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Dystrophy
Kinds of Dystrophy Terms modified by Dystrophy Selected AbstractsThe Role of Flexibility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic DystrophiesCHEMBIOCHEM, Issue 3 2010Matthew D. Disney Prof. Abstract Modularly assembled ligands were designed to target the RNAs that cause two currently untreatable neuromuscular disorders, myotonic dystrophy types 1 (DM1) and 2 (DM2). DM1 is caused by an expanded repeating sequence of CUG, and DM2 is caused by expanded CCUG repeats. Both are present in noncoding regions and fold into hairpins with either repeating 1×1 nucleotide UU (DM1) or 2×2 nucleotide 5,-CU/3,-UC (DM2) internal loops separated by two GC pairs. The repeats are toxic because they sequester the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Rational design of ligands targeting these RNAs was enabled by a database of RNA motif,ligand partners compiled by using two-dimensional combinatorial screening (2DCS). One 2DCS study found that the 6,,-azido-kanamycin A module binds internal loops similar to those found in DM1 and DM2. In order to further enhance affinity and specificity, the ligand was assembled on a peptoid backbone to precisely control valency and the distance between ligand modules. Designed compounds are more potent and specific binders to the toxic RNAs than MBNL1 and inhibit the formation of the RNA,protein complexes with nanomolar IC50 values. This study shows that three important factors govern potent inhibition: 1) the surface area sequestered by the assembled ligands; 2) the spacing between ligand modules since a longer distance is required to target DM2 RNAs than DM1 RNAs; and 3) flexibility in the modular assembly scaffold used to display the RNA-binding module. These results have impacts on the general design of assembled ligands targeting RNAs present in genomic sequence. [source] 3332: The new IC3D nomenclature of corneal dystrophiesACTA OPHTHALMOLOGICA, Issue 2010J WEISS Purpose Advances in genotyping have challenged the significance of the entities called the corneal dystrophies. Although the term corneal dystrophy typically refers to a group of inherited corneal disease that are bilateral, symmetric, slowly progressive and without relation to sytemic disease or environmental factors; exceptions to each part of the definition exist. Mutations in different genes can result in one phenotype and mutations in one gene can result in different allelic dystrophy phenotypes. The phenotypic classification system has become archaic. The International Committee on the Classification of Corneal Dystrophies (ICD3) was created in 2005 to revise the corneal dystrophy nomenclature. Methods A critical evaluation of the literature to remove inaccurate information and distil the facts was performed by an international panel of world experts including geneticists, pathologist and ophthalmologists. A template was created for each dystrophy which summarized the genetic, clinical and pathologic information with accompanying clinical photographs. Each dystrophy was reviewed to determine if there was an identified gene, gene locus and whether it was clinically well defined. Results The dystrophies were organized anatomically and each dystrophy was assigned a category from 1 to 4 indicating the level of evidence supporting the existence of a given dystrophy. Category 1- A well defined dystrophy with known gene locus and gene Category 2- A well defined dystrophy with known gene locus, unknown gene Category 3- A well defined dystrophy with unknown gene locus and gene Category 4- A poorly defined dystrophy with unknown gene locus and gene Conclusion The IC3D nomenclature system is available online at www.corneasociety.org in English and Spanish. A German translation has just been completed. [source] Duchenne Muscular Dystrophy, 3rd ednEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2004K. A. Jellinger No abstract is available for this article. [source] Muscular Dystrophy in Children.EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2000A Guide for Families Irwin M. Siegel. Demos Medical Publishing, New York, NY, 1999. 