox is explained by a single recombinational event between the 2 deleted regions of one of the carrier`s dystrophin genes, giving rise to a son with a partially {open_quotes}repaired{close_quotes} gene retaining only the 5{prime} deletion. 20 refs., 4 figs.