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Sample records for muscular atrophy sma

  1. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... kids, and I also enjoy such hobbies as computer technology and music com- position (including the publication ... treating SMA and moving toward a cure. Medical, computer and assistive technologies enable even very young children ...

  2. Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings.

    PubMed

    Bernal, Sara; Also-Rallo, Eva; Martínez-Hernández, Rebeca; Alías, Laura; Rodríguez-Alvarez, Francisco Javier; Millán, José M; Hernández-Chico, Concepción; Baiget, Montserrat; Tizzano, Eduardo F

    2011-06-01

    Spinal muscular atrophy (SMA) is caused by loss or mutations of the survival motor neuron 1 gene (SMN1). Its highly homologous copy, SMN2, is present in all SMA cases and is a phenotypic modifier. There are cases where asymptomatic siblings of typical SMA patients possess a homozygous deletion of SMN1 just like their symptomatic brothers or sisters. Plastin 3 (PLS3) when over expressed in lymphoblasts from females has been suggested to act as a genetic modifier of SMA. We studied PLS3 expression in four Spanish SMA families with discordant siblings haploidentical for the SMA locus. We excluded PLS3 as a possible modifier in two of our families with female discordant siblings. In the remaining two, we observed small differences in PLS3 expression between male and female discordant siblings. Indeed, we found that values of PLS3 expression in lymphoblasts and peripheral blood ranged from 12 to 200-fold less than those in fibroblasts. These findings warrant further investigation in motor neurons derived from induced pluripotential stem cells of these patients. PMID:21546251

  3. Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors.

    PubMed

    Carré, Amanda; Empey, Candice

    2016-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1 (survival motor neuron) and SMN2 genes as well as the concepts of the "2 + 0" carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor's knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1 gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requiring a detailed knowledge on the genetic counselor's part in order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient. PMID:26250347

  4. Infantile spinal muscular atrophy (SMA) and multiple congenital bone fractures in sibs: a lethal new syndrome.

    PubMed Central

    Borochowitz, Z; Glick, B; Blazer, S

    1991-01-01

    Acute infantile spinal muscular atrophy (SMA type I, Werdnig-Hoffmann disease) has generally been accepted as an autosomal recessive disorder. However, several investigators have noted a slightly increased male to female ratio. We describe here a family with two affected male sibs who had a form of acute infantile SMA with congenital bone fractures, whose parents were first cousins. Pedigree analysis strongly suggested autosomal recessive inheritance, but X linked recessive inheritance could not be ruled out. In view of the heterogeneity of the SMAs, and the distinct clinical features found in our patients, we suggest that their infantile SMA might well be a distinct entity. We suggest that SMA I with congenital contractures and bone fractures appears to be a recognisable disorder that can be distinguished from the more common classic form of SMA I. PMID:1865475

  5. Isolation of cDNA clones from within the spinal muscular atrophy (SMA) disease gene region

    SciTech Connect

    McLean, M.; Roy, N.; Tamai, K.

    1994-09-01

    Spinal muscular atrophy (SMA) is a recessive neuromuscular disease characterized by death of spinal cord {alpha} motor neurons, resulting in skeletal muscle atrophy. The critical SMA disease gene region on 5q13.1 contains families of microsatellite repeat sequences which exist at multiple subloci that are dispersed over a 100 to 200 kbp region. We have detected significant linkage disequilibrium between SMA type 1, the most severe form of the disorder, and two subloci of one such microsatellite, the CATT-1 family of microsatellites. Furthermore, a recombination event in a chromosome of an individual with SMA type 1 mapping between the members of two other extended microsatellite families, including CMS-1, has been observed. Combining this with previously reported recombinants refines the critical SMA region to approximately 300 kbp. P1 artificial chromosome (PAC), YAC and cosmid clones which possess both CMS-1 alleles which bracket this recombination event, as well as CATT-1 alleles showing linkage disequilibrium with SMA, have been used to probe cDNA libraries from human and other mammalian sources in search of genes within this interval; three of these cDNAs are currently being tested as candidates for the SMA gene.

  6. Proximal spinal muscular atrophy (SMA) types II and III in the same sibship are not caused by different alleles at the SMA locus on 5q.

    PubMed Central

    Müller, B; Melki, J; Burlet, P; Clerget-Darpoux, F

    1992-01-01

    Proximal spinal muscular atrophy (SMA) is a group of progressive muscular diseases recently mapped to chromosome 5q. SMA is usually classified into types I-III, and there are cases of two types of SMA in the same sibship. Becker and others later proposed that these sibships might be due to the existence of several alleles at the same locus predisposing to the different forms of the disease. In a sample of four sibships in which both SMA type II and SMA type III occur, this hypothesis was clearly rejected for the SMA locus on 5q, by using information on the segregation of linked markers (P less than .001). Thus the difference between SMA type II and SMA type III is not due to different alleles at the SMA locus on 5q. This finding is suggestive of an involvement of other factors, genetic or environmental, in the determination of disease severity in SMA. PMID:1570842

  7. Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA)

    PubMed Central

    Zanetta, Chiara; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA. PMID:24400925

  8. Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse

    PubMed Central

    Wang, Xueyong; Le, Thanh T.; Le, Hao T.; Beattie, Christine E.; Rich, Mark M.; Burghes, Arthur H. M.

    2015-01-01

    Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons. PMID:26134627

  9. Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls

    PubMed Central

    Czech, Christian; Tang, Wakana; Bugawan, Teodorica; Mano, Calvin; Horn, Carsten; Iglesias, Victor Alejandro; Fröhner, Stefanie; Zaworski, Phillip G.; Paushkin, Sergey; Chen, Karen; Kremer, Thomas

    2015-01-01

    Spinal muscular atrophy is caused by a functional deletion of SMN1 on Chromosome 5, which leads to a progressive loss of motor function in affected patients. SMA patients have at least one copy of a similar gene, SMN2, which produces functional SMN protein, although in reduced quantities. The severity of SMA is variable, partially due to differences in SMN2 copy numbers. Here, we report the results of a biomarker study characterizing SMA patients of varying disease severity. SMN copy number, mRNA and Protein levels in whole blood of patients were measured and compared against a cohort of healthy controls. The results show differential regulation of expression of SMN2 in peripheral blood between patients and healthy subjects. PMID:26468953

  10. A YAC contig of the region containing the spinal muscular atrophy gene (SMA): Identification of an unstable region

    SciTech Connect

    Carpten, J.D.; DiDonato, C.J.; Ingraham, S.E.

    1994-11-15

    The authors report a 3.0-Mb YAC contig of the region 5q11.2-q13.3, which is where the spinal muscular atrophy gene has been localized. Three total genomic YAC libraries were screened by the polymerase chain reaction (PCR), and 45 YACs were recovered. These YACs were characterized for sequence tag site (STS) content, and overlaps were confirmed by vectorette PCR. Of the 45 YACs, 20 were isolated with the polymorphic marker CATT-1, which demonstrates significant allelic association with the SMA gene and maps within the 850-kb interval defined by the markers D5S557 and D5S823. Haplotyping of these YACs and their mother cell line indicates that the majority of YACs from this region contain deletions. Furthermore, a 1.9-Mb CATT-1 YAC that was negative for MAP1B and D5S435 and nonchimeric by FISH analysis provides a minimum distance between MAP1B and D5S435. 30 refs., 2 figs., 3 tabs.

  11. Treatment of scoliosis in intermediate spinal muscular atrophy (SMA type II) in childhood.

    PubMed

    Fujak, Albert; Ingenhorst, Anne; Heuser, Katja; Forst, Raimund; Forst, Jürgen

    2005-04-30

    Summary. Progressive scoliosis with increasing pelvic obliquity in early childhood of patients with SMA type II is a common feature in this disease. Spinal surgery in muscle disorders should be carried out as soon as a progressive curve of more then 20 Celsius Cobb and a preserved FVC of 20-30% is proved. In later stages or severe forms of SMA II spinal stabilization becomes often impossible due to the respiratory insufficiency, the poor general condition and the severity of the scoliosis with marked pelvic obliquity. A special telescope rod was developed in order to enable a lengthening of this instrumentation during growth for children treated in early childhood. In 15 of 20 patients with SMA II in early childhood not satisfactory results after telescope rod implantation were observed. In spite of the telescope technique crankshaft phenomenon appeared and curve progression were observed. So then we stopped telescope rod implantation. This instrumentation could be in principle a good therapeutical tool for this indication, but its technical manufacturing has firstly to be improved decisively. For SMA II patients younger than 10 years with progressive scoliosis our therapeutic recommendation is nowadays a corset until the age of 10-12 years followed by definitive surgical correction using other multisegmental instrumentation like the Isola(R) system. PMID:17615511

  12. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  13. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... myoclonic epilepsy spinal muscular atrophy with progressive myoclonic epilepsy Enable Javascript to view the expand/collapse boxes. ... All Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  14. SMA VALIANT TRIAL: A PROSPECTIVE, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF VALPROIC ACID IN AMBULATORY ADULTS WITH SPINAL MUSCULAR ATROPHY

    PubMed Central

    Kissel, John T.; Elsheikh, Bakri; King, Wendy M.; Freimer, Miriam; Scott, Charles B.; Kolb, Stephen J.; Reyna, Sandra P.; Crawford, Thomas O.; Simard, Louise R.; Krosschell, Kristin J.; Acsadi, Gyula; Schroth, Mary K.; D’Anjou, Guy; LaSalle, Bernard; Prior, Thomas W.; Sorenson, Susan; Maczulski, Jo Anne; Swoboda, Kathryn J.

    2013-01-01

    Introduction An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. Methods There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. Results Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. Conclusions VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults. PMID:23681940

  15. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

    PubMed

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. PMID:26258776

  16. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA)

    PubMed Central

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. PMID:26258776

  17. Allelic association and extended haplotype analysis of the spinal muscular atrophy (SMA) candidate region in the French Candadian population

    SciTech Connect

    Simard, L.R.; Prescott, G.; Rochette, C. |

    1994-09-01

    SMA is a common lower motor neuron disease characterized by progressive proximal limb and trunk muscle weakness. Despite the wide range in phenotypic severity, all three clinical types of childhood SMAs map to chromosome 5q11.2-5q13.3. The proximal (D5S557) flanking markers span about 1 Mb. We have previously demonstrated significant linkage disequilibrium between D5S125, D5S435, D5S351, JK53CA1/2 and SMA in the French Canadian population. We now present data for three new DNA markers mapping between D5S435 and D5S557 kindly provided to us by Drs. B. Wirth (A31), A. Burghes (Ag1) and A. MacKenzie (CATT-40G1). We identified 10 different A31 Alleles whose frequencies were similar for both normal and SMA chromosomes. Ag1 is a complex multi-allelic marker and specific primers amplified 1 (Class I), 2 or rarely 3 (Class II) alleles per chromosome. We observed significant association between Ag1 and SMA. For example, the 100 bp Ag1 fragment was typed on 20 of 73 SMA chromosomes and 0 of 74 normal chromosomes (p=<10{sup -4}). We also observed significant association between Ag1 Class genotypes and phenotypic severity. Class I chromosomes predominated in Type I SMA (p=.001) while Type II SMA individuals were generally heterozygous Class I/Class II (p=.001). Finally, we provide evidence for allelic association between Type I SMA and CATT-40G1, a tri-allelic sublocus of CATT-1. All of our Type I SMA chromosomes (n=20) carried a null allele compared to 40% of normal chromosomes (p=<10{sup -4}). Extended haplotype analyses indicated that > 19% of French Canadian SMA chromosomes appear to be ancestrally related to two unique haplotypes indicating their utility for linkage disequilibrium mapping.

  18. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  19. Analysis of complex repeat sequences within the spinal muscular atrophy (SMA) candidate region in 5q13

    SciTech Connect

    Davies, K.E.; Morrison, K.E.; Daniels, R.I.

    1994-09-01

    We previously reported that the 400 kb interval flanked the polymorphic loci D5S435 and D5S557 contains blocks of a chromosome 5 specific repeat. This interval also defines the SMA candidate region by genetic analysis of recombinant families. A YAC contig of 2-3 Mb encompassing this area has been constructed and a 5.5 kb conserved fragment, isolated from a YAC end clone within the above interval, was used to obtain cDNAs from both fetal and adult brain libraries. We describe the identification of cDNAs with stretches of high DNA sequence homology to exons of {beta} glucuronidase on human chromosome 7. The cDNAs map both to the candidate region and to an area of 5p using FISH and deletion hybrid analysis. Hybridization to bacteriophage and cosmid clones from the YACs localizes the {beta} glucuronidase related sequences within the 400 kb region of the YAC contig. The cDNAs show a polymorphic pattern on hybridization to genomic BamH1 fragments in the size range of 10-250 kb. Further analysis using YAC fragmentation vectors is being used to determine how these {beta} glucuronidase related cDNAs are distributed within 5q13. Dinucleotide repeats within the region are being investigated to determine linkage disequilibrium with the disease locus.

  20. Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, That Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    2011-01-01

    The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by Western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration. PMID:22348181

  1. Proximal spinal muscular atrophy: current orthopedic perspective

    PubMed Central

    Haaker, Gerrit; Fujak, Albert

    2013-01-01

    Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective “survival motor neuron” (SMN) protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach. PMID:24399883

  2. Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability

    PubMed Central

    Liu, Huisheng; Lu, Jianfeng; Chen, Hong; Du, Zhongwei; Li, Xue-Jun; Zhang, Su-Chun

    2015-01-01

    Spinal muscular atrophy (SMA) presents severe muscle weakness with limited motor neuron (MN) loss at an early stage, suggesting potential functional alterations in MNs that contribute to SMA symptom presentation. Using SMA induced pluripotent stem cells (iPSCs), we found that SMA MNs displayed hyperexcitability with increased membrane input resistance, hyperpolarized threshold, and larger action potential amplitude, which was mimicked by knocking down full length survival motor neuron (SMN) in non-SMA MNs. We further discovered that SMA MNs exhibit enhanced sodium channel activities with increased current amplitude and facilitated recovery, which was corrected by restoration of SMN1 in SMA MNs. Together we propose that SMN reduction results in MN hyperexcitability and impaired neurotransmission, the latter of which exacerbate each other via a feedback loop, thus contributing to severe symptoms at an early stage of SMA. PMID:26190808

  3. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 EPH families using 15 polymorphic loci in the region 5q11. 2-q13. 3

    SciTech Connect

    Wirth, B.; Pick, E.; Leutner, A.; Dadze, A.; Voosen, B.; Piechaczek-Wappenschmidt, B.; Rudnik-Schoeneborn, S.; Schoenling, J.; Zerres, K. ); Knapp, M. )

    1994-03-01

    The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q.13.3 in 1990. Here, the authors present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q.13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z[sub max] = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557. The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene. They localized a recently described polymorphic marker, D5S351, close to the SMA. Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, they developed a new reverse primer for the nearest centromeric locus D5S435, a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5s507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q.13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507-D5S6-D5S125-D5S680-D5S435-SMA-D5S557-D5S35 -15[prime]MAP1B-3[prime]MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable. 25 refs., 4 figs., 5 tabs.

  4. Spinal muscular atrophy

    MedlinePlus

    ... type II have less severe symptoms during early infancy, but they become weaker with time. SMA type ... MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence . 2nd ed. Philadelphia, PA: Elsevier; ...

  5. Prenatal prediction of spinal muscular atrophy.

    PubMed Central

    Daniels, R J; Suthers, G K; Morrison, K E; Thomas, N H; Francis, M J; Mathew, C G; Loughlin, S; Heiberg, A; Wood, D; Dubowitz, V

    1992-01-01

    Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses. Images PMID:1348091

  6. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  7. Tongue fasciculations in an infant with spinal muscular atrophy type 1

    PubMed Central

    Giannopoulou, Eleni Z; Martin, Thomas; Wirth, Brunhilde; Yilmaz, Umut; Gortner, Ludwig; Meyer, Sascha

    2015-01-01

    Key Clinical Message Muscular hypotonia in infants may be associated with several conditions, such as spinal muscular atrophy (SMA). We report on an infant with tongue fasciculations and a rare mutation of the SMN1 gene. The presence of tongue fasciculations in combination with a thorough history may be suggestive of SMA. PMID:26509018

  8. Newborn screening for spinal muscular atrophy: Anticipating an imminent need.

    PubMed

    Phan, Han C; Taylor, Jennifer L; Hannon, Harry; Howell, Rodney

    2015-04-01

    Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. Children with type I SMA typically die by the age of 2 years. Recent progress in gene modification and other innovative therapies suggest that improved outcomes may soon be forthcoming. In animal models, therapeutic intervention initiated before the loss of motor neurons alters SMA phenotype and increases lifespan. Presently, supportive care including respiratory, nutritional, physiatry, and orthopedic management can ameliorate clinical symptoms and improve survival rates if SMA is diagnosed early in life. Newborn screening could help optimize these potential benefits. A recent report demonstrated that SMA detection can be multiplexed at minimal additional cost with the assay for severe combined immunodeficiency, already implemented by many newborn screening programs. The public health community should remain alert to the rapidly changing developments in early detection and treatment of SMA. PMID:25979781

  9. Defining new borders of the spinal muscular atrophy (SMA) candidate region by two new microsatellites and isolation of cDNAs

    SciTech Connect

    Wirth, B.; Schoenling, J.; Dadze, A.

    1994-09-01

    A high number of cosmids and phages were identified that contained di-, tri-, and tetranucleotide repeats. These clones were isolated from STSs that map to the SMA region as well as from three cosmid and one phage library that had been prepared from YACs which span the SMA candidate interval. We developed two new microsatellites, A31 (D5S823) and 95/23, which enabled us to define new borders of the SMA region and to reduce it to approximately 700 kb. Physically, the marker A31 maps to the overlapping region of the YACs y116, y55 and y122 at about 550 kb distal to the locus D5S435. A recombination in one SMA type I family places A31 proximal to the SMA gene. The multicopy microsatellite, 95/23, developed from a cosmid including the STS y97U revealed in a consanguine SMA type I family different alleles, while all proximal markers were heterozygous. This suggests a location of 95/23 distal to the SMA gene. Furthermore, we tested 157 German SMA families (100 SMA type I, 50 SMA type II and 20 SMA type III) for linkage disequilibrium with the marker AG1-CA which reveals no recombination with the SMA gene. We found in SMA type I families strong allelic association between the 100 bp allele and the SMA gene. In 7 families we got deletions within the AG1-CA microsatellite. On the way to isolate the SMA gene, we hybridized whole cosmid and YAC inserts to cDNA libraries of spinal cord, brain and muscle. Seven cDNAs were initially identified and cDNA walking was used to begin the isolation of whole transcribed sequences.

  10. Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

    PubMed Central

    El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

    2016-01-01

    Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

  11. RASCH ANALYSIS OF CLINICAL OUTCOME MEASURES IN SPINAL MUSCULAR ATROPHY

    PubMed Central

    CANO, STEFAN J.; MAYHEW, ANNA; GLANZMAN, ALLAN M.; KROSSCHELL, KRISTIN J.; SWOBODA, KATHRYN J.; MAIN, MARION; STEFFENSEN, BIRGIT F.; BÉRARD, CAROLE; GIRARDOT, FRANÇOISE; PAYAN, CHRISTINE A.M.; MERCURI, EUGENIO; MAZZONE, ELENA; ELSHEIKH, BAKRI; FLORENCE, JULAINE; HYNAN, LINDA S.; IANNACCONE, SUSAN T.; NELSON, LESLIE L.; PANDYA, SHREE; ROSE, MICHAEL; SCOTT, CHARLES; SADJADI, REZA; YORE, MACKENSIE A.; JOYCE, CYNTHIA; KISSEL, JOHN T.

    2015-01-01

    Introduction Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. PMID:23836324

  12. Programmed cell death and the gene behind spinal muscular atrophy.

    PubMed Central

    Robinson, A

    1995-01-01

    A gene involved in the development of spinal muscular atrophy (SMA) has been found on human chromosome 5 after a 4-year search. Named the neuronal apoptosis inhibitor protein (NAIP) gene, it is believed to inhibit the normal process of apoptosis--the disintegration of single cells that results from programmed cell death--in motor neurons. The researchers who found the NAIP gene also discovered that healthy people carry one complete copy of the gene along with many other partial copies. Many children with SMA have the partial copies but not the complete gene. This discovery facilitates the accurate genetic diagnosis of SMA. But gene therapy for SMA will not be possible until researchers find a suitable vector to stably introduce activated and intact copies of the gene into the motor neurons of children with SMA in time to stop motor neuron loss. Images p1460-a PMID:7585374

  13. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.

    PubMed

    Genabai, Naresh K; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A; Gangwani, Laxman

    2015-12-15

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  14. Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

    PubMed Central

    Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily R.; Yazdani, Armin; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn2B/− mice but not in the more severe Smn−/−; SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− and Smn−/−; SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels. PMID:27349908

  15. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  16. Dominant spinal muscular atrophy with lower extremity predominance

    PubMed Central

    Harms, M.B.; Allred, P.; Gardner, R.; Fernandes Filho, J.A.; Florence, J.; Pestronk, A.; Al-Lozi, M.; Baloh, R.H.

    2010-01-01

    Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant. GLOSSARY lod = logarithm of the odds; SMA = spinal muscular atrophy; SMA-LED = spinal muscular atrophy–lower extremity, dominant; SNP = single-nucleotide polymorphism. PMID:20697106

  17. Aquatic Therapy for a Child with Type III Spinal Muscular Atrophy: A Case Report

    ERIC Educational Resources Information Center

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales…

  18. Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

    PubMed Central

    Iyer, Chitra C.; McGovern, Vicki L.; Wise, Dawnne O.; Glass, David J.; Burghes, Arthur H. M.

    2014-01-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx−/−–SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. PMID:24656734

  19. Describing nutrition in spinal muscular atrophy: A systematic review.

    PubMed

    Moore, Georgia E; Lindenmayer, Amara W; McConchie, Grace A; Ryan, Monique M; Davidson, Zoe E

    2016-07-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease of variable severity. Progressive muscle wasting and impairment in functional ability in SMA have a profound influence on nutritional outcomes. This systematic review summarises the existing evidence on nutrition in SMA. The search strategy was conducted across five databases in August 2014, and updated in March 2016, using key terms relating to growth, nutrition requirements, dietary intake and nutrition management. Studies were selected for inclusion using a two pass method, and data systematically extracted using standardised forms. Thirty-nine studies met eligibility criteria. Body composition is abnormal in patients with SMA, and feeding and swallowing issues are prevalent among sufferers of SMA types I and II. Nutritional management practices vary internationally. There is a paucity of literature regarding nutrition requirements in SMA, although it appears that energy expenditure may be reduced. Children with SMA require individualised nutritional management in order to address their growth and nutrition requirements. There is an urgent need for larger, coordinated, prospective intervention studies of nutrition in SMA. PMID:27241822

  20. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  1. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    PubMed Central

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  2. Induced pluripotent stem cells from a spinal muscular atrophy patient

    PubMed Central

    Ebert, Allison D.; Yu, Junying; Rose, Ferrill F.; Mattis, Virginia B.; Lorson, Christian L.; Thomson, James A.; Svendsen, Clive N.

    2009-01-01

    Spinal muscular atrophy (SMA) is one of the most common inherited forms of neurological disease leading to infant mortality. Patients exhibit selective loss of lower motor neurons resulting in muscle weakness, paralysis, and often death. Although patient fibroblasts have been used extensively to study SMA, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem (iPS) cells from skin fibroblast samples taken from a child with SMA. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show human iPS cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen novel drug compounds, and develop new therapies. PMID:19098894

  3. Advances in therapeutic development for spinal muscular atrophy

    PubMed Central

    Howell, Matthew D; Singh, Natalia N; Singh, Ravindra N

    2015-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA. PMID:25068989

  4. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

    SciTech Connect

    Melki, J.; Lefebvre, S.; Burglen, L.; Burlet, P.; Clermont, O.; Reboullet, S.; Benichou, B.; Zeviani, M. ); Millasseau, P. ); Le Paslier, D. )

    1994-06-03

    Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

  5. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches. PMID:25920617

  6. Optimization of Spinal Muscular Atrophy subject's muscle activity during gait

    NASA Astrophysics Data System (ADS)

    Umat, Gazlia; Rambely, Azmin Sham

    2014-06-01

    Spinal Muscular Atrophy (SMA) is a hereditary disease related muscle nerve disorder caused by degeneration of the anterior cells of the spinal cord. SMA is divided into four types according to the degree of seriousness. SMA patients show different gait with normal people. Therefore, this study focused on the effects of SMA patient muscle actions and the difference that exists between SMA subjects and normal subjects. Therefore, the electromyography (EMG) test will be used to track the behavior of muscle during walking and optimization methods are used to get the muscle stress that is capable of doing the work while walking. Involved objective function is non-linear function of the quadratic and cubic functions. The study concludes with a comparison of the objective function using the force that sought to use the moment of previous studies and the objective function using the data obtained from EMG. The results shows that the same muscles, peroneus longus and bisepsfemoris, were used during walking activity by SMA subjects and control subjects. Muscle stress force best solution achieved from part D in simulation carried out.

  7. Spinal Muscular Atrophy (SMA) (For Parents)

    MedlinePlus

    ... necessary to ensure adequate nutrition that doesn't overload a child with unnecessary calories. Children who can' ... Use Visit the Nemours Web site. Note: All information on KidsHealth® is for educational purposes only. For ...

  8. [A case of spinal muscular atrophy type 0 in Japan].

    PubMed

    Okamoto, Kentaro; Saito, Kayoko; Sato, Takatoshi; Ishigaki, Keiko; Funatsuka, Makoto; Osawa, Makiko

    2012-09-01

    The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature. PMID:23012868

  9. Isolated exon 8 deletion in type 1 spinal muscular atrophy with bilateral optic atrophy: unusual genetic mutation leading to unusual manifestation?

    PubMed

    Maiti, D; Bhattacharya, M; Yadav, S

    2012-01-01

    Proximal spinal muscular atrophy (SMA) or type 1 SMA is a fatal autosomal recessive disorder usually caused by homozygous deletion of exons 7 and 8 in the survivor motor neuron (SMN) gene. Additional deletion of the neuronal apotosis inhibitory protein (NAIP) gene exacerbates the clinical severity. Isolated exon 8 deletion has been reported in a single case series of SMA types 2 and 3 and never with SMA type 1. While extraocular muscles are typically spared, there are a few case reports documenting associated external ophthalmoplegia. Optic atrophy is a hitherto unreported association of SMA. We report a 10-month-old male infant with SMA type 1 with optic atrophy due to isolated deletion of exon 8 of the SMN gene with intact exon 7 and NAIP gene. PMID:23298926

  10. Developing therapies for spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Sahin, Mustafa

    2016-02-01

    Spinal muscular atrophy is an autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the gene survival of motor neuron 1 (SMN1), leading to loss of function of the full-length SMN protein. SMN has a number of functions in neurons, including RNA splicing and snRNP biogenesis in the nucleus, and RNA trafficking in neurites. The expression level of full-length SMN protein from the SMN2 locus modifies disease severity. Increasing full-length SMN protein by a small amount can lead to significant improvements in the neurological phenotype. Currently available interventions for spinal muscular atrophy patients are physical therapy and orthopedic, nutritional, and pulmonary interventions; these are palliative or supportive measures and do not address the etiology of the disease. In the past decade, there has been a push for developing therapeutics to improve motor phenotypes and increase life span of spinal muscular atrophy patients. These therapies are aimed primarily at restoration of full-length SMN protein levels, but other neuroprotective treatments have been investigated as well. Here, we discuss recent advances in basic and clinical studies toward finding safe and effective treatments of spinal muscular atrophy using gene therapy, antisense oligonucleotides, and other small molecule modulators of SMN expression. PMID:26173388

  11. Spinal muscular atrophy: An update on therapeutic progress

    PubMed Central

    Seo, Joonbae; Howell, Matthew D.; Singh, Natalia N.; Singh, Ravindra N.

    2013-01-01

    Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA. PMID:23994186

  12. Unusual molecular findings in autosomal recessive spinal muscular atrophy.

    PubMed Central

    Matthijs, G; Schollen, E; Legius, E; Devriendt, K; Goemans, N; Kayserili, H; Apäk, M Y; Cassiman, J J

    1996-01-01

    All three types of autosomal recessive spinal muscular atrophy map to chromosome 5q11.2-q13.3 and are associated with deletions or mutations of the SMN (survival motor neurone) gene. The availability of a test to distinguish between the SMN gene and its nearly identical centromeric copy cBCD541 allows molecular diagnosis. We have analysed patients from 24 Belgian and 34 Turkish families for the presence or absence of a deletion in the SMN gene. A homozygous deletion in the SMN gene was seen in 90% of unrelated SMA patients. A non-radioactive SSCP assay allows for a semiquantitative analysis of the copy number of the centromeric and SMN genes. Hence, direct carrier detection has become feasible under certain conditions. We observed a phenotypically normal male, father of an SMA type I patient, presenting with only a single copy of the SMN gene and lacking both copies of the cBCD541 gene. This illustrates that a reduction of the total number of SMN and cBCD541 genes to a single SMN copy is compatible with normal life. In another SMA type I family, there is evidence for a de novo deletion of the centromeric gene in a normal sib. This observation illustrates the susceptibility of the SMA locus to de novo deletions and rearrangements. Images PMID:8782046

  13. Spinal muscular atrophy in Holstein-Friesian calves.

    PubMed

    Pumarola, M; Añor, S; Majó, N; Borrás, D; Ferrer, I

    1997-02-01

    The clinical and neuropathological findings of spinal muscular atrophy (SMA) in Holstein-Friesian calves are described in four females and one male from a dairy farm composed of 150 cows and 2 breeding bulls. Locomotion difficulties started at the age of 15 days, and progressed to paraparesis and tetraparesis in 2 weeks. Signs consistent with denervation were revealed with electromyography. The neuropathological examination showed degeneration and loss of motor neurons in the spinal cord, together with astrocytosis. Among the remaining motor neurons were ghost cells and neurons filled with accumulations of straight filaments measuring 10-12 nm in diameter, which were strongly immunoreactive with antibodies produced against phosphorylated neurofilaments. Degenerating cells in SMA did not stain with the method of in situ labelling of nuclear DNA fragmentation and did not show c-Jun immunoreactivity. This feature contrasts with the in situ labelling of DNA breaks of apoptotic cells and with the strong c-Jun immunoreactivity restricted to dying cells during the whole process of naturally occurring cell death in the developing central nervous system. These features suggest that cell death in SMA differs from programmed cell death during normal development, and that pathological cell death in SMA should not be considered as a mere persistence or reactivation of normally occurring developmental cell death. PMID:9039466

  14. Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

    PubMed Central

    Ripolone, Michela; Ronchi, Dario; Violano, Raffaella; Vallejo, Dionis; Fagiolari, Gigliola; Barca, Emanuele; Lucchini, Valeria; Colombo, Irene; Villa, Luisa; Berardinelli, Angela; Balottin, Umberto; Morandi, Lucia; Mora, Marina; Bordoni, Andreina; Fortunato, Francesco; Corti, Stefania; Parisi, Daniela; Toscano, Antonio; Sciacco, Monica; DiMauro, Salvatore; Comi, Giacomo P.; Moggio, Maurizio

    2016-01-01

    IMPORTANCE The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca’ Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES Respiratory chain activity and mitochondrial content. RESULTS Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator–activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets

  15. Neuronal involvement in muscular atrophy

    PubMed Central

    Cisterna, Bruno A.; Cardozo, Christopher; Sáez, Juan C.

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression. PMID:25540609

  16. Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

    PubMed Central

    San Millan, Beatriz; Fernandez, Jose M.; Navarro, Carmen; Reparaz, Alfredo; Teijeira, Susana

    2016-01-01

    Background: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically and genetically distinct and uncommon variant of SMA that results from irreversible degeneration of α-motor neurons in the anterior horns of the spinal cord and in ganglion cells on the spinal root ganglia. Aims: To describe the clinical, electrophysiological, neuropathological, and genetic findings, at different stages from birth to death, of a Spanish child diagnosed with SMARD1. Patient and methods: We report the case of a 3-month-old girl with severe respiratory insufficiency and, later, intense hypotonia. Paraclinical tests included biochemistry, chest X-ray, and electrophysiological studies, among others. Muscle and nerve biopsies were performed at 5 and 10 months and studied under light and electron microscopy. Post-mortem examination and genetic investigations were performed. Results: Pre- and post-mortem histopathological findings demonstrated the disease progression over time. Muscle biopsy at 5 months of age was normal, however a marked neurogenic atrophy was present in post-mortem samples. Peripheral motor and sensory nerves were severely involved likely due to a primary axonal disorder. Automatic sequencing of IGHMBP2 revealed a compound heterozygous mutation. Conclusions: The diagnosis of SMARD1 should be considered in children with early respiratory insufficiency or in cases of atypical SMA. Direct sequencing of the IGHMBP2 gene should be performed. PMID:26709713

  17. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

    PubMed Central

    Wishart, Thomas M.; Mutsaers, Chantal A.; Riessland, Markus; Reimer, Michell M.; Hunter, Gillian; Hannam, Marie L.; Eaton, Samantha L.; Fuller, Heidi R.; Roche, Sarah L.; Somers, Eilidh; Morse, Robert; Young, Philip J.; Lamont, Douglas J.; Hammerschmidt, Matthias; Joshi, Anagha; Hohenstein, Peter; Morris, Glenn E.; Parson, Simon H.; Skehel, Paul A.; Becker, Thomas; Robinson, Iain M.; Becker, Catherina G.; Wirth, Brunhilde; Gillingwater, Thomas H.

    2014-01-01

    The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA. PMID:24590288

  18. Genetic findings of Cypriot spinal muscular atrophy patients.

    PubMed

    Theodorou, L; Nicolaou, P; Koutsou, P; Georghiou, A; Anastasiadou, V; Tanteles, G; Kyriakides, T; Zamba-Papanicolaou, E; Christodoulou, K

    2015-10-01

    Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families. PMID:26017350

  19. GEMINs: potential therapeutic targets for spinal muscular atrophy?

    PubMed Central

    Borg, Rebecca; Cauchi, Ruben J.

    2014-01-01

    The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the survival motor neuron 1 (SMN1) gene but retain one or more copies of SMN2, a homolog that is incorrectly spliced. Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development. PMID:25360080

  20. Perceptions of Equine Assisted Activities and Therapies by Parents and Children with Spinal Muscular Atrophy

    PubMed Central

    Lemke, Danielle; Rothwell, Erin; Newcomb, Tara M.; Swoboda, Kathryn J.

    2014-01-01

    Purpose To identify the physical and psychosocial effects of equine assisted activities and therapies (EAAT) on children with Spinal Muscular Atrophy (SMA) from the perspective of the child and their parents. Methods The families of all eligible children with SMA, who reported participation in EAAT, from a western metropolitan academic center were contacted and invited to participate. This study implemented qualitative, semi-structured interviews of children with SMA and their parents. Results Three themes emerged from the qualitative content analysis: physical/psychosocial benefits; relationship development with the horses, instructors, and children; and barriers to continued EAAT engagement. Conclusions The data suggest the overall EAAT experience was a source of enjoyment, self-confidence, and normalcy for the children with SMA. The results of this study provide preliminary support for the use of EAAT among children with SMA. PMID:24675128

  1. Analysis of the C9orf72 gene in spinal muscular atrophy patients.

    PubMed

    Alías, Laura; Bernal, Sara; Barceló, Maria J; Martínez-Hernández, Rebeca; Martínez, Elisabeth; Baiget, Montserrat; Tizzano, Eduardo F

    2014-12-01

    Spinal muscular atrophy and amyotrophic lateral sclerosis are both motor neuron disorders. Several studies have tried to establish a link between the two diseases but the subject is still under debate. In amyotrophic lateral sclerosis, large expansions of the hexanucleotide GGGGCC in intron 1 of the C9orf72 gene are responsible for a variable percentage of familial and sporadic cases. We investigated whether the number of the hexanucleotide repeat in C9orf72 was associated with the phenotype and the number of SMN2 copies in a group of 162 SMA patients. Conventional PCR, repeat primed-PCR and Southern blot were used to determine repeat number and characterize large expansions. Results showed that no pathological (> 30 repeats) or premutated alleles (20-30 repeats) were found. The allelic distribution of the C9orf72 gene in spinal muscular atrophy patients overlapped with the data obtained in our control population, discarding putative repeats that may be associated with the disease. No association was observed with either the SMA phenotype or the number of SMN2 copies. In conclusion, the involvement of C9orf72 as a genetic modifier in spinal muscular atrophy is unlikely. Current investigation of modifier genes in SMA and of the link between ALS and SMA should consider other possible candidates. PMID:24998634

  2. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice

    PubMed Central

    Heier, Christopher R.; Satta, Rosalba; Lutz, Cathleen; DiDonato, Christine J.

    2010-01-01

    Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success. PMID:20693262

  3. Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13

    SciTech Connect

    Francis, M.J.; Nesbit, M.A.; Theodosiou, A.M.

    1995-05-20

    The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, the authors identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, they have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed. 20 refs., 1 fig.

  4. A multicopy dinucleotide marker that maps close to the spinal muscular atrophy gene

    SciTech Connect

    Burghes, A.H.M.; Ingraham, S.E.; Kote-Jarai, Z.; Carpten, J.D.; DiDonato, C.J. ); McLean, M.; Surh, L. ); Thompson, T.G.; McPherson, J.D. ); Ikeda, J.E. ); Wirth, B. )

    1994-05-15

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder resulting in loss of motor neurons. The interval containing the SMA gene has been defined by linkage analysis as 5qcen-D5S435-SMA-D5S557-5qter. The authors have isolated a new dinucleotide repeat marker, CATT1, that lies between these two closest markers. The marker CATT1 has 16 alleles and is highly polymorphic. The marker can have 1 to 4 (or more) copies per chromosome, giving rise to individuals with up to 8 (or more) alleles. All of the subloci map between the markers D5S557 and D5S435 and lie in close proximity to one another. The marker CATT1 is linked to the SMA gene with a lod score of Z[sub max] = 34.42 at [theta] = 0 and crosses all available recombinants. Certain alleles occurred more frequently in either the SMA or normal populations, indicating significant allelic association between CATT1 and the SMA locus. Haplotype analysis combining US and Canadian SMA families reveals that one haplotype group (VII) occurs significantly more frequently in the SMA population than in the normal. This confirms the allelic association of CATT1 with the SMA locus. 37 refs., 4 figs., 3 tabs.

  5. Linkage disequilibrium and haplotype analysis among Polish families with spinal muscular atrophy

    SciTech Connect

    Brzustowicz, L.M.; Wang, C.H.; Matseoane, D.; Kleyn, P.W.; Vitale, E.; Das, K.; Penchaszadeh, G.K.; Gilliam, T.C.; Munsat, T.L.; Hausmanowa-Petrusewicz, I.

    1995-01-01

    Spinal muscular atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simple sequence repeat markers were genotyped against 32 Polish families with SMA. The markers span an {approximately}0.7 cM region defined by the SMA flanking markers D5S435 and MAP1B. Significant linkage disequilibrium (corrected P<0.5) was detected at four of these markers, with D/D{sub max} values of {le}.89. Extended haplotype analysis revealed a predominant haplotype associated with SMA. The apparently high mutation rate of some of the markers has resulted in a number of haplotypes that vary slightly from this predominant haplotype. The predominant haplotype and these closely related patterns represent 25% of the disease chromosomes and none of the nontransmitted parental chromosomes. This predominant haplotype is present both in patients with acute (type I) and in chronic (types II and III) forms of SMA and occurs twice in a homozygous state, both times in children with chronic SMA. 34 refs., 2 figs., 2 tabs.

  6. Proteomic assessment of a cell model of spinal muscular atrophy

    PubMed Central

    2011-01-01

    Background Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), a neuromuscular disease characterized by spinal motor neuron death and muscle paralysis. Complete loss of the SMN protein is embryonically lethal, yet reduced levels of this protein result in selective death of motor neurons. Why motor neurons are specifically targeted by SMN deficiency remains to be determined. In this study, embryonic stem (ES) cells derived from a severe SMA mouse model were differentiated into motor neurons in vitro by addition of retinoic acid and sonic hedgehog agonist. Proteomic and western blot analyses were used to probe protein expression alterations in this cell-culture model of SMA that could be relevant to the disease. Results When ES cells were primed with Noggin/fibroblast growth factors (bFGF and FGF-8) in a more robust neural differentiation medium for 2 days before differentiation induction, the efficiency of in vitro motor neuron differentiation was improved from ~25% to ~50%. The differentiated ES cells expressed a pan-neuronal marker (neurofilament) and motor neuron markers (Hb9, Islet-1, and ChAT). Even though SMN-deficient ES cells had marked reduced levels of SMN (~20% of that in control ES cells), the morphology and differentiation efficiency for these cells are comparable to those for control samples. However, proteomics in conjunction with western blot analyses revealed 6 down-regulated and 14 up-regulated proteins with most of them involved in energy metabolism, cell stress-response, protein degradation, and cytoskeleton stability. Some of these activated cellular pathways showed specificity for either undifferentiated or differentiated cells. Increased p21 protein expression indicated that SMA ES cells were responding to cellular stress. Up-regulation of p21 was confirmed in spinal cord tissues from the same SMA mouse model from which the ES cells were derived. Conclusion SMN-deficient ES cells provide a

  7. Feeding problems and malnutrition in spinal muscular atrophy type II.

    PubMed

    Messina, Sonia; Pane, Marika; De Rose, Paola; Vasta, Isabella; Sorleti, Domenica; Aloysius, Annie; Sciarra, Federico; Mangiola, Fortunato; Kinali, Maria; Bertini, Enrico; Mercuri, Eugenio

    2008-05-01

    The aim of the study was to conduct a survey using a dedicated questionnaire to assess feeding difficulties and weight gain in a population of 122 Spinal Muscular Atrophy (SMA) type II patients, aged between 1 and 47 years. All the answers were entered in a database and were analysed subdividing the cohort into age groups (1-5, 6-10, 11-14, 15-19, 20-29, and 30-50 years). Six out of our 122 patients (5%), all younger than 11 years, had weights more than 2SD above the median for age matched controls, whilst 45 (37%) had weights less than 2SD below the median. Chewing difficulties were reported in 34 of the 122 patients (28%) and limitation in the ability to open the mouth in 36 (30%) and both were increasingly more frequent with age. Swallowing difficulties were reported in 30 patients (25%). The results of our survey suggest that a number of patients with SMA type II have limited jaw opening, and chewing and swallowing difficulties. Our findings raise a few issues concerning standards of care that should be implemented in the monitoring and management of feeding difficulties and weight gain. PMID:18420410

  8. Towards identification of the gene for spinal muscular atrophy

    SciTech Connect

    Steege, G. van der; Cobben, J.M.; Draaijers, T.G.