130 pp., ISBN 1,888799,33,1, US$ 19.95 (paperback). [source] Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort,HUMAN MUTATION, Issue 12 2009Kevin M. Flanigan Abstract Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2,Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55. Hum Mutat 30:1657,1666, 2009. © 2009 Wiley-Liss, Inc. [source] Muscle-derived stem cells: Implications for effective myoblast transfer therapyIUBMB LIFE, Issue 11 2005Tracey F. Lee-Pullen Abstract Stem cells have been proposed as a wonder solution for tissue repair in many situations and have attracted much attention in the media for both their therapeutic potential and ethical implications. In addition to the excitement generated by embryonic stem cells, research has now identified a number of stem cells within adult tissues which pose much more realistic targets for therapeutic interventions. Myoblast transfer therapy (MTT) has long been viewed as a potential therapy for the debilitating muscle-wasting disorder Duchenne Muscular Dystrophy. This technique relies on the transplantation of committed muscle precursor cells directly into the muscle fibres but has had little success in clinical trials. The recent discovery of a population of cells within adult muscle with stem cell-like characteristics has interesting implications for the future of such putative cell transplantation therapies. This review focuses on the characterization and application of these potential muscle-derived stem cells (MDSC) to MTT. IUBMB Life, 57: 731-736, 2005 [source] Muscular Dystrophy in female DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2001G. Diane Shelton The most common form of muscular dystrophy in dogs and humans is caused by mutations in the dystrophin gene. The dystrophin gene is located on the X chromosome, and, therefore, disease-causing mutations in dystrophin occur most often in males. Therefore, females with dystrophin deficiency or other forms of muscular dystrophy may be undiagnosed or misdiagnosed. Immunohisto-chemistry was used to analyze dystrophin and a number of other muscle proteins associated with muscular dystrophy in humans, including sarcoglycans and laminin ,2, in muscle biopsy specimens from 5 female dogs with pathologic changes consistent with muscular dystrophy. The female dogs were presented with a variety of clinical signs including generalized weakness, muscle wasting, tremors, exercise intolerance, gait abnormalities, and limb deformity. Serum creatine kinase activity was variably high. One dog had no detectable dystrophin in the muscle; another was mosaic, with some fibers normal and others partly dystrophin-deficient. A 3rd dog had normal dystrophin but no detectable laminin ,2. Two dogs could not be classified. This study demonstrates the occurrence of dystrophin- and laminin ,2-associated muscular dystrophy and the difficulty in clinical diagnosis of these disorders in female dogs. [source] A Severe Case of Complex Regional Pain Syndrome I (Reflex Sympathetic Dystrophy) Managed with Spinal Cord StimulationPAIN PRACTICE, Issue 1 2010Bernard Canlas MD Abstract Complex regional pain syndrome is a condition that usually affects the upper or lower extremities. The cause is not clearly understood. We report a case of a severe form of a rapidly progressive complex regional pain syndrome type I developing after a right shoulder injury managed with spinal cord stimulation (SCS). After failed conservative treatments, a rechargeable SCS system was implanted in the cervical spine. Allodynia and dystonia improved but the patient subsequently developed similar symptoms in lower right extremity followed by her lower left extremity. The patient became wheelchair bound. A second rechargeable SCS with a paddle electrode was implanted for the lower extremity coverage. The patient's allodynia and skin lesions improved significantly. However, over time, her initial symptoms reappeared which included skin breakdown. Due to the need for frequent recharging, the system was removed. During explantation of the surgical paddle lead, it was noted by the neurosurgeon that the contacts of the paddle lead were detached from the lead. After successful implantation of another SCS system, the patient was able to reduce her medications and is now able to ambulate with the use of a left elbow crutch. [source] Noninvasive Ventilation During Gastrostomy Tube Placement in Patients with Severe Duchenne Muscular Dystrophy: Case Reports and Review of the LiteraturePEDIATRIC PULMONOLOGY, Issue 2 2006D.J. Birnkrant MD Abstract Individuals with Duchenne muscular dystrophy may benefit from gastrostomy tube feeding due to progressive dysphagia and malnutrition. However, due to their severely impaired pulmonary function, these individuals are at risk of severe complications when they are sedated or undergo anesthesia for the procedure. We previously described a technique of noninvasive positive pressure ventilation to provide