    1994-09-01

    The proximal spinal muscular atrophies (SMAs) are irreversible lower motor neuron diseases of unknown primary cause. According to age of onset and severity of illness, this group of disorders can be classified into three types: SMA types I, II, and III. All three types of autosomal recessive SMA have been localized to chromosome 5 in bands of q11.2-q13 by genetic analysis. The gene resides in a small genetic interval flanked by the markers D5S435 and D5S557. From a hybrid cell line containing 5q11-q14 as its only human chromosome 5 material we constructed a cosmid library. A cosmid clone mapped by FISH between D5S125 and D5S112 was used to isolate some YACs, from which cosmid libraries were constructed. cDNA libraries are screened by hybridization directly with the YACs and with cosmids that give Northern signals. At present we are analysing 7 different cDNA clones mapping between D5S435 and D5S557.

  9. Clinical Commentary: Obstetric and Respiratory Management of Pregnancy with Severe Spinal Muscular Atrophy

    PubMed Central

    Flunt, Daniel; Andreadis, Natasha; Menadue, Collette; Welsh, Alec W.

    2009-01-01

    We present a combined obstetric and respiratory perspective on two pregnancies for a woman with severe Type 2 Spinal Muscular Atrophy (SMA). Our patient had the lowest prepregnancy weight (20 kg) and vital capacity of 0.34 L (VC 11% predicted) yet to be reported in the sparse literature on pregnancy with SMA. She delivered two live healthy infants via planned caesarean section without pregnancy or neonatal complication. We describe the respiratory and obstetric management techniques used for a pregnancy with this degree of respiratory compromise. PMID:19960049

  10. Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy.

    PubMed Central

    Talbot, K; Rodrigues, N; Bernert, G; Bittner, R; Davies, K

    1996-01-01

    Spinal muscular atrophy is an autosomal recessive disease of motor neurone degeneration which shows a variable phenotype. Two candidate genes show deletions in affected subjects but with no distinction between different forms of the disease. We report an unusual family in which mild and severe SMA coexists and patients are deleted for the SMN gene. The father is affected with late onset SMA; therefore this family shows pseudodominant inheritance. When typed using closely linked flanking markers the severely affected son does not share the same haplotype as his sib, who is deleted for SMN but shows no signs yet of SMA. This supports the hypothesis that differences in SMA phenotype can be explained by a multiple allele model. Images PMID:9004135

  11. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy

    PubMed Central

    Harms, M.B.; Ori-McKenney, K.M.; Scoto, M.; Tuck, E.P.; Bell, S.; Ma, D.; Masi, S.; Allred, P.; Al-Lozi, M.; Reilly, M.M.; Miller, L.J.; Jani-Acsadi, A.; Pestronk, A.; Shy, M.E.; Muntoni, F.; Vallee, R.B.

    2012-01-01

    Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance. PMID:22459677

  12. Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene

    SciTech Connect

    Melki, J.; Burlet, P.; Clermont, O.; Pascal, F.; Paul, B.; Abdelhak, S.; Munnich, A. ); Sherrington, R.; Gurling, H. Middlesex School of Medicine, London ); Nakamura, Yusuke ); Weissenbach, J. Genethon, Evry ); Lathrop, M. )

    1993-03-01

    The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoing linkage analysis was used to establish the best estimate of the SMA gene location. The data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene. 16 refs., 2 figs., 4 tabs.

  13. Spinal Muscular Atrophy: Diagnosis and Management in a New Therapeutic Era

    PubMed Central

    Arnold, W. David; Kassar, Darine; Kissel, John T.

    2014-01-01

    Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. PMID:25346245

  14. Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy

    PubMed Central

    Sen, Anindya; Dimlich, Douglas N.; Guruharsha, K. G.; Kankel, Mark W.; Hori, Kazuya; Yokokura, Takakazu; Brachat, Sophie; Richardson, Delwood; Loureiro, Joseph; Sivasankaran, Rajeev; Curtis, Daniel; Davidow, Lance S.; Rubin, Lee L.; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyros

    2013-01-01

    The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA. PMID:23757500

  15. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

    PubMed Central

    Butchbach, Matthew E. R.

    2016-01-01

    Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases. PMID:27014701

  16. Neurodegeneration in spinal muscular atrophy: from disease phenotype and animal models to therapeutic strategies and beyond

    PubMed Central

    Monani, Umrao R; De Vivo, Darryl C

    2014-01-01

    Of the numerous inherited diseases known to afflict the pediatric population, spinal muscular atrophy (SMA) is among the most common. It has an incidence of approximately one in 10,000 newborns and a carrier frequency of one in 50. Despite its relatively high incidence, SMA remains somewhat obscure among the many neurodegenerative diseases that affect humans. Nevertheless, the last two decades have witnessed remarkable progress in our understanding of the pathology, underlying biology and especially the molecular genetics of SMA. This has led to a genuine expectation within the scientific community that a robust treatment will be available to patients before the end of the decade. The progress made in our understanding of SMA and, therefore, towards a viable therapy for affected individuals is in large measure a consequence of the simple yet fascinating genetics of the disease. Nevertheless, important questions remain. Addressing these questions promises not only to accelerate the march towards a cure for SMA, but also to uncover novel therapies for related neurodegenerative disorders. This review discusses our current understanding of SMA, considers the challenges ahead, describes existing treatment options and highlights state-of-the-art research being conducted as a means to a better, safer and more effective treatment for the disease. PMID:24648831

  17. Clinical and Genetic Study of Algerian Patients with Spinal Muscular Atrophy.

    PubMed

    Sifi, Y; Sifi, K; Boulefkhad, A; Abadi, N; Bouderda, Z; Cheriet, R; Magen, M; Bonnefont, J P; Munnich, A; Benlatreche, C; Hamri, A

    2013-01-01

    Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder. It is divided into the acute Werdnig-Hoffmann disease (type I), the intermediate form (type II), the Kugelberg-Welander disease (type III), and the adult form (type IV). The gene involved in all four forms of SMA, the so-called survival motor neuron (SMN) gene, is duplicated, with a telomeric (tel SMN or SMN1) and a centromeric copy (cent SMN or SMN2). SMN1 is homozygously deleted in over 95% of SMA patients. Another candidate gene in SMA is the neuronal apoptosis inhibitory protein (NAIP) gene; it shows homozygous deletions in 45-67% of type I and 20-42% of type II/type III patients. Here we studied the SMN and NAIP genes in 92 Algerian SMA patients (20 type I, 16 type II, 53 type III, and 3 type IV) from 57 unrelated families, using a semiquantitative PCR approach. Homozygous deletions of SMN1 exons 7 and/or 8 were found in 75% of the families. Deletions of exon 4 and/or 5 of the NAIP gene were found in around 25%. Conversely, the quantitative analysis of SMN2 copies showed a significant correlation between SMN2 copy number and the type of SMA. PMID:26317002

  18. Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations

    SciTech Connect

    Rudnik-Schoeneborn, S.; Zerres, K.; Hahnen, E.

    1996-11-01

    With the evidence that deletions in the region responsible for childhood- and juvenile-onset proximal spinal muscular atrophy (SMA) are on chromosome 5 it is now possible to confirm autosomal recessive inheritance in most patients (denoted {open_quotes}SMA 5q{close_quotes}). Homozygous deletions in the telomeric copy of the survival motor neuron (SMN) gene can be detected in 95%-98% of patients with early-onset SMA (types I and II), whereas as many as 10%-20% of patients with the milder, juvenile-onset form (type III SMA) do not show deletions. In families with affected subjects in two generations, it is difficult to decide whether they are autosomal dominantly inherited or caused by three independent recessive mutations (pseudodominant inheritance). Given an incidence of >1/10,000 of SMA 5q, patients with autosomal recessive SMA have an {approximately}1% recurrence risk to their offspring. Although the dominant forms are not linked to chromosome 5q, pseudodominant families can now be identified by the presence of homozygous deletions in the SMN gene. 5 refs., 1 fig., 1 tab.

  19. Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy* #

    PubMed Central

    Cao, Yan-yan; Qu, Yu-jin; He, Sheng-xi; Li, Yan; Bai, Jin-li; Jin, Yu-wei; Wang, Hong; Song, Fang

    2016-01-01

    The homozygous loss of the survival motor neuron 1 (SMN1) gene is the primary cause of spinal muscular atrophy (SMA), a neuromuscular degenerative disease. A genetically similar gene, SMN2, which is not functionally equivalent in all SMA patients, modifies the clinical SMA phenotypes. We analyzed the methylation levels of 4 CpG islands (CGIs) in SMN2 in 35 Chinese children with SMA by MassARRAY. We found that three CpG units located in CGI 1 (nucleotides (nt) −871, −735) and CGI 4 (nt +999) are significantly hypomethylated in SMA type III compared with type I or II children after receiving Bonferroni correction. In addition to the differentially methylated CpG unit of nt −871, the methylation level of the nt −290/−288/−285 unit was negatively correlated with the expression of SMN2 full-length transcripts (SMN2-fl). In addition, the methylation level at nt +938 was inversely proportional to the ratio of SMN2-fl and lacking exon 7 transcripts (SMN2-(7, fl/(7), and was not associated with the SMN2 transcript levels. Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription. PMID:26739529

  20. Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy.

    PubMed

    Sasongko, Teguh H; Salmi, Abd Razak; Zilfalil, Bin Alwi; Albar, Mohammed Ali; Mohd Hussin, Zabidi Azhar

    2010-01-01

    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA. PMID:21060155

  1. Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy

    PubMed Central

    Sasongko, Teguh H.; Salmi, Abd Razak; Zilfalil, Bin Alwi; Albar, Mohammed Ali; Mohd Hussin, Zabidi Azhar

    2010-01-01

    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA. PMID:21060155

  2. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  3. Spinal muscular atrophy type III: Molecular genetic characterization of Turkish patients.

    PubMed

    Bora-Tatar, Gamze; Yesbek-Kaymaz, Ayse; Bekircan-Kurt, Can Ebru; Erdem-Özdamar, Sevim; Erdem-Yurter, Hayat

    2015-12-01

    Spinal Muscular Atrophy (SMA) is a neurodegenerative disease with autosomal recessive inheritance. Homozygous loss of exon 7 of the Survival of motor neuron 1 (SMN1) gene is the main cause of SMA. Although progressive muscle weakness and atrophy are common symptoms, disease severity varies from severe to mild. Type III is one of the milder and less frequent forms of SMA. In this study, we report molecular genetic characteristics of 24 Turkish type III SMA patients. Homozygous loss of SMN1 exon 7 and 8 was analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex ligation dependent probe amplification (MLPA). SMN2, homologue of SMN1, and Neuronal apoptosis inhibitory protein (NAIP) genes were also evaluated considering their influence on disease severity. We determined that male patients who were born in consanguineous families were predominant in our cohort and these patients mostly carry the homozygous loss of SMN1 exon 7 and 8 and four copies of SMN2 gene without NAIP deletions. PMID:26548498

  4. Construction of a yeast artifical chromosome contig spanning the spinal muscular atrophy disease gene region

    SciTech Connect

    Kleyn, P.W.; Wang, C.H.; Vitale, E.; Pan, J.; Ross, B.M.; Grunn, A.; Palmer, D.A.; Warburton, D.; Brzustowicz, L.M.; Gilliam, T.G. ); Lien, L.L.; Kunkel, L.M. )

    1993-07-15

    The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. 26 refs., 3 figs., 1 tab.

  5. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy

    SciTech Connect

    Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. )

    1994-07-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

  6. A mixed methods exploration of families' experiences of the diagnosis of childhood spinal muscular atrophy.

    PubMed

    Lawton, Sally; Hickerton, Chriselle; Archibald, Alison D; McClaren, Belinda J; Metcalfe, Sylvia A

    2015-05-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 in Australia. Childhood SMA is classified into three types based on the age at which children present with symptoms and the clinical severity. Families' experiences leading up to the diagnosis have not been described, but are important when considering the potential for a diagnostic odyssey. Using a mixed methods approach, data were collected from interviews and a national survey of families of children with SMA to explore their experiences of this journey. The combined findings (n=28) revealed that the journey to receiving a diagnosis was protracted. The time from first noticing symptoms to finally receiving a diagnosis was emotional and frustrating. Once parents or other family members became aware of symptoms, almost all had consulted with multiple different health professionals before the diagnosis was ultimately made. Not surprisingly, receiving the diagnosis was devastating to the families. The nature of the information and the way it was given to them was not always optimal, particularly because of the difficulties predicting clinical severity. Most felt that their child could have been diagnosed earlier and, although there were mixed views around the benefit of this for their child, they felt it may have reduced the emotional impact on families. Overall, families were more in favour of population carrier screening for SMA when compared with newborn screening of the population. Despite an increasing awareness of SMA, the diagnostic delay continues to have negative impacts on families. PMID:25074464

  7. Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

    PubMed Central

    Cherry, Jonathan J.; Kobayashi, Dione T.; Lynes, Maureen M.; Naryshkin, Nikolai N.; Tiziano, Francesco Danilo; Zaworski, Phillip G.; Rubin, Lee L.

    2014-01-01

    Abstract Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons of the anterior horn and proximal muscle weakness. It is the leading cause of genetic mortality in children younger than 2 years. It affects ∼1 in 11,000 live births. In 95% of cases, SMA is caused by homozygous deletion of the SMN1 gene. In addition, all patients possess at least one copy of an almost identical gene called SMN2. A single point mutation in exon 7 of the SMN2 gene results in the production of low levels of full-length survival of motor neuron (SMN) protein at amounts insufficient to compensate for the loss of the SMN1 gene. Although no drug treatments are available for SMA, a number of drug discovery and development programs are ongoing, with several currently in clinical trials. This review describes the assays used to identify candidate drugs for SMA that modulate SMN2 gene expression by various means. Specifically, it discusses the use of high-throughput screening to identify candidate molecules from primary screens, as well as the technical aspects of a number of widely used secondary assays to assess SMN messenger ribonucleic acid (mRNA) and protein expression, localization, and function. Finally, it describes the process of iterative drug optimization utilized during preclinical SMA drug development to identify clinical candidates for testing in human clinical trials. PMID:25147906

  8. Defects in neuromuscular junction remodelling in the Smn(2B/-) mouse model of spinal muscular atrophy.

    PubMed

    Murray, Lyndsay M; Beauvais, Ariane; Bhanot, Kunal; Kothary, Rashmi

    2013-01-01

    Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease caused by mutations and deletions within the survival motor neuron 1 (SMN1) gene. Although other tissues may be involved, motor neurons remain primary pathological targets, with loss of neuromuscular junctions (NMJs) representing an early and significant event in pathogenesis. Although defects in axonal outgrowth and pathfinding have been observed in cell culture and in lower organisms upon Smn depletion, developmental defects in mouse models have been less obvious. Here, we have employed the Smn(2B/-) mouse model to investigate NMJ remodelling during SMA pathology, induced reinnervation, and paralysis. We show that whilst NMJs are capable of remodelling during pathogenesis, there is a marked reduction in paralysis-induced remodelling and in the nerve-directed re-organisation of acetylcholine receptors. This reduction in remodelling potential could not be attributed to a decreased rate of axonal growth. Finally, we have identified a loss of terminal Schwann cells which could contribute to the defects in remodelling/maintenance observed. Our work demonstrates that there are specific defects in NMJ remodelling in an intermediate SMA mouse model, which could contribute to or underlie pathogenesis in SMA. The development of strategies that can promote the remodelling potential of NMJs may therefore be of significant benefit to SMA patients. PMID:22960106

  9. Refinement of the spinal muscular atrophy locus by genetic and physical mapping

    SciTech Connect

    Wang, C.H.; Kleyn, P.W.; Vitale, E.; Ross, B.M.; Xu, J.; Carter, T.A.; Brzustowicz, L.M.; Obici, S.; Lien, L.; Selig, S.

    1995-01-01

    We report the mapping and characterization of 12 microsatellite markers including 11 novel markers. All markers were generated from overlapping YAC clones that span the spinal muscular atrophy (SMA) locus. PCR amplification of 32 overlapping YAC clones show that 9 of the new markers (those set in italics) map to the interval between the two previous closest flanking markers (D5S629 and D5S557):cen - D5S6 - D5S125 - D5S435 - D5S1407 - D5S629 - D5S1410 - D5S1411/D5S1412 - D5S1413 - D5S1414 - D5Z8 - D5Z9 - CATT1 - D5Z10/D5Z6 - D5S557 - D5S1408 - D5S1409 - D5S637 - D5S351 - MAP1B - tel. Four of these new markers detect multiple loci in and out of the SMA gene region. Genetic analysis of recombinant SMA families indicates that D5S1413 is a new proximal flanking locus for the SMA gene. Interestingly, among the 40 physically mapped loci, the 14 multilocus markers map contiguously to a genomic region that overlaps, and perhaps helps define, the minimum genetic region encompassing the SMA gene(s). 24 refs., 5 figs., 1 tab.

  10. Respiratory management of spinal muscular atrophy type 2.

    PubMed

    Gormley, Maurade C

    2014-12-01

    Respiratory insufficiency is the primary cause of morbidity and mortality among patients with spinal muscular atrophy type 2. The primary complications include ineffective cough with decreased airway clearance, nocturnal hypoventilation, diminished lung and chest wall development, and increased risk for pulmonary infection. Respiratory devices including mechanical insufflator-exsufflator and bilevel positive airway pressure are the primary devices of respiratory maintenance and treatment and are associated with decreased morbidity and fewer hospital admissions. This article discusses the primary respiratory complications of spinal muscular atrophy type 2 and the role of respiratory interventions to promote growth and development, improve cough efficacy, reverse nocturnal hypoventilation, and prevent and treat pulmonary infection. PMID:25365058

  11. An ~140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival

    PubMed Central

    Fyfe, John C.; Menotti-Raymond, Marilyn; David, Victor A.; Brichta, Lars; Schäffer, Alejandro A.; Agarwala, Richa; Murphy, William J.; Wedemeyer, William J.; Gregory, Brittany L.; Buzzell, Bethany G.; Drummond, Meghan C.; Wirth, Brunhilde; O'Brien, Stephen J.

    2006-01-01

    The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an ~140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found. PMID:16899656

  12. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part of ... spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of muscles ...

  13. Neuromuscular Junctions as Key Contributors and Therapeutic Targets in Spinal Muscular Atrophy

    PubMed Central

    Boido, Marina; Vercelli, Alessandro

    2016-01-01

    Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, representing the most common fatal pediatric pathology. Even though, classically and in a simplistic way, it is categorized as a motor neuron (MN) disease, there is an increasing general consensus that its pathogenesis is more complex than expected. In particular, neuromuscular junctions (NMJs) are affected by dramatic alterations, including immaturity, denervation and neurofilament accumulation, associated to impaired synaptic functions: these abnormalities may in turn have a detrimental effect on MN survival. Here, we provide a description of NMJ development/maintenance/maturation in physiological conditions and in SMA, focusing on pivotal molecules and on the time-course of pathological events. Moreover, since NMJs could represent an important target to be exploited for counteracting the pathology progression, we also describe several therapeutic strategies that, directly or indirectly, aim at NMJs. PMID:26869891

  14. Autophagy dysregulation in cell culture and animals models of spinal muscular atrophy.

    PubMed

    Custer, Sara K; Androphy, Elliot J

    2014-07-01

    Abnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remain unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam. PMID:24983518

  15. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.

    PubMed

    Woll, Matthew G; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G; Naryshkin, Nikolai A; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M

    2016-07-14

    The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA. PMID:27299569

  16. A novel method for oral delivery of drug compounds to the neonatal SMNΔ7 mouse model of spinal muscular atrophy

    PubMed Central

    Butchbach, Matthew E. R.; Edwards, Jonathan D.; Schussler, Kristie R.; Burghes, Arthur H. M.

    2009-01-01

    Spinal muscular atrophy (SMA) is a devastating motor neuron disease that is one of the leading genetic causes of infant mortality. Currently, there is no cure for SMA. Mouse models that genetically and phenotypically resemble SMA have been generated and have the potential to be used for the discovery of novel therapeutics. Oral administration is a commonly used mode of drug delivery in humans as well as in rodents. Unfortunately, there is no method of drug delivery that can accurately and reliably deliver drug compounds orally to neonatal mice. In this report, we describe a novel method to orally administer compounds to neonatal SMA mice. Oral delivery to neonatal mice, usually starting at postnatal day 4 (PND04), is both rapid and safe to the pup. Oral delivery of two different commonly used vehicle formulations, distilled water and 2-hydroxypropyl-β-cyclodextrin, does not affect the survival of SMA mice. After oral delivery for 3 days, 5-bromo-2′-deoxyuridine could be detected in the kidneys, brains and spinal cords of treated non-SMA as well as SMA neonatal pups. In conclusion, we have developed a method by which drugs can be safely and reliably administered orally to neural targets of neonatal mice. This approach offers a simple and rapid means by which potential therapeutics for SMA can be identified. PMID:17161463

  17. Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene.

    PubMed

    Alías, L; Barceló, M J; Bernal, S; Martínez-Hernández, R; Also-Rallo, E; Vázquez, C; Santana, A; Millán, J M; Baiget, M; Tizzano, E F

    2014-05-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling. PMID:23799925

  18. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, João Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  19. IPLEX Administration Improves Motor Neuron Survival and Ameliorates Motor Functions in a Severe Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Murdocca, Michela; Malgieri, Arianna; Luchetti, Andrea; Saieva, Luciano; Dobrowolny, Gabriella; de Leonibus, Elvira; Filareto, Antonio; Quitadamo, Maria Chiara; Novelli, Giuseppe; Musarò, Antonio; Sangiuolo, Federica

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA. PMID:22669476

  20. Isolation of cDNAs from the spinal muscular atrophy gene region with yeast artificial chromosomes

    SciTech Connect

    Deng, H.X.; He, X.X.; Hung, W.Y.

    1994-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of anterior horn cells, leading to progressive paralysis of voluntary muscles. The SMA gene(s) is located at 5q11.2-q13.3, between D5S435 and D5S112. To isolate potential candidate gene(s) responsible for SMA, we used the YACs within the SMA gene region as probes to screen a human brainstem cDNA library. Thirteen cDNA clones were isolated. Their sizes range from 0.7 kb to 5 kb. Seven clones were found to be unique in sequence; the remaining six clones contain repetitive sequences. Five out of these seven unique clones have been used as probes to screen a phage genomic DNA library. Phage genomic clones isolated with individual unique cDNA were used for fluorescence in situ hybridization to identify the origin of cDNAs. These five unique sequences are all located in the 5q13 region, indicating the reliability of our screening method. All the thirteen clones have been partially sequenced (about 300 bp) from each end. No homology has been found with any known EST or known genes. No cross hybridization was detected among the unique clones, suggesting that there may be distinct new genes encoded in this region.

  1. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

    PubMed Central

    Azzouz, Mimoun; Le, Thanh; Ralph, G. Scott; Walmsley, Lucy; Monani, Umrao R.; Lee, Debbie C.P.; Wilkes, Fraser; Mitrophanous, Kyriacos A.; Kingsman, Susan M.; Burghes, Arthur H.M.; Mazarakis, Nicholas D.

    2004-01-01

    Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed. PMID:15599397

  2. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy.

    PubMed

    Azzouz, Mimoun; Le, Thanh; Ralph, G Scott; Walmsley, Lucy; Monani, Umrao R; Lee, Debbie C P; Wilkes, Fraser; Mitrophanous, Kyriacos A; Kingsman, Susan M; Burghes, Arthur H M; Mazarakis, Nicholas D

    2004-12-01

    Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed. PMID:15599397

  3. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches. PMID:26681261

  4. Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed Central

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

  5. ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

    PubMed

    Heier, Christopher R; DiDonato, Christine J

    2015-01-01

    Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. PMID:25553367

  6. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy

    PubMed Central

    Avila, Amy M.; Burnett, Barrington G.; Taye, Addis A.; Gabanella, Francesca; Knight, Melanie A.; Hartenstein, Parvana; Cizman, Ziga; Di Prospero, Nicholas A.; Pellizzoni, Livio; Fischbeck, Kenneth H.; Sumner, Charlotte J.

    2007-01-01

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression. Repeated daily doses of TSA caused increases in both SMN2-derived transcript and SMN protein levels in neural tissues and muscle, which were associated with an improvement in small nuclear ribonucleoprotein (snRNP) assembly. When TSA was delivered daily beginning on P5, after the onset of weight loss and motor deficit, there was improved survival, attenuated weight loss, and enhanced motor behavior. Pathological analysis showed increased myofiber size and number and increased anterior horn cell size. These results indicate that the hydroxamic acid class of HDAC inhibitors activates SMN2 gene expression in vivo and has an ameliorating effect on the SMA disease phenotype when administered after disease onset. PMID:17318264

  7. Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery. Methods We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies. Results By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients. Conclusions We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in

  8. Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

    PubMed

    Jamrozik, Z; Lugowska, A; Gołębiowski, M; Królicki, L; Mączewska, J; Kuźma-Kozakiewicz, M

    2013-09-25

    A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID:23820084

  9. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Have Reduced Expression of Proteins Important in Neuronal Development

    PubMed Central

    Fuller, Heidi R.; Mandefro, Berhan; Shirran, Sally L.; Gross, Andrew R.; Kaus, Anjoscha S.; Botting, Catherine H.; Morris, Glenn E.; Sareen, Dhruv

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA. PMID:26793058

  10. Use of genetic and physical mapping to locate the spinal muscular atrophy locus between two new highly polymorphic DNA markers

    SciTech Connect

    Clermont, O.; Burlet, P.; Burglen, L.; Lefebvre, S.; Pascal, F.; McPherson, J.; Wasmuth, J.J.; Cohen, D.; Le Paslier, D.; Weissenbach, J.

    1994-04-01

    The gene for autosomal recessive forms of spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q13, within a 4-cM region between the blocks D5S465/D5S125 and MAP-1B/D5S112. The authors identified two new highly polymorphic microsatellite DNA markers - namely, AFM265wf5 (D5S629) and AFM281yh9 (D5S637) - which are the closest markers to the SMA locus. Multilocus analysis by the location-score method was used to establish the best estimate of the SMA gene location. The data suggest that the most likely location for SMA is between locus D5S629 and the block D5S637/D5S351/MAP-1B/D5S112/D5S357. Genetic analysis of inbred SMA families, based on homozygosity by descent and physical mapping using meta-YACs, gave additional information for the loci order as follows: cen-D5S6-D5S125/D5S465-D5S435-D5S629-SMA-D5S637-D5S351-MAP-1B/D5S112-D5S357-D5S39-tel. These data give the direction for bidirectional walking in order to clone this interval and isolate the SMA gene. 16 refs., 4 figs., 2 tabs.

  11. Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

    PubMed

    Sintusek, Palittiya; Catapano, Francesco; Angkathunkayul, Napat; Marrosu, Elena; Parson, Simon H; Morgan, Jennifer E; Muntoni, Francesco; Zhou, Haiyan

    2016-01-01

    Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome. PMID:27163330

  12. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Have Reduced Expression of Proteins Important in Neuronal Development.

    PubMed

    Fuller, Heidi R; Mandefro, Berhan; Shirran, Sally L; Gross, Andrew R; Kaus, Anjoscha S; Botting, Catherine H; Morris, Glenn E; Sareen, Dhruv

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA. PMID:26793058

  13. Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

    PubMed Central

    Sintusek, Palittiya; Catapano, Francesco; Angkathunkayul, Napat; Marrosu, Elena; Parson, Simon H.; Morgan, Jennifer E.; Muntoni, Francesco; Zhou, Haiyan

    2016-01-01

    Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome. PMID:27163330

  14. SMN protein analysis in fibroblast, amniocyte and CVS cultures from spinal muscular atrophy patients and its relevance for diagnosis.

    PubMed

    Patrizi, A L; Tiziano, F; Zappata, S; Donati, M A; Neri, G; Brahe, C

    1999-04-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the homozygous absence of the telomeric copy of the survival motor neuron (SMNt) gene, due to deletion, gene conversion or point mutation. SMNt and its homologous centromeric copy (SMNc) encode the SMN protein, which is diffusely present in the cytoplasm and in dot-like structures, called gems, in the nucleus. We have studied the SMN protein in different cell cultures, including fibroblasts, amniocytes and CVS cells from SMA individuals and controls. By immunofluorescence analysis we found a marked reduction in the number of gems in fibroblasts, amniocytes and chorionic villus cells of all SMA patients and foetuses, independent of the type of the genetic defect. We also show that immunolocalisation of the SMN protein may be a useful tool for the characterisation of particular patients of uncertain molecular diagnosis. PMID:10234506

  15. Preventable Sternocleidomastoid Muscular Atrophy after Neck Dissection

    PubMed Central

    Yamamoto, Nao; Sawai, Natsuko Yoshimura; Ishimoto, Shunsuke; Ogura, Hide; Aikawa, Tomonao; Kogo, Mikihiko

    2015-01-01

    Background: Modified radical neck dissection (mRND) [preserving the sternocleidomastoid muscle (SCM) and the spinal accessory nerve] and supraomohyoid neck dissection have become common surgical procedures for treating head and neck cancer. Postoperative severe asymmetry of the neck and severe atrophy of the SCM, however, have been demonstrated. Methods: Using computed tomographic images, cross-sectional areas of the SCMs were measured in 99 patients with carcinoma of the oral cavity who underwent unilateral mRND or supraomohyoid neck dissection. An asymmetry index was used. Results: Innervation to the SCM was preserved in 91 patients. The spinal accessory nerve and the innervation were sacrificed in 3 patients; the innervation was repaired in 5 patients. Sacrifice of innervation to the SCM resulted in extremely severe asymmetry. Repair of the innervation prevented severe asymmetry in 40%. Preservation of the innervation prevented severe asymmetry in 75% at the middle portion of the neck and in 56% at the lower portion after mRND. Conclusion: Preserving innervation to the SCM and gentle handling of the nerve during neck dissection could prevent severe asymmetry after neck dissection. PMID:26495217

  16. Observational study of spinal muscular atrophy type I and implications for clinical trials

    PubMed Central

    McDermott, Michael P.; Kaufmann, Petra; Darras, Basil T.; Chung, Wendy K.; Sproule, Douglas M.; Kang, Peter B.; Foley, A. Reghan; Yang, Michelle L.; Martens, William B.; Oskoui, Maryam; Glanzman, Allan M.; Flickinger, Jean; Montes, Jacqueline; Dunaway, Sally; O'Hagen, Jessica; Quigley, Janet; Riley, Susan; Benton, Maryjane; Ryan, Patricia A.; Montgomery, Megan; Marra, Jonathan; Gooch, Clifton; De Vivo, Darryl C.

    2014-01-01

    Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I). Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered. Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02). Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design. PMID:25080519

  17. Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling

    PubMed Central

    Dobrowolski, Steven F.; Pham, Ha T.; Pouch-Downes, Frances; Prior, Thomas W.; Naylor, Edwin W.; Swoboda, Kathy J.

    2014-01-01

    BACKGROUND The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn-screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%–98% of affected patients. METHODS We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn-screening tests. RESULTS Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive. CONCLUSIONS This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA-affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening. PMID:22490618

  18. Targeting SR Proteins Improves SMN Expression in Spinal Muscular Atrophy Cells

    PubMed Central

    Hastings, Michelle L.

    2014-01-01

    Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which is nearly identical to SMN1. However, SMN2 cannot compensate for the loss of SMN1 because SMN2 has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from SMN2 lacks exon 7. SMN2 mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving SMN2 exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in SMN2 exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein. Our results identify novel regulators of SMN2 exon 7 inclusion, revealing potential targets for SMA therapeutics. PMID:25506695

  19. TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy

    PubMed Central

    Turner, Bradley J; Bäumer, Dirk; Parkinson, Nicholas J; Scaber, Jakub; Ansorge, Olaf; Talbot, Kevin

    2008-01-01

    Background Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA). Results TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords. Conclusion These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively. PMID:18957104

  20. Prospective cohort study of spinal muscular atrophy types 2 and 3

    PubMed Central

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard S.; Sproule, Douglas M.; Kang, Peter B.; Oskoui, Maryam; Constantinescu, Andrei; Gooch, Clifton L.; Foley, A. Reghan; Yang, Michele L.; Tawil, Rabi; Chung, Wendy K.; Martens, William B.; Montes, Jacqueline; Battista, Vanessa; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Punyanitya, Mark; Montgomery, Megan J.; Marra, Jonathan; Koo, Benjamin

    2012-01-01

    Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers. PMID:23077013

  1. Compensatory mechanisms during walking in response to muscle weakness in spinal muscular atrophy, type III.

    PubMed

    Matjacić, Zlatko; Olensek, Andrej; Krajnik, Janez; Eymard, Bruno; Zupan, Anton; Praznikar, Ales

    2008-05-01

    Our knowledge on altered neurological control of walking due to weakness of various muscle groups of the lower extremities is limited. The aim of this study was to assess kinematic, kinetic and electromyographic (EMG) walking patterns in a functionally homogeneous group of seven subjects with spinal muscular atrophy, type III (SMA group) and compare them with normal data obtained from nine healthy subjects (CONTROL group) in order to identify characteristic compensatory changes. Muscle strength at the ankle and knee joints was assessed using isokinetic dynamometry to determine variability in muscle strength: this was found to be similar in the two groups. Kinematic, kinetic and EMG patterns were assessed during walking in the SMA and CONTROL groups. The results showed changes in the activity of ankle plantarflexors and associated control of the center of pressure during loading response and midstance, which facilitated minimization of the external flexion moment acting on the knee and hip in the SMA group. Additionally, we identified distinct and consistent changes in the control of hip rotators that act to rapidly extend the hip early in stance phase and in the control of contralateral hip abductors that act delay weight shift onto the leg entering the stance phase. From these results we can conclude that the most important muscle groups compensating for reduced strength in knee and hip muscles are the ankle plantarflexors, hip rotators and hip abductors. This finding would have direct application in rehabilitation treatment programs. PMID:17980600

  2. Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy.

    PubMed

    Parra, Juan; Martínez-Hernández, Rebeca; Also-Rallo, Eva; Alias, Laura; Barceló, María Jesús; Amenedo, María; Medina, Carmen; Senosiain, Raquel; Calaf, Joaquim; Baiget, Montserrat; Bernal, Sara; Tizzano, Eduardo F

    2011-02-01

    We studied spinal muscular atrophy (SMA) during human development to identify possible delays or alterations in fetal movements detectable by ultrasound. We evaluated 29 pregnancies at risk for severe SMA performing 2D-ultrasound around 11-14 weeks, prior to prenatal molecular testing of the SMN1 gene. We charted the occurrence of generalized body movements, isolated movements of arms and legs, head movements, startle and hiccup. Fetuses were diagnosed as healthy (n=12), carriers (n=10) or affected (n=7) according to the SMN1 molecular testing results obtained. SMN2 copies were also tested in the seven affected fetuses, six of whom showed two SMN2 copies and one a unique SMN2 copy. The movements under study were observed in all recordings, regardless of group and the SMN2 copies. At the gestational age examined, we did not observe a qualitative early limitation of movements in fetuses with SMA, even in cases predicted to develop a severe neonatal form. PMID:21194946

  3. Evidence of a segregation ratio distortion of SMN1 alleles in spinal muscular atrophy.

    PubMed

    Alias, Laura; Barceló, Maria J; Gich, Ignasi; Estapé, Marta; Parra, Juan; Amenedo, Maria; Baiget, Montserrat; Tizzano, Eduardo F

    2007-10-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterised by degeneration and loss of the motor neurons of the anterior horn of the spinal cord. The absence of SMN1 is determinant to have SMA and parents of SMA patients are regarded as carriers of the disease. We compared the segregation ratio of the mutated allele and the wild-type allele of all the confirmed carrier parents assuming Mendelian proportions. Results of transmissions in 235 prenatal tests and in 128 unaffected siblings showed a statistically significant deviation in favour of the wild-type SMN1 allele. The number of affected foetuses and carriers were lower than that expected. No significant differences in the sex ratio or in the progenitor origin of the transmitted allele to the carriers were found. One hypothesis that has been advanced to account for the distortion observed in affected foetuses is the negative postzygote selection due to early miscarriage. However, given that the number of carriers in our series was lower than expected, prezygote events such as meiotic drive, survival of gametes or preferential fertilisation should also be considered. PMID:17625510

  4. SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

    PubMed Central

    Pagliarini, Vittoria; Pelosi, Laura; Bustamante, Maria Blaire; Nobili, Annalisa; Berardinelli, Maria Grazia; D’Amelio, Marcello; Musarò, Antonio

    2015-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre–messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3′ splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model. PMID:26438828

  5. Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1

    PubMed Central

    Vanoli, Fiammetta; Rinchetti, Paola; Porro, Francesca; Parente, Valeria; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans. PMID:26095024

  6. PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Little, Daniel; Valori, Chiara F; Mutsaers, Chantal A; Bennett, Ellen J; Wyles, Matthew; Sharrack, Basil; Shaw, Pamela J; Gillingwater, Thomas H; Azzouz, Mimoun; Ning, Ke

    2015-01-01

    Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA. PMID:25369768

  7. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID:26123042

  8. Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

    PubMed Central

    Yoshida, Michiko; Kitaoka, Shiho; Egawa, Naohiro; Yamane, Mayu; Ikeda, Ryunosuke; Tsukita, Kayoko; Amano, Naoki; Watanabe, Akira; Morimoto, Masafumi; Takahashi, Jun; Hosoi, Hajime; Nakahata, Tatsutoshi; Inoue, Haruhisa; Saito, Megumu K.

    2015-01-01

    Summary Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients’ motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using MNs derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches. PMID:25801509

  9. Systems Biology Investigation of cAMP Modulation to Increase SMN Levels for the Treatment of Spinal Muscular Atrophy

    PubMed Central

    Mack, Sean G.; Cook, Daniel J.; Dhurjati, Prasad; Butchbach, Matthew E. R.

    2014-01-01

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA. PMID:25514431

  10. Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies

    SciTech Connect

    Wirth, B.; Voosen, B.; Roehrig, D.; Piechaczek, B.; Ruonk-Schoeneborn, S.; Zerres, K. ); Knapp, M. )

    1993-01-01

    The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene which allowed us to narrow the SMA region to about 4cM and to define a new proximal genetic border by the locus D5S125 EF(TG/AG)[sub n]. Based on haplotype analysis and specific recombination event,the following order of the loci was determined: 5cen- D5S76-D5S6-D5S125-SMA-(5[prime]MAP-1B-3[prime]MApP[center dot]1 B)/D5S112-JK53CAI/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5Sl25 and MAP[center dot]1B is further supported by multipoint linkage analysis. 18 refs., 3 figs., 4 tabs.

  11. An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

    PubMed Central

    Yang, Chung-Wei; Chen, Chien-Lin; Chou, Wei-Chun; Lin, Ho-Chen; Jong, Yuh-Jyh; Tsai, Li-Kai; Chuang, Chun-Yu

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy. PMID:27331400

  12. An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy.

    PubMed

    Yang, Chung-Wei; Chen, Chien-Lin; Chou, Wei-Chun; Lin, Ho-Chen; Jong, Yuh-Jyh; Tsai, Li-Kai; Chuang, Chun-Yu

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy. PMID:27331400

  13. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

    PubMed Central

    Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

    2013-01-01

    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

  14. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  15. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy.

    PubMed

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term "minipolyfasciculations" may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  16. Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.

    PubMed

    Johnson, W G; Wigger, H J; Karp, H R; Glaubiger, L M; Rowland, L P

    1982-01-01

    A 24-year-old Ashkenazi Jewish man was evaluated for a nine-year history of progressive leg weakness with fasciculations. Electromyography, nerve conduction velocities, muscle biopsy, and serum creatine kinase were consistent with anterior horn cell disease. On rectal biopsy, ganglion cells were filled with membranous cytoplasmic bodies and an unusual submucosal layer of periodic acid-Schiff positive histiocytes filled with granules was seen. Hexosaminidase A in serum and leukocytes was severely decreased in the patient and partially decreased in parents and a brother. A paternal relative had classic infantile Tay-Sachs disease. Juvenile spinal muscular atrophy in this patient, closely resembling the Kugelberg-Welander phenotype, resulted from an alpha-locus hexosaminidase deficiency disorder, possibly a genetic compound of HEX alpha 2 and a milder hexosaminidase alpha-locus allele. Other cases of hexosaminidase deficiency have included anterior horn cell disease as part of a more complex disorder, but this is the first case, to our knowledge, of a hexosaminidase deficiency disorder presenting as spinal muscular atrophy. PMID:6460466

  17. Clinical features of spinal and bulbar muscular atrophy

    PubMed Central

    Rhodes, Lindsay E.; Freeman, Brandi K.; Auh, Sungyoung; Kokkinis, Angela D.; La Pean, Alison; Chen, Cheunju; Lehky, Tanya J.; Shrader, Joseph A.; Levy, Ellen W.; Harris-Love, Michael; Di Prospero, Nicholas A.

    2009-01-01

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models. PMID:19846582

  18. DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2016-09-01

    We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by γ-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After γ-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phospho-p53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA. PMID:27452406

  19. Coilin forms the bridge between Cajal bodies and SMN, the spinal muscular atrophy protein.

    PubMed

    Hebert, M D; Szymczyk, P W; Shpargel, K B; Matera, A G

    2001-10-15

    Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the human survival of motor neuron 1 gene, SMN1. SMN protein is part of a large complex that is required for biogenesis of various small nuclear ribonucleoproteins (snRNPs). Here, we report that SMN interacts directly with the Cajal body signature protein, coilin, and that this interaction mediates recruitment of the SMN complex to Cajal bodies. Mutation or deletion of specific RG dipeptide residues within coilin inhibits the interaction both in vivo and in vitro. Interestingly, GST-pulldown experiments show that coilin also binds directly to SmB'. Competition studies show that coilin competes with SmB' for binding sites on SMN. Ectopic expression of SMN and coilin constructs in mouse embryonic fibroblasts lacking endogenous coilin confirms that recruitment of SMN and splicing snRNPs to Cajal bodies depends on the coilin C-terminal RG motif. A cardinal feature of SMA patient cells is a defect in the targeting of SMN to nuclear foci; our results uncover a role for coilin in this process. PMID:11641277

  20. Isolation and characterization of candidate genes of the 5q13 region in spinal muscular atrophy

    SciTech Connect

    Lefebvre, S.; Reboullet, S.; Benichou, B.

    1994-09-01

    Based on a fine genetic and physical map of the region deleted in spinal muscular atrophy, we defined the smallest rearrangements encompassing the SMA gene. This interval is entirely contained in the 903D1 YAC clone. Several approaches to identify candidate genes were applied, including the search for interspecies conservation, exon trapping amplification and direct cDNA selection. Combining these strategies, six different cDNA molecules mapping to the YAC contig were isolated. Four cDNA molecules were isolated using the exon trapping system. They map to chromosome 5p and to more than one locus within the 5q13 region. They are homologous to each other and share sequence homology with the {beta}-glucuronidase gene. Based on interspecies conservation, a fifth candidate gene was identified. Sequence analyses of the cDNAs revealed no homologies with any other described genes. This gene mapped to two loci within the 5q13 region. Two other cDNA molecules isolated by direct cDNA selection are also under investigation. Complete characterization and fine physical mapping of those genes with respect to the physical interval defined by the deletions of the SMA region will allow the identification of the disease gene (or genes).

  1. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy

    SciTech Connect

    Merette, C.; Gilliam, T.C.; Brzustowicz, L.M. ); Daniels, R.J.; Davies, K.E. ); Melki, J.; Munnich, A. ); Pericak-Vance, M.A. ); Siddique, T. ); Voosen, B. )

    1994-05-01

    The authors performed linkage analysis of 161 families with spinal muscular atrophy (SMA) in which affected individuals suffer from the intermediate or mild form of the disease (Types II or III). Markers for six loci encompassing the chromosome 5q11.2-q13.3 region were typed. The best map location for the disease locus was found to be between D5S6 and MAP1B. The corresponding 1 lod unit support interval is confined to this interval and spans 0.5 cM. The data strongly support the hypothesis of linkage heterogeneity (likelihood ratio, 1.14 [times] 10[sup 4]), with 5% of the families unlinked. Four families have a probability of less than 50% of segregating the SMA gene linked to the region 5q11.2-q13.3. A likelihood approach to test for linkage disequilibrium revealed no significant departure from Hardy-Weinberg equilibrium with any marker under study. 28 refs., 4 figs., 3 tabs.

  2. Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13

    SciTech Connect

    Theodosiou, A.M.; Nesbit, A.M.; Daniels, R.J.; Campbell, L.; Francis, M.J.; Christodoulou, Z.; Morrison, K.E.; Davies, K.E. |

    1994-12-01

    Childhood-onset proximal spinal muscular atrophy (SMA) is a heritable neurological disorder, which has been mapped by genetic linkage analysis to chromosome 5q13, in the interval between markers D5S435 and D5S557. Here, we present gene sequences that have been isolated from this interval, several of which show sequence homologies to exons of {beta}-glucuronidase. These gene sequences are repeated several times across the candidate region and are also present on chromosome 5p. The arrangement of these repetitive gene motifs is polymorphic between individuals. The high degree of variability observed may have some influence on the expression of the genes in the region. Since SMA is not inherited as a classical autosomal recessive disease, novel genomic rearrangements arising from aberrant recombination events between the complex repeats may be associated with the phenotype observed.

  3. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice.

    PubMed

    Zhou, Haiyan; Janghra, Narinder; Mitrpant, Chalermchai; Dickinson, Rachel L; Anthony, Karen; Price, Loren; Eperon, Ian C; Wilton, Stephen D; Morgan, Jennifer; Muntoni, Francesco

    2013-03-01

    In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27), and PMO20 (-10, -29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 μg/g and 2-fold at 40 μg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-μg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo-Morpholino and have potential for future SMA clinical applications. PMID:23339722

  4. Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene

    PubMed Central

    Seo, Joonbae; Singh, Natalia N.; Ottesen, Eric W.; Sivanesan, Senthilkumar; Shishimorova, Maria; Singh, Ravindra N.

    2016-01-01

    Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Loss of SMN1 leads to spinal muscular atrophy (SMA), the most frequent genetic cause of infant mortality. While SMN2 cannot compensate for the loss of SMN1 due to predominant skipping of exon 7, correction of SMN2 exon 7 splicing holds the promise of a cure for SMA. Previously, we used cell-based models coupled with a multi-exon-skipping detection assay (MESDA) to demonstrate the vulnerability of SMN2 exons to aberrant splicing under the conditions of oxidative stress (OS). Here we employ a transgenic mouse model and MESDA to examine the OS-induced splicing regulation of SMN2 exons. We induced OS using paraquat that is known to trigger production of reactive oxygen species and cause mitochondrial dysfunction. We show an overwhelming co-skipping of SMN2 exon 5 and exon 7 under OS in all tissues except testis. We also show that OS increases skipping of SMN2 exon 3 in all tissues except testis. We uncover several new SMN2 splice isoforms expressed at elevated levels under the conditions of OS. We analyze cis-elements and transacting factors to demonstrate the diversity of mechanisms for splicing misregulation under OS. Our results of proteome analysis reveal downregulation of hnRNP H as one of the potential consequences of OS in brain. Our findings suggest SMN2 as a sensor of OS with implications to SMA and other diseases impacted by low levels of SMN protein. PMID:27111068

  5. Sodium vanadate combined with l-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Methods Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Results Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation

  6. Cytokine profiles in multifocal motor neuropathy and progressive muscular atrophy.

    PubMed

    Vlam, L; Stam, M; de Jager, W; Cats, E A; van den Berg, L H; van der Pol, W L

    2015-09-15

    Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the 16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA. PMID:26298317

  7. Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe.

    PubMed

    Bladen, Catherine L; Thompson, Rachel; Jackson, Jacqueline M; Garland, Connie; Wegel, Claire; Ambrosini, Anna; Pisano, Paolo; Walter, Maggie C; Schreiber, Olivia; Lusakowska, Anna; Jedrzejowska, Maria; Kostera-Pruszczyk, Anna; van der Pol, Ludo; Wadman, Renske I; Gredal, Ole; Karaduman, Ayse; Topaloglu, Haluk; Yilmaz, Oznur; Matyushenko, Vitaliy; Rasic, Vedrana Milic; Kosac, Ana; Karcagi, Veronika; Garami, Marta; Herczegfalvi, Agnes; Monges, Soledad; Moresco, Angelica; Chertkoff, Lilien; Chamova, Teodora; Guergueltcheva, Velina; Butoianu, Niculina; Craiu, Dana; Korngut, Lawrence; Campbell, Craig; Haberlova, Jana; Strenkova, Jana; Alejandro, Moises; Jimenez, Alatorre; Ortiz, Genaro Gabriel; Enriquez, Gracia Viviana Gonzalez; Rodrigues, Miriam; Roxburgh, Richard; Dawkins, Hugh; Youngs, Leanne; Lahdetie, Jaana; Angelkova, Natalija; Saugier-Veber, Pascal; Cuisset, Jean-Marie; Bloetzer, Clemens; Jeannet, Pierre-Yves; Klein, Andrea; Nascimento, Andres; Tizzano, Eduardo; Salgado, David; Mercuri, Eugenio; Sejersen, Thomas; Kirschner, Jan; Rafferty, Karen; Straub, Volker; Bushby, Kate; Verschuuren, Jan; Beroud, Christophe; Lochmüller, Hanns

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning. PMID:24162038

  8. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

    PubMed Central

    Jordanova, Albena

    2014-01-01

    Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

  9. Independent mobility after early introduction of a power wheelchair in spinal muscular atrophy.

    PubMed

    Dunaway, Sally; Montes, Jacqueline; O'Hagen, Jessica; Sproule, Douglas M; Vivo, Darryl C De; Kaufmann, Petra

    2013-05-01

    Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills. PMID:22772161

  10. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Oliván, Sara; Calvo, Ana C.; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F.; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons “in vitro” and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease. PMID:27605908

  11. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Oliván, Sara; Calvo, Ana C; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons "in vitro" and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease. PMID:27605908

  12. Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

    PubMed

    Chen, Huan-Xiong; Tang, Sheng-Ping; Gao, Fu-Tang; Xu, Jiang-Long; Jiang, Xian-Ping; Cao, Juan; Fu, Gui-Bing; Sun, Ke; Liu, Shi-Zhe; Shi, Wei

    2014-11-01

    In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin-proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the

  13. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

    PubMed Central

    Stabley, Deborah L; Harris, Ashlee W; Holbrook, Jennifer; Chubbs, Nicholas J; Lozo, Kevin W; Crawford, Thomas O; Swoboda, Kathryn J; Funanage, Vicky L; Wang, Wenlan; Mackenzie, William; Scavina, Mena; Sol-Church, Katia; Butchbach, Matthew E R

    2015-01-01

    Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples. PMID:26247043

  14. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

    PubMed Central

    Chong, Jessica X; Oktay, A Afşin; Dai, Zunyan; Swoboda, Kathryn J; Prior, Thomas W; Ober, Carole

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity. PMID:21610747

  15. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number.

    PubMed Central

    McAndrew, P E; Parsons, D W; Simard, L R; Rochette, C; Ray, P N; Mendell, J R; Prior, T W; Burghes, A H

    1997-01-01

    The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number. Images Figure 1 Figure 2 Figure 3 PMID:9199562

  16. Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

    PubMed Central

    Cherry, Jonathan J; Osman, Erkan Y; Evans, Matthew C; Choi, Sungwoon; Xing, Xuechao; Cuny, Gregory D; Glicksman, Marcie A; Lorson, Christian L; Androphy, Elliot J

    2013-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA. PMID:23740718

  17. The Smn-Independent Beneficial Effects of Trichostatin A on an Intermediate Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Murray, Lyndsay M.; Beauvais, Ariane; Kothary, Rashmi

    2014-01-01

    Spinal muscular atrophy is an autosomal recessive neuromuscular disease characterized by the progressive loss of alpha motor neurons in the spinal cord. Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. It is currently unclear whether TSA specifically targets the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-SMN mediated pathway. TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/- mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Of interest, TSA treatment did not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. In addition, no change in the level of Smn transcripts or protein in the brain or spinal cord of TSA-treated SMA model mice was observed. Furthermore, TSA did not increase Smn protein levels in the hind limb muscle, heart, or liver of Smn2B/- mice. We therefore conclude that TSA likely exerts its effects independent of the endogenous mouse Smn gene. As such, identification of the pathways regulated by TSA in the Smn2B/- mice could lead to the development of novel therapeutics for treating SMA. PMID:24984019

  18. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

    PubMed Central

    Sleigh, James N.; Gillingwater, Thomas H.; Talbot, Kevin

    2011-01-01

    Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration. PMID:21708901

  19. Neuropsychological Investigation in Chinese Patients with Progressive Muscular Atrophy

    PubMed Central

    Cui, Bo; Cui, Liying; Liu, Mingsheng; Li, Xiaoguang; Ma, Junfang; Fang, Jia; Ding, Qingyun

    2015-01-01

    Background Progressive muscular atrophy (PMA) is a rare type of degenerative motor neuron disease (MND) of which the onset happens in adult period. Despite its well-defined clinical characteristics, its neuropsychological profile has remained poorly understood, considering the consensus of cognitive and behavioral impairment reached in amyotrophic lateral sclerosis (ALS). Methods We conducted a cross-sectional evaluation of Chinese PMA patients with a series of comprehensive batteries emphasizing the executive and attention function, and covering other domains of memory, language, visuospatial function, calculation and behavior as well. Their performances were compared with those of age- and education-matched ALS and healthy controls (HC). Results 21 patients newly diagnosed with PMA were consecutively enrolled into our ALS and other MND registry platform, accounting for 14.7% of all the incident MND cases registered during the same period. 20 patients who completed the neuropsychological batteries were included into analysis. Compared with HC, PMA performed significantly worse in maintenance function of attention, while they exhibited quantitative similarity to ALS in all behavioral inventories and neuropsychological tests except the time for Stroop interference effect. Conclusion PMA could display mild cognitive dysfunction in the same frontal-mediated territory of ALS but in a lesser degree, whereas they did not differ from ALS behaviorally. PMID:26042930

  20. Molecular prenatal diagnosis of autosomal recessive childhood spinal muscular atrophies (SMAs).

    PubMed

    Essawi, Mona L; Al-Attribi, Ghada M; Gaber, Khaled R; El-Harouni, Ashraf A

    2012-11-01

    Autosomal recessive childhood spinal muscular atrophy (SMAs) is the second most common neuromuscular disorder and a common cause of infant disability and mortality. SMA patients are classified into three clinical types based on age of onset, and severity of symptoms. About 94% of patients have homozygous deletion of exon 7 in survival motor neuron (SMN1) gene. The neuronal apoptosis inhibitory protein (NAIP) gene was found to be more frequently deleted in the severest form of the disease. This study aimed to comment on the implementation of genetic counseling and prenatal diagnosis of SMAs for 85 fetuses from 75 Egyptian couples at risk of having an affected child. The homozygous deletion of exon 7 in SMN1 gene and the deletion of exon 5 of the NAIP gene were detected using PCR-REFLP and multiplex PCR methods respectively. Eighteen fetuses showed homozygous deletion of exon 7 in SMN1 gene and deletion of exon 5 in NAIP gene. In conclusion prenatal diagnosis is an important tool for accurate diagnosis and genetic counseling that help decision making in high risk families. PMID:22921322

  1. A Dominant Mutation in FBXO38 Causes Distal Spinal Muscular Atrophy with Calf Predominance

    PubMed Central

    Sumner, Charlotte J.; d’Ydewalle, Constantin; Wooley, Joe; Fawcett, Katherine A.; Hernandez, Dena; Gardiner, Alice R.; Kalmar, Bernadett; Baloh, Robert H.; Gonzalez, Michael; Züchner, Stephan; Stanescu, Horia C.; Kleta, Robert; Mankodi, Ami; Cornblath, David R.; Boylan, Kevin B.; Reilly, Mary M.; Greensmith, Linda; Singleton, Andrew B.; Harms, Matthew B.; Rossor, Alexander M.; Houlden, Henry

    2013-01-01

    Spinal muscular atrophies (SMAs) are a heterogeneous group of inherited disorders characterized by degeneration of anterior horn cells and progressive muscle weakness. In two unrelated families affected by a distinct form of autosomal-dominant distal SMA initially manifesting with calf weakness, we identified by genetic linkage analysis and exome sequencing a heterozygous missense mutation, c.616T>C (p.Cys206Arg), in F-box protein 38 (FBXO38). FBXO38 is a known coactivator of the transcription factor Krüppel-like factor 7 (KLF7), which regulates genes required for neuronal axon outgrowth and repair. The p.Cys206Arg substitution did not alter the subcellular localization of FBXO38 but did impair KLF7-mediated transactivation of a KLF7-responsive promoter construct and endogenous KLF7 target genes in both heterologously expressing human embryonic kidney 293T cells and fibroblasts derived from individuals with the FBXO38 missense mutation. This transcriptional dysregulation was associated with an impairment of neurite outgrowth in primary motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons. PMID:24207122

  2. Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy

    PubMed Central

    Ottesen, Eric W.; Howell, Matthew D.; Singh, Natalia N.; Seo, Joonbae; Whitley, Elizabeth M.; Singh, Ravindra N.

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility. PMID:26830971

  3. Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes.

    PubMed

    Rossoll, Wilfried; Bassell, Gary J

    2009-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease that results from loss of function of the SMN1 gene, encoding the ubiquitously expressed survival of motor neuron (SMN) protein, a protein best known for its housekeeping role in the SMN-Gemin multiprotein complex involved in spliceosomal small nuclear ribonucleoprotein (snRNP) assembly. However, numerous studies reveal that SMN has many interaction partners, including mRNA binding proteins and actin regulators, suggesting its diverse role as a molecular chaperone involved in mRNA metabolism. This review focuses on studies suggesting an important role of SMN in regulating the assembly, localization, or stability of axonal messenger ribonucleoprotein (mRNP) complexes. Various animal models for SMA are discussed, and phenotypes described that indicate a predominant function for SMN in neuronal development and synapse formation. These models have begun to be used to test different therapeutic strategies that have the potential to restore SMN function. Further work to elucidate SMN mechanisms within motor neurons and other cell types involved in neuromuscular circuitry hold promise for the potential treatment of SMA. PMID:19343312

  4. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5

    SciTech Connect

    Steege, G. van der; Grootscholten, P.M.; Cobben, J.M.; Scheffer, H.; Buys, C.H.C.M.

    1996-10-01

    The survival motor neuron (SMN) gene has been described as a determining gene for spinal muscular atrophy (SMA). SMN has a closely flanking, nearly identical copy ({sup C}BCD541). Gene and copy gene can be discriminated by sequence differences in exons 7 and 8. The large majority of SMA patients show homozygous deletions of at least exons 7 and 8 of the SMN gene. A minority of patients show absence of SMN exon 7 but retention of exon 8. This is explained by results of our present analysis of 13 such patients providing evidence for apparent gene-conversion events between SMN and the centromeric copy gene. Instead of applying a separate analysis for absence or presence of SMN exons 7 and 8, we used a contiguous PCR from intron 6 to exon 8. In every case we found a chimeric gene with a fusion of exon 7 of the copy gene and exon 8 of SMN and absence of a normal SMN gene. Similar events, including the fusion counterpart, were observed in a group of controls, although in the presence of a normal SMN gene. Chimeric genes as the result of fusions of parts of SMN and {sup C}BCD541 apparently are far from rare and may partly explain the frequently observed SMN deletions in SMA patients. 23 refs., 4 figs.

  5. Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.

    PubMed

    Ohsawa, Yutaka; Hagiwara, Hiroki; Nakatani, Masashi; Yasue, Akihiro; Moriyama, Keiji; Murakami, Tatsufumi; Tsuchida, Kunihiro; Noji, Sumihare; Sunada, Yoshihide

    2006-11-01

    Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients. PMID:17039257

  6. [Aran-Duchenne? Duchenne-Aran? The quarrel around progressive muscular atrophy].

    PubMed

    Bonduelle, M

    1990-01-01

    A description of progressive muscular atrophy, the first item in neuro-muscular nosography, figures in the memoir published by F.A. Aran in 1850. There, all the essential features of the disease can be found: its usual onset at the distal end of the upper limbs, its slowly progressive worsening, with muscular atrophy sparing certain muscles or muscular fascicles, its peculiar "claw hand", its muscular "fasciculations" and cramps, with untouched sensitivity. After praising Aran's "beautiful description", G.B. Duchenne de Boulogne subsequently persisted in claiming paternity, untiringly referring to a memoir on "muscular atrophy with fatty transformation" said to have been submitted to the Académie des Sciences in 1849. There is no trace of this memoir, and while it is true that the "localized electrisation" technique was applied by Duchenne to all the patients in Aran's memoir, and that he was the sole author of two of his observations, it is Aran who must be credited with the clinical description, the synthetic presentation and the appellation of "progressive muscular atrophy". Initially, this term covered a number of disparate facts which were later identified and put in their proper nosological place, even though this dismemberment left standing what Charcot called "Duchenne-Aran disease" before the Aran-Duchenne denomination prevailed. This denomination is now customary, and rightly so. PMID:2181591

  7. Onset Manifestations of Spinal and Bulbar Muscular Atrophy (Kennedy's Disease).

    PubMed

    Finsterer, Josef; Soraru, Gianni

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) is regarded as a disorder with adult onset between third and fifth decade of life. However, there is increasing evidence that SBMA may start already before adulthood. The present study investigated the following: (1) Which clinical manifestations have been described so far in the literature as initial manifestations? (2) Which was the age at onset of these manifestations? and (3) Is age at onset dependent on the CAG-repeat length if non-motor manifestations are additionally considered? Data for this review were identified by searches of MEDLINE using appropriate search terms. Onset manifestations in SBMA can be classified as frequent, rare, motor, non-motor, or questionable. Frequent are muscle weakness, cramps, fasciculations/twitching, tremor, dysarthria, dysphagia, or gynecomastia. Rare are myalgia, easy fatigability, exercise intolerance, polyneuropathy, hyper-CKemia, under-masculinized genitalia, scrotal hypospadias, microphallus, laryngospasm, or oligospermia. Questionable manifestations include sensory disturbances, cognitive impairment, increased pituitary volume, diabetes, reduced tongue pressure, elevated creatine-kinase, or low androgens/high estrogens. Age at onset is highly variable ranging from 4-76 years. Non-motor manifestations develop usually before motor manifestations. Age at onset depends on what is considered as an onset manifestation. Considering non-motor onset manifestations, age at onset is independent of the CAG-repeat size. In conclusion, age at onset of SBMA depends on what is regarded as onset manifestation. If non-motor manifestations are additionally considered, age at onset is independent of the CAG-repeat length. Since life expectancy is hardly reduced in SBMA, re-investigation of patients from published studies with regard to their initial disease profiles is recommended. PMID:26482145

  8. The loss of the snoRNP chaperone Nopp140 from Cajal bodies of patient fibroblasts correlates with the severity of spinal muscular atrophy

    PubMed Central

    Renvoisé, Benoît; Colasse, Sabrina; Burlet, Philippe; Viollet, Louis; Meier, U. Thomas; Lefebvre, Suzie

    2009-01-01

    Spinal muscular atrophy (SMA) is a common autosomal recessive neurodegenerative disease caused by reduced survival motor neuron (SMN) levels. The assembly machinery containing SMN is implicated in the biogenesis of the spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN is present in both the cytoplasm and nucleus, where it transiently accumulates in subnuclear domains named Cajal bodies (CBs) and functions in the maturation of snRNPs and small nucleolar (sno)RNPs. The impact of lowering SMN levels on the composition of CBs in SMA cells is still not completely understood. Here, we analyse the CB composition in immortalized and primary fibroblasts from SMA patients. We show that the U snRNA export factors PHAX and chromosome region maintenance 1 and the box C/D snoRNP core protein fibrillarin concentrate in CBs from SMA cells, whereas the box H/ACA core proteins GAR1 and NAP57/dyskerin show reduced CB localization. Remarkably, the functional deficiency in SMA cells is associated with decreased localization of the snoRNP chaperone Nopp140 in CBs that correlates with disease severity. Indeed, RNA interference knockdown experiments in control fibroblasts demonstrate that SMN is required for accumulation of Nopp140 in CBs. Conversely, overexpression of SMN in SMA cells restores the CB localization of Nopp140, whereas SMN mutants found in SMA patients are defective in promoting the association of Nopp140 with CBs. Taken together, we demonstrate that only a subset of CB functions (as indicated by the association of representative factors) are impaired in SMA cells and, importantly, we identify the decrease of Nopp140 localization in CBs as a phenotypic marker for SMA. PMID:19129172

  9. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience.

    PubMed

    Haché, Manon; Swoboda, Kathryn J; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M

    2016-06-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children. PMID:26823478

  10. Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy.

    PubMed

    Montague, Karli; Malik, Bilal; Gray, Anna L; La Spada, Albert R; Hanna, Michael G; Szabadkai, Gyorgy; Greensmith, Linda

    2014-07-01

    Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerative disease, including polyglutamine disorders such as Huntington's disease and in motor neuron disease, where cellular stress disrupts functioning of the endoplasmic reticulum, leading to induction of the unfolded protein response. We examined whether endoplasmic reticulum stress is also involved in the pathogenesis of spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy mice that carry 100 pathogenic polyglutamine repeats in the androgen receptor, and develop a late-onset neuromuscular phenotype with motor neuron degeneration, were studied. We observed a disturbance in endoplasmic reticulum-associated calcium homeostasis in cultured embryonic motor neurons from spinal and bulbar muscular atrophy mice, which was accompanied by increased endoplasmic reticulum stress. Furthermore, pharmacological inhibition of endoplasmic reticulum stress reduced the endoplasmic reticulum-associated cell death pathway. Examination of spinal cord motor neurons of pathogenic mice at different disease stages revealed elevated expression of markers for endoplasmic reticulum stress, confirming an increase in this stress response in vivo. Importantly, the most significant increase was detected presymptomatically, suggesting that endoplasmic reticulum stress may play an early and possibly causal role in disease pathogenesis. Our results therefore indicate that the endoplasmic reticulum stress pathway could potentially be a therapeutic target for spinal and bulbar muscular atrophy and related polyglutamine diseases. PMID:24898351

  11. Nutritional practices at a glance: spinal muscular atrophy type I nutrition survey findings.

    PubMed

    Davis, Rebecca Hurst; Godshall, Barbara J; Seffrood, Erin; Marcus, Mary; LaSalle, Bernard A; Wong, Brenda; Schroth, Mary K; Swoboda, Kathryn J

    2014-11-01

    Proactive nutritional management for children with spinal muscular atrophy type I can provide insight into improved spinal muscular atrophy care. This observational study consisted of a nutritional and medical history survey of children with spinal muscular atrophy type I collected in 2009-2011. Forty-four caregiver survey responses were evaluated using descriptive statistics. Average age of spinal muscular atrophy type I subjects was 5 years (5 mo-16 y). The subject cohort was composed of 22 males, 21 females, and 1 unreported. Nutrition support via feeding tube was utilized by 43 of 44 subjects. A majority of respondents reported using elemental or semi-elemental formula for subjects' essential caloric intake (34 of 44). Formula intolerance issues were reported by many caregivers (27 of 44). Half of caregivers implemented dietary changes on their own or with guidance from other families; 15 caregivers consulted a registered dietitian. Survey responses and comments indicate need for evidence-based nutritional guidelines for spinal muscular atrophy. PMID:24097849

  12. D5S351 and D5S1414 located at the spinal muscular atrophy critical region represent novel informative markers in the Iranian population

    PubMed Central

    Sedghi, Maryam; Vallian, Sadeq

    2015-01-01

    Spinal muscular atrophy (SMA) is a degenerative neuromuscular disease associated with progressive symmetric weakness and atrophy of the limb muscles. In view of the involvement of numerous point mutations and deletions associated with the disease, the application of polymorphic markers flanking the SMA critical region could be valuable in molecular diagnosis of the disease. In the present study, D5S351 and D5S1414 polymorphic markers located at the SMA critical region in the Iranian populations were characterized. Genotyping of the markers indicated the presence of six and nine different alleles for D5S351 and D5S1414, respectively. Haplotype frequency estimation in 25 trios families and 75 unrelated individuals indicated the presence of six informative haplotypes with frequency higher than 0.05 in the studied population. Furthermore, the D′ coefficient and the χ2 value for D5S351 and D5S1414 markers revealed the presence of linkage disequilibrium between the two markers in the Iranians. These data suggested that D5S351 and D5S1414 could be suggested as informative markers for linkage analysis and molecular diagnosis of SMA in the Iranian population. PMID:26693404

  13. Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability

    PubMed Central

    Also-Rallo, Eva; Alías, Laura; Martínez-Hernández, Rebeca; Caselles, Lidia; Barceló, María J; Baiget, Montserrat; Bernal, Sara; Tizzano, Eduardo F

    2011-01-01

    Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by mutations in the SMN1 gene. The homologous copy (SMN2) is always present in SMA patients. SMN1 gene transcripts are usually full-length (FL), but exon 7 is spliced out in a high proportion of SMN2 transcripts (delta7) (Δ7). Advances in drug therapy for SMA have shown that an increase in SMN mRNA and protein levels can be achieved in vitro. We performed a systematic analysis of SMN expression in primary fibroblasts and EBV-transformed lymphoblasts from seven SMA patients with varying clinical severity and different SMN1 genotypes to determine expression differences in two accessible tissues (skin and blood). The basal expression of SMN mRNA FL and Δ7 in fibroblasts and lymphoblasts was analyzed by quantitative real-time PCR. The FL-SMN and FL/Δ7 SMN ratios were higher in control cells than in patients. Furthermore, we investigated the response of these cell lines to hydroxyurea, valproate and phenylbutyrate, drugs previously reported to upregulate SMN2. The response to treatments with these compounds was heterogeneous. We found both intra-patient and inter-patient variability even within haploidentical siblings, suggesting that tissue and individual factors may affect the response to these compounds. To optimize the stratification of patients in clinical trials, in vitro studies should be performed before enrolment so as to define each patient as a responder or non-responder to the compound under investigation. PMID:21610752

  14. Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability.

    PubMed

    Also-Rallo, Eva; Alías, Laura; Martínez-Hernández, Rebeca; Caselles, Lidia; Barceló, María J; Baiget, Montserrat; Bernal, Sara; Tizzano, Eduardo F

    2011-10-01

    Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by mutations in the SMN1 gene. The homologous copy (SMN2) is always present in SMA patients. SMN1 gene transcripts are usually full-length (FL), but exon 7 is spliced out in a high proportion of SMN2 transcripts (delta7) (Δ7). Advances in drug therapy for SMA have shown that an increase in SMN mRNA and protein levels can be achieved in vitro. We performed a systematic analysis of SMN expression in primary fibroblasts and EBV-transformed lymphoblasts from seven SMA patients with varying clinical severity and different SMN1 genotypes to determine expression differences in two accessible tissues (skin and blood). The basal expression of SMN mRNA FL and Δ7 in fibroblasts and lymphoblasts was analyzed by quantitative real-time PCR. The FL-SMN and FL/Δ7 SMN ratios were higher in control cells than in patients. Furthermore, we investigated the response of these cell lines to hydroxyurea, valproate and phenylbutyrate, drugs previously reported to upregulate SMN2. The response to treatments with these compounds was heterogeneous. We found both intra-patient and inter-patient variability even within haploidentical siblings, suggesting that tissue and individual factors may affect the response to these compounds. To optimize the stratification of patients in clinical trials, in vitro studies should be performed before enrolment so as to define each patient as a responder or non-responder to the compound under investigation. PMID:21610752

  15. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy

    PubMed Central

    Swoboda, Kathryn J.; Darras, Basil T.; Iannaccone, Susan T.; Montes, Jacqueline; De Vivo, Darryl C.; Norris, Daniel A.; Bennett, C. Frank; Bishop, Kathie M.

    2016-01-01

    Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. Results: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9–14 months postdose (5.8 points; p = 0.008) during the extension study. Conclusions: Results from this study support continued development of nusinersen for treatment of SMA. Classification of evidence: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. PMID:26865511

  16. In vitro gene manipulation of spinal muscular atrophy fibroblast cell line using gene-targeting fragment for restoration of SMN protein expression.

    PubMed

    Rashnonejad, A; Gündüz, C; Süslüer, S Y; Onay, H; Durmaz, B; Bandehpour, M; Özkınay, F

    2016-01-01

    The reduced level of survival motor neuron (SMN) protein, caused by homozygous deletions in the SMN gene, led to a common neurodegenerative disorder known as spinal muscular atrophy (SMA). In spite of extensive efforts to find a cure for SMA, there is currently no effective treatment available for this devastating disease. In this study, restoration of SMN expression through 'gene-targeting' method in SMA fibroblast cells was attempted. We designed a 2697-bp gene-targeting cassette; it consisted of an SMN1 open reading frame expressing 38 kD SMN protein and the upstream and downstream regions of exon 1 of SMN1 gene at the ends as the homology arms. SMA fibroblast cells were transfected by gene-targeting cassette using Lipofectamine LTX-PLUS reagent. Occurrence of homologous recombination in selected cells was investigated by PCR analysis. Increased expression of SMN protein was shown by real-time PCR and western blotting analysis. The immunofluorescence analysis results demonstrated that the number of SMN nuclear structures, Gems, was the same as or greater than the number of Gems found in normal fibroblasts. The results of this study indicate that gene-targeting methods do, in fact, present as an alternative for restoration of SMN expression in SMA patients-derived cells in vitro. PMID:26331341

  17. The relationship of spinal muscular atrophy to motor neuron disease: investigation of SMN and NAIP gene deletions in sporadic and familial ALS.

    PubMed

    Orrell, R W; Habgood, J J; de Belleroche, J S; Lane, R J

    1997-01-01

    Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10% of cases. Of these familial cases around 20% are associated with mutations of SOD-1. The genetic basis of the disease in the remaining familial cases, and genetic risk factors in sporadic cases, are unknown. Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with both familial and sporadic motor neuron disease show only lower motor neuron signs, in common with SMA patients, and families containing individuals with phenotypes of both childhood SMA and adult motor neuron disease have been reported. We therefore examined the SMA locus as a candidate for ALS, in 54 patients with sporadic motor neuron disease, and 10 single-generation familial patients (with no evidence of SOD-1 mutations), and in a single patient with Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were detected. The difficulties of classification of lower motor neuron presentations of motor neuron diseases are discussed. The demonstration that mutations diagnostic of SMA are not found in ALS patients helps distinguish these conditions. PMID:9073029

  18. Observational study of caloric and nutrient intake, bone density, and body composition in infants and children with Spinal Muscular Atrophy type I

    PubMed Central

    Poruk, Katherine E; Davis, Rebecca Hurst; Smart, Abby L; Chisum, Benjamin S; LaSalle, Bernie A; Chan, Gary M; Gill, Gurmail; Reyna, Sandra P; Swoboda, Kathryn J

    2012-01-01

    Clinical experience supports a critical role for nutrition in patients with spinal muscular atrophy (SMA). Three-day dietary intake records were analyzed for 156 visits in 47 SMA type I patients, 25 males and 22 females, ages 1 month-13 years (median 9.8 months) and compared to dietary reference intakes for gender and age along with anthropometric measures and dual-energy x-ray absorptiometry (DEXA) data. Using standardized growth curves, twelve patients met criteria for failure to thrive (FTT) with weight for age < 3rd percentile; eight met criteria based on weight for height. Percentage of body fat mass was not correlated with weight for height and weight for age across percentile categories. DEXA analysis further demonstrated that SMA type I children have higher fat mass and lower fat free mass than healthy peers (p<0.001). DEXA and dietary analysis indicates a strong correlation with magnesium intake and bone mineral density (r=0.65, p<0.001). Average caloric intake for 1–3 year olds was 68.8 ±15.8 kcal/kg - 67% of peers’ recommended intake. Children with SMA type I may have lower caloric requirements than healthy age-matched peers, increasing risk for over and undernourished states and deficiencies of critical nutrients. Standardized growth charts may overestimate FTT status in SMA type I. PMID:22832342

  19. A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

    PubMed Central

    Nishimura, Agnes L.; Mitne-Neto, Miguel; Silva, Helga C. A.; Richieri-Costa, Antônio; Middleton, Susan; Cascio, Duilio; Kok, Fernando; Oliveira, João R. M.; Gillingwater, Tom; Webb, Jeanette; Skehel, Paul; Zatz, Mayana

    2004-01-01

    Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking. PMID:15372378

  20. A family of juvenile proximal spinal muscular atrophy with dominant inheritance.

    PubMed Central

    Cao, A; Cainchetti, C; Calisti, L; Tangheroni, W

    1976-01-01

    A family with juvenile proximal spinal muscular atrophy with dominant inheritance and complete penetrance is reported. The disease occurred in three generations and showed high variations in the age of onset and progression among the affected members. A characteristic feature was the constant involvement of facial nuclei. Images PMID:933110

  1. Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy.

    PubMed

    He, Jin; Zhang, Qi-Jie; Lin, Qi-Fang; Chen, Ya-Fang; Lin, Xiao-Zhen; Lin, Min-Ting; Murong, Shen-Xing; Wang, Ning; Chen, Wan-Jin

    2013-04-15

    Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disorder, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. Additionally, the phenotype is modified by several genes nearby SMN1 in the 5q13 region. In this study, we analyzed mutations in SMN1 and quantified the modifying genes, including SMN2, NAIP, GTF2H2, and H4F5 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), multiplex ligation-dependent probe amplification (MLPA), TA cloning, allele-specific long-range PCR, and Sanger sequencing in 157 SMA patients. Most SMA patients (94.90%) possessed a homozygous SMN1 deletion, while 10 patients demonstrated only the absence of exon 7, but the presence of exon 8. Two missense mutations (c.689 C>T and c.844 C>T) were identified in 2 patients who both carried a single copy of SMN1. We found inverse correlations between SMN2, the NAIP copy number, and the clinical severity of the disease. Furthermore, 7 severe type I patients possessed large-scale deletions, including SMN1, NAIP, and GTF2H2. We conclude that SMN1 gene conversion, SMN1 subtle mutations, SMN2 copy number, and the extent of deletion in the 5q13 region should all be considered in the genotype-phenotype analysis of SMA. PMID:23352792

  2. A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy.

    PubMed

    Sanchez, Gabriel; Bondy-Chorney, Emma; Laframboise, Janik; Paris, Geneviève; Didillon, Andréanne; Jasmin, Bernard J; Côté, Jocelyn

    2016-04-01

    Loss of 'Survival of Motor Neurons' (SMN) leads to spinal muscular atrophy (SMA), a disease characterized by degeneration of spinal cord alpha motor neurons, resulting in muscle weakness, paralysis and death during early childhood. SMN is required for assembly of the core splicing machinery, and splicing defects were documented in SMA. We previously uncovered that Coactivator-Associated Methyltransferase-1 (CARM1) is abnormally up-regulated in SMA, leading to mis-regulation of a number of transcriptional and alternative splicing events. We report here that CARM1 can promote decay of a premature terminating codon (PTC)-containing mRNA reporter, suggesting it can act as a mediator of nonsense-mediated mRNA decay (NMD). Interestingly, this pathway, while originally perceived as solely a surveillance mechanism preventing expression of potentially detrimental proteins, is now emerging as a highly regulated RNA decay pathway also acting on a subset of normal mRNAs. We further show that CARM1 associates with major NMD factor UPF1 and promotes its occupancy on PTC-containing transcripts. Finally, we identify a specific subset of NMD targets that are dependent on CARM1 for degradation and that are also misregulated in SMA, potentially adding exacerbated targeting of PTC-containing mRNAs to the already complex array of molecular defects associated with this disease. PMID:26656492

  3. Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.

    PubMed

    Vill, K; Müller-Felber, W; Teusch, V; Blaschek, A; Gerstl, L; Huetker, S; Albert, M H

    2016-01-01

    Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug. PMID:27068298

  4. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

    PubMed Central

    Bogdanik, Laurent P.; Osborne, Melissa A.; Davis, Crystal; Martin, Whitney P.; Austin, Andrew; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen M.

    2015-01-01

    Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system. PMID:26460027

  5. The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy.

    PubMed

    Diep Tran, T; Kroepfl, T; Saito, M; Nagura, M; Ichiseki, H; Kubota, M; Toda, T; Sakakihara, Y

    2001-08-01

    Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder with progressive weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is present in two highly homologous copies (SMN1 and SMN2) on chromosome 5q13. Homozygous deletion of exons 7 and 8 of SMN1 is responsible for spinal muscular atrophy. In spinal muscular atrophy patients, SMN2 partially compensates for the lack of SMN1. Previously, we reported the relatively high incidence of a large deletion including the SMN1 region in Japanese spinal muscular atrophy type I patients. In order to further establish the genetic background of Japanese spinal muscular atrophy type I patients, we investigated the SMN1/SMN2 ratio in the carriers. In normal individuals, there is one copy of each gene on the chromosome (the SMN1/SMN2 ratio was 1). Among 15 carriers (14 parents and one carrier sibling of Japanese type I spinal muscular atrophy patients with homozygous deletion of exons 7 and 8 of SMN1), we found that the SMN1/SMN2 ratio was 0.5 or 1 in 11 (73.3%) carriers. The remaining four carriers had an SMN1/SMN2 ratio of 1/3. This finding supports the idea that deletion rather than conversion is the main genetic event in type I spinal muscular atrophy. In addition, the ratio of SMN1/SMN2 among Japanese carriers, which was thought to be higher than that of the Western population, was compatible with the results obtained in Western populations. For further insight into the characteristic genetic background of spinal muscular atrophy in Japanese, determination of the gene copy number is essential. PMID:11504604

  6. Cardiorespiratory responses to exercise in patients with spinal muscular atrophy and limb-girdle dystrophy.

    PubMed

    Silva, A C; Russo, A K; Piçarro, I C; Schmidt, B; Gabbai, A; Oliveira, A S; Tarasantchi, J

    1987-01-01

    Maximum oxygen consumption, maximum heart rate and maximum ventilation during cycle ergometer exercise were studied in individuals with spinal muscular atrophy (N = 8) and limb-girdle dystrophy (N = 8). The limiting factors in aerobic power may be related to loss of functional muscular mass rather than to changes in the oxygen transport system. There was no correlation between VO2 max values and muscle strength as determined by a manual test of the affected muscles recruited for bicycle exercise. The results, therefore, do not support the possibility of a correlation between these indices previously proposed on the basis of clinical evidence. PMID:3452446

  7. Congenital cervical spinal muscular atrophy: a non-familial, non progressive condition of the upper limbs.

    PubMed Central

    Hageman, G; Ramaekers, V T; Hilhorst, B G; Rozeboom, A R

    1993-01-01

    Two patients with congenital cervical spinal muscular atrophy had symmetrical severe muscle weakness and wasting confined to the upper limbs, areflexia and congenital contractures. The shoulders were internally rotated, elbows extended and wrists flexed. There were no sensory or bulbar symptoms, scoliosis, long tract signs or lower limb involvement. This condition should be regarded as a neurogenic type of arthrogryposis, limited to the upper limbs. Images PMID:8482956

  8. Muscle fatigue, nNOS and muscle fiber atrophy in limb girdle muscular dystrophy.

    PubMed

    Angelini, Corrado; Tasca, Elisabetta; Nascimbeni, Anna Chiara; Fanin, Marina

    2014-12-01

    Muscle fatigability and atrophy are frequent clinical signs in limb girdle muscular dystrophy (LGMD), but their pathogenetic mechanisms are still poorly understood. We review a series of different factors that may be connected in causing fatigue and atrophy, particularly considering the role of neuronal nitric oxide synthase (nNOS) and additional factors such as gender in different forms of LGMD (both recessive and dominant) underlying different pathogenetic mechanisms. In sarcoglycanopathies, the sarcolemmal nNOS reactivity varied from absent to reduced, depending on the residual level of sarcoglycan complex: in cases with complete sarcoglycan complex deficiency (mostly in beta-sarcoglycanopathy), the sarcolemmal nNOS reaction was absent and it was always associated with early severe clinical phenotype and cardiomyopathy. Calpainopathy, dysferlinopathy, and caveolinopathy present gradual onset of fatigability and had normal sarcolemmal nNOS reactivity. Notably, as compared with caveolinopathy and sarcoglycanopathies, calpainopathy and dysferlinopathy showed a higher degree of muscle fiber atrophy. Males with calpainopathy and dysferlinopathy showed significantly higher fiber atrophy than control males, whereas female patients have similar values than female controls, suggesting a gender difference in muscle fiber atrophy with a relative protection in females. In female patients, the smaller initial muscle fiber size associated to endocrine factors and less physical effort might attenuate gender-specific muscle loss and atrophy. PMID:25873780

  9. Bioelectrical impedance analysis can be a useful screen for excess adiposity in spinal muscular atrophy.

    PubMed

    Sproule, Douglas M; Montes, Jacqueline; Dunaway, Sally L; Montgomery, Megan; Battista, Vanessa; Shen, Wei; Punyanitya, Mark; De Vivo, Darryl C; Kaufmann, Petra

    2010-11-01

    Accurate, noninvasive measures of body composition are needed for management of patients with spinal muscular atrophy. Fat mass index (fat mass/height(2) in kg/m(2)) was measured in 16 subjects with spinal muscular atrophy using 5 bioelectrical impedance analysis equations and compared with a reference method, dual-energy x-ray absorptiometry. The machine default equation, validated by Cordain, was the primary analysis. Fat mass index calculated by impedance measures differed by between -2.5 kg/m(2) and 1.7 kg/m(2) from the reference mean (8.3 ± 5.0 kg/m(2)). The Cordain equation provided the smallest difference (-0.4 ± 2.0 kg/m(2)), with correlation coefficient of 0.92. The Cordain equation showed high sensitivity (85.7%) and specificity (100%) for prediction of ''at risk for overweight'' (fat mass index > 85th percentile for age and gender). Although insufficiently accurate for use as a research tool, bioelectrical impedance can have application as a well-tolerated, noninvasive, easily used screening tool for excess adiposity in patients with spinal muscular atrophy. PMID:20388937

  10. Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients.