respiratory support during gastrostomy tube placement in such patients, but this technique had risks and limitations. In this case report, we examine two alternative techniques we used to provide respiratory support successfully to patients with severe muscular dystrophy and malnutrition who underwent percutaneous endoscopic gastrostomy tube placement. We then review the literature and discuss the potential benefits, risks, and limitations of the above techniques and of other options for gastrostomy placement in people with severe muscular dystrophy. Pediatr Pulmonol. © 2005 Wiley-Liss, Inc. [source] A de Novo PABPN1 Germline Mutation in a Patient with Oculopharyngeal Muscular Dystrophy,THE LARYNGOSCOPE, Issue 1 2006Nicolas Gürtler Abstract Background: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominantly inherited disorder characterized by dysphagia, ptosis, and proximal limb weakness and is caused by germline mutations (triplet repeat expansions) in the polyadenylate binding protein nuclear 1 (PABPN1) gene. Objective: To describe a 70-year-old female patient with OPMD on the clinical and molecular genetic level and to develop a rapid and efficient molecular genetic screening method to study large patient groups. Methods: Detailed family history and clinical assessment of the OPMD patient were followed by mutation analysis of the PABPN1 gene by direct DNA sequencing and by our newly developed method, fluorescent PABPN1 polymerase chain reaction (PCR) product (flPPP) method. A cohort of 50 healthy Swiss probands was screened using the flPPP to assess the frequency of the (GCG)7 allele in the Swiss population. Cricopharyngeal myotomy was performed as treatment for dysphagia. Results: A heterozygous (GCG)9 triplet repeat expansion in PABPN1 was identified. Since the family history proved to be negative, the mutation is likely to have occurred de novo. The frequency of the (GCG)7 allele among healthy Swiss controls amounted to 1%. The flPPP method showed a sensitivity and specificity of 100%. Two years after cricopharyngeal myotomy, the patient is still relieved of dysphagia. Conclusions: An otolaryngologist should include OPMD in the differential diagnosis of a patient presenting with dysphagia, as this symptom can be the first sign of the disease and family history can be negative. Molecular genetic testing represents a highly accurate and rapid way to confirm the clinical diagnosis of OPMD. Cricopharyngeal myotomy relieves the patient of dysphagia in the majority of cases. [source] Age Dependence of the Human Skeletal Muscle Stem Cell in Forming Muscle TissueARTIFICIAL ORGANS, Issue 3 2006Ralf Schäfer Abstract:, Human skeletal muscle stem cells from healthy donors aged 2,82 years (n = 13) and from three children suffering from Duchenne Muscular Dystrophy (DMD) were implanted into soleus muscles of immunoincompetent mice and were also expanded in vitro until senescence. Growth of implanted cells was quantified by structural features and by the amount of human DNA present in a muscle. Proliferative capacity in vitro and in vivo was inversely related to age of the donor. In vitro, a decline of about two mean population doublings (MPDs) per 10 years of donor's age was observed. Muscle stem cells from DMD children were prematurely aged. In general, cell preparations with low or decreasing content in desmin-positive cells produced more MPDs than age-matched high-desmin preparations and upon implantation more human DNA and more nonmyogenic than myogenic tissue. Thus, a "Desmin Factor" was derived which predicts "quality" of the human muscle tissue growing in vivo. This factor may serve as a prognostic tool. [source] 2461: Increasing complexity of ocular genetic diseases : the case of BEST diseaseACTA OPHTHALMOLOGICA, Issue 2010M ABITBOL Purpose Monogenic diseases until recently appeared simple from a molecular genetics point of view but correlations between genotypes and phenotypes still remain difficult to establish in many diseases and for many genes. For autosomal dominant diseases such as Best Vitelliform Macular Dystrophy, supposed to be a juvenile disease, it appears that mutations of BEST1 gene can cause multiple phenotypes including early onset and late onset phenotypes as well as unexpected phenotypes such as RP. We report several novel mutations and their associated phenotypes and describe phenotypes linked to previously reoported mutations for which the phenotype had not been describe at all previously. The role of SOX9, MITF and OTX2 in the incomplete penetrance and the variable expressivity of BVMDs is duscussed as well the potential roles of SNPs occuring in coding exons Methods We used genomic PCR with appropriate primers flanking all the exons of the BEST1 gene in order to amplify them. This Genomic PCR was followed by automated sequencing and careful analysis of the sequences obtained. Results We report the case of an unusual family where the Mother II2 of the proband III1, his maternal aunt II3, his brother III3 and his first cousin IIIIV, the son of his maternal aunt, carry a missense mutatation causing apparently only electrophysiological abnormalities. The Father II1 of the proband III1 turned out to carry a stop codon instead of the fifth normal BEST1 codon. The father did not display any electrophysiological nor any clinical abnormality and has a perfect monocular and binocular vision. In contrast the proband III1 carries both mutations with a severe phenotype. Conclusion This report exemplifies the necessity to study all family members in the case of BVMDs. [source] Parents' perspectives on coping with Duchenne muscular dystrophyCHILD: CARE, HEALTH AND DEVELOPMENT, Issue 4 2005C. L. Webb Abstract Background, The author, who has a grown son with Duchenne Muscular Dystrophy (DMD), has personally experienced a lack of available information for parents about coping with DMD. Therefore, as a longtime personal goal, she developed this study to address that lack of information. Methods, Fifteen semi-structured interviews were conducted with 23 parents (n = 7 with both parents; n = 1 with two sisters; n = 6 with mothers only; n = 1 with father only). The purpose of the interviews was to examine the strategies parents use to cope when their sons have DMD. The interviews were conducted in 12 states, taped and transcribed. Results, Grounded theory analysis of the interview data indicated the willingness of these parents to share information to empower others like themselves. Conclusions, Parents want to be heard and valued as experts on DMD by medical and other professionals who interact with their sons. In addition, they want to proactively participate in their sons' lives and to encourage other parents to do the same. [source] Evaluation of Biventricular Functions With Tissue Doppler Imaging in Patients With Myotonic DystrophyCLINICAL CARDIOLOGY, Issue 3 2010Tolga Ozyigit MD Background: Myotonic dystrophy (MD) is characterized by myotonia with dystrophic involvement of the muscles. Cardiac involvement is usually not evident in the early stages of MD. Hypothesis: We investigated biventricular functions by tissue Doppler imaging (TDI) in MD patients with no overt cardiac involvement to explore the value of TDI in the early detection of myocardial dysfunction. Methods: A total of 21 MD patients (15 male, age: 32.2 ± 12.3 yrs) and 21 healthy controls (13 male, age: 32.2 ± 7.8 yrs) were included. In addition to conventional echocardiography, pulsed Doppler and TDI were performed including measurement of myocardial performance index (MPI); peak systolic (Sm) and early (Em) and atrial (Am) diastolic myocardial velocities at the basal mitral and tricuspid annulus. Results: All patients and controls had normal ejection fraction. Transmitral E peak velocity was significantly lower while both deceleration time of E velocity and isovolumic relaxation time were significantly longer in MD patients (P = 0.007, P = 0.001, and P < 0.001, respectively). Sm, Em and Am peak velocities were significantly lower in MD patients in all segments except for Em of the mitral anterior annulus and Am of the tricuspid lateral annulus. Both left and right ventricular MPI were significantly higher in MD patients (P < 0.001 and P = 0.013, respectively). Conclusion: There are changes in myocardial systolic and diastolic functions in MD patients although they have no overt heart failure. Myocardial tissue velocities and MPI are useful in identifying subclinical biventricular involvement in these patients. Copyright © 2010 Wiley Periodicals, Inc. [source] Surgical Treatment of Ingrown Toenail without MatricectomyDERMATOLOGIC SURGERY, Issue 1 2008BERNARD NOËL MD BACKGROUND Partial excision of the nail matrix (matricectomy) is generally considered necessary in the surgical treatment of ingrown toenail. Recurrences may occur, however, and poor cosmetic results are frequently observed. OBJECTIVE The objective is to present a new surgical procedure for ingrown toenail with complete preservation of the nail matrix. METHODS Twenty-three patients with ingrown toenail were included in this study. The surgical