    PubMed

    Brkušanin, Miloš; Kosać, Ana; Jovanović, Vladimir; Pešović, Jovan; Brajušković, Goran; Dimitrijević, Nikola; Todorović, Slobodanka; Romac, Stanka; Milić Rašić, Vedrana; Savić-Pavićević, Dušanka

    2015-11-01

    Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e-16, P=4.264e-10, P=2.722e-8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e-16), SERF1A (P<2e-16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype. PMID:26311540

  11. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

    PubMed Central

    Wirth, B; Schmidt, T; Hahnen, E; Rudnik-Schöneborn, S; Krawczak, M; Müller-Myhsok, B; Schönling, J; Zerres, K

    1997-01-01

    Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families. PMID:9345102

  12. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

    PubMed

    Wirth, B; Schmidt, T; Hahnen, E; Rudnik-Schöneborn, S; Krawczak, M; Müller-Myhsok, B; Schönling, J; Zerres, K

    1997-11-01

    Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families. PMID:9345102

  13. An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy

    PubMed Central

    Singh, Natalia N.; Lawler, Mariah N.; Ottesen, Eric W.; Upreti, Daya; Kaczynski, Jennifer R.; Singh, Ravindra N.

    2013-01-01

    Here, we report a long-distance interaction (LDI) as a critical regulator of alternative splicing of Survival Motor Neuron 2 (SMN2) exon 7, skipping of which is linked to spinal muscular atrophy (SMA), a leading genetic disease of children and infants. We show that this LDI is linked to a unique intra-intronic structure that we term internal stem through LDI-1 (ISTL1). We used site-specific mutations and Selective 2′-Hydroxyl Acylation analyzed by Primer Extension to confirm the formation and functional significance of ISTL1. We demonstrate that the inhibitory effect of ISTL1 is independent of hnRNP A1/A2B1 and PTB1 previously implicated in SMN2 exon 7 splicing. We show that an antisense oligonucleotide-mediated sequestration of the 3′ strand of ISTL1 fully corrects SMN2 exon 7 splicing and restores high levels of SMN and Gemin2, a SMN-interacting protein, in SMA patient cells. Our results also reveal that the 3′ strand of ISTL1 and upstream sequences constitute an inhibitory region that we term intronic splicing silencer N2 (ISS-N2). This is the first report to demonstrate a critical role of a structure-associated LDI in splicing regulation of an essential gene linked to a genetic disease. Our findings expand the repertoire of potential targets for an antisense oligonucleotide-mediated therapy of SMA. PMID:23861442

  14. Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis

    PubMed Central

    2013-01-01

    Background The diagnosis of neuromuscular diseases is strongly based on the histological characterization of muscle biopsies. However, this morphological analysis is mostly a subjective process and difficult to quantify. We have tested if network science can provide a novel framework to extract useful information from muscle biopsies, developing a novel method that analyzes muscle samples in an objective, automated, fast and precise manner. Methods Our database consisted of 102 muscle biopsy images from 70 individuals (including controls, patients with neurogenic atrophies and patients with muscular dystrophies). We used this to develop a new method, Neuromuscular DIseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images. NDICIA characterizes muscle tissues by representing each image as a network, with fibers serving as nodes and fiber contacts as links. Results After a ‘training’ phase with control and pathological biopsies, NDICIA was able to quantify the degree of pathology of each sample. We validated our method by comparing NDICIA quantification of the severity of muscular dystrophies with a pathologist’s evaluation of the degree of pathology, resulting in a strong correlation (R = 0.900, P <0.00001). Importantly, our approach can be used to quantify new images without the need for prior ‘training’. Therefore, we show that network science analysis captures the useful information contained in muscle biopsies, helping the diagnosis of muscular dystrophies and neurogenic atrophies. Conclusions Our novel network analysis approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials. PMID:23514382

  15. Shift from extracellular signal-regulated kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells.

    PubMed

    Branchu, Julien; Biondi, Olivier; Chali, Farah; Collin, Thibault; Leroy, Felix; Mamchaoui, Kamel; Makoukji, Joelle; Pariset, Claude; Lopes, Philippe; Massaad, Charbel; Chanoine, Christophe; Charbonnier, Frédéric

    2013-03-01

    Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein. We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of the SMN2 genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation. Here, we provide the first compelling evidence for a competition between the MEK/ERK/Elk-1 and the phosphatidylinositol 3-kinase/AKT/CREB signaling pathways for SMN2 gene regulation in the spinal cord of type 1 SMA-like mice. The inhibition of the MEK/ERK/Elk-1 pathway promotes the AKT/CREB pathway activation, leading to (1) an enhanced SMN expression in the spinal cord of SMA-like mice and in human SMA myotubes and (2) a 2.8-fold lifespan extension in SMA-like mice. Furthermore, we identified a crosstalk between ERK and AKT signaling pathways that involves the calcium-dependent modulation of CaMKII activity. Together, all these data open new perspectives to the therapeutic strategy for SMA patients. PMID:23467345

  16. Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene.

    PubMed

    Castro-Gago, Manuel; Dacruz-Alvarez, David; Pintos-Martínez, Elena; Beiras-Iglesias, Andrés; Arenas, Joaquín; Martín, Miguel Ángel; Martínez-Azorín, Francisco

    2016-01-01

    Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern). PMID:26006750

  17. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy.

    PubMed

    Murray, Lyndsay M; Comley, Laura H; Thomson, Derek; Parkinson, Nick; Talbot, Kevin; Gillingwater, Thomas H

    2008-04-01

    Proximal spinal muscular atrophy (SMA) is a common autosomal recessive childhood form of motor neuron disease. Previous studies have highlighted nerve- and muscle-specific events in SMA, including atrophy of muscle fibres and post-synaptic motor endplates, loss of lower motor neuron cell bodies and denervation of neuromuscular junctions caused by loss of pre-synaptic inputs. Here we have undertaken a detailed morphological investigation of neuromuscular synaptic pathology in the Smn-/-;SMN2 and Smn-/-;SMN2;Delta7 mouse models of SMA. We show that neuromuscular junctions in the transversus abdominis (TVA), levator auris longus (LAL) and lumbrical muscles were disrupted in both mouse models. Pre-synaptic inputs were lost and abnormal accumulations of neurofilament were present, even in early/mid-symptomatic animals in the most severely affected muscle groups. Neuromuscular pathology was more extensive in the postural TVA muscle compared with the fast-twitch LAL and lumbrical muscles. Pre-synaptic pathology in Smn-/-;SMN2;Delta7 mice was reduced compared with Smn-/-;SMN2 mice at late-symptomatic time-points, although post-synaptic pathology was equally severe. We demonstrate that shrinkage of motor endplates does not correlate with loss of motor nerve terminals, signifying that one can occur in the absence of the other. We also demonstrate selective vulnerability of a subpopulation of motor neurons in the caudal muscle band of the LAL. Paralysis with botulinum toxin resulted in less terminal sprouting and ectopic synapse formation in the caudal band compared with the rostral band, suggesting that motor units conforming to a Fast Synapsing (FaSyn) phenotype are likely to be more vulnerable than those with a Delayed Synapsing (DeSyn) phenotype. PMID:18065780

  18. Selective type II fibre muscular atrophy in patients with osteoarthritis of the hip.

    PubMed

    Sĭrca, A; Susec-Michieli, M

    1980-01-01

    The size and the distribution of type I and tye II fibres was determined in the gluteus maximus (21 cases), gluteus medius (56 cases) and tensor faciae latae (27 cases) muscles of patients with osteoarthritis of the hip. The patients were of both sexes, aged between 37 and 64 years (younger group) and between 65 and 78 years (older group). Autopsy material of the two comparable age groups and of a group of "normal" adults (aged 22-44 years) served as controls. It was shown statistically that the diameter of both types of fibres and the relative number of type II fibres diminished with progressing age. In patients with osteoarthritis the degree of the selective atrophy of type II fibres was significantly higher than in the control groups. The atrophy is interpreted as a consequence of diminished muscular activity. No neurogenic lesions were detected either in the muscles of the patients or in those of the control groups. PMID:6444440

  19. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2.

    PubMed

    Rossor, Alexander M; Oates, Emily C; Salter, Hannah K; Liu, Yang; Murphy, Sinead M; Schule, Rebecca; Gonzalez, Michael A; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan; Herrmann, David N; Blake, Julian; Sowden, Janet E; Acsadi, Gyuda; Rodriguez, Michael L; Menezes, Manoj P; Clarke, Nigel F; Auer Grumbach, Michaela; Bullock, Simon L; Muntoni, Francesco; Reilly, Mary M; North, Kathryn N

    2015-02-01

    Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu

  20. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2

    PubMed Central

    Rossor, Alexander M.; Oates, Emily C.; Salter, Hannah K.; Liu, Yang; Murphy, Sinead M.; Schule, Rebecca; Gonzalez, Michael A.; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A.; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan; Herrmann, David N.; Blake, Julian; Sowden, Janet E.; Acsadi, Gyuda; Rodriguez, Michael L.; Menezes, Manoj P.; Clarke, Nigel F.; Auer Grumbach, Michaela; Bullock, Simon L.; Muntoni, Francesco; North, Kathryn N.

    2015-01-01

    Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible ‘hot spot’ mutation, p.Ser107

  1. Effects of Electromagnetic Fields in Spinal Muscular Atrophy: A Case Report

    NASA Astrophysics Data System (ADS)

    Cañedo, L.; Martínez-Mata, J.; Serrano-Luna, G.

    2004-09-01

    Spinal Muscular Atrophy Type I is a disease that rapidly progress to death in early infancy. A case report of a child with Werdnig-Hoffmann disease Type I that recovered at three years of age after two years exposure to electromagnetic fields (ELF) is presented. The child is now eleven years old and with the exception of slightly abnormal gait, the muscle mass of tights and gluteus, high, weight and his everyday activities correspond to those of a normal child his age. Hypothetical explanations for the effects of the electromagnetic fields are discussed.

  2. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease

    SciTech Connect

    Hahnen, E.; Schoenling, J.; Zerres, K.

    1996-11-01

    Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5{prime} end of the SMN genes, suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-simulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the {alpha}-globin cluster, and the polymerase {alpha} arrest sites. This may explain why independent hybrid SMN genes show identical sequences. 35 refs., 4 figs., 1 tab.

  3. SMN, the Spinal Muscular Atrophy Protein, Forms a Pre-Import Snrnp Complex with Snurportin1 and Importin β

    PubMed Central

    Narayanan, Usha; Ospina, Jason K.; Frey, Mark R.; Hebert, Michael D.; Matera, A. Gregory

    2006-01-01

    The survival of motor neuron (SMN) protein is mutated in patients with spinal muscular atrophy (SMA). SMN is part of a multiprotein complex required for biogenesis of the Sm class of small nuclear ribonucleoproteins (snRNPs). Following assembly of the Sm core domain, snRNPs are transported to the nucleus via importin β. Sm snRNPs contain a nuclear localization signal (NLS) consisting of a 2,2,7-trimethylguanosine (TMG) cap and the Sm core. Snurportin1 (SPN) is the adaptor protein that recognizes both the TMG cap and importin β. Here, we report that a mutant SPN construct lacking the importin β binding domain (IBB), but containing an intact TMG cap-binding domain, localizes primarily to the nucleus, whereas full-length SPN localizes to the cytoplasm. The nuclear localization of the mutant SPN was not a result of passive diffusion through the nuclear pores. Importantly, we found that SPN interacts with SMN, Gemin3, Sm snRNPs and importin β. In the presence of ribonucleases, the interactions with SMN and Sm proteins were abolished, indicating that snRNAs mediate this interplay. Cell fractionation studies showed that SPN binds preferentially to cytoplasmic SMN complexes. Notably, we found that SMN directly interacts with importin β in a GST-pulldown assay, suggesting that the SMN complex might represent the Sm core NLS receptor predicted by previous studies. Therefore, we conclude that, following Sm protein assembly, the SMN complex persists until the final stages of cytoplasmic snRNP maturation and may provide somatic cell RNPs with an alternative NLS. PMID:12095920

  4. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.

    PubMed

    Alías, Laura; Bernal, Sara; Fuentes-Prior, Pablo; Barceló, María Jesus; Also, Eva; Martínez-Hernández, Rebeca; Rodríguez-Alvarez, Francisco J; Martín, Yolanda; Aller, Elena; Grau, Elena; Peciña, Ana; Antiñolo, Guillermo; Galán, Enrique; Rosa, Alberto L; Fernández-Burriel, Miguel; Borrego, Salud; Millán, José M; Hernández-Chico, Concepción; Baiget, Montserrat; Tizzano, Eduardo F

    2009-02-01

    Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II-III) predominated in males (p<0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1-SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T>G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN-SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein. PMID:19050931

  5. Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy.

    PubMed

    Garcia, Eric L; Wen, Ying; Praveen, Kavita; Matera, A Gregory

    2016-08-01

    Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies. PMID:27268418

  6. Association of copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein gene with the natural history in a Chinese spinal muscular atrophy cohort.

    PubMed

    Qu, Yu-jin; Ge, Xiu-shan; Bai, Jin-li; Wang, Li-wen; Cao, Yan-yan; Lu, Yan-yu; Jin, Yu-wei; Wang, Hong; Song, Fang

    2015-03-01

    We evaluated survival motor neuron 2 (SMN2) and neuronal apoptosis inhibitory protein (NAIP) gene copy distribution and the association of copy number with survival in 232 Chinese spinal muscular atrophy (SMA) patients. The SMN2 and NAIP copy numbers correlated positively with the median onset age (r = 0.72 and 0.377). The risk of death for patients with fewer copies of SMN2 or NAIP was much higher than for those with more copies (P < .01). The survival probabilities at 5 years were 5.1%, 90.7%, and 100% for 2, 3, and 4 SMN2 copies and 27.9%, 66.7%, and 87.2% for 0, 1, and 2 NAIP copies, respectively. Our results indicated that combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age and poorer survival probability. Better survival status for Chinese type I SMA might due to a higher proportion of 3 SMN2 and a lower rate of zero NAIP. PMID:25330799

  7. Distally pronounced infantile spinal muscular atrophy with severe axonal and demyelinating neuropathy associated with the S230L mutation of SMN1.

    PubMed

    Rudnik-Schöneborn, Sabine; Barisić, Nina; Eggermann, Katja; Ortiz Brüchle, Nadina; Grđan, Petra; Zerres, Klaus

    2016-02-01

    Two Croatian siblings with atypical clinical findings in the presence of SMN1 gene mutations are reported. The girl presented with delayed motor development and weakness in hands and feet in her first year of life. She never stood or walked and developed scoliosis and joint contractures during childhood. Her hands and feet were non-functional when last seen at age 14 years. Her 4-year-old brother was more severely affected and had a clinical picture resembling infantile spinal muscular atrophy (SMA) type 1. He also showed unusual distally pronounced weakness and facial weakness. Both patients had no sensory deficits but gave evidence of a mixed axonal and demyelinating neuropathy with pronounced slowing in the distal nerve segments. Unexpectedly, both siblings showed a compound heterozygous SMN1 mutation (heterozygous deletion and missense mutation c.689C > T; p.S230L), thus confirming infantile SMA. In addition, next generation sequencing of 52 genes for hereditary neuropathies revealed a heterozygous missense mutation c.505T > C; p.Y169H in the SH3TC2 gene that was transmitted by the healthy father. Our observations widen the phenotypic consequences of SMN1 gene mutations and support the notion to look for additional genetic factors which may modify the clinical picture in atypical cases. PMID:26794302

  8. Refined mapping of the G[sub M2] activator protein (GM2A) locus to 5q31. 3-q33. 1, distal to the spinal muscular atrophy locus

    SciTech Connect

    Heng, H.H.Q.; Xie, B.; Shi, X.M.; Tsui, L.C.; Mahuran, D.J. )

    1993-11-01

    The G[sub M2] activator locus (GM2A) had previously been considered as a candidate gene for some forms of spinal muscular atrophy (SMA; mapped to 5q11.2-q13.3). It was eliminated as a possible candidate because PCR-based mapping failed to localize the gene to chromosome 5, as was previously reported using an ELISA-based methodology. However, the authors demonstrated that the PCR primers used preferentially amplified a processed pseudogene (GM2AP) that was mapped to chromosome 3 and that GM2A was located on chromosome 5. In this report, they reconsider the candidacy of GM2A by refining its localization on chromosome 5 using fluorescence in situ hybridization. They localize GM2A to 5q31.3-q33.1; thus, it is not a candidate gene for SMA. 11 refs., 2 figs.

  9. Insulinlike Growth Factor (IGF)-1 Administration Ameliorates Disease Manifestations in a Mouse Model of Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Rinaldi, Carlo; Bott, Laura C; Chen, Ke-lian; Harmison, George G; Katsuno, Masahisa; Sobue, Gen; Pennuto, Maria; Fischbeck, Kenneth H

    2012-01-01

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1–treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease. PMID:22952056

  10. Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy.

    PubMed

    Li, Mei; Chevalier-Larsen, Erica S; Merry, Diane E; Diamond, Marc I

    2007-02-01

    In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single approximately 50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA. PMID:17121819

  11. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy.

    PubMed

    Todd, Tiffany W; Kokubu, Hiroshi; Miranda, Helen C; Cortes, Constanza J; La Spada, Albert R; Lim, Janghoo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA. PMID:26308581

  12. Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy.

    PubMed

    Araki, Kunihiko; Nakanishi, Hirotaka; Nakamura, Tomohiko; Atsuta, Naoki; Yamada, Shinichiro; Hijikata, Yasuhiro; Hashizume, Atsushi; Suzuki, Keisuke; Katsuno, Masahisa; Sobue, Gen

    2015-11-01

    We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles. PMID:26363965

  13. Clinical Trials in Spinal and Bulbar Muscular Atrophy-Past, Present, and Future.

    PubMed

    Weydt, Patrick; Sagnelli, Anna; Rosenbohm, Angela; Fratta, Pietro; Pradat, Pierre-François; Ludolph, Albert C; Pareyson, Davide

    2016-03-01

    Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials. PMID:26572537

  14. Towards a European Registry and Biorepository for Patients with Spinal and Bulbar Muscular Atrophy.

    PubMed

    Pareyson, Davide; Fratta, Pietro; Pradat, Pierre-François; Sorarù, Gianni; Finsterer, Josef; Vissing, John; Jokela, Manu E; Udd, Bjarne; Ludolph, Albert C; Sagnelli, Anna; Weydt, Patrick

    2016-03-01

    Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures render design and conduction of clinical trials a challenging task. Therefore, it is fundamental to strengthen the network of clinical centers interested in SBMA for clinical trial readiness. We propose to create and maintain an International SBMA Registry where as many well-characterized patients as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents. PMID:26744358

  15. Spinal muscular atrophy with respiratory distress syndrome (SMARD1): Case report and review of literature

    PubMed Central

    Lingappa, Lokesh; Shah, Nikit; Motepalli, Ananth Sagar; Shaik, Farhan

    2016-01-01

    Spinal muscular atrophy with respiratory distress syndrome (SMARD1) is a rare cause of early infantile respiratory failure and death. No cases have been currently described from India. Two low-birth-weight infants presented prior to 6 months of age with recurrent apnea and respiratory distress. Both required prolonged ventilation, and had distal arthrogryposis and diaphragmatic eventration. Nerve conduction study revealed motor sensory axonopathy. Genetic testing confirmed mutations in immunoglobulin mu binding protein (IGHMBP2). These two cases establish presence of SMARD1 in our population. Both infants died on discontinuation of ventilation. Antenatal diagnoses done in one pregnancy. Though rare, high index of suspicion is essential in view of poor outcome and aid antenatal counseling. PMID:27570397

  16. Spinal muscular atrophy with respiratory distress syndrome (SMARD1): Case report and review of literature.

    PubMed

    Lingappa, Lokesh; Shah, Nikit; Motepalli, Ananth Sagar; Shaik, Farhan

    2016-01-01

    Spinal muscular atrophy with respiratory distress syndrome (SMARD1) is a rare cause of early infantile respiratory failure and death. No cases have been currently described from India. Two low-birth-weight infants presented prior to 6 months of age with recurrent apnea and respiratory distress. Both required prolonged ventilation, and had distal arthrogryposis and diaphragmatic eventration. Nerve conduction study revealed motor sensory axonopathy. Genetic testing confirmed mutations in immunoglobulin mu binding protein (IGHMBP2). These two cases establish presence of SMARD1 in our population. Both infants died on discontinuation of ventilation. Antenatal diagnoses done in one pregnancy. Though rare, high index of suspicion is essential in view of poor outcome and aid antenatal counseling. PMID:27570397

  17. Atelocollagen-mediated systemic administration of myostatin-targeting siRNA improves muscular atrophy in caveolin-3-deficient mice.

    PubMed

    Kawakami, Emi; Kinouchi, Nao; Adachi, Taro; Ohsawa, Yutaka; Ishimaru, Naozumi; Ohuchi, Hideyo; Sunada, Yoshihide; Hayashi, Yoshio; Tanaka, Eiji; Noji, Sumihare

    2011-01-01

    Small interfering RNA (siRNA)-mediated silencing of gene expression is rapidly becoming a powerful tool for molecular therapy. However, the rapid degradation of siRNAs and their limited duration of activity require efficient delivery methods. Atelocollagen (ATCOL)-mediated administration of siRNAs is a promising approach to disease treatment, including muscular atrophy. Herein, we report that ATCOL-mediated systemic administration of a myostatin-targeting siRNA into a caveolin-3-deficient mouse model of limb-girdle muscular dystrophy 1C (LGMD1C) induced a marked increase in muscle mass and a significant recovery of contractile force. These results provide evidence that ATCOL-mediated systemic administration of siRNAs may be a powerful therapeutic tool for disease treatment, including muscular atrophy. PMID:21261610

  18. Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients.

    PubMed

    Grunseich, Christopher; Zukosky, Kristen; Kats, Ilona R; Ghosh, Laboni; Harmison, George G; Bott, Laura C; Rinaldi, Carlo; Chen, Ke-lian; Chen, Guibin; Boehm, Manfred; Fischbeck, Kenneth H

    2014-10-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy. PMID:24925468

  19. X-linked lethal infantile spinal muscular atrophy: From clinical description to molecular mapping

    SciTech Connect

    Baumbach, L.; Schiavi, A.

    1994-09-01

    The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on two unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.

  20. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

    PubMed

    Lieberman, Andrew P; Yu, Zhigang; Murray, Sue; Peralta, Raechel; Low, Audrey; Guo, Shuling; Yu, Xing Xian; Cortes, Constanza J; Bennett, C Frank; Monia, Brett P; La Spada, Albert R; Hung, Gene

    2014-05-01

    Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients. PMID:24746732

  1. Infantile spinal muscular atrophy with respiratory distress type I presenting without respiratory involvement: Novel mutations and review of the literature.

    PubMed

    Luan, Xinghua; Huang, Xiaojun; Liu, Xiaoli; Zhou, Haiyan; Chen, Shengdi; Cao, Li

    2016-08-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as distal spinal muscular atrophy 1 (DSMA1) or distal hereditary motor neuropathies type 6 (dHMN6), is a rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, distal muscular weakness and muscle atrophy. The disease is caused by mutations in the gene encoding immunoglobulinm-binding protein 2 (IGHMBP2). We present a female child with novel compound heterozygous mutations in IGHMBP2 gene c.344C>T (p.115T>M) and c.1737C>A (p.579F>L), displaying distal limbs weakness and atrophy without signs of diaphragmatic palsy or respiratory insufficiency. We review 20 reported SMARD1 cases that have no respiratory involvement or have late onsets. We propose that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity. Diaphragmatic palsy and respiratory distress may be absent and SMARD1 should be considered in infantile with the onset of peripheral neuropathies. PMID:26922252

  2. Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres.

    PubMed

    Trollet, Capucine; Anvar, Seyed Yahya; Venema, Andrea; Hargreaves, Iain P; Foster, Keith; Vignaud, Alban; Ferry, Arnaud; Negroni, Elisa; Hourde, Christophe; Baraibar, Martin A; 't Hoen, Peter A C; Davies, Janet E; Rubinsztein, David C; Heales, Simon J; Mouly, Vincent; van der Maarel, Silvère M; Butler-Browne, Gillian; Raz, Vered; Dickson, George

    2010-06-01

    Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)(8-13) expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets. PMID:20207626

  3. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy

    PubMed Central

    Todd, Tiffany W; Kokubu, Hiroshi; Miranda, Helen C; Cortes, Constanza J; La Spada, Albert R; Lim, Janghoo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA. DOI: http://dx.doi.org/10.7554/eLife.08493.001 PMID:26308581

  4. Absence of disturbed axonal transport in spinal and bulbar muscular atrophy

    PubMed Central

    Malik, Bilal; Nirmalananthan, Niranjanan; Bilsland, Lynsey G.; La Spada, Albert R.; Hanna, Michael G.; Schiavo, Giampietro; Gallo, Jean-Marc; Greensmith, Linda

    2011-01-01

    Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a late-onset motor neuron disease (MND) caused by an abnormal expansion of the CAG repeat in the androgen receptor (AR) gene on the X-chromosome, encoding a polyglutamine (poly-Q) sequence in the protein product. Mutant poly-Q-expanded AR protein is widely expressed but leads to selective lower motoneuron death. Although the mechanisms that underlie SBMA remain unclear, defective axonal transport has been implicated in MND and other forms of poly-Q disease. Transcriptional dysregulation may also be involved in poly-Q repeat pathology. We therefore examined axonal transport in a mouse model of SBMA recapitulating many aspects of the human disease. We found no difference in the expression levels of motor and the microtubule-associated protein tau, in the spinal cord and sciatic nerve of wild-type (WT) and SBMA mice at various stages of disease progression. Furthermore, we found no alteration in binding properties of motor proteins and tau to microtubules. Moreover, analysis of axonal transport rates both in cultured primary motoneurons in vitro and in vivo in the sciatic nerve of adult WT and mutant SBMA mice demonstrated no overt axonal transport deficits in these systems. Our results therefore indicate that unlike other motoneuron and poly-Q diseases, axonal transport deficits do not play a significant role in the pathogenesis of SBMA. PMID:21317158

  5. CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy

    PubMed Central

    Furukawa, Takahiro; Fujita, Koji; Nodera, Hiroyuki; Shimizu, Fumitaka; Miyamoto, Katsuichi; Takahashi, Yukitoshi; Kanda, Takashi; Kusunoki, Susumu; Izumi, Yuishin; Kaji, Ryuji

    2015-01-01

    Objective: We aimed to compare the cytokine and chemokine profiles of patients with multifocal motor neuropathy (MMN) with those of patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) to investigate immunologic differences in the CNS. Methods: CSF from 12 patients with MMN, 8 with PMA, 26 with sporadic ALS, and 10 with other noninflammatory neurologic disorders was analyzed for 27 cytokines and chemokines using the multiplex bead array assay. Cytokine titers of the 4 groups were compared, and correlations between the titers of relevant cytokines and clinical parameters were evaluated. Results: There were no obvious intrathecal changes except for interleukin (IL)-1 receptor antagonist in patients with MMN. In contrast, IL-4, IL-7, IL-17, eotaxin/CCL11, fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), and platelet-derived growth factor BB titers were significantly elevated in patients with PMA and ALS; of these, FGF-2 and G-CSF titers were elevated compared with those in patients with MMN. IL-4 and IL-10 titers were high in patients with ALS, particularly patients with possible ALS presenting with a slowly progressive course or mild symptoms. Conclusions: The CSF cytokine profile of patients with MMN is distinct from that of patients with PMA and ALS. The similarity of the cytokine profiles between patients with PMA and ALS suggests that PMA shares common immunologic features with ALS in the CNS, even without clinical evidence of upper motor neuron involvement. PMID:26280014

  6. Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia

    PubMed Central

    Oates, Emily C.; Rossor, Alexander M.; Hafezparast, Majid; Gonzalez, Michael; Speziani, Fiorella; MacArthur, Daniel G.; Lek, Monkol; Cottenie, Ellen; Scoto, Mariacristina; Foley, A. Reghan; Hurles, Matthew; Houlden, Henry; Greensmith, Linda; Auer-Grumbach, Michaela; Pieber, Thomas R.; Strom, Tim M.; Schule, Rebecca; Herrmann, David N.; Sowden, Janet E.; Acsadi, Gyula; Menezes, Manoj P.; Clarke, Nigel F.; Züchner, Stephan; Muntoni, Francesco; North, Kathryn N.; Reilly, Mary M.

    2013-01-01

    Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons. PMID:23664120

  7. Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

    PubMed Central

    Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W.; Breedlove, S. Marc

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. PMID:25663674

  8. MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-lian; Harmison, George G; Bott, Laura C; Katsuno, Masahisa; Sobue, Gen; Burnett, Barrington G; Fischbeck, Kenneth H; Rinaldi, Carlo

    2016-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. PMID:26755334

  9. MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy.

    PubMed

    Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-Lian; Harmison, George G; Bott, Laura C; Katsuno, Masahisa; Sobue, Gen; Burnett, Barrington G; Fischbeck, Kenneth H; Rinaldi, Carlo

    2016-05-01

    Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. PMID:26755334

  10. Accuracy of marker analysis, quantitative real-time polymerase chain reaction, and multiple ligation-dependent probe amplification to determine SMN2 copy number in patients with spinal muscular atrophy.

    PubMed

    Alías, Laura; Bernal, Sara; Barceló, Maria J; Also-Rallo, Eva; Martínez-Hernández, Rebeca; Rodríguez-Alvarez, Francisco J; Hernández-Chico, Concepción; Baiget, Montserrat; Tizzano, Eduardo F

    2011-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by absence of or mutations in the survival motor neuron1 gene (SMN1). All SMA patients have a highly homologous copy of SMN1, the SMN2 gene. Severe (type I) SMA patients present one or two SMN2 copies, whereas milder chronic forms (type II-III) usually have three or four SMN2 copies. SMN2 dosage is important to stratify patients for motor function tests and clinical trials. Our aim was to compare three methods, marker analysis, real-time quantitative polymerase chain reaction using the LightCycler instrument, and multiple ligation-dependent probe amplification (MLPA), to characterize their accuracy in quantifying SMN2 genes. We studied a group of 62 genetically confirmed SMA patients, 54 with homozygous absence of exons 7 and 8 of SMN1 and 8 with SMN2-SMN1 hybrid genes. A complete correlation using the three methods was observed in 32 patients (51.6%). In the remaining 30 patients, discordances between the three methods were found, including under or overestimation of SMN2 copies by marker analysis with respect to the quantitative methods (LightCycler and MLPA) because of lack of informativeness of markers, 3' deletions of SMN genes, and breakpoints in SMN2-SMN1 hybrid genes. The technical limitations and advantages and disadvantages of these methods are discussed. We conclude that the three methods complement each other in estimating the SMN2 copy number in most cases. However, MLPA offers additional information to characterize SMA cases with particular rearrangements such as partial deletions and hybrid genes. PMID:21548796

  11. Differences in F-Wave Characteristics between Spinobulbar Muscular Atrophy and Amyotrophic Lateral Sclerosis

    PubMed Central

    Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Li, Xiaoguang; Li, Dawei; Cui, Bo; Shen, Dongchao; Ding, Qingyun

    2016-01-01

    There is limited data on the differences in F-wave characteristics between spinobulbar muscular atrophy (SBMA) and lower motor neuron dominant (LMND) amyotrophic lateral sclerosis (ALS). We compared the parameters of F-waves recorded bilaterally from the median, ulnar, tibial, and deep peroneal nerves in 32 SBMA patients, 37 patients with LMND ALS, and 30 normal controls. The maximum F-wave amplitudes, frequencies of giant F-waves, and frequencies of patients with giant F-waves in all nerves examined were significantly higher in the SBMA patients than in the ALS patients and the normal controls. The mean F-wave amplitude, maximum F-wave amplitude, frequency of giant F-waves, and frequency of patients with giant F-waves in the median and deep peroneal nerves were comparable between the ALS patients and normal controls. Giant F-waves were detected in multiple nerves and were often symmetrical in the SBMA patients compared with the ALS patients. The number of nerves with giant F-waves seems to be the most robust variable for differentiation of SBMA from ALS, with an area under the curve of 0.908 (95% CI: 0.835–0.982). A cut-off value of the number of nerves with giant F-waves (≥3) for diagnosing SBMA showed high sensitivity and specificity: 85% sensitivity and 81% specificity vs. ALS patients. No significant correlations were found between the pooled frequency of giant F-waves and disease duration in the SBMA (r = 0.162, P = 0.418) or ALS groups (r = 0.107, P = 0.529). Our findings suggested that F-waves might be used to discriminate SBMA from ALS, even at early stages of disease. PMID:27014057

  12. A randomized controlled trial of exercise in spinal and bulbar muscular atrophy

    PubMed Central

    Shrader, Joseph A; Kats, Ilona; Kokkinis, Angela; Zampieri, Cris; Levy, Ellen; Joe, Galen O; Woolstenhulme, Joshua G; Drinkard, Bart E; Smith, Michaele R; Ching, Willie; Ghosh, Laboni; Fox, Derrick; Auh, Sungyoung; Schindler, Alice B; Fischbeck, Kenneth H; Grunseich, Christopher

    2015-01-01

    Objective To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA). Methods Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up and go, sit-to-stand test, health-related quality of life, creatine kinase, and insulin-like growth factor-1. Results Functional exercise was well tolerated but did not lead to significant group differences in the primary outcome measure or any of the secondary measures. The functional exercise did not produce significantly more adverse events than stretching, and was not perceived to be difficult. To determine whether a subset of the subjects may have benefited, we divided them into high and low functioning based on baseline AMAT scores and performed a post hoc subgroup analysis. Low-functioning individuals receiving the intervention increased AMAT functional subscale scores compared to the control group. Interpretation Although these trial results indicate that functional exercise had no significant effect on total AMAT scores or on mobility, strength, balance, and quality of life, post hoc findings indicate that low-functioning men with SBMA may respond better to functional exercises, and this warrants further investigation with appropriate exercise intensity. PMID:26273686

  13. SMA type 2 unrelated to chromosome 5q13.

    PubMed

    Nevo, Y; Kramer, U; Legum, C; Shomrat, R; Fatal, A; Soffer, D; Harel, S; Shapira, Y

    1998-01-13

    We describe two brothers with clinical and histological findings of type 2 spinal muscular atrophy (SMA) associated with small head circumference (<2%) and normal cognitive development. No survival motor neuron (SMN) or neuronal apoptosis-inhibitory protein (NAIP) deletions were detected in these sibs, and they were discordant for the haplotypes determined by DNA markers flanking the 5q13 SMA locus. These findings support the presence of a distinct anterior horn disease unrelated to 5q13. This entity may have either autosomal recessive or X-linked inheritance. PMID:9450884

  14. Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat

    PubMed Central

    Grunseich, Christopher; Kats, Ilona R.; Bott, Laura C.; Rinaldi, Carlo; Kokkinis, Angela; Fox, Derrick; Chen, Ke-lian; Schindler, Alice B.; Mankodi, Ami K.; Shrader, Joseph A.; Schwartz, Daniel P.; Lehky, Tanya J.; Liu, Chia-Ying; Fischbeck, Kenneth H.

    2014-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29 year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor. PMID:25047668

  15. Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis

    PubMed Central

    Riku, Yuichi; Atsuta, Naoki; Yoshida, Mari; Tatsumi, Shinsui; Iwasaki, Yasushi; Mimuro, Maya; Watanabe, Hirohisa; Ito, Mizuki; Senda, Jo; Nakamura, Ryoichi; Koike, Haruki; Sobue, Gen

    2014-01-01

    Objective Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases. Design Retrospective, observational. Setting Autopsied patients. Participants We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included. Primary outcome measures Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles. Results Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology. Conclusions PMA has three neuropathological background patterns. A combination of UMN and LMN

  16. Hypothermia improves disease manifestations in SMA mice via SMN augmentation.

    PubMed

    Tsai, Li-Kai; Chen, Chien-Lin; Tsai, Yi-Chieh; Ting, Chen-Hung; Chien, Yin-Hsio; Lee, Ni-Chong; Hwu, Wuh-Liang

    2016-02-15

    Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein. In this study, we evaluated the efficacy of intermittent transient hypothermia in a mouse model of SMA. SMA mice were exposed to ice for 50 s to achieve transient hypothermia (below 25°C) daily beginning on postnatal day 1. Neonatal SMA mice (Smn(-/-)SMN2(+/-)) who received daily transient hypothermia exhibited reduced motor neuron degeneration and muscle atrophy and preserved the architecture of neuromuscular junction when compared with untreated controls at day 8 post-treatment. Daily hypothermia also prolonged the lifespan, increased body weight and improved motor coordination in SMA mice. Quantitative polymerase chain reaction and western blot analyses showed that transient hypothermia led to an increase in SMN transcript and protein levels in the spinal cord and brain. In in vitro studies using an SMN knockdown motor neuron-like cell-line, transient hypothermia increased intracellular SMN protein expression and length of neurites, confirming the direct effect of hypothermia on motor neurons. These data indicate that the efficacy of intermittent transient hypothermia in improving outcome in an SMA mouse model may be mediated, in part, via an upregulation of SMN levels in the motor neurons. PMID:26647309

  17. Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures.

    PubMed

    Knierim, Ellen; Hirata, Hiromi; Wolf, Nicole I; Morales-Gonzalez, Susanne; Schottmann, Gudrun; Tanaka, Yu; Rudnik-Schöneborn, Sabine; Orgeur, Mickael; Zerres, Klaus; Vogt, Stefanie; van Riesen, Anne; Gill, Esther; Seifert, Franziska; Zwirner, Angelika; Kirschner, Janbernd; Goebel, Hans Hilmar; Hübner, Christoph; Stricker, Sigmar; Meierhofer, David; Stenzel, Werner; Schuelke, Markus

    2016-03-01

    Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system. PMID:26924529

  18. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons

    PubMed Central

    Lee, Young il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

    2011-01-01

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precedes the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5 days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development. PMID:21658376

  19. [On the Role of Titin Phosphorylation in Development of Muscular Atrophy].

    PubMed

    Salmov, N N; Gritsyna, Yu V; Ulanova, A D; Vikhlyantsev, I M; Podlubnaya, Z A

    2015-01-01

    From our earlier experiments on the study of changes in titin content and the level of its phosphorylation in skeletal muscles, atrophied during space flight, hibernation, and also because of the development of alcohol-induced lesions it has been suggested that an increase in the degree of titin phosphorylation results in increased proteolytic degradation of this protein, that contributes to the development of skeletal muscle atrophy. PMID:26394485

  20. Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy.

    PubMed

    Borg, Rebecca M; Fenech Salerno, Benji; Vassallo, Neville; Bordonne, Rémy; Cauchi, Ruben J

    2016-10-01

    The neuromuscular disorder, spinal muscular atrophy (SMA), results from insufficient levels of the survival motor neuron (SMN) protein. Together with Gemins 2-8 and Unrip, SMN forms the large macromolecular SMN-Gemins complex, which is known to be indispensable for chaperoning the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). It remains unclear whether disruption of this function is responsible for the selective neuromuscular degeneration in SMA. In the present study, we first show that loss of wmd, the Drosophila Unrip orthologue, has a negative impact on the motor system. However, due to lack of a functional relationship between wmd/Unrip and Gemin3, it is likely that Unrip joined the SMN-Gemins complex only recently in evolution. Second, we uncover that disruption of either Tgs1 or pICln, two cardinal players in snRNP biogenesis, results in viability and motor phenotypes that closely resemble those previously uncovered on loss of the constituent members of the SMN-Gemins complex. Interestingly, overexpression of both factors leads to motor dysfunction in Drosophila, a situation analogous to that of Gemin2. Toxicity is conserved in the yeast S. pombe where pICln overexpression induces a surplus of Sm proteins in the cytoplasm, indicating that a block in snRNP biogenesis is partly responsible for this phenotype. Importantly, we show a strong functional relationship and a physical interaction between Gemin3 and either Tgs1 or pICln. We propose that snRNP biogenesis is the pathway connecting the SMN-Gemins complex to a functional neuromuscular system, and its disturbance most likely leads to the motor dysfunction that is typical in SMA. PMID:27388936

  1. Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

    PubMed Central

    Beitel, Lenore K.; Alvarado, Carlos; Mokhtar, Shaza; Paliouras, Miltiadis; Trifiro, Mark

    2013-01-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA. PMID:23720649

  2. Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo; Cicardi, Maria Elena; Meroni, Marco; Galbiati, Mariarita; Piccolella, Margherita; Messi, Elio; Giorgetti, Elisa; Lieberman, Andrew P.; Milioto, Carmelo; Rocchi, Anna; Aggarwal, Tanya; Pennuto, Maria; Crippa, Valeria; Poletti, Angelo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. PMID:26490709

  3. Novel microsatellite repeats (MSRs) and linkage disequilibrium analysis in the SMA region of 5q13.1

    SciTech Connect

    Yaraghi, Z.; Roy, N.; MacKenzie, A.E.

    1994-09-01

    The spinal muscular atrophies (SMA) are characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular atrophy associated with progressive paralysis. The gene involved in SMA has been mapped by linkage analysis to a region of 5q13.1 flanked centromerically by D5S435 and telomerically by D5S557. We are in the process of identifying new microsatellite repeats to further define the genetic map of the SMA region. A contiguous array of YAC clones covering the SMA containing D5S435-D56S112 interval of 5q13.1 was established. From this contig, a 700 kb clone 76C1, which contains the 200 kb CMS-1/CATT-1 critical region, was used to generate a partial Sau3A1 phage library. We have previously shown that 2 CATT-1 subloci are in linkage disequilibrium with type I SMA. The 76C1 subloci are in linkage disequilibrium with type I SMA. The 76C1 phage library has been screened for human MSRs. To date we have identified two novel polymorphic microsatellites and four further candidates are being characterized. Results of linkage disequilibrium studies currently underway will be presented. The identification of a linkage disequilibrium maximum will be helpful in the further narrowing of the SMA region.

  4. Identification of key recombinants in multiplex SMA families

    SciTech Connect

    Van Der Steege, G.; Cobben, J.M.; Osinga, J.