excision was performed 1 week after the completion of treatment of the initial infection. A large volume of soft tissue surrounding the nail plate was removed under local anesthesia. No matrix excision was performed. RESULTS Short-term results were excellent. No recurrences or severe complications were observed during the minimum 12-months follow-up period. Cosmetic results were remarkable. CONCLUSIONS Ingrown toenail results from the compression of the lateral nail folds on the nail plate. This study shows that ingrown toenail can be surgically treated without matricectomy. A large volume of soft tissue surrounding the nail plate should be removed to decompress the nail and reduce inflammation. Cosmetic results are excellent and superior to the classical Emmert plasty. Postoperative nail dystrophies and spicule formation are not observed. The main advantage of this surgical approach is the complete preservation of the anatomy and function of the nail to improve both therapeutic and cosmetic results. [source] Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retinaDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2008Ann C. Morris Abstract Development of therapies to treat visual system dystrophies resulting from the degeneration of rod and cone photoreceptors may directly benefit from studies of animal models, such as the zebrafish, that display continuous retinal neurogenesis and the capacity for injury-induced regeneration. Previous studies of retinal regeneration in fish have been conducted on adult animals and have relied on methods that cause acute damage to both rods and cones, as well as other retinal cell types. We report here the use of a genetic approach to study progenitor cell responses to photoreceptor degeneration in the larval and adult zebrafish retina. We have compared the responses to selective rod or cone degeneration using, respectively, the XOPS-mCFP transgenic line and zebrafish with a null mutation in the pde6c gene. Notably, rod degeneration induces increased proliferation of progenitors in the outer nuclear layer (ONL) and is not associated with proliferation or reactive gliosis in the inner nuclear layer (INL). Molecular characterization of the rod progenitor cells demonstrated that they are committed to the rod photoreceptor fate while they are still mitotic. In contrast, cone degeneration induces both Müller cell proliferation and reactive gliosis, with little change in proliferation in the ONL. We found that in both lines, proliferative responses to photoreceptor degeneration can be observed as 7 days post fertilization (dpf). These two genetic models therefore offer new opportunities for investigating the molecular mechanisms of selective degeneration and regeneration of rods and cones. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008. [source] EFNS guideline on diagnosis and management of limb girdle muscular dystrophiesEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2007F. Norwood The limb girdle muscular dystrophies (LGMD) are termed as such as they share the characteristic feature of muscle weakness predominantly affecting the shoulder and pelvic girdles; their classification has been completely revised in recent years because of elucidation of many of the underlying genetic and protein alterations in the various subtypes. An array of diagnostic measures is possible but with varying ease of use and availability. Several aspects of muscle cell function appear to be involved in the causation of muscle pathology. These cellular variations may confer some specific clinical features thus permitting recognition of the LGMD subtype and hence directing appropriate levels of monitoring and intervention. Despite an extensive literature on the individual limb girdle dystrophies, these publications may be impenetrable for the general neurologist in this increasingly complex field. The proposed guidelines suggest an approach to the diagnosis and monitoring of the limb girdle dystrophies in a manner accessible to general neurologists. [source] The calpain 1,,-actinin interactionFEBS JOURNAL, Issue 23 2003Resting complex between the calcium-dependant protease, its target in cytoskeleton Calpain 1 behaviour toward cytoskeletal targets was investigated using two ,-actinin isoforms from smooth and skeletal muscles. These two isoforms which are, respectively, sensitive and resistant to calpain cleavage, interact with the protease when using in vitro binding assays. The stability of the complexes in EGTA [Kd(,Ca2+) = 0.5 ± 0.1 µm] was improved in the presence of 1 mm calcium ions [Kd(+Ca2+) = 0.05 ± 0.01 µm]. Location of the binding structures shows that the C-terminal domain of ,-actinin and each calpain subunit, 28 and 80 kDa, participates in the interaction. In particular, the autolysed calpain form (76/18) affords a similar binding compared to the 80/28 intact enzyme, with an identified binding site in the catalytic subunit, located in the C-terminal region of the chain (domain III,IV). The in vivo colocalization of calpain 1 and ,-actinin was shown to be likely in the presence of calcium, when permeabilized muscle fibres were supplemented by exogenous calpain 1 and the presence of calpain 1 in Z-line cores was shown by gold-labelled antibodies. The demonstration of such a colocalization was brought by coimmunoprecipitation experiments of calpain 1 and ,-actinin from C2.7 myogenic cells. We propose that calpain 1 interacts in a resting state with cytoskeletal targets, and that this binding is strengthened in pathological conditions, such as ischaemia and dystrophies, associated with high calcium concentrations. [source] Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype,phenotype correlations and impact on genetic counseling,,HUMAN MUTATION, Issue 1 2007Valérie Pelletier Abstract X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6,20%; RPGR: 78.4% vs. 55,90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years. Hum Mutat 28(1), 81,91, 2007. © 2006 Wiley-Liss, Inc. [source] CRB1 mutation spectrum in inherited retinal dystrophies,HUMAN MUTATION, Issue 5 2004Anneke I. den Hollander Abstract Mutations in the Crumbs homologue 1 (CRB1) gene have been reported in patients with a variety of autosomal recessive retinal dystrophies, including retinitis pigmentosa (RP) with preserved paraarteriolar retinal pigment epithelium (PPRPE), RP with Coats-like exudative vasculopathy, early onset RP without PPRPE, and Leber congenital amaurosis (LCA). We extended our investigations of CRB1 in these retinal dystrophies, and identified nine novel CRB1 sequence variants. In addition, we screened patients with "classic" RP and classic Coats disease (without RP), but no pathologic sequence variants were found in the CRB1 gene. In total, 71 different sequence variants have been identified on 184 CRB1 alleles of patients with retinal dystrophies, including amino acid substitutions, frameshift, nonsense, and splice site mutations, in-frame deletions, and large insertions. Recent studies in two animal models, mouse and Drosophila, and in vivo high-resolution microscopy in patients with LCA, have shed light on the role of CRB1 in the pathogenesis of retinal dystrophies and its function in the photoreceptors. In this article, we provide an overview of the currently known CRB1 sequence variants, predict their effect, and propose a genotype,phenotype correlation model for CRB1 mutations. Hum Mutat 24:355,369, 2004. © 2004 Wiley-Liss, Inc. [source] Is muscle spindle proprioceptive function spared in muscular dystrophies?MUSCLE AND NERVE, Issue 6 2004A muscle tendon vibration study Abstract Muscular dystrophies (MDs) are characterized by the degeneration of skeletal muscle fibers. The aim of the present study was to determine whether the intrafusal fibers of muscle spindles are also affected in MD. The functional integrity of muscle spindles was tested by analyzing their involvement in the perception of body segment movements and in the control of posture. Twenty MD patients (4 with dystrophinopathy, 5 with myotonic dystrophies, 5 with fascioscapulohumeral MD, and 6 with limb-girdle dystrophies) and 10 healthy subjects participated in the study. The MD patients perceived passive movements and experienced illusory movements similar to those perceived by healthy subjects in terms of their direction and velocity. Vibratory stimulation applied to the neck and ankle muscle tendons induced postural responses in MD patients with spatial and temporal characteristics similar to those produced by healthy subjects. These results suggest that the proprioceptive function of muscle spindles is spared in muscular dystrophies. Muscle Nerve 29: 861,866, 2004 [source] Environmental Effects on the Photochemistry of A2-E, a Component of Human Retinal Lipofuscin,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2001Laura Ragauskaite ABSTRACT Several retinal dystrophies are associated with the accumulation of lipofuscin, a pigment mixture, in the retinal pigment epithelium (RPE). One of the major fluorophores of this mixture has been identified as the bis-retinoid pyridinium