    1994-07-01

    Recent reports have provided evidence that a major gene for autosomal recessive proximal spinal muscular atrophy (SMA) resides in a small genetic interval in bands q12-q13 of chromosome 5, a 4-cM region proximally flanked by D5S125 (EF(TG/AG)n) and distally by MAP1B/D5S112 or a 0.7-cM interval (range 0.1-2.1 cM) flanked by D5S435 proximally and MAP1B/D5S112 distally. The authors present the identification of key recombinants between SMA and the closest flanking DNA-markers in an analysis of Dutch and Italian SMA families. These crossovers may serve as reference points for new markers in this region and may thus be instrumental in a further refined mapping of the SMA gene. Two markers, D5S351 (I105) and D5S357 (Mfd151), could be mapped distally to SMA in the interval SMA-D5S112. 26 refs., 3 figs., 1 tab.

  5. Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels.

    PubMed

    Cea, Luis A; Balboa, Elisa; Puebla, Carlos; Vargas, Aníbal A; Cisterna, Bruno A; Escamilla, Rosalba; Regueira, Tomás; Sáez, Juan C

    2016-10-01

    Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X7 receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca(2+) signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NFκB activation and increased mRNA levels of TNF-α in control but not in Cx43/Cx45 expression-deficient myofibers. Finally, a prolonged DEX treatment (7days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker. PMID:27437607

  6. An Autosomal Recessive Syndrome of Joint Contractures, Muscular Atrophy, Microcytic Anemia, and Panniculitis-Associated Lipodystrophy

    PubMed Central

    Garg, Abhimanyu; Hernandez, Maria Dolores; Sousa, Ana Berta; Subramanyam, Lalitha; Martínez de Villarreal, Laura; dos Santos, Heloísa G.; Barboza, Oralia

    2010-01-01

    Context: Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. Objective: The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome. Results: We report the detailed phenotype of two males and one female patient, 26–34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well. Conclusions: We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated. PMID:20534754

  7. Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

    PubMed Central

    Querin, Giorgia; Bertolin, Cinzia; Da Re, Elisa; Volpe, Marco; Zara, Gabriella; Pegoraro, Elena; Caretta, Nicola; Foresta, Carlo; Silvano, Maria; Corrado, Domenico; Iafrate, Massimo; Angelini, Lorenzo; Sartori, Leonardo; Pennuto, Maria; Gaiani, Alessandra; Bello, Luca; Semplicini, Claudio; Pareyson, Davide; Silani, Vincenzo; Ermani, Mario; Ferlin, Alberto; Sorarù, Gianni

    2016-01-01

    Objective To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. PMID:26503015

  8. Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy

    PubMed Central

    Malik, Bilal; Nirmalananthan, Niranjanan; Gray, Anna L.; La Spada, Albert R.; Hanna, Michael G.

    2013-01-01

    Spinal and bulbar muscular atrophy, also known as Kennedy’s disease, is an adult-onset hereditary neurodegenerative disorder caused by an expansion of the polyglutamine repeat in the first exon in the androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with arimoclomol, a co-inducer of the heat shock stress response, delays disease progression in the mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis, a fatal motor neuron disease. We therefore evaluated the therapeutic potential of arimoclomol in mice with spinal and bulbar muscular atrophy. Arimoclomol was administered orally, in drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease. Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with arimoclomol may have therapeutic potential in the treatment of spinal and bulbar muscular atrophy and may also

  9. Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

    PubMed Central

    Saal, Lena; Briese, Michael; Kneitz, Susanne; Glinka, Michael

    2014-01-01

    Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy. PMID:25246652

  10. Transcriptional Profile of Muscle following Acute Induction of Symptoms in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy

    PubMed Central

    Halievski, Katherine; Mo, Kaiguo; Westwood, J. Timothy; Monks, Douglas A.

    2015-01-01

    Background Kennedy’s disease/Spinobulbar muscular atrophy (KD/SBMA) is a degenerative neuromuscular disease affecting males. This disease is caused by polyglutamine expansion mutations of the androgen receptor (AR) gene. Although KD/SBMA has been traditionally considered a motor neuron disease, emerging evidence points to a central etiological role of muscle. We previously reported a microarray study of genes differentially expressed in muscle of three genetically unique mouse models of KD/SBMA but were unable to detect those which are androgen-dependent or are associated with onset of symptoms. Methodology/Principal Findings In the current study we examined the time course and androgen-dependence of transcriptional changes in the HSA-AR transgenic (Tg) mouse model, in which females have a severe phenotype after acute testosterone treatment. Using microarray analysis we identified differentially expressed genes at the onset and peak of muscle weakness in testosterone-treated Tg females. We found both transient and persistent groups of differentially expressed genes and analysis of gene function indicated functional groups such as mitochondrion, ion and nucleotide binding, muscle development, and sarcomere maintenance. Conclusions/Significance By comparing the current results with those from the three previously reported models we were able to identify KD/SBMA candidate genes that are androgen dependent, and occur early in the disease process, properties which are promising for targeted therapeutics. PMID:25719894

  11. Morphological changes of skeletal muscle in spinal and bulbar muscular atrophy (SBMA), Kennedy's disease: a case report.

    PubMed

    Acewicz, Albert; Wierzba-Bobrowicz, Teresa; Lewandowska, Eliza; Sienkiewicz-Jarosz, Halina; Sulek, Anna; Antczak, Jakub; Rakowicz, Maria; Ryglewicz, Danuta

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked recessive disease affecting lower motor neurons. In the present case report, we describe morphological changes in a muscle biopsy obtained from a 62-year-old patient with gynecomastia and with the following neurological symptoms: dysphagia, dysarthria, wasting and fasciculation of the tongue, proximal weakness, fasciculations in the limb muscles, and an absence of all tendon reflexes. Neurogenic alternations were predominantly observed using light and electron microscopy. The angulated atrophic muscle fibers formed bundles. The numerous nuclei were pyknotic or pale, some of them were also ubiquitin positive; they were grouped inside so-called "nuclear sacks". At the ultrastructural level, atrophic muscle fibers revealed disruption and loss of sarcomeres, duplication of Z-line, and rod-like structures. The nuclei, often with irregular shapes, revealed varying degrees of chromatin condensation, from dispersed to highly condensed, like pyknotic nuclei. Occasionally electron-dense inclusions in the nuclei were found. Some myogenic features like hypertrophic muscle fibers and proliferation of connective tissue were also visible. The neurogenic and myogenic pathological changes suggested SBMA, which was confirmed with genetic analysis (trinucleotide CAG (glutamie)-repeat expansion in the androgen-receptor gene). PMID:25828775

  12. Assessing Function and Endurance in Adults with Spinal and Bulbar Muscular Atrophy: Validity of the Adult Myopathy Assessment Tool

    PubMed Central

    Harris-Love, Michael O.; Fernandez-Rhodes, Lindsay; Joe, Galen; Shrader, Joseph A.; Kokkinis, Angela; La Pean Kirschner, Alison; Auh, Sungyoung; Chen, Cheunju; Li, Li; Levy, Ellen; Davenport, Todd E.; Di Prospero, Nicholas A.; Fischbeck, Kenneth H.

    2014-01-01

    Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA). Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Results. Lower AMAT scores were associated with longer disease duration (r = −0.29; P < 0.03) and lower serum androgen levels (r = 0.49–0.59; P < 0.001). The AMAT was significantly correlated with strength and functional status (r = 0.82–0.88; P < 0.001). The domains of the AMAT exhibited good internal consistency (Cronbach's α = 0.77–0.89; P < 0.001). Conclusions. The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifier NCT00303446. PMID:24876969

  13. Spinal and bulbar muscular atrophy and Charcot-Marie-Tooth type 1A: Co-existence of two rare neuromuscular genetic diseases in the same patient.

    PubMed

    Sagnelli, Anna; Scaioli, Vidmer; Piscosquito, Giuseppe; Salsano, Ettore; Dalla Bella, Eleonora; Gellera, Cinzia; Pareyson, Davide

    2015-10-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling. PMID:26298608

  14. Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study.

    PubMed

    Vlam, Lotte; Piepers, Sanne; Sutedja, Nadia A; Jacobs, Bart C; Tio-Gillen, Anne P; Stam, Marloes; Franssen, Hessel; Veldink, Jan H; Cats, Elisabeth A; Notermans, Nicolette C; Bloem, Andries C; Wadman, Renske I; van der Pol, W-Ludo; van den Berg, Leonard H

    2015-03-01

    Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN. PMID:25549972

  15. Human Adipose-Derived Mesenchymal Stem Cells as a New Model of Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Rusmini, Paola; Giorgetti, Elisa; Canazza, Alessandra; Tosetti, Valentina; Salsano, Ettore; Sagnelli, Anna; Mariotti, Caterina; Gellera, Cinzia; Navone, Stefania Elena; Marfia, Giovanni; Alessandri, Giulio; Corsi, Fabio; Parati, Eugenio Agostino; Pareyson, Davide; Poletti, Angelo

    2014-01-01

    Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA. PMID:25392924

  16. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model.

    PubMed

    Adachi, Hiroaki; Waza, Masahiro; Tokui, Keisuke; Katsuno, Masahisa; Minamiyama, Makoto; Tanaka, Fumiaki; Doyu, Manabu; Sobue, Gen

    2007-05-01

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA. PMID:17494697

  17. Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

    PubMed Central

    Lin, Te-Lin; Chen, Tai-Heng; Hsu, Ya-Yun; Cheng, Yu-Hua; Juang, Bi-Tzen; Jong, Yuh-Jyh

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deficiency of the survival of motor neuron (SMN) protein, which leads to synaptic defects and spinal motor neuron death. Neuromuscular junction (NMJ) abnormalities have been found to be involved in SMA pathogenesis in the SMNΔ7 SMA mouse model. However, whether similar NMJ pathological findings present in another commonly used mouse model, the Taiwanese SMA mouse, has not been fully investigated. To examine the NMJs of the Taiwanese severe SMA mouse model (Smn-/-; SMN2tg/0), which is characterized by severe phenotype and death before postnatal day (P) 9, we investigated 25 axial and appendicular muscles from P1 to P9. We labelled the muscles with anti-neurofilament and anti-synaptophysin antibodies for nerve terminals and α-bungarotoxin for acetylcholine receptors (AChRs). We found that severe NMJ denervation (<50% fully innervated endplates) selectively occurred in the flexor digitorum brevis 2 and 3 (FDB-2/3) muscles from P5, and an increased percentage of fully denervated endplates correlated with SMA progression. Furthermore, synaptophysin signals were absent at the endplate compared to control littermate mice, suggesting that vesicle transport might only be affected at the end stage. Subsequently, we treated the Taiwanese severe SMA mice with morpholino (MO) antisense oligonucleotides (80 μg/g) via subcutaneous injection at P0. We found that MO significantly reversed the NMJ denervation in FDB-2/3 muscles and extended the survival of Taiwanese severe SMA mice. We conclude that early NMJ denervation in the FDB-2/3 muscles of Taiwanese severe SMA mice can be reversed by MO treatment. The FDB-2/3 muscles of Taiwanese severe SMA mice provide a very sensitive platform for assessing the effectiveness of drug treatments in SMA preclinical studies. PMID:27124114

  18. Cure SMA

    MedlinePlus

    ... real progress toward a treatment and a cure. Latest News August 29, 2016 2016 SMA Researcher Meeting ... Fundraisers Connect with Us Sign up for the latest SMA information Let us help you connect to ...

  19. Isolation and characterization of genes from the SMA candidate region

    SciTech Connect

    Thompson, T.G.; Ta, D.; Wasmuth, J.J.

    1994-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting alpha motor neutrons. SMA has been mapped to 5q12-13, between the genetic markers D5S435 and 38.3. The distance between these markers, which are closest on the opposite sides of the SMA locus, is {approximately}750 kb. An extensive physical map of this region has been constructed by radiation hybrid (RH) mapping and YAC contig assembly. Further analysis of the YAC contig of the SMA region revealed many deletions and duplications within the YACs. The extensive rearrangements in these YACs makes it very difficult to use them to construct a cosmid contig. The YACs and cosmids isolated thus far have been used to isolate expressed sequences using the method of exon amplification. Putative exons were then used to screen various cDNA libraries to isolate the corresponding cDNAs. Genomic sequences that cross-hybridize very strongly to many of the cDNAs are present in two different regions of chromosome 5, in the SMA region and in 5p13-14. These duplications appear to represent genes and partially processed psuedogenes in one or both of the regions and it has been difficult to determine which of the two loci is the functional gene. Other cDNAs located exclusively in the SMA region have also been found. From the two classes of cDNAs (duplicated or single copy), there are four that are good candidates for the disease gene. These include a cDNA that shows homology to a chicken neuronal specific myosin heavy chain gene, an expressed variant of promelanin concentrating hormone, k-cadherin and a glutathion-S-transferase Mu class protein. We are isolating the full length transcripts for each of these and will use them in DGGE and SSCP gel analysis of SMA patients.

  20. Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63

    PubMed Central

    von Grabowiecki, Yannick; Abreu, Paula; Blanchard, Orphee; Palamiuc, Lavinia; Benosman, Samir; Mériaux, Sophie; Devignot, Véronique; Gross, Isabelle; Mellitzer, Georg; Gonzalez de Aguilar, José L; Gaiddon, Christian

    2016-01-01

    Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63. DOI: http://dx.doi.org/10.7554/eLife.10528.001 PMID:26919175

  1. Spinal Muscular Atrophy

    MedlinePlus

    ... or missing gene known as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a protein essential to motor neurons. Without this protein, lower motor neurons in the ...

  2. Spinal Muscular Atrophy

    MedlinePlus

    ... with symptoms and prevent complications. They may include machines to help with breathing, nutritional support, physical therapy, and medicines. NIH: National Institute of Neurological Disorders and Stroke

  3. Spinal muscular atrophy

    MedlinePlus

    ... tendon reflexes Twitches ( muscle fasciculation ) of the tongue muscle Tests: Aldolase Erythrocyte sedimentation rate (ESR) CPK levels DNA testing to confirm diagnosis Electromyography (EMG) Lactate/pyruvate MRI of the spine Muscle ...

  4. Spinal Muscular Atrophy

    MedlinePlus

    ... diseases that progressively destroy lower motor neurons—nerve cells in the brain stem and spinal cord that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing. ...

  5. An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy.

    PubMed

    Ohsawa, Yutaka; Okada, Tadashi; Nishimatsu, Shin-Ichiro; Ishizaki, Masatoshi; Suga, Tomohiro; Fujino, Masahiro; Murakami, Tatsufumi; Uchino, Makoto; Tsuchida, Kunihiro; Noji, Sumihare; Hinohara, Atsushi; Shimizu, Toshiyuki; Shimizu, Kiyoshi; Sunada, Yoshihide

    2012-08-01

    Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3(P104L)) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-β) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-β type I receptor (TβRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-β1, -β2, and -β3 signaling. Here, we show that a TβRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-β1, as well as CAV3(P104L). Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3(P104L) mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-β family members in muscle. These data indicate that both TGF-β-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TβRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-β signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings. PMID:22584670

  6. Pathological impact of SMN2 mis-splicing in adult SMA mice

    PubMed Central

    Sahashi, Kentaro; Ling, Karen K Y; Hua, Yimin; Wilkinson, John Erby; Nomakuchi, Tomoki; Rigo, Frank; Hung, Gene; Xu, David; Jiang, Ya-Ping; Lin, Richard Z; Ko, Chien-Ping; Bennett, C Frank; Krainer, Adrian R

    2013-01-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently no animal model for adult-onset SMA, and the tissue-specific pathogenesis of post-developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis-splicing. Intracerebroventricular ASO injection in adult SMN2-transgenic mice phenocopies key aspects of adult-onset SMA, including delayed-onset motor dysfunction and relevant histopathological features. SMN2 mis-splicing increases during late-stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis-splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose–response and time-course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing-correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult-onset and early-onset SMA. PMID:24014320

  7. Refinement of the spinal muscular atrophy locus to the interval between D5S435 and MAP1B

    SciTech Connect

    Soares, V.M.; Brzustowicz, L.M.; Kleyn, P.W.; Knowles, J.A.; Palmer, D.A.; Asokan, S.; Penchaszadeh, G.K.; Gilliam, T.C. ); Munsat, T.L. )

    1993-02-01

    The childhood-onset SMA locus has been mapped to chromosome 5q13, in a region bounded by the proximal locus, D5S6, and the closely linked distal loci, D5S112 and MAP1B. We now describe a highly polymorphic, tightly linked microsatellite marker (D5S435) that is very likely the closet proximal marker to the SMA locus. Multipoint linkage analysis firmly establishes the following order of markers at 5q13; centromere-D5S76-D5S6-D5S435-MAP1B/D5S112-D5S39-telomere. The data indicate that SMA resides in an approximately 0.7-cM (range 01.-2.1) region between D5S435 and MAP1B. This finding reduces by approximately fourfold the genetic region that most likely harbors the SMA locus and will facilitate the physical mapping and cloning of the disease gene region. 24 refs., 3 figs., 1 tab.

  8. Upper Limb Evaluation and One-Year Follow Up of Non-Ambulant Patients with Spinal Muscular Atrophy: An Observational Multicenter Trial

    PubMed Central

    Canal, Aurélie; Decostre, Valérie; Diebate, Oumar; Le Moing, Anne Gaëlle; Gidaro, Teresa; Deconinck, Nicolas; Van Parys, Frauke; Vereecke, Wendy; Wittevrongel, Sylvia; Annoussamy, Mélanie; Mayer, Michèle; Maincent, Kim; Cuisset, Jean-Marie; Tiffreau, Vincent; Denis, Severine; Jousten, Virginie; Quijano-Roy, Susana; Voit, Thomas; Hogrel, Jean-Yves; Servais, Laurent

    2015-01-01

    Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials. Trial Registration ClinicalTrials.gov NCT00993161 PMID:25861036

  9. The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats

    NASA Technical Reports Server (NTRS)

    Chakravarthy, M. V.; Booth, F. W.; Spangenburg, E. E.

    2001-01-01

    Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy.

  10. Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.

    PubMed

    Giráldez, Beatriz G; Guerrero-López, Rosa; Ortega-Moreno, Laura; Verdú, Alfonso; Carrascosa-Romero, M Carmen; García-Campos, Óscar; García-Muñozguren, Susana; Pardal-Fernández, José Manuel; Serratosa, José M

    2015-03-01

    Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease. PMID:25578555

  11. SMN deficiency does not induce oxidative stress in SMA iPSC-derived astrocytes or motor neurons.

    PubMed

    Patitucci, Teresa N; Ebert, Allison D

    2016-02-01

    Spinal muscular atrophy (SMA) is a genetic disorder characterized by loss of motor neurons in the spinal cord leading to muscle atrophy and death. Although motor neurons (MNs) are the most obviously affected cells in SMA, recent evidence suggest dysfunction in multiple cell types. Astrocytes are a crucial component of the motor circuit and are intimately involved with MN health and maintenance. We have previously shown that SMA astrocytes are altered both morphologically and functionally early in disease progression, though it is unclear what causes astrocytes to become reactive. Oxidative stress is a common feature among neurodegenerative diseases. Oxidative stress can both induce apoptosis in neurons and can cause astrocytes to become reactive, which are features observed in the SMA induced pluripotent stem cell (iPSC) cultures. Therefore, we asked if oxidative stress contributes to SMA astrocyte pathology. We examined mitochondrial bioenergetics, transcript and protein levels of oxidative and anti-oxidant factors, and reactive oxygen species (ROS) production and found little evidence of oxidative stress. We did observe a significant increase in endogenous catalase expression in SMA iPSCs. While catalase knockdown in SMA iPSCs increased ROS production above basal levels, levels of ROS remained lower than in controls, further arguing against robust oxidative stress in this system. Viral delivery of survival motor neuron (SMN) reversed astrocyte activation and restored catalase levels to normal, without changing mitochondrial respiration or expression of oxidative stress markers. Taken together, these data indicate that SMN deficiency induces astrocyte reactivity, but does not do so through an oxidative stress-mediated process. PMID:26643950

  12. The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/CCdh1 ubiquitin ligase complex

    PubMed Central

    Bott, Laura C.; Salomons, Florian A.; Maric, Dragan; Liu, Yuhong; Merry, Diane; Fischbeck, Kenneth H.; Dantuma, Nico P.

    2016-01-01

    Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/CCdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/CCdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/CCdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA. PMID:27312068

  13. Paternal isodisomy for chromosome 5 in a child with spinal muscular atropy

    SciTech Connect

    Brzustowicz, L.M.; Penchaszadeh, G.K.; Gilliam, T.C.; Allitto, B.A.; Theve, R.; Michaud, L.; Sugarman, E.; Handelin, B.L.; Chatkupt, S.; Koenigsberger, M.R. )

    1994-03-01

    Paternal isodisomy for chromosomes 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3. to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanism of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder. 37 refs., 2 figs., 1 tab.

  14. SMN1 gene copy number analyses for SMA healthy carriers in Italian population

    PubMed Central

    Patitucci, Alessandra; Magariello, Angela; Ungaro, Carmine; Muglia, Maria; Conforti, Francesca L.; Gabriele, Anna L.; Citrigno, Luigi; Sproviero, William; Mazzei, Rosalucia

    2012-01-01

    The routine molecular test for spinal muscular atrophy (SMA) diagnosis is based on the detection of a homozygous deletion of exons 7 and 8 of the telomeric copy of the survival motor neuron gene (SMN1). The presence of the centromeric copy of the SMN gene (SMN2) does not allow the detection of the hemizygous absence of the SMN1 gene, which characterizes the disease carriers. The demand for a quantitative SMN1 test is permanently growing because there is a high incidence of carriers. The disease is severe and to date there are no effective pharmacological treatments. Here, we present a non-radioactive assay based on real time quantitative polymerase chain reaction. We analyzed eight SMA patients, 14 SMA relatives and 50 health individuals from Southern Italy by real time quantitative method in order to identify haploid deletion occurring in SMA carriers. SMN1 copy number was determined by the comparative threshold cycle method (ΔΔCt). The results confirmed the deletion in all homozygous patients and permitted an evaluation of the number of alleles in the healthy carriers. This method is fast, reproducible, and enables us to discriminate carriers from healthy homozygous, which is impossible with normal techniques.

  15. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model.

    PubMed

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID:26030275

  16. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model

    PubMed Central

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID:26030275

  17. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy. Disuse atrophy occurs from a lack of physical activity. In most people, muscle atrophy is caused by not using the ...

  18. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy: disuse and neurogenic. Disuse atrophy is caused by not using the muscles enough . This type of atrophy can often be ...

  19. Learning about Spinal Muscular Atrophy

    MedlinePlus

    ... Features Funding Divisions Funding Opportunities Funded Programs and Projects Grant Information NIH Common Fund NIH RePORTER Research ... Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers Genomic ...

  20. Motor neuron pathology and behavioral alterations at late stages in a SMA mouse model.

    PubMed

    Fulceri, Federica; Bartalucci, Alessia; Paparelli, Silvio; Pasquali, Livia; Biagioni, Francesca; Ferrucci, Michela; Ruffoli, Riccardo; Fornai, Francesco

    2012-03-01

    Spinal muscular atrophy (SMA) is a neurogenetic autosomal recessive disorder characterized by degeneration of lower motor neurons. The validation of appropriate animal models is key in fostering SMA research. Recent studies set up an animal model showing long survival and slow disease progression. This model is knocked out for mouse SMN (Smn(-/-)) gene and carries a human mutation of the SMN1 gene (SMN1A2G), along with human SMN2 gene. In the present study we used this knock out double transgenic mouse model (SMN2(+/+); Smn(-/-); SMN1A2G(+/-)) to characterize the spinal cord pathology along with motor deficit at prolonged survival times. In particular, motor neuron loss was established stereologically (44.77%) after motor deficit reached a steady state. At this stage, spared motor neurons showed significant cell body enlargement. Moreover, similar to what was described in patients affected by SMA we found neuronal heterotopy (almost 4% of total motor neurons) in the anterior white matter. The delayed disease progression was likely to maintain fair motor activity despite a dramatic loss of large motor neurons. This provides a wonderful tool to probe novel drugs finely tuning the survival of motor neurons. In fact, small therapeutic effects protracted over considerable time intervals (even more than a year) are expected to be magnified. PMID:22306031

  1. SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression.

    PubMed

    Murdocca, Michela; Ciafrè, Silvia Anna; Spitalieri, Paola; Talarico, Rosa Valentina; Sanchez, Massimo; Novelli, Giuseppe; Sangiuolo, Federica

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. PMID:27483257

  2. SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression

    PubMed Central

    Murdocca, Michela; Ciafrè, Silvia Anna; Spitalieri, Paola; Talarico, Rosa Valentina; Sanchez, Massimo; Novelli, Giuseppe; Sangiuolo, Federica

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. PMID:27483257

  3. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor.

    PubMed

    Bernal, S; Alías, L; Barceló, M J; Also-Rallo, E; Martínez-Hernández, R; Gámez, J; Guillén-Navarro, E; Rosell, J; Hernando, I; Rodríguez-Alvarez, F J; Borrego, S; Millán, J M; Hernández-Chico, C; Baiget, M; Fuentes-Prior, P; Tizzano, E F

    2010-09-01

    Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity. PMID:20577007

  4. Association between AgI-CA alleles and severity of autosomal recessive proximal spina lmuscular atrophy

    SciTech Connect

    DiDonato, C.J.; Carpten, J.D.; Fuerst, P.; Ingraham, S.E.; Mendell, J.R.; Burghes, A.H.M.; Morgan, K.; Prescott, G.; Simard, L.R.; McPherson, J.D.

    1994-12-01

    The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has been mapped to an 850-kb interval on 5q11.2-q13.3, between the centromeric D5S823 and telomeric D5S557 markers. We report a new complex marker, Ag1-CA, that lies in this interval, whose primers produce one, two, or rarely three amplification-fragment-length variants (AFLVs) per allele. Class I chromosomes are those which amplify a single AFLV allele, and class II chromosomes are those which amplify an allele with two or three AFLVs. Ag1-CA shows highly significant allelic association with type I SMA in both the French Canadian (Hopital Sainte-Justine (HSJ)) and American (Ohio State University (OSU)) populations (P < .0001). Significant association between the Ag1-CA genotype and disease severity was also observed. Type I patients were predominantly homozygous for class I chromosomes (P = .0003 OSU; P = 0.0012 HSJ), whereas the majority of type II patients were heterozygous for class I and II chromosomes (P = .0014 OSU; P = .001 HSJ). There was no significant difference in Ag1-CA genotype frequencies between type III patients (P = .5 OSU; P = .25 HSJ) and the paired normal chromosomes from both carrier parents. Our results indicate that Ag1-CA is the most closely linked marker to SMA and defines the critical candidate-gene region. Finally, we have proposed a model that should be taken into consideration when screening candidates SMA genes.

  5. Splicing changes in SMA mouse motoneurons and SMN-depleted neuroblastoma cells: Evidence for involvement of splicing regulatory proteins

    PubMed Central

    Huo, Qing; Kayikci, Melis; Odermatt, Philipp; Meyer, Kathrin; Michels, Olivia; Saxena, Smita; Ule, Jernej; Schümperli, Daniel

    2014-01-01

    Spinal Muscular Atrophy (SMA) is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The second gene copy, SMN2, produces some, but not enough, functional SMN protein. SMN is essential to assemble small nuclear ribonucleoproteins (snRNPs) that form the spliceosome. However, it is not clear whether SMA is caused by defects in this function that could lead to splicing changes in all tissues, or by the impairment of an additional, less well characterized, but motoneuron-specific SMN function. We addressed the first possibility by exon junction microarray analysis of motoneurons (MNs) isolated by laser capture microdissection from a severe SMA mouse model. This revealed changes in multiple U2-dependent splicing events. Moreover, splicing appeared to be more strongly affected in MNs than in other cells. By testing mutiple genes in a model of progressive SMN depletion in NB2a neuroblastoma cells, we obtained evidence that U2-dependent splicing changes occur earlier than U12-dependent ones. As several of these changes affect genes coding for splicing regulators, this may acerbate the splicing response induced by low SMN levels and induce secondary waves of splicing alterations. PMID:25692239

  6. Cerebral Atrophy

    MedlinePlus

    ... In brain tissue, atrophy describes a loss of neurons and the connections between them. Atrophy can be ... syndrome, which interfere with the basic functions of neurons multiple sclerosis , which causes inflammation, myelin damage, and ...

  7. YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p

    SciTech Connect

    Wedemeyer, N.; Lengeling, A.; Ronsiek, M.

    1996-03-05

    Despite rapid progress in the physical characterization of murine and human genomes, little molecular information is available on certain regions, e.g., proximal mouse chromosome 11 (Chr 11) and human chromosome 2p (Chr2p). We have localized the wobbler spinal atrophy gene wr to proximal mouse Chr 11, tightly linked to Rab1, a gene coding for a small GTP-binding protein, and Glns-ps1, an intronless pseudogene of the glutamine synthetase gene. We have not used these markers to construct a 1.3-Mb yeast artificial chromosome (YAC) contig of the Rab1 region on mouse Chr 11. Four YAC clones isolated from two independent YAC libraries were characterized by rare-cutting analysis, fluorescence in situ hybridization (FISH), and sequence-tagged site (STS) isolation and mapping. Rab1 and Glns-ps1 were found to be only 200 kb apart. A potential CpG island near a methylated NarI site and a trapped exon, ETG1.1, were found over 250 kb from Rab1. Two overlapping YACs were identified that contained a 150-kb region of human Chr 2p, comprising the RAB1 locus, AHY1.1, and the human homologue of ETG1.1, indicating a high degree of conservation of this region in the two species. We mapped AHY1.1 and thus human RAB1 on Chr 2p13.4-p14 using somatic cell hybrids and a radiation hybrid panel, thus extending a known region of conserved synteny between mouse Chr 11 and human Chr 2p. Recently, the gene LMGMD2B for a human recessive neuromuscular disease, limb girdle muscular dystrophy type 2B, has been mapped to 2p13-p16. The conservation between the mouse Rab1 and human RAB1 regions will be helpful in identifying candidate genes for the wobbler spinal muscular atrophy and in clarifying a possible relationship between wr and LMGMD2B. 33 refs., 7 figs., 3 tabs.

  8. Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model

    PubMed Central

    Bebee, Thomas W.; Dominguez, Catherine E.; Samadzadeh-Tarighat, Somayeh; Akehurst, Kristi L.; Chandler, Dawn S.

    2012-01-01

    Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease associated with low levels of the essential survival motor neuron (SMN) protein. Reduced levels of SMN is due to the loss of the SMN1 gene and inefficient splicing of the SMN2 gene caused by a C>T mutation in exon 7. Global analysis of the severe SMNΔ7 SMA mouse model revealed altered splicing and increased levels of the hypoxia-inducible transcript, Hif3alpha, at late stages of disease progression. Severe SMA patients also develop respiratory deficiency during disease progression. We sought to evaluate whether hypoxia was capable of altering SMN2 exon 7 splicing and whether increased oxygenation could modulate disease in a severe SMA mouse model. Hypoxia treatment in cell culture increased SMN2 exon 7 skipping and reduced SMN protein levels. Concordantly, the treatment of SMNΔ7 mice with hyperoxia treatment increased the inclusion of SMN2 exon 7 in skeletal muscles and resulted in improved motor function. Transfection splicing assays of SMN minigenes under hypoxia revealed that hypoxia-induced skipping is dependent on poor exon definition due to the SMN2 C>T mutation and suboptimal 5′ splice site. Hypoxia treatment in cell culture led to increased hnRNP A1 and Sam68 levels. Mutation of hnRNP A1-binding sites prevented hypoxia-induced skipping of SMN exon 7 and was found to bind both hnRNP A1 and Sam68. These results implicate hypoxic stress as a modulator of SMN2 exon 7 splicing in disease progression and a coordinated regulation by hnRNP A1 and Sam68 as modifiers of hypoxia-induced skipping of SMN exon 7. PMID:22763238

  9. Multiple System Atrophy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy Information Page Condensed from Multiple System Atrophy ... Trials Organizations Publicaciones en Español What is Multiple System Atrophy? Multiple system atrophy (MSA) is a progressive ...

  10. Muscular dystrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001190.htm Muscular dystrophy To use the sharing features on this page, please enable JavaScript. Muscular dystrophy is a group of inherited disorders that cause ...

  11. Muscular Dystrophy

    MedlinePlus

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...

  12. Sudeck atrophy.

    PubMed

    Staunton, H

    2006-01-01

    This paper reviews the contribution of Sudeck to the understanding of the condition commonly referred to as 'Sudeck's atrophy' and which is commonly used as a synonym for a condition variously called reflex sympathetic dystrophy, causalgia, algodystrophy and others. Sudeck came to show in his later papers that the so-called atrophy was, in the majority of cases, a normal inflammatory process of bone change in the course of healing after an inflammatory/infective or traumatic insult. Contrary to the views of much current literature, the vast majority of such cases had a good prognosis. In those cases which became pathological and had a correspondingly poorer prognosis, the characteristic clinical picture becomes associated with radiological and pathological changes, which, uniquely, are described by Sudeck. A knowledge of such radiological and pathological substrate for clinical symptomatology is important in the analysis of pain following trauma. PMID:17274178

  13. Intramuscular scAAV9-SMN injection mediates widespread gene delivery to the spinal cord and decreases disease severity in SMA mice.

    PubMed

    Benkhelifa-Ziyyat, Sofia; Besse, Aurore; Roda, Marianne; Duque, Sandra; Astord, Stéphanie; Carcenac, Romain; Marais, Thibaut; Barkats, Martine

    2013-02-01

    We have recently demonstrated the remarkable efficiency of self-complementary (sc) AAV9 vectors for central nervous system (CNS) gene transfer following intravenous delivery in mice and larger animals. Here, we investigated whether gene delivery to motor neurons (MNs) could also be achieved via intramuscular (i.m.) scAAV9 injection and subsequent retrograde transport along the MNs axons. Unexpectedly, we found that a single injection of scAAV9 into the adult mouse gastrocnemius (GA) mediated widespread MN transduction along the whole spinal cord, without limitation to the MNs connected to the injected muscle. Spinal cord astrocytes and peripheral organs were also transduced, indicating vector spread from the injected muscle to both the CNS and the periphery through release into the blood circulation. Moreover, we showed that i.m. injection of scAAV9 vectors expressing "survival of motor neuron" (Smn) in spinal muscular atrophy (SMA) mice mediated high survival motor neuron (SMN) expression levels at both the CNS and the periphery, and increased the median lifespan from 12 days to 163 days. These findings represent to date the longest extent in survival obtained in SMA mice following i.m. viral vector gene delivery, and might generate a renewed interest in the use of i.m. adeno-associated viruses (AAV) delivery for the development of gene therapy strategies for MN diseases. PMID:23295949

  14. Micromechanical analysis of porous SMA

    NASA Astrophysics Data System (ADS)

    Sepe, V.; Auricchio, F.; Marfia, S.; Sacco, E.

    2015-08-01

    The present paper deals with computational micromechanical analyses of porous shape memory alloy (SMA). Porous SMAs are considered composite materials made of a dense SMA matrix including voids. A three-dimensional constitutive law is presented for the dense SMA able to reproduce the pseudo-elastic as well as the shape memory effects and, moreover, to account for the different elastic properties of the austenite and martensite phases. Furthermore, a numerical procedure is developed and the overall behavior of the porous SMA is recovered studying a representative volume element. Comparisons between the numerical results, recovered using the proposed modeling, and experimental data available in the literature are presented. The case of closed and open porosity is investigated. Parametric studies have been conducted in order to investigate the influence of the porosity, the shape and orientation of the pores on the overall mechanical response and, mainly, on the energy absorption dissipation capability.

  15. Geographic Atrophy

    PubMed Central

    Bird, Alan C.; Phillips, Rachel L.; Hageman, Gregory S.

    2014-01-01

    IMPORTANCE Geographic atrophy (GA) is the major cause of blind registration in Western communities, although, with few exceptions, it is less common than choroidal neovascular disease. The variation of phenotype implies that age-related macular degeneration (AMD) does not follow the same course from one case to another and that phenotyping may be important before initiating a therapeutic trial. OBJECTIVE To document photoreceptor and retinal pigment epithelium (RPE) cell loss and other changes at the RPE-choroid interface in donated human eyes in which visual loss was deemed to be due to GA. DESIGN, SETTING, AND PARTICIPANTS Histological study of a consecutive series of eyes donated by individuals previously diagnosed clinically as having GA. Donors were chosen on the basis of available clinical records (from MidAmerica Transplant Services, St Louis, Missouri; the Iowa Lions Eye Bank, Iowa City; and the Utah Lions Eye Bank, Salt Lake City) and selected were those considered to have GA due to AMD. Tissues in the regions of atrophy were examined with light, electron, and autofluorescence microscopy. RESULTS In most of the 37 donors examined, there was marked loss of photoreceptor cells for variable distances distal from the edge of the GA. Rod loss was greater than cone loss. An inverse relationship existed between the quantity of autofluorescent inclusions in the RPE and the thickness of sub-RPE basal laminar deposit. Integrity of the choroid varied from one eye to another and was not related strictly to photoreceptor survival. In some eyes, photoreceptor loss existed in the absence of obvious morphological changes in the Bruch membrane or RPE. CONCLUSIONS AND RELEVANCE The findings support the view that photoreceptor loss occurs early in AMD in a proportion of cases and imply that photoreceptor-cell loss may contribute to the functional loss recorded in early stages of AMD at least in part. The variation of changes from one eye to another implies that patients

  16. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

    PubMed Central

    2011-01-01

    Background Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. Methods Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. Results After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. Trial Registration ClinicalTrials.gov: NCT01033331 PMID:21435220

  17. NERVE LESIONS IN INDUSTRY—Atrophy of Disuse as a Confusing Element in Diagnosis; The Value of Electromyography

    PubMed Central

    Marinacci, A. A.; Rand, Carl W.

    1958-01-01

    Traumatic peripheral nerve lesions characteristically result in denervation muscular atrophy. Atrophy of disuse may take place concomitantly, either proximal, adjacent to or distal to the denervation muscular atrophy. The degree of atrophy of disuse depends upon the severity of the nerve lesion. Clinically, it is difficult to determine where true denervation muscular atrophy ends and accompanying atrophy of disuse begins. In such circumstances a clinician may be misled into belief that the cause of so apparently extensive a lesion is elsewhere. The patient then is often submitted to other complex diagnostic procedures and treatments. This difficulty can usually be dissipated by the use of electromyography, for each specific type of muscular atrophy produces its own characteristic electromyographic changes. Disuse atrophy produces no changes in electrical activity, whereas denervation atrophy manifests itself by typical denervation activity. Moreover it is possible to determine what part of muscular atrophy in a given area is owing to damage to a nerve and what part is owing only to disuse without denervation. PMID:13489511

  18. SMA DOE Student Fellowship Initiative

    SciTech Connect

    Steel Manufacturers Association

    2004-12-24

    Steel companies in many areas of the country have found it increasingly difficult to attract talented recent graduates of college and university engineering and applied science programs to the Electric Arc Furnace iron & steel industry. College student involvement in co-operative programs at steel companies can attract needed talent to the industry. Additionally, certain R & D needs identified in the Steel Industry Technology Roadmap are addressed as co-operative program activities. The Steel Manufacturers Association (''SMA'') therefore established a co-operative education program for selected college students who have completed the first or second year of a four or five-year college program, to be recognized as SMA Co-Operative Fellows, in regard to their summer and fall semester projects with SMA's member companies.

  19. Muscular Dystrophy

    MedlinePlus

    ... in Duchenne muscular dystrophy. Dev. Med. Child Neurol. Mar 1995;37(3):260-269. 4. Centers for ... DM1) . The International Myotonic Dystrophy Consortium (IDMC). Neurology. Mar 28 2000;54(6):1218-1221. 5. Harper ...

  20. Muscular Dystrophy

    MedlinePlus

    ... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

  1. Meaning of Muscular Dystrophy

    MedlinePlus

    ... Help White House Lunch Recipes The Meaning of Muscular Dystrophy KidsHealth > For Kids > The Meaning of Muscular Dystrophy ... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ...

  2. Optic nerve atrophy

    MedlinePlus

    Optic atrophy; Optic neuropathy ... There are many causes of optic atrophy. The most common is poor blood flow. This is called ischemic optic neuropathy. The problem most often affects older adults. ...

  3. Multiple system atrophy

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000757.htm Multiple system atrophy To use the sharing features on this page, please enable JavaScript. Multiple system atrophy (MSA) is a rare condition that causes ...

  4. Systemic Administration of a Recombinant AAV1 Vector Encoding IGF-1 Improves Disease Manifestations in SMA Mice

    PubMed Central

    Tsai, Li-Kai; Chen, Chien-Lin; Ting, Chen-Hung; Lin-Chao, Sue; Hwu, Wuh-Liang; Dodge, James C; Passini, Marco A; Cheng, Seng H

    2014-01-01

    Spinal muscular atrophy is a progressive motor neuron disease caused by a deficiency of survival motor neuron. In this study, we evaluated the efficacy of intravenous administration of a recombinant adeno-associated virus (AAV1) vector encoding human insulin-like growth factor-1 (IGF-1) in a severe mouse model of spinal muscular atrophy. Measurable quantities of human IGF-1 transcripts and protein were detected in the liver (up to 3 months postinjection) and in the serum indicating that IGF-1 was secreted from the liver into systemic circulation. Spinal muscular atrophy mice administered AAV1-IGF-1 on postnatal day 1 exhibited a lower extent of motor neuron degeneration, cardiac and muscle atrophy as well as a greater extent of innervation at the neuromuscular junctions compared to untreated controls at day 8 posttreatment. Importantly, treatment with AAV1-IGF-1 prolonged the animals' lifespan, increased their body weights and improved their motor coordination. Quantitative polymerase chain reaction and western blot analyses showed that AAV1-mediated expression of IGF-1 led to an increase in survival motor neuron transcript and protein levels in the spinal cord, brain, muscles, and heart. These data indicate that systemically delivered AAV1-IGF-1 can correct several of the biochemical and behavioral deficits in spinal muscular atrophy mice through increasing tissue levels of survival motor neuron. PMID:24814151

  5. The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

    NASA Technical Reports Server (NTRS)

    Goldspink, G.; Goldspink, D.; Loughna, P.

    1984-01-01

    The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

  6. Muscular dystrophy - resources

    MedlinePlus

    Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association -- www.mdausa.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih. ...

  7. Myotonic Muscular Dystrophy

    MedlinePlus

    ... a Difference How to Get Involved Donate Myotonic Muscular Dystrophy (MMD) Share print email share facebook twitter google plus linkedin Myotonic Muscular Dystrophy (MMD) What is myotonic muscular dystrophy (MMD)? Myotonic ...

  8. Two SMA-Actuated Miniature Mechanisms

    NASA Technical Reports Server (NTRS)

    Willey, Cliff E.