compound, A2-E. Because this compound absorbs incident radiation that is transmitted by the anterior segment of the human eye, photophysical and photochemical studies were performed to determine if A2-E could photosensitize potentially damaging reactions. Steady-state fluorescence measurements indicate that the fluorescence emission maximum and quantum yield are very sensitive to the chemical environment and a correlation between these two parameters and the solvent dielectric constant is observed. Time-resolved absorption experiments of A2-E in pure organic solvents showed no formation of transient species on the timescale of our experiments. However, when these measurements were repeated for A2-E in Triton X-100 micelles, a short-lived (,, 14 ,s), weak absorption was observed. This species is quenched by oxygen (k= 2 × 109M,1 s,1) and by the addition of the antioxidants, cysteine and N,N,N,,N, -tetramethylphenylenediamine. Quenching of this species by 2,3,5-trimethylhydroquinone results in the formation of the 2,3,5-trimethylsemiquinone free radical and an increase in yield of the A2-E,derived species. Sensitization of the A2-E triplet excited state indicates that the species observed in micelles upon direct excitation is not consistent with the triplet excited state. Based on these data we tentatively assign this absorption to a free radical. In the RPE these initial processes can ultimately lead to damage to the tissue through the formation of peroxides and other oxidized species. [source] Linkage Validation of RP25 Using the 10K GeneChip Array and Further Refinement of the Locus by New Linked FamiliesANNALS OF HUMAN GENETICS, Issue 4 2008I. Barragán Summary Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies, characterised by rod photoreceptor cell degeneration with autosomal recessive RP (arRP) as the commonest form worldwide. To date, a total of 26 loci have been reported for arRP, each having a prevalence of 1,5%, except for the RP25 locus which was identified as the genetic cause of 14% of arRP cases in Spain. In order to validate the original linkage of RP25, we undertook a total genome scan using the 10K GeneChip mapping array on three of the previously linked families. The data obtained supported the initial findings of linkage. Additionally, linkage analysis in 18 newly ascertained arRP families was performed using microsatellite markers spanning the chromosome 6p12.1-q15 interval. Five out of the 18 families showed suggestive evidence of linkage to RP25, hence supporting the high prevalence of this locus in the Spanish population. Furthermore, the finding of a crossover in one of these families is likely to have refined the disease interval from the original 16 cM to only a 2.67 cM region between D6S257 and D6S1557. [source] RNA-mediated neurodegeneration in repeat expansion disordersANNALS OF NEUROLOGY, Issue 3 2010Peter K. Todd MD Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases. ANN NEUROL 2010;67:291,300 [source] A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathyARTHRITIS & RHEUMATISM, Issue 9 2010Lisa Christopher-Stine Objective Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy. Methods Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from 35S-methionine,labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31. Results Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixty-three percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers. Conclusion An anti,200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy. [source] Structure of the lamin A/C R482W mutant responsible for dominant familial partial lipodystrophy (FPLD)ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2009Eugenia Magracheva Proteins of the A-type lamin family, which consists of two members, lamin A and lamin C, are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A-type lamins have recently become the focus of extensive functional studies as a consequence of the linking of at least eight congenital diseases to mutations in the lamin A/C gene (LMNA). This spectrum of pathologies, which mostly manifest themselves as dominant traits, includes muscle dystrophies, dilated cardiomyopathies, the premature aging syndrome Hutchinson,Guilford progeria and familial partial lipodystrophy (FPLD). The crystal structure of the lamin A/C mutant R482W, a variant that causes FPLD, has been determined at 1.5,Å resolution. A completely novel aggregation state of the C-terminal globular domain and the position of the mutated amino-acid residue suggest means by which the mutation may affect