    2005-01-01

    The figures depict two miniature mechanisms actuated by strips made of shape-memory alloy (SMA). A typical SMA is a nickel-titanium alloy known by the trade name "Flexinol" or "Nitinol." In preparation for a typical application, a suitably sized and shaped piece of an SMA is deformed by a predetermined amount at the lower of two operating temperatures, then mounted in a mechanism. When stroking of the mechanism in one direction is desired, the piece of SMA is heated above a transition temperature to make it return to the "remembered" undeformed state. When stroking of the mechanism in the opposite direction is desired, the SMA is cooled below the transition temperature to make it return to the deformed state. Also, the SMA alloy chosen for a specific application is one that has a transition temperature somewhat above the ambient temperature, so that stroking in one direction or the opposite direction can be achieved by heating the SMA, or refraining from heating the SMA, respectively, above the transition temperature. In the present mechanisms as in typical other SMA mechanisms, the heating is effected by electric currents applied via electrical contacts at the ends of the SMA strips. The purpose served by the mechanism of Figure 1 is to lock or release a flexible latch attachment. In preparation for use in this mechanism, two initially straight SMA strips are deformed into curved springs that, when mounted in the mechanism at ambient temperature, clamp the knob at the lower end of the flexible latch attachment. When heated above their transition temperature by an electric current, the SMA strips return to their original straight configuration, thereby releasing the knob. This mechanism is redundant in the sense that as long as at least one of the two SMA strips straightens when commanded to do so, the knob is released. The mechanism of Figure 2 is suited to any of a variety of applications in which there are requirements for a small mechanism that affords

  9. Transcriptional profile of a myotube starvation model of atrophy

    NASA Technical Reports Server (NTRS)

    Stevenson, Eric J.; Koncarevic, Alan; Giresi, Paul G.; Jackman, Robert W.; Kandarian, Susan C.

    2005-01-01

    Skeletal muscle wasting is a pervasive phenomenon that can result from a wide range of pathological conditions as well as from habitual muscular inactivity. The present work describes a cell-culture condition that induces significant atrophy in skeletal muscle C2C12 myotubes. The failure to replenish differentiation media in mature myotubes leads to rapid atrophy (53% in diameter), which is referred to here as starvation. Affymetrix microarrays were used to develop a transcriptional profile of control (fed) vs. atrophied (nonfed) myotubes. Myotube starvation was characterized by an upregulation of genes involved in translational inhibition, amino acid biosynthesis and transport, and cell cycle arrest/apoptosis, among others. Downregulated genes included several structural and regulatory elements of the extracellular matrix as well as several elements of Wnt/frizzled and TGF-beta signaling pathways. Interestingly, the characteristic transcriptional upregulation of the ubiquitin-proteasome system, calpains, and cathepsins known to occur in multiple in vivo models of atrophy were not seen during myotube starvation. With the exception of the downregulation of extracellular matrix genes, serine protease inhibitor genes, and the upregulation of the translation initiation factor PHAS-I, this model of atrophy in cell culture has a transcriptional profile quite distinct from any study published to date with atrophy in whole muscle. These data show that, although the gross morphology of atrophied muscle fibers may be similar in whole muscle vs. myotube culture, the processes by which this phenotype is achieved differ markedly.

  10. Optic nerve atrophy

    MedlinePlus

    Optic nerve atrophy is damage to the optic nerve. The optic nerve carries images of what the eye sees to ... problem most often affects older adults. The optic nerve can also be damaged by shock, toxins, radiation, ...

  11. Structural behavior of SMA composite beams

    SciTech Connect

    Hebda, D.A.; White, S.R.

    1995-12-31

    Shape memory alloy (SMA) composites are one class of adaptive materials in which SMA wires are embedded in a polymer matrix composite material. By selectively activating the SMA, wires, the beam shape can be controlled or {open_quotes}adapted{close_quotes} to different loading conditions. For instance, an adaptive beam could be used as a torque box for an aircraft wing where coupled bending-twisting behavior may be desirable. SMA composite beams were manufactured using a procedure developed previously and mechanically tested under static loading conditions. Nitinol (SMA) wires composed of 55% nickel and 45% titanium were trained for two-way shape memory (TWSM) and tested to determine the transformation temperatures. Once trained, the wires undergo a reversible phase transformation from martensite to austenite as the temperature is increased. This transformation leads to shape recovery and associated recovery strains. These recovery strains are used to apply forces which deflect the SMA beams during static actuation. Their structural behavior is correlated using simple beam theory. Thermal effects during processing are shown to have a major influence on structural behavior.

  12. Genetics Home Reference: spinal and bulbar muscular atrophy

    MedlinePlus

    ... provides instructions for making a protein called an androgen receptor . This receptor attaches (binds) to a class of hormones called androgens, which are involved in male sexual development. Androgens ...

  13. Flexibility and Muscular Strength.

    ERIC Educational Resources Information Center

    Liemohn, Wendell

    1988-01-01

    This definition of flexibility and muscular strength also explores their roles in overall physical fitness and focuses on how increased flexibility and muscular strength can help decrease or eliminate lower back pain. (CB)

  14. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J. (Editor); Talbot, J. M. (Editor)

    1984-01-01

    Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

  15. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.

    PubMed

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  16. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

    PubMed Central

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  17. Limb Girdle Muscular Dystrophy (LGMD): Case Report.

    PubMed

    Kanitkar, Shubhangi A; Kalyan, Meenakshi; Gaikwad, Anu N; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower's sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  18. Limb Girdle Muscular Dystrophy (LGMD): Case Report

    PubMed Central

    Kalyan, Meenakshi; Gaikwad, Anu N.; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower’s sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  19. [Muscle fiber atrophy].

    PubMed

    Nonaka, Ikuya

    2012-01-01

    Muscle fibers have been classified into two major forms of red (slow twitch) and white (fast twitch) muscles. The red muscle utilizes lipid as energy source through mitochondrial metabolism and function to sustain the position against gravity (sometimes called as antigravity muscle). Under microgravity the red muscle is selectively involved. In our unloading study by hindlimb suspension experiment on rats, the one of the representative red muscle of soleus muscle underwent rapid atrophy; they reduced their weights about 50% after 2 week-unloading. In addition, myofibrils were occasionally markedly disorganized with selective thin filament loss. Mitochondria in the degenerated area were decreased in number. The white muscle fibers in the soleus muscle had mostly transformed to the red ones. It took about 1 month to recover morphologically. The satellite cell playing a major role in muscle regeneration was not activated. There still remained unsolved what are the mechanosensors to keep muscle function under normal gravity. Dr Nikawa's group proposed that one of ubiquitin ligases, Cbl-b is activated under microgravity and induces muscle fiber degeneration. There might be many factors to induce muscle atrophy and degeneration under microgravity. Further study is necessary to explore the pathomechanism of muscle atrophy in disused and under immobility conditions. PMID:23196603

  20. Getting SMaRT in California

    SciTech Connect

    Malloy, M.G.

    1997-02-01

    With the year 2000 fast approaching, Waste Management`s Davis Street SMaRT Station in the San Francisco Bay Area is ramping up its yard and wood waste components to reach the magic 50% recycling figure required of california jurisdictions. Waste Management`s Davis Street Station in San Leandro, Calif., is in a growth spurt. Late last year the SMaRT facility--which stands for station for materials recycling and transfer--added 50 tph of yard and wood waste capacity, making it one of the largest facilities in the country that deal with organic wastes, and bringing the multimaterial facility to a total of more than 3,000 tpd of overall capacity.

  1. BISMAC control using SMA resistance feedback

    NASA Astrophysics Data System (ADS)

    Villanueva, Alex; Priya, Shashank

    2010-04-01

    Recently, bio-inspired shape memory alloy composite (BISMAC) actuators have been shown to be promising for the design of medusae rowing propulsion. BISMAC actuators were able to recreate bell deformation of Aurelia aurita by controlling shape memory alloy (SMA) deformation that allowed matching the contraction-relaxation deformation profile. In this study, we improve upon the control system and demonstrate feedback control using SMA wire resistance to decrease contraction time and power consumption. The controller requires the knowledge of threshold resistance and safe current inputs which were determined experimentally. The overheating effect of SMA wires was analyzed for BioMetal Fiber (BMF) and Flexinol 100 μm diameter wires revealing an increase in resistance as the wires overheated. The controller was first characterized on a SMA wire with bias spring system for a BMF 100 using Ihi = 0.5 A and Ilow = 0.2 A, where hi corresponds to peak current for fast actuation and low corresponds to the safe current which prevents overheating and maintains desired deformation. A contraction of 4.59% was achieved in 0.06 s using the controller and the deformation was maintained for 2 s at low current. The BISMAC actuator was operated using the controller with Ihi = 1.1 A and Ilow = 0.65 A achieving a 67% decrease in contraction time compared to using a constant driving current of Ilow = 0.2 A and a 60% decrease in energy consumption compared to using constant Ihi = 0.5 A while still exceeding the contraction requirements of the Aurelia aurita.

  2. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-10-01

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously. PMID:26292164

  3. Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J; Lehmann, Manja; Schott, Jonathan M; Rabinovici, Gil D; Rossor, Martin N; Fox, Nick C

    2013-01-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management. PMID:22265212

  4. [Muscular power of masticating muscles and mandibular osteoporosis].

    PubMed

    Morii, Hirotoshi; Takaishi, Yoshitomo

    2006-02-01

    Whereas the most powerful stimuli for bone formation is supposed to be a stretching of muscles, Frost HM classified the effect of muscle on bone mineral density (BMD) into various types: 1. age-related loss of bone mineral density (BMD) is partly due to loss of muscular wasting, 2. the increase of BMD in obesity is due to the increase in muscular power to support the increased body weight and 3. the decrease of BMD in chronic wasting disease is partly due to the decrease in muscular power. Likewise, the decrease in BMD in mandibular alveolar bones will be partly due to the decrease in the power of masticating muscles, if such exists. A case report of mitochondrial encephalo-myopathy associated with impaired function of cranial nerves involving trigeminus nerves and impaired function of masticating muscles and dysphagia. This patient showed decrease in alveolar BMD and atrophy of mandibular. PMID:16465028

  5. Inflammatory myopathy with severe tongue atrophy in Pembroke Welsh Corgi dogs.

    PubMed

    Toyoda, Kaoru; Uchida, Kazuyuki; Matsuki, Naoaki; Sakai, Hideo; Kitagawa, Masato; Saito, Miyoko; Sasaki, Jun; Nakayama, Hiroyuki

    2010-11-01

    A disease characterized by tongue and facial muscle atrophy has been recognized sporadically among Pembroke Welsh Corgi (PWC) dogs in Japan. The present study describes the pathologic findings of this canine syndrome. Histopathologic examinations were performed in 2 dogs, including a case of muscular biopsy. Identification and characterization of autoantibodies were attempted by fluorescent antibody test (FAT) and Western blot (WB) by using sera from 7 PWC dogs with typical clinical features, 6 PWC dogs with other clinical signs, and 2 from other breeds with polymyositis. Clinically, the 7 affected PWC dogs exhibited dysphagia with severe tongue atrophy, facial muscular atrophy, and occasional walking difficulty. Histopathologic examinations of the 2 dogs with clinical symptoms revealed moderate to severe inflammatory lesions characterized by lymphohistiocytic infiltration and muscular atrophy in the tongue and/or femoral muscles. The tongue lesions were very severe and accompanied by diffuse fatty infiltration. There were no major lesions in the nervous tissues examined. By FAT, an autoantibody against the cross striation of skeletal muscle was detected in sera from 5 affected PWC dogs. By using WB analysis, the autoantibodies recognized a 42-kDa molecule in striated muscle but not in the nervous tissues. All of the findings indicated that the unique disease of PWC dogs might be generalized inflammatory myopathy, whereas the detailed etiology concerning the dominant involvement of tongue muscles and the role of the autoantibody in the canine disease remain to be clarified. PMID:21088170

  6. Genetics Home Reference: optic atrophy type 1

    MedlinePlus

    ... Conditions optic atrophy type 1 optic atrophy type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Optic atrophy type 1 is a condition that affects vision. Individuals with ...

  7. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury.

    PubMed

    Wang, Meng; Zhang, Xiao Ming; Yang, Sheng Bo

    2016-01-01

    Glycyl-tRNA synthetase (GlyRS) is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR) affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA) treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI), decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb). The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis. PMID:27274754

  8. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury

    PubMed Central

    Wang, Meng; Zhang, Xiao Ming; Yang, Sheng Bo

    2016-01-01

    Glycyl-tRNA synthetase (GlyRS) is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR) affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA) treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI), decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb). The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis. PMID:27274754

  9. [Calpain-3 gene defect causing limb gird muscular dystrophy in a Hungarian family].

    PubMed

    Horváth, Rita; Walter, Maggie C; Lochmüller, Hanns; Hübner, Angela; Karcagi, Veronika; Pikó, Henriett; Timár, László; Komoly, Sámuel

    2005-01-20

    Limb gird muscular dystrophies (LGMD2) are a clinically and genetically heterogeneous group of hereditary diseases with autosomal recessive trait, characterized by progressive atrophy and weakness predominantly in the proximal limb muscles. The authors present clinical, histological, immunohistochemical and immunoblot results of two sisters suffering from so far unclassified autosomal recessive limb girdle muscular dystrophy. Haplotype analysis for genes possibly involved in autosomal recessive limb girdle muscular dystrophies was performed in the genetically informative family. All of the results pointed to a molecular genetic defect of the calpain-3 (CAPN3) gene. Direct sequencing of the CAPN3 gene revealed compound heterozygous state for two mutations previously described in association with limb girdle muscular dystrophy, proving pathogenicity. The authors would like to emphasize the importance of the above described combined strategy in diagnosing limb girdle muscular dystrophies. PMID:15884399

  10. [Multiple system atrophy].

    PubMed

    Damon-Perrière, Nathalie; Tison, François; Meissner, Wassilios G

    2010-09-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology. It is the most frequent disorder among atypical parkinsonism with an estimated prevalence of 2 to 5 per 100 000 inhabitants. The clinical symptoms are rapidly progressing with a mean survival ranging between 6 to 9 years. The diagnosis is based on consensus criteria that have been revised in 2008. The diagnostic criteria allow defining "possible", "probable" and "definite" MSA. The latter requires post mortem confirmation of striatonigral and olivopontocerebellar degeneration with alpha-synuclein containing glial cytoplasmic inclusions. The diagnosis of "possible" and "probable" MSA is based on the variable presence and severity of parkinsonism, cerebellar dysfunction, autonomic failure and pyramidal signs. According to the revised criteria, atrophy of putamen, pons, middle cerebellar peduncle (MCP) or cerebellum on brain magnetic resonance imaging are considered to be additional features for the diagnosis of "possible" MSA. T2-weighted brain imaging may further reveal a putaminal hypointensity, a hyperintense lateral putaminal rim, the so called "hot cross bun sign" and MCP hyperintensities. Cardiovascular examination, urodynamic testing and anal sphincter electromyography may be helpful for the diagnosis of autonomic failure. Some patients may respond to levodopa, but usually to a lesser extent than those suffering from Parkinson's disease, and high doses are already required in early disease stages. No specific therapy is available for cerebellar dysfunction, while effective treatments exist for urinary and cardiovascular autonomic failure. Physical therapy may help to improve the difficulties of gait and stance, and to prevent their complications. In later disease stages, speech therapy becomes necessary for the treatment of dysarthria and dysphagia. Percutaneous gastrostomy is sometimes necessary in patients with severe dysphagia. Beyond these strategies, psychological

  11. Facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... of cases, the parents do not carry the gene. Facioscapulohumeral muscular dystrophy affects about 5 out of 100,000 people. ... Treatment There is no ... worse. Physical therapy may help maintain muscle strength. Other possible treatments ...

  12. Becker muscular dystrophy

    MedlinePlus

    ... and wheelchairs may improve movement and self-care. Genetic counseling may be recommended. Daughters of a man with ... Genetic counseling may be advised if there is a family history of Becker muscular dystrophy.

  13. Correlating interfacial properties with stress transfer in SMA composites

    SciTech Connect

    Kline, G.E.; Jonnalagadda, K.; Sottos, N.R.

    1995-12-31

    Shape memory alloy (SMA) wires have been proposed as large strain actuators for use in smart structures. SMA wires can be embedded in a host material to alter the stiffness or modal response and provide vibration control. The interaction between the embedded SMA and the host material is critical to applications requiring transfer of loads or strain from the wire to the host. Paine, Jones and Rogers have asserted the importance of interfacial adhesion between embedded SMA wires and the host material. When the SMA wires are actuated, large shear strains are generated at the SMA/host interface. The stronger the interface, the greater the transfer of strain from the actuator to the host material. Although there has been a significant amount of research dedicated to characterizing and modeling the response of SMA alone, little work has been done to understand the behavior of embedded SMA wires. Maximum displacement, load transfer and repeatability of actuation of the embedded wire are particularly critical in assessing the effects of the host material. This work continues to investigate the interaction between SMA wires and a host polymer matrix. High resolution photoelasticity was utilized to study the internal stresses induced during actuation of an embedded shape memory alloy wire in a polymer matrix. The influence of several wire surface treatments on the resulting stresses and load transfer was investigated. Four different surface treatments were considered: untreated, acid etched, hand sanded and sandblasted. Pull-out data indicated that sandblasting of wires increased the SMA/polymer interfacial bond strength while hand sanding and acid cleaning actually decreased the bond strength. Wires with greater adhesion (sandblasted) resulted in higher stresses induced in the polymer while those with lower adhesion transferred less load. Overall, properties of the SMA/polymer interface were shown to significantly affect the performance of the embedded SMA actuator.

  14. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2016-08-26

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

  15. Fabrication and Characterization of SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Lach, Cynthia L.; Cano, Robert J.

    2001-01-01

    Results from an effort to fabrication shape memory alloy hybrid composite (SMAHC) test specimens and characterize the material system are presented in this study. The SMAHC specimens are conventional composite structures with an embedded SMA constituent. The fabrication and characterization work was undertaken to better understand the mechanics of the material system, address fabrication issues cited in the literature, and provide specimens for experimental validation of a recently developed thermomechanical model for SMAHC structures. Processes and hardware developed for fabrication of the SMAHC specimens are described. Fabrication of a SMA14C laminate with quasi-isotropic lamination and ribbon-type Nitinol actuators embedded in the 0' layers is presented. Beam specimens are machined from the laminate and are the focus of recent work, but the processes and hardware are readily extensible to more practical structures. Results of thermomechanical property testing on the composite matrix and Nitinol ribbon are presented. Test results from the Nitinol include stress-strain behavior, modulus versus temperature. and constrained recovery stress versus temperature and thermal cycle. Complex thermomechanical behaviors of the Nitinol and composite matrix are demonstrated, which have significant implications for modeling of SMAHC structures.

  16. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J.; Talbot, J. M.

    1984-01-01

    A trophy of skeletal muscle; muscle a trophy associated with manned space flight; the nature, causes, and mechanisms of muscle atrophy associated with space flight, selected physiological factors, biochemical aspects, and countermeasures are addressed.

  17. Dentatorubral-pallidoluysian atrophy.

    PubMed

    Tsuji, Shoji

    2012-01-01

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA. PMID:21827919

  18. Investigation on low velocity impact resistance of SMA composite material

    NASA Astrophysics Data System (ADS)

    Hu, Dianyin; Zhang, Long; Wang, Rongqiao; Zhang, Xiaoyong

    2016-04-01

    A method to improve low velocity impact resistance of aeroengine composite casing using shape memory alloy's properties of shape memory(SM) and super-elasticity(SE) is proposed in this study. Firstly, a numerical modeling of SMA reinforced composite laminate under low velocity impact load with impact velocity of 10 m/s is established based on its constitutive model implemented by the VUMAT subroutine of commercial software ABAQUS. Secondly, the responses of SMA composite laminate including stress and deflection distributions were achieved through transient analysis under low velocity impact load. Numerical results show that both peak stress and deflection values of SMA composite laminate are less than that without SMA, which proves that embedding SMA into the composite structure can effectively improve the low velocity impact performance of composite structure. Finally, the influence of SM and SE on low velocity impact resistance is quantitatively investigated. The values of peak stress and deflection of SMA composite based on SM property decrease by 18.28% and 9.43% respectively, compared with those without SMA, instead of 12.87% and 5.19% based on SE. In conclusion, this proposed model described the impact damage of SMA composite structure and turned to be a more beneficial method to enhance the impact resistance by utilizing SM effect.

  19. SMA actuators: a viable practical technology (Presentation Video)

    NASA Astrophysics Data System (ADS)

    Browne, Alan L.; Brown, Jeffrey; Hodgson, Darel E.

    2015-04-01

    Diverse products either based solely on or incorporating Shape Memory Alloys (SMA) have and are being made in a wide range of industries, and IP is being captured. Why then compared to SE (superelastic) Nitinol, and especially conventional technology, do so few ideas reach production? This presentation delves deeply into this topic in reaching the final assessment that SMA actuators are indeed now a viable practical technology. The presentation begins with an introduction to and description of the fundamental basis of SMA actuator technology. Examples of multiple commercially available geometric forms of SMA actuators are given and the functionalities that they provide are described. This is followed by examples of multiple commercial products incorporating such SMA actuators. Given that there are literally millions of commercial products incorporating conventional actuator technologies, indications are given as to why there are their less than 1000 that utilize SMA. Experience based challenges to the commercial use of SMA actuators are described. Besides having to compete with existing non-SMA technology which is quite mature additional challenges that are unique to SM actuators are indicated these including a wider than expected set of technical engineering problems and challenges and that a broader scope of dynamics is required.

  20. Switchable Shape Memory Alloys (SMA) Thermal Materials Project

    NASA Technical Reports Server (NTRS)

    Falker, John; Zeitlin, Nancy; Williams, Martha; Fesmire, James

    2014-01-01

    Develop 2-way switchable thermal systems for use in systems that function in cold to hot temperature ranges using different alloy designs for SMA system concepts. In this project, KSC will specifically address designs of two proof of concept SMA systems with transition temperatures in the 65-95 C range and investigate cycle fatigue and "memory loss" due to thermal cycling.

  1. Evaluation of Limb-Girdle Muscular Dystrophy

    ClinicalTrials.gov

    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)

  2. How Is Muscular Dystrophy Diagnosed?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How is muscular dystrophy diagnosed? Skip sharing on social media links Share this: Page Content The first step in diagnosing muscular dystrophy (MD) is a visit with a health care ...

  3. Duchenne muscular dystrophy.

    PubMed

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. PMID:25752877

  4. Relationship between input power and power density of SMA spring

    NASA Astrophysics Data System (ADS)

    Park, Cheol Hoon; Ham, Sang Yong; Son, Young Su

    2016-04-01

    The important required characteristics of an artificial muscle for a human arm-like manipulator are high strain and high power density. From this viewpoint, an SMA (shape memory alloy) spring is a good candidate for the actuator of a robotic manipulator that utilizes an artificial muscle. In this study, the maximum power density of an SMA spring was evaluated with respect to the input power. The spring samples were fabricated from SMA wires of different diameters ranging between 0.1 and 0.3 mm. For each diameter, two types of wires with different transition temperatures were used. The relationship between the transition temperature and maximum power density was also evaluated. Each SMA spring was stretched downward by an attached weight and the temperature was increased through the application of an electric current. The displacement, velocity, and temperature of the SMA spring were measured by laser displacement sensors and a thermocouple. Based on the experimental data, it was determined that the maximum power densities of the different SMA springs ranged between 1,300 and 5,500 W/kg. This confirmed the applicability of an SMA spring to human arm-like robotic manipulators. The results of this study can be used as reference for design.

  5. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy.

    PubMed

    Madej-Pilarczyk, A; Kochański, A

    2016-01-01

    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. PMID:27179216

  6. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy. PMID:26177134

  7. Miniature High-Force, Long-Stroke SMA Linear Actuators

    NASA Technical Reports Server (NTRS)

    Cummin, Mark A.; Donakowski, William; Cohen, Howard

    2008-01-01

    Improved long-stroke shape-memory-alloy (SMA) linear actuators are being developed to exert significantly higher forces and operate at higher activation temperatures than do prior SMA actuators. In these actuators, long linear strokes are achieved through the principle of displacement multiplication, according to which there are multiple stages, each intermediate stage being connected by straight SMA wire segments to the next stage so that relative motions of stages are additive toward the final stage, which is the output stage. Prior SMA actuators typically include polymer housings or shells, steel or aluminum stages, and polymer pads between successive stages of displacement-multiplication assemblies. Typical output forces of prior SMA actuators range from 10 to 20 N, and typical strokes range from 0.5 to 1.5 cm. An important disadvantage of prior SMA wire actuators is relatively low cycle speed, which is related to actuation temperature as follows: The SMA wires in prior SMA actuators are typically made of a durable nickel/titanium alloy that has a shape-memory activation temperature of 80 C. An SMA wire can be heated quickly from below to above its activation temperature to obtain a stroke in one direction, but must then be allowed to cool to somewhat below its activation temperature (typically, less than or equal to 60 C in the case of an activation temperature of 80 C) to obtain a stroke in the opposite direction (return stroke). At typical ambient temperatures, cooling times are of the order of several seconds. Cooling times thus limit cycle speeds. Wires made of SMA alloys having significantly higher activation temperatures [denoted ultra-high-temperature (UHT) SMA alloys] cool to the required lower return-stroke temperatures more rapidly, making it possible to increase cycle speeds. The present development is motivated by a need, in some applications (especially aeronautical and space-flight applications) for SMA actuators that exert higher forces, operate

  8. Genetics Home Reference: multiple system atrophy

    MedlinePlus

    ... OPCA progressive autonomic failure with multiple system atrophy SDS Shy-Drager syndrome sporadic olivopontocerebellar atrophy Related Information ... A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, ...

  9. [Preferential distal muscle involvement in case of oculopharyngeal muscular dystrophy with (GCG) 13 expansion].

    PubMed

    Nakashima, Dainari; Nakajima, Hideto; Ishida, Shimon; Sugino, Masakazu; Kimura, Fumiharu; Hanafusa, Toshiaki

    2003-09-01

    We reported a 52-year-old woman with oculopharyngeal muscular dystrophy (OPMD) harboring expanded (GCG) 13 mutation of the poly (A) binding protein 2 gene. She presented not only ptosis and dysphagia but distal dominant muscle atrophy in four extremities. CT demonstrated distal muscle atrophy with marked fat replacement in the biceps femoris, semitendinosus, membraneous, soleus, and gastrocnemius muscles. Although OPMD is considered to be a muscle disease, this patient showed even neurogenic features in the electrophysiological and pathological findings. Although previous reports indicate that OPMD is genetically homogeneous disease, some cases with OPMD may show some atypical features associated with neurogenic involvement. PMID:14727564

  10. Dynamics of an impact oscillator with SMA constraint

    NASA Astrophysics Data System (ADS)

    Sitnikova, E.; Pavlovskaia, E.; Wiercigroch, M.

    2008-12-01

    The dynamic behaviour of an impact oscillator with an SMA constraint has been modelled and analysed. Following the formulation proposed by Bernardini and his co-authors [1,2] describing thermo-mechanics of SMA elements, we obtain a compact thermo-mechanical model of an impact pseudoelastic oscillator. Due to the mechanical characteristics of SMA element and non-smooth nature of the impacts, five different modes of operation can be distinguished for this system. The undertaken numerical investigation suggests that the system can exhibit complex dynamic responses which if appropriately controlled can be used for vibration reduction. For this reason alone a comparison with an equivalent elastic oscillator was made. It was found out that low amplitude regimes are not affected by the presence of SMA element. On contrary, for the large amplitude responses a significant vibration reduction was achieved due to the phase transformations.

  11. Seismic Protection of an Ancient Aqueduct Using SMA Devices

    SciTech Connect

    Chrysostomou, Christis Z.; Demetriou, Themos; Stassis, Andreas; Hamdaoui, Karim

    2008-07-08

    The effectiveness of the use of Cu-based shape memory alloy (SMA) prestressing devices on an ancient aqueduct is examined in this paper. The dynamic characteristics of the aqueduct were measured within the span of three years and computational models were developed that matched very closely its dynamic behaviour. Using this as a bench mark, SMA prestressing devices were applied on the structure and the effects on its dynamic characteristics were assessed. It was noted that the SMA prestressing devices have a significant effect on the dynamic response of the structure. This is attributed to the stiffening of the structure due to the increase in contact between the masonry units and hence the increase of its stiffness through the increase of the modulus of elasticity of the masonry matrix. It can be concluded that the SMA prestressing devices can provide an inconspicuous means of stiffening masonry structures and increase their resistance to earthquake loads.

  12. The eSMA: description and first results

    NASA Astrophysics Data System (ADS)

    Bottinelli, Sandrine; Young, Ken H.; Chamberlin, Richard; Tilanus, Remo P. J.; Gurwell, Mark A.; Wilner, Dave J.; Shinnaga, Hiroko; Yoshida, Hiroshige; Friberg, Per; van Langevelde, Huib Jan; van Dishoeck, Ewine F.; Hogerheijde, Michiel R.; Hughes, A. Meredith; Christensen, Robert D.; Hills, Richard E.; Richer, John S.; Curtis, Emily

    2008-07-01

    The eSMA ("expanded SMA") combines the SMA, JCMT and CSO into a single facility, providing enhanced sensitivity and spatial resolution owing to the increased collecting area at the longest baselines. Until ALMA early science observing (2011), the eSMA will be the facility capable of the highest angular resolution observations at 345 GHz. The gain in sensitivity and resolution will bring new insights in a variety of fields, such as protoplanetary/ transition disks, high-mass star formation, solar system bodies, nearby and high-z galaxies. Therefore the eSMA is an important facility to prepare the grounds for ALMA and train scientists in the techniques. Over the last two years, and especially since November 2006, there has been substantial progress toward making the eSMA into a working interferometer. In particular, (i) new 345-GHz receivers, that match the capabilities of the SMA system, were installed at the JCMT and CSO; (ii) numerous tests have been performed for receiver, correlator and baseline calibrations in order to determine and take into account the effects arising from the differences between the three types of antennas; (iii) First fringes at 345 GHz were obtained on August 30 2007, and the array has entered the science-verification stage. We report on the characteristics of the eSMA and its measured performance at 230 GHz and that expected at 345 GHz. We also present the results of the commissioning and some initial science-verification observations, including the first absorption measurement of the C/CO ratio in a galaxy at z=0.89, located along the line of sight to the lensed quasar PKS 1830-211, and on the imaging of the vibrationally excited HCN line towards IRC+10216.

  13. Homogenization techniques for the analysis of porous SMA

    NASA Astrophysics Data System (ADS)

    Sepe, V.; Auricchio, F.; Marfia, S.; Sacco, E.

    2016-05-01

    In this paper the mechanical response of porous Shape Memory Alloy (SMA) is modeled. The porous SMA is considered as a composite medium made of a dense SMA matrix with voids treated as inclusions. The overall response of this very special composite is deduced performing a micromechanical and homogenization analysis. In particular, the incremental Mori-Tanaka averaging scheme is provided; then, the Transformation Field Analysis procedure in its uniform and nonuniform approaches, UTFA and NUTFA respectively, are presented. In particular, the extension of the NUTFA technique proposed by Sepe et al. (Int J Solids Struct 50:725-742, 2013) is presented to investigate the response of porous SMA characterized by closed and open porosity. A detailed comparison between the outcomes provided by the Mori-Tanaka, the UTFA and the proposed NUTFA procedures for porous SMA is presented, through numerical examples for two- and three-dimensional problems. In particular, several values of porosity and different loading conditions, inducing pseudoelastic effect in the SMA matrix, are investigated. The predictions assessed by the Mori-Tanaka, the UTFA and the NUTFA techniques are compared with the results obtained by nonlinear finite element analyses. A comparison with experimental data available in literature is also presented.

  14. Nuclear Factor-kappa B Signaling in Skeletal Muscle Atrophy

    PubMed Central

    Li, Hong; Malhotra, Shweta; Kumar, Ashok

    2008-01-01

    Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-κB) is one of most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-κB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-κB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-κB in skeletal muscle with particular reference to different models of muscle-wasting and the development of novel therapy. PMID:18574572

  15. Genetics Home Reference: tibial muscular dystrophy

    MedlinePlus

    ... Names for This Condition tardive tibial muscular dystrophy TMD Udd distal myopathy Udd-Markesbery muscular dystrophy Udd ... titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008 Dec;18(12):922-8. ...

  16. Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

    PubMed Central

    Randolph, Matthew E; Luo, Qingwei; Ho, Justin; Vest, Katherine E; Sokoloff, Alan J; Pavlath, Grace K

    2014-01-01

    The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia. PMID:25326455

  17. Cardio-Muscular Conditioner

    NASA Technical Reports Server (NTRS)

    1993-01-01

    In the mid-sixties, Gary Graham, a Boeing designer, developed a cardiovascular conditioner for a planned Air Force orbiting laboratory. After the project was cancelled, Graham participated in space station conditioning studies for the Skylab program. Twenty years later, he used this expertise to develop the Shuttle 2000-1, a physical therapy and athletic development conditioner, available through Contemporary Designs. The machine is used by football teams, sports clinics and medical rehabilitation centers. Cardiovascular fitness and muscular strength development are promoted through both kinetic and plyometric exercises.

  18. Congenital muscular torticollis.

    PubMed

    Nilesh, Kumar; Mukherji, Srijon

    2013-07-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy. PMID:24205484

  19. Congenital muscular torticollis

    PubMed Central

    Nilesh, Kumar; Mukherji, Srijon

    2013-01-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy. PMID:24205484

  20. Finite element analysis of SMA beam bending using COMSOL

    NASA Astrophysics Data System (ADS)

    Yang, Shibin; Seelecke, Stefan S.; Li, Qifu

    2009-03-01

    Shape memory alloys (SMAs) represent a class of smart materials that has been extensively used in many engineering applications due to their unique material properties. To facilitate these new developments, an efficient computational tool like the finite element method has to be used in order to simulate the highly nonlinear, load-history and temperature dependent responses of SMA materials. The particular focus of this paper is on the aspects of modeling and simulation of the inhomogeneous beam bending problem. Based on small deformation Euler-Bernoulli beam theory, the SMA beam is treated as consisting of several layers. Each governed by a 1-D free energy SMA model. The SMA beam is implemented in the finite element software COMSOL using its general PDE form. The ordinary differential equations describing the kinetics of the phase transformations are treated as degenerated PDEs without a flux term and coupled with the mechanical equilibrium equation and the heat transfer equation. In this paper, we study the quasiplastic and superelastic isothermal behavior of an SMA cantilever beam at constant low and high temperature, respectively. Keywords: finite element analysis, shape memory alloy, COMSOL

  1. Performance of SMA-reinforced composites in an aerodynamic profile

    NASA Astrophysics Data System (ADS)

    Simpson, John; Boller, Christian

    2002-07-01

    Within the European collaborative applied fundamental research project ADAPT, fundamentals of SMA-reinforced composites were evaluated and the specific manufacturing techniques for these composites developed and realised. The involved partners are listed at the end. To demonstrate applicability of these composites a realistically scaled aerodynamic profile of around 0.5m span by 0.5m root chord was designed, manufactured and assembled. The curved skins were manufactured as SMA composites with two layers of SMA-wires integrated into the layup of aramid fibre prepregs. All SMA wires were connected such that they can be operated as individual sets of wires and at low voltages, similar to the conditions for electrical energy generation in a real aircraft. The profile was then mounted on a vibration test rig and activated and excited by a shaker at its tip which allowed to test the dynamic performance of the profile under different external loading conditions with various internal actuation conditions through the SMA wires. The paper includes some background of the design and manufacturing of the aerodynamic profile and will discuss some of the results determined recently on the test rig. A view with regard to future wind tunnel testing will be given as well.

  2. Prosthetic leg powered by MR brake and SMA wires

    NASA Astrophysics Data System (ADS)

    Nguyen, The; Munguia, Vicente; Calderon, Jose

    2014-04-01

    Current knee designs for prosthetic legs rely on electric motors for both moving and stationary states. The electric motors draw an especially high level of current to sustain a fixed position. The advantage of using magnetorheological (MR) fluid is that it requires less current and can have a variable braking torque. Besides, the proposed prosthetic leg is actuated by NiTinol wire, a popular shape memory alloy (SMA). The incorporation of NiTinol gives the leg more realistic weight distribution with appropriate arrangement of the batteries and wires. The prosthesis in this research was designed with MR brake as stopping component and SMA wire network as actuating component at the knee. The MR brake was designed with novel non-circular shape for the rotor that improved the braking torque while minimizing the power consumption. The design also helped simplify the control of braking process. The SMA wire network was design so that the knee motion was actively rotated in both directions. The SMA wires were arranged and played very similar role as the leg's muscles. The study started with the overall solid design of the knee including both MR and SMA parts. Theoretical models were derived and programmed in Simulink for both components. The simulation was capable of predicting the power required for moving the leg or hold it in a fixed position for a certain amount of time. Subsequently, the design was prototyped and tested to validate the theoretical prediction. The theoretical models were updated accordingly to correlate with the experimental data.

  3. FE Simulation of SMA Seal for Mars Sample Return

    NASA Technical Reports Server (NTRS)

    Bao, Xiaoqi; Younse, Paulo; Bhandari, Pradeep

    2013-01-01

    Several NASA rovers and landers have been on Mars and performed successful in-situ exploration. Returning Martian samples to Earth for extensive analysis is of great interest to the planetary science community. Current Mars sample return architecture would require leaving the acquired samples on Mars for years before being retrieved by subsequent mission. Each sample would be sealed securely to keep its integrity. A reliable seal technique that does not affect the integrity of the samples and uses a simple low-mass tool is required. The shape memory alloy (SMA) seal technique is a promising candidate. A study of the thermal performances of several primary designs of a SMA seal for sample tubes by finite element (FE) simulation are presented in this paper. The results show sealing the sample tube by SMA plugs and controlling the sample temperature below the allowed temperature level are feasible.

  4. Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy.

    PubMed

    Whitehead, Nicholas P

    2016-04-01

    Autophagy has recently emerged as an important cellular process for the maintenance of skeletal muscle health and function. Excessive autophagy can trigger muscle catabolism, leading to atrophy. In contrast, reduced autophagic flux is a characteristic of several muscle diseases, including Duchenne muscular dystrophy, the most common and severe inherited muscle disorder. Recent evidence demonstrates that enhanced reactive oxygen species (ROS) production by CYBB/NOX2 impairs autophagy in muscles from the dmd/mdx mouse, a genetic model of Duchenne muscular dystrophy. Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle. Therefore, we treated dmd/mdx mice with simvastatin and showed decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction. This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production. Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy. PMID:26890413

  5. Adaptive and energy efficient SMA-based handling systems

    NASA Astrophysics Data System (ADS)

    Motzki, P.; Kunze, J.; Holz, B.; York, A.; Seelecke, S.

    2015-04-01

    Shape Memory Alloys (SMA's) are known as actuators with very high energy density. This fact allows for the construction of very light weight and energy-efficient systems. In the field of material handling and automated assembly process, the avoidance of big moments of inertia in robots and kinematic units is essential. High inertial forces require bigger and stronger robot actuators and thus higher energy consumption and costs. For material handling in assembly processes, many different individual grippers for various work piece geometries are used. If one robot has to handle different work pieces, the gripper has to be exchanged and the assembly process is interrupted, which results in higher costs. In this paper, the advantages of using high energy density Shape Memory Alloy actuators in applications of material-handling and gripping-technology are explored. In particular, light-weight SMA actuated prototypes of an adaptive end-effector and a vacuum-gripper are constructed via rapid-prototyping and evaluated. The adaptive end-effector can change its configuration according to the work piece geometry and allows the handling of multiple different shaped objects without exchanging gripper tooling. SMA wires are used to move four independent arms, each arm adds one degree of freedom to the kinematic unit. At the tips of these end-effector arms, SMA-activated suction cups can be installed. The suction cup prototypes are developed separately. The flexible membranes of these suction cups are pulled up by SMA wires and thus a vacuum is created between the membrane and the work piece surface. The self-sensing ability of the SMA wires are used in both prototypes for monitoring their actuation.

  6. Micro-Ball-Lens Optical Switch Driven by SMA Actuator

    NASA Technical Reports Server (NTRS)

    Yang, Eui-Hyeok

    2003-01-01

    The figure is a simplified cross section of a microscopic optical switch that was partially developed at the time of reporting the information for this article. In a fully developed version, light would be coupled from an input optical fiber to one of two side-by-side output optical fibers. The optical connection between the input and the selected output fiber would be made via a microscopic ball lens. Switching of the optical connection from one output fiber to another would be effected by using a pair of thin-film shape-memory-alloy (SMA) actuators to toggle the lens between two resting switch positions. There are many optical switches some made of macroscopic parts by conventional fabrication techniques and some that are microfabricated and, hence, belong to the class of microelectromechanical systems (MEMS). Conventionally fabricated optical switches tend to be expensive. MEMS switches can be mass-produced at relatively low cost, but their attractiveness has been diminished by the fact that, heretofore, MEMS switches have usually been found to exhibit high insertion losses. The present switch is intended to serve as a prototype of low-loss MEMS switches. In addition, this is the first reported SMA-based optical switch. The optical fibers would be held in V grooves in a silicon frame. The lens would have a diameter of 1 m; it would be held by, and positioned between, the SMA actuators, which would be made of thin films of TiNi alloy. Although the SMA actuators are depicted here as having simple shapes for the sake of clarity of illustration, the real actuators would have complex, partly net-like shapes. With the exception of the lens and the optical fibers, the SMA actuators and other components of the switch would be made by microfabrication techniques. The components would be assembled into a sandwich structure to complete the fabrication of the switch. To effect switching, an electric current would be passed through one of the SMA actuators to heat it above

  7. Development of an artificial urethral valve using SMA actuators

    NASA Astrophysics Data System (ADS)

    Chonan, S.; Jiang, Z. W.; Tani, J.; Orikasa, S.; Tanahashi, Y.; Takagi, T.; Tanaka, M.; Tanikawa, J.

    1997-08-01

    The development of an artificial urethral valve for the treatment of urinary incontinence which occurs frequently in the aged is described. The prototype urethral valve is assembled in hand-drum form with four thin shape memory alloy (SMA) (nickel - titanium alloy) plates of 0.3 mm thickness. The shape memory effect in two directions is used to replace the urinary canal sphincter muscles and to control the canal opening and closing functions. The characteristic of the SMA is to assume the shape of a circular arc at normal temperatures and a flat shape at higher temperatures. Experiments have been conducted using a canine bladder and urinary canal.

  8. Vulvar Skin Atrophy Induced by Topical Glucocorticoids

    PubMed Central

    Johnson, Elisabeth; Groben, Pamela; Eanes, Alisa; Iyer, Priya; Ugoeke, Joseph; Zolnoun, Denniz

    2011-01-01

    Steroid induced skin atrophy is the most frequent and perhaps most important cutaneous side effect of topical glucocorticoid therapy. To date, it has not been described in vulvar skin. We describe a patient with significant vulvar skin atrophy following prolonged steroid application to treat vulvar dermatitis. The extensive atrophy in the perineum resulted in secondary ‘webbing’ and partial obstruction of genital hiatus and superimposed dyspareunia. Prolonged topical steroids may result in atrophic changes in vulvar skin. Therefore, further research in clinical correlates of steroid-induced atrophy in the vulvar region is warranted. PMID:22594868

  9. Soft and smart modular structures actuated by shape memory alloy (SMA) wires as tentacles of soft robots

    NASA Astrophysics Data System (ADS)

    Jin, Hu; Dong, Erbao; Xu, Min; Liu, Chunshan; Alici, Gursel; Jie, Yang

    2016-08-01

    This paper introduces the design and fabrication of a multi-layered smart modular structure (SMS) that has been inspired by the muscular organs and modularity in soft animals. The SMS is capable of planar reciprocal motion of bending in heating process and recovering in cooling process when SMA wires carry out phase transformation. An adaptive regulation heating strategy is applied to avoid overheating and achieve bending range control of the SMS based on the resistance feedback of the SMA wires which as actuator of the SMS. The SMS can modular assemble soft robots with multiple morphologies such as lateral robots, bilateral robots and actinomorphic robots. A five-armed actinomorphic soft robot is conducted to crawling in terrestrial ground (max speed: 140 mm s‑1, 0.7 body s‑1), swimming in underwater environment (max speed: 67 mm s‑1, 2.5 height s‑1) and griping fragile objects (max object weight: 0.91 kg, 15 times the weight of itself). Those demonstrate that the performance of the SMS is good enough to be modular units to establish soft robots which possess a high speed of response, good adaptability and a safe interaction with their environments.

  10. Pregnancy and Childbirth with Neuromuscular Disease

    MedlinePlus

    ... dystrophy type 2 (MMD2, or DM2) paramyotonia congenita (PC) spinal muscular atrophy (SMA) Complication Factors fatigue and ... failure • worsening of respiratory problems • possible worsening of PC symptoms • worsening of weakness and increased fatigue • increased ...

  11. Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H.

    PubMed

    Kudryashova, Elena; Kramerova, Irina; Spencer, Melissa J

    2012-05-01

    Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32-/- mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32-/- muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wild-type muscles. Moreover, Trim32-/- muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia. PMID:22505452

  12. Unilateral calf atrophy secondary to a de novo mutation of the caveolin-3 gene.

    PubMed

    Arias Gómez, Manuel; Alberte-Woodwar, Miguel; Arias-Rivas, Susana; Dapena, Dolores; Pintos, Elena; Navarro, Carmen

    2011-07-01

    A 23-year-old man was evaluated for atrophy of the left calf. He had a myopathic pattern on electromyography. Light microscopy showed dystrophic changes and reduced immunostaining for dysferlin and caveolin-3. The subsarcolemmal space was enlarged, and abnormal vesicles were visible with electron microscopy. A genetic study showed a heterozygous A45T mutation at exon 2 of the caveolin-3 gene. Such a mutation has been reported previously with limb-girdle muscular dystrophy type 1C and rippling muscle disease phenotypes. PMID:21660982

  13. Fabricating Composite-Material Structures Containing SMA Ribbons

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Cano, Roberto J.; Lach, Cynthia L.

    2003-01-01

    An improved method of designing and fabricating laminated composite-material (matrix/fiber) structures containing embedded shape-memory-alloy (SMA) actuators has been devised. Structures made by this method have repeatable, predictable properties, and fabrication processes can readily be automated. Such structures, denoted as shape-memory-alloy hybrid composite (SMAHC) structures, have been investigated for their potential to satisfy requirements to control the shapes or thermoelastic responses of themselves or of other structures into which they might be incorporated, or to control noise and vibrations. Much of the prior work on SMAHC structures has involved the use SMA wires embedded within matrices or within sleeves through parent structures. The disadvantages of using SMA wires as the embedded actuators include (1) complexity of fabrication procedures because of the relatively large numbers of actuators usually needed; (2) sensitivity to actuator/ matrix interface flaws because voids can be of significant size, relative to wires; (3) relatively high rates of breakage of actuators during curing of matrix materials because of sensitivity to stress concentrations at mechanical restraints; and (4) difficulty of achieving desirable overall volume fractions of SMA wires when trying to optimize the integration of the wires by placing them in selected layers only.

  14. Morphing of composite plate and beam actuated by SMA

    NASA Astrophysics Data System (ADS)

    Cho, Maenghyo; Kim, Sanghaun

    2004-07-01

    One way Shape Memory Effect (SME) is not suitable mechanism for application to the repeated actuation of an Shape Memory Alloy(SMA) wire because the host structure does not return to its initial shape after it cools down. In the present study, the two-way SME under residual stress is considered. A structure using the two-way effect returns to its initial shape by increasing or decreasing temperature under an initially given residual stress. A thermo-mechanical constitutive equation of SMA proposed by Lagoudas et al. was employed in the present study. Laminated composite beams and plates are considered as simple morphing structural components. The modeling of beams and plates are based on first-order shear deformable laminated composite beam and plate theories with large deflections. Numerical results of fully coupled SMA-composite structures are presented. The proposed actuation mechanism based on the two-way SMA effect and a simulation algorithm can be used as a powerful morphing mechanism and simulation tool for structures.

  15. Multiple System Atrophy with Orthostatic Hypotension (Shy-Drager Syndrome)

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy with Orthostatic Hypotension Information Page Synonym(s): Shy- ... being done? Clinical Trials Organizations What is Multiple System Atrophy with Orthostatic Hypotension? Multiple system atrophy with ...

  16. Crustacean muscles: atrophy and regeneration during molting

    SciTech Connect

    Mykles, D.L.; Skinner, D.M.

    1981-01-01

    The ultrastructural basis of atrophy of claw closer muscle of the land crab and the organization of myofibrils and sacroplasmic reticulum during the hydrolysis of protein that occurs during proecdysis was examined. The changes that occur in contractile proteins during claw muscle atrophy and the involvement of Ca/sup 2 +/-dependent proteinases (CDP) in myofilament degradation were investigated. (ACR)

  17. Improvement of Continuous Hydrologic Models and HMS SMA Parameters Reduction

    NASA Astrophysics Data System (ADS)

    Rezaeian Zadeh, Mehdi; Zia Hosseinipour, E.; Abghari, Hirad; Nikian, Ashkan; Shaeri Karimi, Sara; Moradzadeh Azar, Foad

    2010-05-01

    Hydrological models can help us to predict stream flows and associated runoff volumes of rainfall events within a watershed. There are many different reasons why we need to model the rainfall-runoff processes of for a watershed. However, the main reason is the limitation of hydrological measurement techniques and the costs of data collection at a fine scale. Generally, we are not able to measure all that we would like to know about a given hydrological systems. This is very particularly the case for ungauged catchments. Since the ultimate aim of prediction using models is to improve decision-making about a hydrological problem, therefore, having a robust and efficient modeling tool becomes an important factor. Among several hydrologic modeling approaches, continuous simulation has the best predictions because it can model dry and wet conditions during a long-term period. Continuous hydrologic models, unlike event based models, account for a watershed's soil moisture balance over a long-term period and are suitable for simulating daily, monthly, and seasonal streamflows. In this paper, we describe a soil moisture accounting (SMA) algorithm added to the hydrologic modeling system (HEC-HMS) computer program. As is well known in the hydrologic modeling community one of the ways for improving a model utility is the reduction of input parameters. The enhanced model developed in this study is applied to Khosrow Shirin Watershed, located in the north-west part of Fars Province in Iran, a data limited watershed. The HMS SMA algorithm divides the potential path of rainfall onto a watershed into five zones. The results showed that the output of HMS SMA is insensitive with the variation of many parameters such as soil storage and soil percolation rate. The study's objective is to remove insensitive parameters from the model input using Multi-objective sensitivity analysis. Keywords: Continuous Hydrologic Modeling, HMS SMA, Multi-objective sensitivity analysis, SMA Parameters

  18. Wasting Mechanisms in Muscular Dystrophy

    PubMed Central

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

    2013-01-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

  19. Alternative splicing and muscular dystrophy

    PubMed Central

    Pistoni, Mariaelena; Ghigna, Claudia; Gabellini, Davide

    2013-01-01

    Alternative splicing of pre-mRNAs is a major contributor to proteomic diversity and to the control of gene expression in higher eukaryotic cells. For this reasons, alternative splicing is tightly regulated in different tissues and developmental stages and its disruption can lead to a wide range of human disorders. The aim of this review is to focus on the relevance of alternative splicing for muscle function and muscle disease. We begin by giving a brief overview of alternative splicing, muscle-specific gene expression and muscular dystrophy. Next, to illustrate these concepts we focus on two muscular dystrophy, myotonic muscular dystrophy and facioscapulohumeral muscular dystrophy, both associated to disruption of splicing regulation in muscle. PMID:20603608

  20. Myoglobin in Primary Muscular Disease: I. Duchenne Muscular Dystrophy: and: II. Muscular Dystrophy of Distal Type

    PubMed Central

    Romero-Herrera, A. E.; Lehmann, H.; Tomlinson, B. E.; Walton, J. N.

    1973-01-01

    Skeletal myoglobin from two cases of muscular dystrophy, one of Duchenne muscular dystrophy, and one of muscular dystrophy of distal type, have been examined and no differences from normal human myoglobin were found. The opportunity has been taken to discuss the nature of minor fractions of myoglobin-like material which are found when human skeletal myoglobin is isolated. Those which have been observed in the present study have been artefacts and it was possible to demonstrate that they were due to deamidation of certain glutamine and asparagine residues. Images PMID:4590363

  1. Biomechanical simulation of atrophy in MR images

    NASA Astrophysics Data System (ADS)

    Castellano Smith, Andrew D.; Crum, William R.; Hill, Derek L. G.; Thacker, Neil A.; Bromiley, Paul A.

    2003-05-01

    Progressive cerebral atrophy is a physical component of the most common forms of dementia - Alzheimer's disease, vascular dementia, Lewy-Body disease and fronto-temporal dementia. We propose a phenomenological simulation of atrophy in MR images that provides gold-standard data; the origin and rate of progression of atrophy can be controlled and the resultant remodelling of brain structures is known. We simulate diffuse global atrophic change by generating global volumetric change in a physically realistic biomechanical model of the human brain. Thermal loads are applied to either single, or multiple, tissue types within the brain to drive tissue expansion or contraction. Mechanical readjustment is modelled using finite element methods (FEM). In this preliminary work we apply these techniques to the MNI brainweb phantom to produce new images exhibiting global diffuse atrophy. We compare the applied atrophy with that measured from the images using an established quantitative technique. Early results are encouraging and suggest that the model can be extended and used for validation of atrophy measurement techniques and non-rigid image registration, and for understanding the effect of atrophy on brain shape.

  2. Gene discovery for facioscapulohumeral muscular dystrophy by machine learning techniques.

    PubMed

    González-Navarro, Félix F; Belanche-Muñoz, Lluís A; Gámez-Moreno, María G; Flores-Ríos, Brenda L; Ibarra-Esquer, Jorge E; López-Morteo, Gabriel A

    2016-04-28

    Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder that shows a preference for the facial, shoulder and upper arm muscles. FSHD affects about one in 20-400,000 people, and no effective therapeutic strategies are known to halt disease progression or reverse muscle weakness or atrophy. Many genes may be incorrectly regulated in affected muscle tissue, but the mechanisms responsible for the progressive muscle weakness remain largely unknown. Although machine learning (ML) has made significant inroads in biomedical disciplines such as cancer research, no reports have yet addressed FSHD analysis using ML techniques. This study explores a specific FSHD data set from a ML perspective. We report results showing a very promising small group of genes that clearly separates FSHD samples from healthy samples. In addition to numerical prediction figures, we show data visualizations and biological evidence illustrating the potential usefulness of these results. PMID:26960968

  3. SMA Hybrid Composites for Dynamic Response Abatement Applications

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2000-01-01

    A recently developed constitutive model and a finite element formulation for predicting the thermomechanical response of Shape Memory Alloy (SMA) hybrid composite (SMAHC) structures is briefly described. Attention is focused on constrained recovery behavior in this study, but the constitutive formulation is also capable of modeling restrained or free recovery. Numerical results are shown for glass/epoxy panel specimens with embedded Nitinol actuators subjected to thermal and acoustic loads. Control of thermal buckling, random response, sonic fatigue, and transmission loss are demonstrated and compared to conventional approaches including addition of conventional composite layers and a constrained layer damping treatment. Embedded SMA actuators are shown to be significantly more effective in dynamic response abatement applications than the conventional approaches and are attractive for combination with other passive and/or active approaches.

  4. Optimization of SMA layers in composite structures to enhance damping

    NASA Astrophysics Data System (ADS)

    Haghdoust, P.; Cinquemani, S.; Lecis, N.; Bassani, P.

    2016-04-01

    The performance of lightweight structures can be severely affected by vibration. New design concepts leading to lightweight, slender structural components can increase the vulnerability of the components to failure due to excessive vibration. The intelligent approach to address the problem would be the use of materials which are more capable in dissipating the energy due to their high value of loss factor. Among the different materials available to achieve damping, much attention has been attached to the use of shape memory alloys (SMAs) because of their unique microstructure, leading to good damping capacity. This work describes the design and optimization of a hybrid layered composite structure for the passive suppression of flexural vibrations in slender and light structures. Embedding the SMA layers in composite structure allows to combine different properties: the lightness of the base composite (e.g. fiber glass), the mechanical strength of the insert of metallic material and the relevant damping properties of SMA, in the martensitic phase. In particular, we put our attention on embedding the CuZnAl in the form of thin sheet in a layered composite made by glass fiber reinforced epoxy. By appropriately positioning of the SMA sheets so that they are subjected to the maximum curvature, the damping of the hybrid system can be considerably enhanced. Accordingly analytical method for evaluating the energy dissipation of the thin sheets with different shapes and patterns is developed and is followed by a shape optimization based on genetic algorithm. Eventually different configurations of the hybrid beam structure with different patterns of SMA layer are proposed and compared in the term of damping capacity.

  5. Atypical manifestation of late onset limb girdle muscular dystrophy presenting with recurrent falling and shoulder dysfunction: a case report

    PubMed Central

    Schofer, Markus Dietmar; Patzer, Thilo; Quante, Markus

    2008-01-01

    Introduction Myopathies can be sub-classified into congenital, hereditary, mitochondrial, and secondary myopathies. Congenital myopathies are usually diagnosed post partal or in early childhood. Manifestation in adolescence is uncommon and most cases occur as sporadic mutations. Therefore, there is a risk of under diagnosing this disease in middle-aged patients showing pain, dysfunction, recurrent trauma or falls, where muscle atrophy is seen as a secondary injury. Case presentation Our report is about a 54 year old Caucasian woman with an extended history of pain, loss of function and weakness in her right shoulder. The clinical picture showed a frozen right shoulder. The main finding was a marked limb-muscle atrophy of both delta- und biceps-muscles and a rotator cuff tear that had developed over years. Previous medical consultations attributed the atrophy to recurrent falls, shoulder dysfunction and pain. Conservative treatment (analgesics, physiotherapy, training) had failed. The familiar anamnesis was free of any neurological diseases or other genetic diseases. MRI showed a sub-total proximal muscular limb atrophy and a rotator cuff tear in both shoulders. An incision-biopsy of the right delta- and biceps-muscle revealed a chronical myopathy. The level of creatinkinasis was expected to be high but measurements showed values only slightly above normal. Immunohistochemistry, eventually revealed a mild form of LGMD (type 2I). Due to the pattern of symptoms and diagnostic results we described the case as atypical LGMD. Conclusion Our case presents a phenotype of a late onset of limb girdle muscular dystrophy syndrome associated with shoulder pain and dysfunction and recurrent falls. This kind of disease is not very common. In particular, muscle atrophy in the elderly is generally seen as a secondary injury. This case should remind us of the importance of a differential diagnosis of a late onset of muscular dystrophy-syndrome in the elderly, since an early

  6. [Muscular isokinetic dynamometry].

    PubMed

    Svetlize, H D

    1991-01-01

    In the past, muscular strength has primarily been measured using isometric, isotonic or tensiometric techniques. The advent of isokinetic dynamometers has supplied an objective method of measuring peak torque throughout a full range of motion at a predetermined speed of contraction. An isokinetic contraction is a refinement of the controlled motion concept. The isokinetic contraction is dynamic, but the speed of the motion is held constant by a special device. In this way, resistance is in direct ratio to the varying force applied through the full course of a natural movement. The purpose of this study was to determine the peak torque of quadriceps (Q), and hamstrings (H), and their biomechanical angle of production, H to Q ratio and bilateral comparisons of these variables for the first time in a Southamerican population. Twenty healthy and voluntary males (age: 21.9 +/- 3.1 years, height 193.2 +/- 6.5 cm, weight: 84.2 +/- 5.2 kgs.), were tested on the Cybex II Dynamometer and Cybex Data Reduction Computer (CDRC). Quadriceps and hamstrings peak torque (pkTQ), in Newton-meters, were obtained at angular velocities of 60, 180 and 240 degrees. sec-1. Also, the angle of the range of motion at which peak torque occurred in both directions, H and Q peak torque to body weight ratios, H to Q ratio were measured. Finally, CDRC provided the bilateral comparison of the different variables expressed in percentages. All measurements were automatically corrected for the effect of gravity. The absolute maximal pkTQ of dominant (D), and non-dominant (ND), quadriceps at 60 degrees/sec was DQ 297 +/- 25 Nwm and nDQ 303 +/- 13 Nwm.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1921692

  7. Facioscapulohumeral muscular dystrophy.

    PubMed

    Sacconi, Sabrina; Salviati, Leonardo; Desnuelle, Claude

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:24882751

  8. Analysis of SMA Hybrid Composite Structures using Commercial Codes

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Patel, Hemant D.

    2004-01-01

    A thermomechanical model for shape memory alloy (SMA) actuators and SMA hybrid composite (SMAHC) structures has been recently implemented in the commercial finite element codes MSC.Nastran and ABAQUS. The model may be easily implemented in any code that has the capability for analysis of laminated composite structures with temperature dependent material properties. The model is also relatively easy to use and requires input of only fundamental engineering properties. A brief description of the model is presented, followed by discussion of implementation and usage in the commercial codes. Results are presented from static and dynamic analysis of SMAHC beams of two types; a beam clamped at each end and a cantilevered beam. Nonlinear static (post-buckling) and random response analyses are demonstrated for the first specimen. Static deflection (shape) control is demonstrated for the cantilevered beam. Approaches for modeling SMAHC material systems with embedded SMA in ribbon and small round wire product forms are demonstrated and compared. The results from the commercial codes are compared to those from a research code as validation of the commercial implementations; excellent correlation is achieved in all cases.

  9. Analysis of SMA hybrid composite structures using commercial codes

    NASA Astrophysics Data System (ADS)

    Turner, Travis L.; Patel, Hemant D.

    2004-07-01

    A thermomechanical model for shape memory alloy (SMA) actuators and SMA hybrid composite (SMAHC) structures has been recently implemented in the commercial finite element codes MSC.Nastran and ABAQUS. The model may be easily implemented in any code that has the capability for analysis of laminated composite structures with temperature dependent material properties. The model is also relatively easy to use and requires input of only fundamental engineering properties. A brief description of the model is presented, followed by discussion of implementation and usage in the commercial codes. Results are presented from static and dynamic analysis of SMAHC beams of two types; a beam clamped at each end and a cantilevered beam. Nonlinear static (post-buckling) and random response analyses are demonstrated for the first specimen. Static deflection (shape) control is demonstrated for the cantilevered beam. Approaches for modeling SMAHC material systems with embedded SMA in ribbon and small round wire product forms are demonstrated and compared. The results from the commercial codes are compared to those from a research code as validation of the commercial implementations; excellent correlation is achieved in all cases.

  10. STUDY OF THE RHIC BPM SMA CONNECTOR FAILURE PROBLEM

    SciTech Connect

    LIAW,C.; SIKORA, R.; SCHROEDER, R.

    2007-06-25

    About 730 BPMs are mounted on the RHIC CQS and Triplet super-conducting magnets. Semi-rigid coaxial cables are used to bring the electrical signal from the BPM feedthroughs to the outside flanges. at the ambient temperature. Every year around 10 cables will lose their signals during the operation. The connection usually failed at the warm end of the cable. The problems were either the solder joint failed or the center conductor retracted out of the SMA connector. Finite element analyses were performed to understand the failure mechanism of the solder joint. The results showed that (1) The SMA center conductor can separate from the mating connector due to the thermal retraction. (2) The maximum thermal stress at the warm end solder joint can exceed the material strength of the Pb37/Sn63 solder material and (3) The magnet ramping frequency (-10 Hz), during the machine startup, can possibly resonant the coaxial cable and damage the solder joints, especially when a fracture is initiated. Test results confirmed that by using the silver bearing solder material (a higher strength material) and by crimping the cable at the locations close to the SMA connector (to prevent the center conductor from retracting) can effectively resolve the connector failure problem.

  11. Passive base isolation with superelastic nitinol SMA helical springs

    NASA Astrophysics Data System (ADS)

    Huang, Bin; Zhang, Haiyang; Wang, Han; Song, Gangbing

    2014-06-01

    Seismic isolation of structures such as multi-story buildings, nuclear reactors, bridges, and liquid storage tanks should be designed to preserve structural integrity. By implementing seismic isolation technology, the deformation of superstructures can be dramatically reduced, consequently helping to protect their safety as well. In this paper, an innovative type of passive base isolation system, which is mainly composed of superelastic nitinol SMA helical springs, is developed. In order to verify the effectiveness of the proposed system, a two-story experimental steel frame model is constructed, and two superelastic SMA helical springs are thermo-mechanically built in the laboratory. To describe the nonlinear mechanical properties of the superelastic SMA helical springs under reciprocating load, a phenomenological model is presented in terms of a series of tensile tests. Afterwards, a numerical model of the two-story frame with the suggested isolation system is set up to simulate the response of the isolated frame subjected to an earthquake. Both the experimental and the numerical simulation results indicate that the proposed base isolation system can remarkably suppress structural vibrations and has improved isolation effects when compared with a steel spring isolation system. Due to the capabilities of energy dissipation as well as fully re-centering, it is very applicable to utilize the suggested isolation system in base isolated structures to resist earthquakes.

  12. Infraspinatus muscle atrophy from suprascapular nerve compression.

    PubMed

    Cordova, Christopher B; Owens, Brett D

    2014-02-01

    Muscle weakness without pain may signal a nerve compression injury. Because these injuries should be identified and treated early to prevent permanent muscle weakness and atrophy, providers should consider suprascapular nerve compression in patients with shoulder muscle weakness. PMID:24463748

  13. On the estimation and correction of bias in local atrophy estimations using example atrophy simulations.

    PubMed

    Sharma, Swati; Rousseau, François; Heitz, Fabrice; Rumbach, Lucien; Armspach, Jean-Paul

    2013-01-01

    Brain atrophy is considered an important marker of disease progression in many chronic neuro-degenerative diseases such as multiple sclerosis (MS). A great deal of attention is being paid toward developing tools that manipulate magnetic resonance (MR) images for obtaining an accurate estimate of atrophy. Nevertheless, artifacts in MR images, inaccuracies of intermediate steps and inadequacies of the mathematical model representing the physical brain volume change, make it rather difficult to obtain a precise and unbiased estimate. This work revolves around the nature and magnitude of bias in atrophy estimations as well as a potential way of correcting them. First, we demonstrate that for different atrophy estimation methods, bias estimates exhibit varying relations to the expected atrophy and these bias estimates are of the order of the expected atrophies for standard algorithms, stressing the need for bias correction procedures. Next, a framework for estimating uncertainty in longitudinal brain atrophy by means of constructing confidence intervals is developed. Errors arising from MRI artifacts and bias in estimations are learned from example atrophy simulations and anatomies. Results are discussed for three popular non-rigid registration approaches with the help of simulated localized brain atrophy in real MR images. PMID:23988649

  14. Models of Multiple System Atrophy

    PubMed Central

    Fellner, Lisa; Wenning, Gregor K.; Stefanova, Nadia

    2016-01-01

    Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson’s disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells. This pathological hallmark, also called glial cytoplasmic inclusions (GCIs), is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson’s syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies. PMID:24338664

  15. What Are the Treatments for Muscular Dystrophy?

    MedlinePlus

    ... Resources and Publications What are the treatments for muscular dystrophy? Skip sharing on social media links Share this: ... available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  16. Calpain 3 Expression Pattern during Gastrocnemius Muscle Atrophy and Regeneration Following Sciatic Nerve Injury in Rats

    PubMed Central

    Wu, Ronghua; Yan, Yingying; Yao, Jian; Liu, Yan; Zhao, Jianmei; Liu, Mei

    2015-01-01

    Calpain 3 (CAPN3), also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA) of gastrocnemius muscle were decreased gradually from 1–14 days and then recovery from 14–28 days. The active form of CAPN3 (~62 kDa) protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA) injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury. PMID:26569227

  17. Derivation of human embryonic stem cell from spinal muscular atrophy patient.

    PubMed

    Xie, Pingyuan; Zhou, Hao; Zhou, Xiaoying; Zhao, Xiaomeng; Du, Juan; Lu, Guangxiu; Lin, Ge; Ouyang, Qi

    2016-03-01

    We established a human embryonic stem cell (hESC) line chHES-427 from the abnormal embryo carrying homozygous deletion of exon 7 of survival motor neuron gene (SMN). This cell line maintained a normal karyotype 46, XX during long-term culture. Further characteristic analysis suggested that the cells expressed the pluripotency-related markers and had the capacity to differentiate into the derivatives from the three germ layers in vitro. PMID:27345972

  18. [General anesthetic management of a patient with spinal muscular atrophy type III].

    PubMed

    Inamori, Masayuki; Imashuku, Yasuhiko; Sonobe, Shota; Sukenaga, Chikahiko; Yabuta, Koichi; Hashimura, Toshiya; Kura, Masahiro; Otada, Hideki

    2013-06-01

    We report a 61-year-old woman (weight 49 kg, height 156 cm) with Kugelberg-Welander disease who was scheduled for bilateral mastectomy under general anesthesia. We administered rocuronium 10 mg (0.20 mg x kg(-1)) for tracheal intubation. After 80 min, train-of-four ratio (TOFR) was 46%. During the operation, we did not administer rocuronium. After surgery, TOFR was 62%. Therefore, we administered sugammadex 100 mg (2 mg x kg(-1)). After 4 min, TOFR became above 90%, and the patient was extubated. There was no respiratory distress, muscle weakness, or neurologic untoward event after the use of sugammadex in the postoperative period. Sugammadex was effective in reversing rocuronium induced neuromuscular block in a patient with Kugelberg-Welander disease. PMID:23814997

  19. Genetics Home Reference: spinal muscular atrophy with respiratory distress type 1

    MedlinePlus

    ... a protein involved in copying (replicating) DNA ; producing RNA, a chemical cousin of DNA; and producing proteins. ... aid in DNA replication and the production of RNA and proteins. These problems particularly affect alpha-motor ...

  20. Can endoscopic atrophy predict histological atrophy? Historical study in United Kingdom and Japan

    PubMed Central

    Kono, Shin; Gotoda, Takuji; Yoshida, Shigeaki; Oda, Ichiro; Kondo, Hitoshi; Gatta, Luigi; Naylor, Greg; Dixon, Michael; Moriyasu, Fuminori; Axon, Anthony

    2015-01-01

    AIM: To assess the diagnostic concordance between endoscopic and histological atrophy in the United Kingdom and Japan. METHODS: Using published data, a total of 252 patients, 126 in the United Kingdom and 126 in Japan, aged 20 to 80 years, were evaluated. The extent of endoscopic atrophy was classified into five subgroups according to a modified Kimura-Takemoto classification system and was compared with histological findings of atrophy at five biopsy sites according to the updated Sydney system. RESULTS: The strength of agreement of the extent of atrophy between histology and visual endoscopic inspection showed good reproducibility, with a weighted kappa value of 0.76 (P < 0.001). Multivariate analysis showed that three factors were associated with decreased concordance: Japanese ethnicity [odds ratio (OR) 0.22, 95% confidence interval (CI) 0.11-0.43], older age (OR = 0.32, 95%CI: 0.16-0.66) and endoscopic atrophy (OR = 0.10, 95%CI: 0.03-0.36). The strength of agreement between endoscopic and histological atrophy, assessed by cancer risk-oriented grading, was reproducible, with a kappa value of 0.81 (95%CI: 0.75-0.87). Only nine patients (3.6%) were endoscopically underdiagnosed with antral predominant rather than extensive atrophy and were considered false negatives. CONCLUSION: Endoscopic grading can predict histological atrophy with few false negatives, indicating that precancerous conditions can be identified during screening endoscopy, particularly in patients in western countries. PMID:26673849

  1. Glucocorticoid-induced skeletal muscle atrophy.

    PubMed

    Schakman, O; Kalista, S; Barbé, C; Loumaye, A; Thissen, J P

    2013-10-01

    Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23806868

  2. Porcine models of muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  3. Modifying muscular dystrophy through TGFβ

    PubMed Central

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through candidate gene approaches as well as genomewide surveys. Multiple lines of experimental evidence have now converged on the TGFβ pathway as a modifier for muscular dystrophy. TGFβ signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or altered extracellular matrix. Given the important biological role of the TGFβ pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGFβ pathway and approaches to modulate TGFβ activity to ameliorate muscle disease. PMID:23551962

  4. Wasting mechanisms in muscular dystrophy.

    PubMed

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

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23669245

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

    PubMed Central

    Yis, Uluç; Baydan, Figen; Karakaya, Mert; Hız Kurul, Semra; Cirak, Sebahattin

    2016-01-01

    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. PMID:27123443

  6. NASA Keynote at the 2015 Trilateral SMA Conference, Frascati, Italy

    NASA Technical Reports Server (NTRS)

    Groen, Frank

    2015-01-01

    The purpose of this presentation is to illustrate some new directions within NASA's safety and mission function in response to changes in missions, technology, and practices. The presentation lists last year's highlights from NASA's human and robotic spaceflight missions, and discusses anticipated highlights for the coming year taken from existing Agency presentations. It will highlight changes to NASA's mission and the way NASA does business, as described in the 2014 strategic plan. It will then discuss how these changes pose challenges to trusted SMA practices, and provide some examples of initiatives NASA is taking action to address these challenges.

  7. Pregnancy and delivery in Leyden-Möbius muscular dystrophy. Case Report.

    PubMed

    Vavrinkova, Blanka; Binder, Tomas

    2015-01-01

    Leyden-Möbius muscular dystrophy is an autosomal recessive hereditary disease of unknown aetiology; it is a congenital disorder of protein metabolism primarily affecting proximal muscle groups leading to progressive muscular dystrophy. It later spreads to the muscles of the pelvic floor and lower extremities. The estimated incidence is 1:200,000. This paper describe a case of pregnancy and delivery in woman with progressive Leyden-Moebius muscular dystrophy. Cesarean section was performed due to progression of the underlying disease. First postoperative day DIC occure and surgical revision of abdominal cavity was performed. Although the uterine suture was strong, diffuse bleeding was present. Blood was not coagulating. Supravaginal amputation of the uterus was performed including left-sided adnexectomy due to bleeding from the left ovarium. Due to the severity of the condition and assumed necessity of long-term controlled ventilation, the patient was transferred to the intensive medicine department. She was dismissed home after 91 days of hospitalisation. Gravidity in advanced muscular dystrophy is rare and associated with a high risk. Due to muscle weakness, diaphragm weakness, atrophy of individual muscle groups, spine deformities and often dislocation of thoracic organs, these patients cannot avoid the caesarean section to end their pregnancy, followed by prolonged intubation and controlled ventilation. During pregnancy, the growing uterus elevates the diaphragm and impairs breathing. Therefore, pregnancies in such patients will probably always have to be ended prematurely. PMID:26313391

  8. Ret finger protein mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy.

    PubMed

    Joung, Hosouk; Eom, Gwang Hyeon; Choe, Nakwon; Lee, Hye Mi; Ko, Jeong-Hyeon; Kwon, Duk-Hwa; Nam, Yoon Seok; Min, Hyunki; Shin, Sera; Kook, Jeewon; Cho, Young Kuk; Kim, Jeong Chul; Seo, Sang Beom; Baik, Yung Hong; Nam, Kwang-Il; Kook, Hyun

    2014-10-01

    Skeletal muscle atrophy results from the net loss of muscular proteins and organelles and is caused by pathologic conditions such as nerve injury, immobilization, cancer, and other metabolic diseases. Recently, ubiquitination-mediated degradation of skeletal-muscle-specific transcription factors was shown to be involved in muscle atrophy, although the mechanisms have yet to be defined. Here we report that ret finger protein (RFP), also known as TRIM27, works as an E3 ligase in Pax7-induced degradation of MyoD. Muscle injury induced by sciatic nerve transection up-regulated RFP and RFP physically interacted with both Pax7 and MyoD. RFP and Pax7 synergistically reduced the protein amounts of MyoD but not the mRNA. RFP-induced reduction of MyoD protein was blocked by proteasome inhibitors. The Pax7-induced reduction MyoD was attenuated by RFP siRNA and by MG132, a proteasome inhibitor. RFPΔR, an RFP construct that lacks the RING domain, failed to reduce MyoD amounts. RFP ubiquitinated MyoD, but RFPΔR failed to do so. Forced expression of RFP, but not RFPΔR, enhanced Pax7-induced ubiquitination of MyoD, whereas RFP siRNA blocked the ubiquitination. Sciatic nerve injury-induced muscle atrophy as well the reduction in MyoD was attenuated in RFP knockout mice. Taken together, our results show that RFP works as a novel E3 ligase in the Pax7-mediated degradation of MyoD in response to skeletal muscle atrophy. PMID:25025573

  9. A three-phase cylinder model for residual and transformational stresses in SMA composites

    SciTech Connect

    Berman, J.B.; White, S.R.

    1994-12-31

    SMA composites are a class of smart materials in which shape memory alloy (SMA) actuators are embedded in a polymer matrix composite. The difference in thermal expansion between the SMA and the host material leads to residual stresses during processing. Similarly, the SMA transformations from martensite to austenite, or the reverse, also generate stresses. These stresses acting in combination can lead to SMA/epoxy interfacial debonding. In this study the residual and transformational stresses are investigated for an SMA wire embedded in a graphite/epoxy composite. A three phase micromechanical model is developed. The SMA wire is assumed to behave as a thermoelastic material. Nitinol{trademark} SMA austenitic and martensitic transformations are modeled using linear piecewise interpolation of the experimental data. The interphase is modeled as a thermoelastic polymer. A transversely isotropic thermoelastic composite is used for the outer phase. Stress-free conditions are assumed immediately before cool down from the cure temperature. The effect of SMA and coating properties on residual and transformational stresses are evaluated. A decrease in stresses at the composite/coating interface is predicted through the use of thick, compliant coatings. Reducing the recovery strain and moving the transformation to higher temperatures are also effective in reducing residual stresses.

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

    ClinicalTrials.gov

    2016-08-02

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

  11. Multi-Scale Dynamics of Twinning in SMA

    NASA Astrophysics Data System (ADS)

    Faran, Eilon; Shilo, Doron

    2015-06-01

    The mechanical response of shape memory alloys (SMA) is determined by the dynamics of discrete twin boundaries, and is quantified through constitutive material laws called kinetic relations. Extracting reliable kinetic relations, as well as revealing the physical characteristics of the energy barriers that dictate these relations, are essential for understanding and modeling the overall twinning phenomena. Here, we present a comprehensive, multi-scale study of discrete twin boundary dynamics in a ferromagnetic SMA, NiMnGa. The combination of dynamic-pulsed magnetic field experiments, in conjunction with low-rate uniaxial compression tests, leads to the identification of the dominant energy barriers for twinning. In particular, we show how different mechanisms of motion for overcoming the atomic-scale lattice potential give rise to several kinetic relations that are valid at different ranges of the driving force. In addition, a unique statistical analysis of the low-rate loading curve allows distinguishing between events at different length scales. This analysis leads to the identification of a characteristic length scale (~15 μm) for the distance between barriers that are responsible for the twinning stress property. This characteristic distance is in agreement with the typical thickness of the internal micro-twin structure, which was recently found in these materials.

  12. Shape Memory Alloy (SMA)-Based Launch Lock

    NASA Technical Reports Server (NTRS)

    Badescu, Mircea; Bao, Xiaoqi; Bar-Cohen, Yoseph

    2014-01-01

    Most NASA missions require the use of a launch lock for securing moving components during the launch or securing the payload before release. A launch lock is a device used to prevent unwanted motion and secure the controlled components. The current launch locks are based on pyrotechnic, electro mechanically or NiTi driven pin pullers and they are mostly one time use mechanisms that are usually bulky and involve a relatively high mass. Generally, the use of piezoelectric actuation provides high precession nanometer accuracy but it relies on friction to generate displacement. During launch, the generated vibrations can release the normal force between the actuator components allowing shaft's free motion which could result in damage to the actuated structures or instruments. This problem is common to other linear actuators that consist of a ball screw mechanism. The authors are exploring the development of a novel launch lock mechanism that is activated by a shape memory alloy (SMA) material ring, a rigid element and an SMA ring holding flexure. The proposed design and analytical model will be described and discussed in this paper.

  13. Structural design of morphing trailing edge actuated by SMA

    NASA Astrophysics Data System (ADS)

    Wang, Qi; Xu, Zhiwei; Zhu, Qian

    2013-09-01

    In this paper, the morphing trailing edge is designed to achieve the up and down deflection under the aerodynamic load. After a detailed and accurate computational analysis to determine the SMA specifications and layout programs, a solid model is created in CATIA and the structures of the morphing wing trailing edge are produced by CNC machining. A set of DSP measurement and control system is designed to accomplish the controlling experiment of the morphing wing trailing edge. At last, via the force analysis, the trailing edge is fabricated with four sections of aluminum alloy, and the arrangement scheme of SMA wires is determined. Experiment of precise control integral has been performed to survey the control effect. The experiment consists of deflection angle tests of the third joint and the integral structure. Primarily, the ultimate deflection angle is tested in these two experiments. Therefore, the controlling experiment of different angles could be performed within this range. The results show that the deflection error is less than 4%and response time is less than 6.7 s, the precise controlling of the morphing trailing edge is preliminary realized.

  14. Shape Memory Alloy (SMA)-based launch lock

    NASA Astrophysics Data System (ADS)

    Badescu, Mircea; Bao, Xiaoqi; Bar-Cohen, Yoseph

    2014-04-01

    Most NASA missions require the use of a launch lock for securing moving components during the launch or securing the payload before release. A launch lock is a device used to prevent unwanted motion and secure the controlled components. The current launch locks are based on pyrotechnic, electro mechanically or NiTi driven pin pullers and they are mostly one time use mechanisms that are usually bulky and involve a relatively high mass. Generally, the use of piezoelectric actuation provides high precession nanometer accuracy but it relies on friction to generate displacement. During launch, the generated vibrations can release the normal force between the actuator components allowing free motion of the shaft, which could result in damage to the actuated structures or instruments. This problem is common to other linear actuators that consist of a ball screw mechanism. The authors are exploring the development of a novel launch lock mechanism that is activated by a shape memory alloy (SMA) material ring, a rigid element and an SMA ring holding flexure. The proposed design and analytical model will be described and discussed in this paper.

  15. Redox control of skeletal muscle atrophy.

    PubMed

    Powers, Scott K; Morton, Aaron B; Ahn, Bumsoo; Smuder, Ashley J

    2016-09-01

    Skeletal muscles comprise the largest organ system in the body and play an essential role in body movement, breathing, and glucose homeostasis. Skeletal muscle is also an important endocrine organ that contributes to the health of numerous body organs. Therefore, maintaining healthy skeletal muscles is important to support overall health of the body. Prolonged periods of muscle inactivity (e.g., bed rest or limb immobilization) or chronic inflammatory diseases (i.e., cancer, kidney failure, etc.) result in skeletal muscle atrophy. An excessive loss of muscle mass is associated with a poor prognosis in several diseases and significant muscle weakness impairs the quality of life. The skeletal muscle atrophy that occurs in response to inflammatory diseases or prolonged inactivity is often associated with both oxidative and nitrosative stress. In this report, we critically review the experimental evidence that provides support for a causative link between oxidants and muscle atrophy. More specifically, this review will debate the sources of oxidant production in skeletal muscle undergoing atrophy as well as provide a detailed discussion on how reactive oxygen species and reactive nitrogen species modulate the signaling pathways that regulate both protein synthesis and protein breakdown. PMID:26912035

  16. Development of damage suppression system using embedded SMA foil in CFRP laminates

    NASA Astrophysics Data System (ADS)

    Ogisu, Toshimichi; Nomura, Masato; Ando, Norio; Takaki, Junji; Kobayashi, Masakazu; Okabe, Tomonaga; Takeda, Nobuo

    2001-07-01

    Some recent studies have suggested possible applications of Shape Memory Alloy (SMA) for a smart health monitoring and suppression of damage growth. The authors have been conducting research and development studies on applications of embedded SMA foil actuators in CFRP laminates as the basic research for next generation aircrafts. First the effective surface treatment for improvement of bonding properties between SMA and CFRP was studied. It was certified that the anodic oxide treatment by 10% NaOH solution was the most effective treatment from the results of peel resistance test and shear strength test. Then, CFRP laminates with embedded SMA foils were successfully fabricated using this effective surface treatment. The damage behavior of quasi-isotropic CFRP laminates with embedded SMA foils was characterized in both quasi-static load-unload and fatigue tests. The relationship between crack density and applied strain was obtained. The recovery stress generated by embedded SMA foils could increase the onset strain of transverse cracking by 0.2%. The onset strain of delmination in CFRP laminates was also increased accordingly. The shear-lag analysis was also conducted to predict the damage evolution in CFRP laminates with embedded SMA foils. The adhesive layers on both sides of SMA foils were treated as shear elements. The theoretical analysis successfully predicted the experimental results.