lamin A/C,protein and protein,DNA interactions. [source] Purification, crystallization and preliminary X-ray diffraction of wild-type and mutant recombinant human transforming growth factor ,-induced protein (TGFBIp)ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2009Kasper Runager Transforming growth factor ,-induced protein (TGFBIp) has been linked to several corneal dystrophies as certain point mutations in the protein may give rise to a progressive accumulation of insoluble protein material in the human cornea. Little is known about the biological functions of this extracellular protein, which is expressed in various tissues throughout the human body. However, it has been found to interact with a number of extracellular matrix macromolecules such as collagens and proteoglycans. Structural information about TGFBIp might prove to be a valuable tool in the elucidation of its function and its role in corneal dystrophies caused by mutations in the TGFBI gene. A simple method for the purification of wild-type and mutant forms of recombinant human TGFBIp from human cells under native conditions is presented here. Moreover, the crystallization and preliminary X-ray analysis of TGFBIp are reported. [source] 1314: Corneal dystrophies and hereditary anterior eye segment disorders: anterior eye segment photo, clinical details, TD OCT, SD OCT and SS OCT scans, diagnosis and conclusionACTA OPHTHALMOLOGICA, Issue 2010A NOWINSKA [source] 2464: Phenotype/genotype evolution in corneal dystrophiesACTA OPHTHALMOLOGICA, Issue 2010F CHIAMBARETTA Purpose The corneal dystrophies are a group of genetically determined diseases usually characterized by loss of corneal transparency, which may be caused by a progressive accumulation of abnormal material within the cornea. The genetic characterization of corneal dystrophies revealed both genetic heterogeneity, that is, different genes (KRT3 and KRT12) causing a single dystrophy phenotype (Meesmann dystrophy), and phenotypic heterogeneity with a single gene (TGFBI) causing different allelic dystrophy phenotypes (RBCD, TBCD, granular type 1, granular type 2, and lattice type 1). But less is known about the evolution of the phenotype during life. Methods We were interesting in following the corneal phénotype progressive evolution during childhood. During several years we analyzed corneal phénotype of families of Lattice type 1 and granular type 1, using Scheimpflug camera. Results We were able to follow the accumulation of abnormal material, his corneal localisation and evolution during years. Conclusion The phenotype of both Lattice type 1 and granular type 1 is totally different in childhood, with subepithelial localization. [source] 2111: Adaptive optics imaging in hereditary macular diseasesACTA OPHTHALMOLOGICA, Issue 2010K NAKASHIMA Purpose This research aimed at exploring and characterizing differences in vivo between healthy and pathology retinas, hereditary macular diseases at the microscopic scale using a compact adaptive optics (AO) retinal camera and high resolution OCT. Methods Seven RP patients, Cone-rod dystrophies (3), Stargardt diseases (5), Occult macular dystrophies (4) and indeterminate macular dystrophies (4) had undergone en face retinal imaging by AO camera "rtx1" (Imagine Eyes, France). AO images were taken at the eccentricities from 0 deg to 6 deg temporal and nasal from fovea. Each patient was examined using high resolution spectral domain (SD)-OCT and infrared SLO (Spectralis OCT). Results Cellular-resolution images could be obtained in most cases. In inherited retinal dystrophies, AO helped to better evaluate losses of cone cells across the retina. Other microstructures, slightly larger in size than cones, were also visible in several pathological retinas. Hereditary macular disease cases showed loss of cone mosaics. Some of these cases, there were patchy areas of increased reflectance. In Cone rod dystrophy and some other cases, the RPE mosaic was visible where cone had disappeared. Conclusion Cellular-resolution images could be obtained in most cases. In inherited retinal dystrophies, AO helped to better evaluate losses of cone cells across the retina. Other microstructures, slightly larger in size than cones, were also visible in several pathological retinas. Hereditary macular disease cases showed loss of cone mosaics. Some of these cases, there were patchy areas of increased reflectance. In Cone rod dystrophy and some other cases, the RPE mosaic was visible where cone had disappeared. [source] | |||||||||||||||||||||||||||||||||||||