  17. Multifunctional SMA-based smart inhaler system for improved aerosol drug delivery: design and fabrication

    NASA Astrophysics Data System (ADS)

    Pausley, Matthew E.; Seelecke, Stefan

    2008-03-01

    This paper documents the development of a prototype smart aerosol drug inhaler system using shape memory alloy (SMA) actuators. Unlike conventional dispersed-release inhalers, the smart inhaler system releases the aerosol drug in a very small area within the mouth inlet. Kleinstreuer and Zhang [1] have found that controlled release in the mouth inlet increases drug efficiency and allows targeting of specific sites within the lung. The methodology has been validated numerically and experimentally using fixed-exit position inhalers. The design presented in this work, however, allows for variation of nozzle exit position using SMA wire actuators in a combined actuator/sensor role. In contrast to other possible mechanisms, SMA wires are lightweight, require low power, and are the least obstructive to the flow of air through the inhaler. The dual actuator/sensor nature of the SMA wires (via resistance measurement) further simplifies the design. Solutions and insights into several SMA actuator design challenges are presented. SMA wire actuator characteristics such as achievable stroke and their effect on the design are highlighted. Consideration of actuator force requirements and the capabilities of SMA wires and studied. The problems posed by the thermal characteristics of SMA wires and innovative solutions are reported.

  18. Genomic characterization and integrative properties of phiSMA6 and phiSMA7, two novel filamentous bacteriophages of Stenotrophomonas maltophilia.

    PubMed

    Petrova, Mayya; Shcherbatova, Natalya; Kurakov, Anton; Mindlin, Sofia

    2014-06-01

    Two novel filamentous phages, phiSMA6 and phiSMA7, were isolated from Stenotrophomonas maltophilia environmental strain Khak84. We identified and annotated 11 potential open reading frames in each phage. While the overall layout of the functional gene groups of both phages was similar to that of the known filamentous phages, they differed from them in their molecular structure. The genome of phiSMA6 is a mosaic that evolved by acquiring genes from at least three different filamentous S. maltophilia phages and one Xanthomonas campestris phage related to Cf1. In the phiSMA6 genome, a gene similar to the bacterial gene encoding the mating pair formation protein trbP was also found. We showed that phiSMA6 possesses lysogenic properties and upon induction produces high-titer lysates. The genome of phiSMA7 possesses a unique structure and was found to be closely related to a prophage present in the chromosome of the completely sequenced S. maltophilia clinical strain D457. We suggest that the other three filamentous phages of S. maltophilia described previously also have the capacity to integrate into the genome of their bacterial host. PMID:24327089

  19. Application of SMA technology to auxiliary functions in appliances

    NASA Astrophysics Data System (ADS)

    Johnson, Bart; Brei, Diann E.; Patera, John

    2002-07-01

    Traditionally smart material actuation has been reserved for high technology industries such as space and aerospace; however, as the field matures more and more instances are found in low-cost, high production areas. This paper describes one such instance - the application of shape memory alloys to auxiliary functions in appliances. This investigation focused on lid locks for washing machines because it is representative of several other applications found in appliances including valves, dispensers, locks, brakes, etc. Several competing concepts for SMA actuated lid locks are discussed including simple analytical design models and experimental characterization of proof-of-concept prototypes. A comparison of these designs based on performance (force, response times), energy (power requirements) and economic metrics is given. From this study, a final concept was developed based upon the best attributes of the different concepts. The resulting proof-of-concept prototype demonstrated improved performance over the current state with a potential for cost reduction.

  20. Nonlinear Thermoelastic Model for SMAs and SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2004-01-01

    A constitutive mathematical model has been developed that predicts the nonlinear thermomechanical behaviors of shape-memory-alloys (SMAs) and of shape-memory-alloy hybrid composite (SMAHC) structures, which are composite-material structures that contain embedded SMA actuators. SMAHC structures have been investigated for their potential utility in a variety of applications in which there are requirements for static or dynamic control of the shapes of structures, control of the thermoelastic responses of structures, or control of noise and vibrations. The present model overcomes deficiencies of prior, overly simplistic or qualitative models that have proven ineffective or intractable for engineering of SMAHC structures. The model is sophisticated enough to capture the essential features of the mechanics of SMAHC structures yet simple enough to accommodate input from fundamental engineering measurements and is in a form that is amenable to implementation in general-purpose structural analysis environments.

  1. Experimental Validation of a Thermoelastic Model for SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2001-01-01

    This study presents results from experimental validation of a recently developed model for predicting the thermomechanical behavior of shape memory alloy hybrid composite (SMAHC) structures, composite structures with an embedded SMA constituent. The model captures the material nonlinearity of the material system with temperature and is capable of modeling constrained, restrained, or free recovery behavior from experimental measurement of fundamental engineering properties. A brief description of the model and analysis procedures is given, followed by an overview of a parallel effort to fabricate and characterize the material system of SMAHC specimens. Static and dynamic experimental configurations for the SMAHC specimens are described and experimental results for thermal post-buckling and random response are presented. Excellent agreement is achieved between the measured and predicted results, fully validating the theoretical model for constrained recovery behavior of SMAHC structures.

  2. Artificial heart for humanoid robot using coiled SMA actuators

    NASA Astrophysics Data System (ADS)

    Potnuru, Akshay; Tadesse, Yonas

    2015-03-01

    Previously, we have presented the design and characterization of artificial heart using cylindrical shape memory alloy (SMA) actuators for humanoids [1]. The robotic heart was primarily designed to pump a blood-like fluid to parts of the robot such as the face to simulate blushing or anger by the use of elastomeric substrates for the transport of fluids. It can also be used for other applications. In this paper, we present an improved design by using high strain coiled SMAs and a novel pumping mechanism that uses sequential actuation to create peristalsis-like motions, and hence pump the fluid. Various placements of actuators will be investigated with respect to the silicone elastomeric body. This new approach provides a better performance in terms of the fluid volume pumped.

  3. Progressive hemifacial atrophy. A natural history study.

    PubMed Central

    Miller, M T; Spencer, M A

    1995-01-01

    PURPOSE: To describe two very different natural history courses in 2 patients with hemifacial atrophy. Progressive hemifacial atrophy (Parry-Romberg syndrome, Romberg syndrome, PHA) is characterized by slowly progressive atrophy, frequently involving only one side of the face, primarily affecting the subcutaneous tissue and fat. The onset usually occurs during the first 2 decades of life. The cause and pathophysiology are unknown. Ophthalmic involvement is common, with progressive enophthalmos a frequent finding. Pupillary disturbances, heterochromia, uveitis, pigmentary disturbances of the ocular fundus, and restrictive strabismus have also been reported. Neurologic findings may be present, but the natural history and progression of ocular findings are often not described in the literature. METHODS: We studied the records and present findings of 2 patients with progressive hemifacial atrophy who were observed in our institution over a 10-year period. RESULTS: Both patients showed progression of ophthalmic findings, primarily on the affected side. One patient has had chronic uveitis with secondary cataract and glaucoma, in addition to retinal pigmentary changes. She also had a third-nerve paresis of the contralateral eye and mild seizure activity. The other patient had mild uveitis, some progression of unilateral retinal pigmentary changes, and a significant increase in hyperopia in the affected eye, in addition to hypotony at age 19 without a clear cause, but with secondary retinal and refractive changes. CONCLUSION: Ocular manifestations of progressive hemifacial atrophy are varied, but can progress from mild visual impairment to blindness. Images FIGURE 1 FIGURE 2 FIGURE 3A FIGURE 3B FIGURE 4 FIGURE 5 FIGURE 6 PMID:8719679

  4. The influence of exercise on bone atrophy

    NASA Technical Reports Server (NTRS)

    1978-01-01

    The relationship between the skeletal system, the muscular system, and exercise in bed rest studies are described. The regime of exercises performed, the mineral balance data derived, and the bone densitometric data obtained are discussed. A brief review of some of the histological results are also given.

  5. Age-Related Differences in Muscular Strength and Muscular Endurance among Female Masters Swimmers.

    ERIC Educational Resources Information Center

    Dummer, Gail M.; And Others

    1985-01-01

    This study investigated age-related differences in muscular strength and muscular endurance among 73 female masters swimmers aged 24 to 71 years. While an age-related decline in muscular strength was apparent, the results failed to reveal a similar trend for endurance, suggesting that swimming influences endurance more than strength among women.…

  6. SMA-SH: Modified Styrene-Maleic Acid Copolymer for Functionalization of Lipid Nanodiscs.

    PubMed

    Lindhoud, Simon; Carvalho, Vanessa; Pronk, Joachim W; Aubin-Tam, Marie-Eve

    2016-04-11

    Challenges in purification and subsequent functionalization of membrane proteins often complicate their biochemical and biophysical characterization. Purification of membrane proteins generally involves replacing the lipids surrounding the protein with detergent molecules, which can affect protein structure and function. Recently, it was shown that styrene-maleic acid copolymers (SMA) can dissolve integral membrane proteins from biological membranes into nanosized discs. Within these nanoparticles, proteins are embedded in a patch of their native lipid bilayer that is stabilized in solution by the amphipathic polymer that wraps the disc like a bracelet. This approach for detergent-free purification of membrane proteins has the potential to greatly simplify purification but does not facilitate conjugation of functional compounds to the membrane proteins. Often, such functionalization involves laborious preparation of protein variants and optimization of labeling procedures to ensure only minimal perturbation of the protein. Here, we present a strategy that circumvents several of these complications through modifying SMA by grafting the polymer with cysteamine. The reaction results in SMA that has solvent-exposed sulfhydrils (SMA-SH) and allows tuning of the coverage with SH groups. Size exclusion chromatography, dynamic light scattering, and transmission electron microscopy demonstrate that SMA-SH dissolves lipid bilayer membranes into lipid nanodiscs, just like SMA. In addition, we demonstrate that, just like SMA, SMA-SH solubilizes proteoliposomes into protein-loaded nanodiscs. We covalently modify SMA-SH-lipid nanodiscs using thiol-reactive derivatives of Alexa Fluor 488 and biotin. Thus, SMA-SH promises to simultaneously tackle challenges in purification and functionalization of membrane proteins. PMID:26974006

  7. Validity of Field Tests of Upper Body Muscular Strength.

    ERIC Educational Resources Information Center

    Pate, Russell, R; And Others

    1993-01-01

    Examined the validity of field tests of elementary students' upper body muscular strength and endurance. Field tests were found to be moderately valid measures of weight-relative muscular strength but not of absolute strength and muscular endurance. (SM)

  8. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    MedlinePlus

    ... Health Conditions Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Emery-Dreifuss muscular dystrophy is a condition that chiefly affects muscles used ...

  9. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    MedlinePlus

    ... Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Muscular dystrophies are a group of genetic conditions characterized by ...

  10. Muscular Calf Injuries in Runners.

    PubMed

    Fields, Karl B; Rigby, Michael D

    2016-01-01

    Calf pain is a common complaint among runners of all ages but is most frequent in masters athletes. This article focuses on injuries to the triceps surae or true 'calf muscles.' The most common calf injury is a tear of the medial gastrocnemius muscle (Tennis Leg) but other structures including the lateral gastrocnemius, plantaris and soleus also may be the cause of muscular pain. This article looks at the presentation, evaluation, and treatment of these injuries. We also highlight some examples of musculoskeletal ultrasound which is a valuable tool for rapid diagnosis of the cause and extent of injury. PMID:27618240

  11. Arrhythmias in the muscular dystrophies.

    PubMed

    Rajdev, Archana; Groh, William J

    2015-06-01

    In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occurs with variable prevalence, mirroring the phenotypic variability seen among and within the various hereditary myopathies. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The noncardiac manifestations can lead to delayed recognition of symptoms, affect the decision to implant a prophylactic device, and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  12. Tracheobronchial smooth muscle atrophy and separation.

    PubMed

    Mehta, Atul C; Zaki, Khawaja Salman; Banga, Amit; Singh, Jarmanjeet; Gildea, Thomas R; Arrossi, Valeria

    2015-01-01

    We report a case series involving 4 patients with chronic obstructive pulmonary disease who were on an appropriate medical regimen including a high dose of inhaled corticosteroids (ICS). During bronchoscopy, patients were found to have an excessive dynamic collapse of the posterior wall and its separation from the ends of the adjacent cartilaginous rings. This was causing a near-total occlusion of the tracheal and bronchial lumen during exhalation, thereby presenting with an obstructive pattern on the pulmonary functions. We suspect that this was caused by the atrophy of the smooth muscles of the tracheobronchial wall. We reviewed the literature to explore the mechanisms causing atrophy of the bronchial smooth muscle, focusing on the potential role of long-term ICS use. PMID:26138002

  13. [Posterior cortical atrophy with progressive visual agnosia].

    PubMed

    Zarranz, J J; Lasa, A; Fernández, M; Lezcano, E; Pérez Bas, M; Varona, L; Ruiz, J; Beristain, X

    1995-03-01

    Interest in progressive focal cerebral syndromes associated with classical degenerative diseases has increased in recent years. Descriptions of posterior cortical atrophy with progressive visual agnosia are relatively rare. We present 5 patients (2 women) ranging in age between 57 and 72 years old. In all cases symptoms began and progressed with no known etiology. All cases were sporadic. The main clinical signs are difficulty in recognizing objects, colors, persons or places; topographical disorientation and visual memory alterations; alexia, simultagnosia, loss of ocular fixing and optic ataxia. Some patients presented other disturbances of praxis or memory and 2 progressed to global dementia. Language function was preserved and behavioral disturbances did not develop. The amplitude of the P100 visual evoked potential was low but latency was normal in 4 patients and prolonged in 1. Brain images showed atrophy and hypoperfusion in the parieto-occipital area. The neuropathology status of these patients is unknown. PMID:7756009

  14. Nutrition Considerations in Duchenne Muscular Dystrophy.

    PubMed

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. PMID:25977513

  15. Monotonic and cyclic bond behavior of confined concrete using NiTiNb SMA wires

    NASA Astrophysics Data System (ADS)

    Choi, Eunsoo; Chung, Young-Soo; Kim, Yeon-Wook; Kim, Joo-Woo

    2011-07-01

    This study conducts bond tests of reinforced concrete confined by shape memory alloy (SMA) wires which provide active and passive confinement of concrete. This study uses NiTiNb SMA which usually shows wide temperature hysteresis; this is a good advantage for the application of shape memory effects. The aims of this study are to investigate the behavior of SMA wire under residual stress and the performance of SMA wire jackets in improving bond behavior through monotonic-loading tests. This study also conducts cyclic bond tests and analyzes cyclic bond behavior. The use of SMA wire jackets transfers the bond failure from splitting to pull-out mode and satisfactorily increases bond strength and ductile behavior. The active confinement provided by the SMA plays a major role in providing external pressure on the concrete because the developed passive confinement is much smaller than the active confinement. For cyclic behavior, slip and circumferential strain are recovered more with larger bond stress. This recovery of slip and circumferential strain are mainly due to the external pressure of the SMA wires since cracked concrete cannot provide any elastic recovery.

  16. Pattern Differences of Small Hand Muscle Atrophy in Amyotrophic Lateral Sclerosis and Mimic Disorders

    PubMed Central

    Fang, Jia; Liu, Ming-Sheng; Guan, Yu-Zhou; Du, Hua; Li, Ben-Hong; Cui, Bo; Ding, Qing-Yun; Cui, Li-Ying

    2016-01-01

    Background: Amyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. Methods: We compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. Results: The ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P < 0.001) than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (P < 0.001) and the HD patients (P < 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients (P = 0.004). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P < 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls (P = 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥4.5) were observed exclusively in the ALS patients. Conclusions: The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders. PMID:26996473

  17. The Muscular Dystrophies: From Genes to Therapies

    PubMed Central

    Porter, Neil C; Bloch, Robert J

    2015-01-01

    The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275

  18. Space travel directly induces skeletal muscle atrophy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

    1999-01-01

    Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

  19. Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite.

    PubMed

    Liewluck, Teerin; Tracy, Jennifer A; Sorenson, Eric J; Engel, Andrew G

    2013-02-01

    Scapuloperoneal muscular dystrophy is a group of genetically heterogeneous disorders that share the phenotype of progressive weakness of scapular and anterior distal leg muscles. Recessive mutations in C-terminal domains of TRIM32 result in limb-girdle muscular dystrophy 2H and sarcotubular myopathy, a rare congenital myopathy commonly seen in Hutterites. A scapuloperoneal phenotype has never been reported in sarcotubular myopathy. We here report a 23-year-old Hutterite man with a one-year history of progressive weakness predominantly involving the anterior tibial and left scapular muscles, and hyperCKemia. Biopsy of the anterior tibial muscle showed an active myopathy with non-rimmed vacuoles and mild denervation atrophy associated with reinnervation. The vacuoles are similar to those described in sarcotubular myopathy. TRIM32 sequencing revealed the common c.1459G>A mutation at homozygosity. A search for mutations in TRIM32 should be considered in patients with scapuloperoneal muscular dystrophy, and especially in patients of Hutterite origin or with an atypical vacuolar myopathy. PMID:23142638

  20. Evaluation of 2'-Deoxy-2'-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy.

    PubMed

    Jirka, Silvana M G; Tanganyika-de Winter, Christa L; Boertje-van der Meulen, Joke W; van Putten, Maaike; Hiller, Monika; Vermue, Rick; de Visser, Peter C; Aartsma-Rus, Annemieke

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder typically caused by frame-shifting mutations in the DMD gene. Restoration of the reading frame would allow the production of a shorter but partly functional dystrophin protein as seen in Becker muscular dystrophy patients. This can be achieved with antisense oligonucleotides (AONs) that induce skipping of specific exons during pre-mRNA splicing. Different chemical modifications have been developed to improve AON properties. The 2'-deoxy-2'-fluoro (2F) RNA modification is attractive for exon skipping due to its ability to recruit ILF2/3 proteins to the 2F/pre-mRNA duplex, which resulted in enhanced exon skipping in spinal muscular atrophy models. In this study, we examined the effect of two different 2'-substituted AONs (2'-F phosphorothioate (2FPS) and 2'-O-Me phosphorothioate (2OMePS)) on exon skipping in DMD cell and animal models. In human cell cultures, 2FPS AONs showed higher exon skipping levels than their isosequential 2OMePS counterparts. Interestingly, in the mdx mouse model, 2FPS was less efficient than 2OMePS and suggested safety issues as evidenced by increased spleen size and weight loss. Our results do not support a clinical application for 2FPS AON. PMID:26623937

  1. Percutaneous Thrombin Injection to Complete SMA Pseudoaneurysm Exclusion After Failing of Endograft Placement

    SciTech Connect

    Szopinski, Piotr Ciostek, Piotr; Pleban, Eliza; Iwanowski, Jaroslaw; Krol, Malgorzata Serafin-; Marianowska, Agnieszka; Noszczyk, Wojciech

    2005-05-15

    Visceral aneurysms are potentially life-threatening vascular lesions. Superior mesenteric artery (SMA) pseudoaneurysms are a rare but well-recognized complication of chronic pancreatitis. Open surgical repair of such an aneurysm, especially in patients after previous surgical treatment, might be dangerous and risky. Stent graft implantation makes SMA pseudoaneurysm exclusion possible and therefore avoids a major abdominal operation. Percutaneous direct thrombin injection is also one of the methods of treating aneurysms in this area. We report a first case of percutaneous ultrasound-guided thrombin injection to complete SMA pseudoaneurysm exclusion after an unsuccessful endograft placement. Six-month follow-up did not demonstrate any signs of aneurysm recurrence.

  2. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

    PubMed Central

    Schmidt, Wolfgang M.; Rutledge, S. Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E.

    2015-01-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  3. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia.

    PubMed

    Schmidt, Wolfgang M; Rutledge, S Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E

    2015-12-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  4. Limb-girdle muscular dystrophy type 2a with mutation in CAPN3: the first report in Taiwan.

    PubMed

    Wang, Chien-Hua; Liang, Wen-Chen; Minami, Narihiro; Nishino, Ichizo; Jong, Yuh-Jyh

    2015-02-01

    The autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 (CAPN3) gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. We report a 33-year-old woman with initial presentations of exercise intolerance and running difficulty at age 15 years. At presentation, waddling gait, positive Gowers' sign, and marked muscle atrophy in pelvic and leg muscles were noted. Muscle computed tomography (CT) imaging demonstrated symmetric involvement of the posterior thigh muscles with relative sparing of vastus lateralis, sartorius, and gracilis. Muscle biopsy revealed a dystrophic change and many lobulated fibers on NADH-tetrazolium reductase staining. Genetic analysis of the CAPN3 gene identified a novel homozygous mutation of c2047_2050 del4, p.Lys683fs mutation, confirming the first LGMD2A patient in Taiwan. PMID:23597518

  5. Seismic Risk Mitigation of Historical Minarets Using SMA Wire Dampers

    SciTech Connect

    El-Attar, Adel G.; Saleh, Ahmed M.; El-Habbal, Islam R.

    2008-07-08

    This paper presents the results of a research program sponsored by the European Commission through project WIND-CHIME (Wide Range Non-INtrusive Devices toward Conservation of HIstorical Monuments in the MEditerranean Area), in which the possibility of using advanced seismic protection technologies to preserve historical monuments in the Mediterranean area is investigated. In the current research, two outstanding Egyptian Mamluk-Style minarets, are investigated. The first is the southern minaret of Al-Sultaniya (1340 A.D, 739 Hijri Date (H.D.)), the second is the minaret of Qusun minaret (1337 A.D, 736 H.D.), both located within the city of Cairo. Based on previous studies on the minarets by the authors, a seismic retrofit technique is proposed. The technique utilizes shape memory alloy (SMA) wires as dampers for the upper, more flexible, parts of the minarets in addition to vertical pre-stressing of the lower parts found to be prone to tensile cracking under ground excitation. The effectiveness of the proposed technique is numerically evaluated via nonlinear transient dynamic analyses. The results indicate the effectiveness of the technique in mitigating the seismic hazard, demonstrated by the effective reduction in stresses and in dynamic response.

  6. Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy.

    PubMed

    Malavaki, C J; Sakkas, G K; Mitrou, G I; Kalyva, A; Stefanidis, I; Myburgh, K H; Karatzaferi, C

    2015-12-01

    Disuse atrophy is the loss of skeletal muscle mass due to inactivity or lower than 'normal' use. It is not only a furtive component of the 'modern' sedentary lifestyle but also a part of numerous pathologies, where muscle loss is linked to disease specific and/or other toxicity factors, eventually leading to wasting (cachexia). Whether disuse-or-disease induced, muscle loss leads to weakness and metabolic comorbidities with a high societal and financial cost. This review discusses the intricate network of interacting signalling pathways including Atrogin-1/MAFbx, IGF1-Akt, myostatin, glucocorticoids, NF-kB, MAPKs and caspases that seem to regulate disuse atrophy but also share common activation patterns in other states of muscle loss such as sarcopenia or cachexia. Reactive oxygen species are also important regulators of cell signalling pathways that can accelerate proteolysis and depress protein synthesis. Exercise is an effective countermeasure and antioxidants may show some benefit. We discuss how the experimental model used can crucially affect the outcome and hence our understanding of atrophy. Timing of sampling is crucial as some signalling mechanisms reach their peak early during the atrophy process to rapidly decline thereafter, while other present high levels even weeks and months after study initiation. The importance of such differences lays in future consideration of appropriate treatment targets. Apart from attempting to correct defective genes or negate their effects, technological advances in new rational ways should aim to regulate specific gene expression at precise time points for the treatment of muscle atrophy in therapeutic protocols depending on the origin of atrophy induction. PMID:26728748

  7. Structural health monitoring of an asymmetrical SMA reinforced composite using embedded FBG sensors

    NASA Astrophysics Data System (ADS)

    Ho, Mei-po; Lau, Kin-tak; Au, Ho-yin; Dong, Yu; Tam, Hwa-yaw

    2013-12-01

    Embedded actuator and sensor technology provides accurate structural health monitoring and proper structural response of a structure in any harsh servicing situation. This paper describes the fabrication of a smart composite by embedding shape memory alloy (SMA) wires and fibre Bragg grating (FBG) sensors into a glass fabric reinforced polymeric composite. Mechanical performances of the composite under martensitic and austenitic stages of the SMA wires were studied, and its natural frequencies were also measured accordingly. The result shows that the shift of the natural frequency arises from temperature change, thus changing the mechanical properties of the SMA wires. The changes of strain, stress, curvature, and damping ratio were predicted from an asymmetrical lamination model. It was found that this model demonstrates certain attractive effects, including mechanical properties, the change of shape, and the natural frequency upon activation of the SMA wires.

  8. Dynamically programmable surface micro-wrinkles on PDMS-SMA composite

    NASA Astrophysics Data System (ADS)

    Ko, Ping-Liang; Chang, Fu-Long; Li, Chih-Hung; Chen, Jian-Zhang; Cheng, I.-Chun; Tung, Yi-Chung; Chang, Shih-Hang; Lin, Pei-Chun

    2014-10-01

    We report on the development of a PDMS-SMA composite whose surface micro wrinkles can be dynamically programmed by an electrical current supplied to the SMA wire. It is advantageous over other techniques for surface topographical modulation, including portability, real-time programmability, no requirement for specific surface chemistry, operability under ambient conditions, and relative ease of control. A simplified mechanical model is also developed to describe the force-deflection balance of the PDMS-SMA composite. The wavelengths and amplitudes of the wrinkles when different currents applied to the SMA are characterized, and the experimental results agree with the theoretical model. The developed composite device can be applied to programmable modulations of surface adhesion, friction, wettability, etc.

  9. Finite Element Analysis of Adaptive-Stiffening and Shape-Control SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Gao, Xiu-Jie; Turner, Travis L.; Burton, Deborah; Brinson, L. Catherine

    2005-01-01

    The usage of shape memory materials has extended rapidly to many fields, including medical devices, actuators, composites, structures and MEMS devices. For these various applications, shape memory alloys (SMAs) are available in various forms: bulk, wire, ribbon, thin film, and porous. In this work, the focus is on SMA hybrid composites with adaptive-stiffening or morphing functions. These composites are created by using SMA ribbons or wires embedded in a polymeric based composite panel/beam. Adaptive stiffening or morphing is activated via selective resistance heating or uniform thermal loads. To simulate the thermomechanical behavior of these composites, a SMA model was implemented using ABAQUS user element interface and finite element simulations of the systems were studied. Several examples are presented which show that the implemented model can be a very useful design and simulation tool for SMA hybrid composites.

  10. Finite Element Analysis of Adaptive-Stiffening and Shape-Control SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Gao, Xiujie; Burton, Deborah; Turner, Travis L.; Brinson, Catherine

    2005-01-01

    Shape memory alloy hybrid composites with adaptive-stiffening or morphing functions are simulated using finite element analysis. The composite structure is a laminated fiber-polymer composite beam with embedded SMA ribbons at various positions with respect to the neutral axis of the beam. Adaptive stiffening or morphing is activated via selective resistance heating of the SMA ribbons or uniform thermal loads on the beam. The thermomechanical behavior of these composites was simulated in ABAQUS using user-defined SMA elements. The examples demonstrate the usefulness of the methods for the design and simulation of SMA hybrid composites. Keywords: shape memory alloys, Nitinol, ABAQUS, finite element analysis, post-buckling control, shape control, deflection control, adaptive stiffening, morphing, constitutive modeling, user element

  11. Animal Models of Muscular Dystrophy

    PubMed Central

    Ng, Rainer; Banks, Glen B.; Hall, John K.; Muir, Lindsey A.; Ramos, Julian N.; Wicki, Jacqueline; Odom, Guy L.; Konieczny, Patryk; Seto, Jane; Chamberlain, Joel R.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies (MDs) represent a diverse collection of inherited human disorders, which affect to varying degrees skeletal, cardiac, and sometimes smooth muscle (Emery, 20021). To date, more than 50 different genes have been implicated as causing one or more types of MD (Bansal et al., 20032). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (Arnett et al., 20093). The large number of genes that are associated with MD and the tremendous number of animal models that have been developed preclude a complete discussion of each in the context of this review. However, we summarize here a number of the more commonly used models together with a mixture of different types of gene and MD, which serves to give a general overview of the value of animal models of MD for research and therapeutic development. PMID:22137430

  12. Arrhythmias in the Muscular Dystrophies

    PubMed Central

    Rajdev, Archana; Groh, William J.

    2015-01-01

    Synopsis In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occur with variable prevalence mirroring the phenotypic variability seen among and within the various hereditary myopathies. These patients are at risk for development for bradyarrhythmias and tachyarrhythmias including sudden cardiac death. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The non-cardiac manifestations can lead to delayed recognition of symptoms (limited mobility and respiratory weakness masking cardiac manifestations), affect decision to implant prophylactic device (quantity vs. quality of life) and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  13. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844

  14. Energy-dissipating and self-repairing SMA-ECC composite material system

    NASA Astrophysics Data System (ADS)

    Li, Xiaopeng; Li, Mo; Song, Gangbing

    2015-02-01

    Structural component ductility and energy dissipation capacity are crucial factors for achieving reinforced concrete structures more resistant to dynamic loading such as earthquakes. Furthermore, limiting post-event residual damage and deformation allows for immediate re-operation or minimal repairs. These desirable characteristics for structural ‘resilience’, however, present significant challenges due to the brittle nature of concrete, its deformation incompatibility with ductile steel, and the plastic yielding of steel reinforcement. Here, we developed a new composite material system that integrates the unique ductile feature of engineered cementitious composites (ECC) with superelastic shape memory alloy (SMA). In contrast to steel reinforced concrete (RC) and SMA reinforced concrete (SMA-RC), the SMA-ECC beams studied in this research exhibited extraordinary energy dissipation capacity, minimal residual deformation, and full self-recovery of damage under cyclic flexural loading. We found that the tensile strain capacity of ECC, tailored up to 5.5% in this study, allows it to work compatibly with superelastic SMA. Furthermore, the distributed microcracking damage mechanism in ECC is critical for sufficient and reliable recovery of damage upon unloading. This research demonstrates the potential of SMA-ECC for improving resilience of concrete structures under extreme hazard events.

  15. Domain General Sequence Operations Contribute to Pre-SMA Involvement in Visuo-spatial Processing.

    PubMed

    Leek, E Charles; Yuen, Kenneth S L; Johnston, Stephen J

    2016-01-01

    This study used 3T MRI to elucidate the functional role of supplementary motor area (SMA) in relation to visuo-spatial processing. A localizer task contrasting sequential number subtraction and repetitive button pressing was used to functionally delineate non-motor sequence processing in pre-SMA, and activity in SMA-proper associated with motor sequencing. Patterns of BOLD responses in these regions were then contrasted to those from two tasks of visuo-spatial processing. In one task participants performed Mental Rotation (MR) in which recognition memory judgments were made to previously memorized 2D novel patterns across image-plane rotations. The other task involved abstract grid navigation (GN) in which observers computed a series of imagined location shifts in response to directional (arrow) cues around a mental grid. The results showed overlapping activation in pre-SMA for sequential subtraction and both visuo-spatial tasks. These results suggest that visuo-spatial processing is supported by non-motor sequence operations that involve pre-SMA. More broadly, these data further highlight the functional heterogeneity of pre-SMA, and show that its role extends to processes beyond the planning and online control of movement. PMID:26858623

  16. Behavior of NiTiNb SMA wires under recovery stress or prestressing

    PubMed Central

    2012-01-01

    The recovery stress of martensitic shape-memory alloy [SMA] wires can be used to confine concrete, and the confining effectiveness of the SMA wires was previously proved through experimental tests. However, the behavior of SMA wires under recovery stress has not been seriously investigated. Thus, this study conducted a series of tests of NiTiNb martensitic SMA wires under recovery stress with varying degrees of prestrain on the wires and compared the behavior under recovery stress with that under prestressing of the wires. The remaining stress was reduced by the procedure of additional strain loading and unloading. More additional strains reduced more remaining stresses. When the SMA wires were heated up to the transformation temperature under prestress, the stress on the wires increased due to the state transformation. Furthermore, the stress decreased with a decreasing temperature of the wires down to room temperature. The stress of the NiTiNb wires was higher than the prestress, and the developed stress seemed to depend on the composition of the SMAs. When an additional strain was subsequently loaded and unloaded on the prestressed SMA wires, the remaining stress decreased. Finally, the remaining stress becomes zero when loading and unloading a specific large strain. PMID:22222096

  17. Behavior of NiTiNb SMA wires under recovery stress or prestressing

    NASA Astrophysics Data System (ADS)

    Choi, Eunsoo; Nam, Tae-Hyun; Chung, Young-Soo; Kim, Yeon-Wook; Lee, Seung-Yong

    2012-01-01

    The recovery stress of martensitic shape-memory alloy [SMA] wires can be used to confine concrete, and the confining effectiveness of the SMA wires was previously proved through experimental tests. However, the behavior of SMA wires under recovery stress has not been seriously investigated. Thus, this study conducted a series of tests of NiTiNb martensitic SMA wires under recovery stress with varying degrees of prestrain on the wires and compared the behavior under recovery stress with that under prestressing of the wires. The remaining stress was reduced by the procedure of additional strain loading and unloading. More additional strains reduced more remaining stresses. When the SMA wires were heated up to the transformation temperature under prestress, the stress on the wires increased due to the state transformation. Furthermore, the stress decreased with a decreasing temperature of the wires down to room temperature. The stress of the NiTiNb wires was higher than the prestress, and the developed stress seemed to depend on the composition of the SMAs. When an additional strain was subsequently loaded and unloaded on the prestressed SMA wires, the remaining stress decreased. Finally, the remaining stress becomes zero when loading and unloading a specific large strain.

  18. Behavior of NiTiNb SMA wires under recovery stress or prestressing.

    PubMed

    Choi, Eunsoo; Nam, Tae-Hyun; Chung, Young-Soo; Kim, Yeon-Wook; Lee, Seung-Yong

    2012-01-01

    The recovery stress of martensitic shape-memory alloy [SMA] wires can be used to confine concrete, and the confining effectiveness of the SMA wires was previously proved through experimental tests. However, the behavior of SMA wires under recovery stress has not been seriously investigated. Thus, this study conducted a series of tests of NiTiNb martensitic SMA wires under recovery stress with varying degrees of prestrain on the wires and compared the behavior under recovery stress with that under prestressing of the wires. The remaining stress was reduced by the procedure of additional strain loading and unloading. More additional strains reduced more remaining stresses. When the SMA wires were heated up to the transformation temperature under prestress, the stress on the wires increased due to the state transformation. Furthermore, the stress decreased with a decreasing temperature of the wires down to room temperature. The stress of the NiTiNb wires was higher than the prestress, and the developed stress seemed to depend on the composition of the SMAs. When an additional strain was subsequently loaded and unloaded on the prestressed SMA wires, the remaining stress decreased. Finally, the remaining stress becomes zero when loading and unloading a specific large strain. PMID:22222096

  19. Stiffness and Confinement Ratios of SMA Wire Jackets for Confining Concrete

    NASA Astrophysics Data System (ADS)

    Choi, Eunsoo; Kim, Dong Joo; Youn, Heejung

    2014-07-01

    This article discusses the effects of the stiffness and confinement ratios of shape memory alloy (SMA) wire jackets on the behavior of confined concrete. SMA wire jackets are an effective confining material to improve concrete behavior; for example, by increasing peak strength and failure strain. The stiffness and confinement ratios of fiber-reinforced polymer jackets have been extensively discussed and their effects are well known. However, assessment of the stiffness and confinement ratios of SMA wire jackets has not previously been conducted. In this study, we investigate the effects of the stiffness and confinement ratios of steel jackets, and then compare the results with those of SMA wire jackets. In general, the stiffness ratios of SMA wire jackets are relatively smaller than those of steel jackets, and most of them have lower stiffness ratios because the Young's moduli of the SMAs are relatively small. The active confining pressure of the SMA wires does not improve the lower stiffness-ratio effect since the amount of active confining pressure is not sufficiently large.

  20. Domain General Sequence Operations Contribute to Pre-SMA Involvement in Visuo-spatial Processing

    PubMed Central

    Leek, E. Charles; Yuen, Kenneth S. L; Johnston, Stephen J.

    2016-01-01

    This study used 3T MRI to elucidate the functional role of supplementary motor area (SMA) in relation to visuo-spatial processing. A localizer task contrasting sequential number subtraction and repetitive button pressing was used to functionally delineate non-motor sequence processing in pre-SMA, and activity in SMA-proper associated with motor sequencing. Patterns of BOLD responses in these regions were then contrasted to those from two tasks of visuo-spatial processing. In one task participants performed Mental Rotation (MR) in which recognition memory judgments were made to previously memorized 2D novel patterns across image-plane rotations. The other task involved abstract grid navigation (GN) in which observers computed a series of imagined location shifts in response to directional (arrow) cues around a mental grid. The results showed overlapping activation in pre-SMA for sequential subtraction and both visuo-spatial tasks. These results suggest that visuo-spatial processing is supported by non-motor sequence operations that involve pre-SMA. More broadly, these data further highlight the functional heterogeneity of pre-SMA, and show that its role extends to processes beyond the planning and online control of movement. PMID:26858623

  1. Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway.

    PubMed

    Chiu, Chen-Yuan; Yang, Rong-Sen; Sheu, Meei-Ling; Chan, Ding-Cheng; Yang, Ting-Hua; Tsai, Keh-Sung; Chiang, Chih-Kang; Liu, Shing-Hwa

    2016-02-01

    Diabetic myopathy, a less studied complication of diabetes, exhibits the clinical observations characterized by a less muscle mass, muscle weakness and a reduced physical functional capacity. Accumulation of advanced glycation end-products (AGEs), known to play a role in diabetic complications, has been identified in ageing human skeletal muscles. However, the role of AGEs in diabetic myopathy remains unclear. Here, we investigated the effects of AGEs on myogenic differentiation and muscle atrophy in vivo and in vitro. We also evaluated the therapeutic potential of alagebrium chloride (Ala-Cl), an inhibitor of AGEs. Muscle fibre atrophy and immunoreactivity for AGEs, Atrogin-1 (a muscle atrophy marker) and phosphorylated AMP-activated protein kinase (AMPK) expressions were markedly increased in human skeletal muscles from patients with diabetes as compared with control subjects. Moreover, in diabetic mice we found increased blood AGEs, less muscle mass, lower muscular endurance, atrophic muscle size and poor regenerative capacity, and increased levels of muscle AGE and receptor for AGE (RAGE), Atrogin-1 and phosphorylated AMPK, which could be significantly ameliorated by Ala-Cl. Furthermore, in vitro, AGEs (in a dose-dependent manner) reduced myotube diameters (myotube atrophy) and induced Atrogin-1 protein expression in myotubes differentiated from both mouse myoblasts and primary human skeletal muscle-derived progenitor cells. AGEs exerted a negative regulation of myogenesis of mouse and human myoblasts. Ala-Cl significantly inhibited the effects of AGEs on myotube atrophy and myogenesis. We further demonstrated that AGEs induced muscle atrophy/myogenesis impairment via a RAGE-mediated AMPK-down-regulation of the Akt signalling pathway. Our findings support that AGEs play an important role in diabetic myopathy, and that an inhibitor of AGEs may offer a therapeutic strategy for managing the dysfunction of muscle due to diabetes or ageing. PMID:26586640

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

    PubMed Central

    Muelas, Nuria; Köehler, Katrin; Huebner, Angela; Hudson, Gavin; Chinnery, Patrick F.; Barresi, Rita; Eagle, Michelle; Polvikoski, Tuomo; Bailey, Geraldine; Miller, James; Radunovic, Aleksander; Hughes, Paul J.; Roberts, Richard; Krause, Sabine; Walter, Maggie C.; Laval, Steven H.; Straub, Volker; Lochmüller, Hanns; Bushby, Kate

    2014-01-01

    The limb girdle muscular dystrophies (LGMDs) are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, LGMD2L and non-dysferlin Miyoshi muscular dystrophy (MMD3). We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic SNP and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised creatinine kinase (CK) values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20s to 50s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high CK and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult LGMD patients. PMID:21186264

  3. [Susceptibility gene in multiple system atrophy (MSA)].

    PubMed

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress. PMID:25672683

  4. Cardiac atrophy after bed rest and spaceflight

    NASA Technical Reports Server (NTRS)

    Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

    2001-01-01

    Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

  5. Short-term muscle atrophy caused by botulinum toxin-A local injection impairs fracture healing in the rat femur.

    PubMed

    Hao, Yongqiang; Ma, Yongcheng; Wang, Xuepeng; Jin, Fangchun; Ge, Shengfang

    2012-04-01

    Damaged bone is sensitive to mechanical stimulation throughout the remodeling phase of bone healing. Muscle damage and muscular atrophy associated with open fractures and subsequent fixation are not beneficial to maintaining optimum conditions for mechanical stability. The aim of this study was to investigate whether local muscle atrophy and dysfunction affect fracture healing in a rat femur fracture model. We combined the rat model of a short period atrophy of the quadriceps with femur fracture. Forty-four-month-old male Wistar rats were adopted for this study. Two units of botulinum toxin-A (BXTA) were administered locally into the right side of the quadriceps of each rat, while the same dose of saline was injected into the contralateral quadriceps. After BXTA had been fully absorbed by the quadriceps, osteotomy was performed in both femurs with intramedullary fixation. Gross observation and weighing of muscle tissue, X-ray analysis, callus histology, and bone biomechanical testing were performed at different time points up to 8 weeks post-surgery. Local injection of BXTA led to a significant decrease in the volume and weight of the quadriceps compared to the control side. At the eighth week, the left side femurs of the saline-injected quadriceps almost reached bony union, and fibrous calluses were completely calcified into woven bone. However, a gap was still visible in the BXTA-treated side on X-ray images. As showed by bone histology, there were no mature osseous calluses or woven bone on the BXTA-treated side, but a resorption pattern was evident. Biomechanical testing indicated that the femurs of the BXTA-treated side exhibited inferior mechanical properties compared with the control side. The inferior outcome following BXTA injection, compared with saline injection, in terms of callus resistance may be the consequence of unexpected load and mechanical unsteadiness caused by muscle atrophy and dysfunction. PMID:21919046

  6. Reality television and the muscular male ideal.

    PubMed

    Dallesasse, Starla L; Kluck, Annette S

    2013-06-01

    Although researchers have examined the negative effects of viewing reality television (RTV) on women's body image, this research has not been extended to men. Exploring the extent to which RTV depicts men who embody the muscular ideal may enhance our understanding of the potential influence of this media genre. We explored the extent to which RTV depicted men who embodied the muscular ideal using a quantitative content analysis. Based on binomial tests, the primary male cast members of programs airing on networks popular among young adult men during the Fall 2009 broadcast season were more muscular, with lower levels of body fat, than average U.S. men. The chest-to-waist and shoulder-to-waist ratios of these cast members did not differ as a function of program type (i.e., reality drama, endurance, and romance). Young men who view RTV programs included in the present study would be exposed to an unrepresentative muscular ideal. PMID:23523084

  7. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    MedlinePlus

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., ... expertise and patient preferences. The goals of any physical therapy plan of care are to assist patients to:  ...

  8. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    MedlinePlus

    ... and walking. Fukuyama congenital muscular dystrophy also impairs brain development. People with this condition have a brain abnormality ... cobblestones). These changes in the structure of the brain lead to significantly delayed development of speech and motor skills and moderate to ...

  9. Muscular Oxygen Uptake Kinetics in Aged Adults.

    PubMed

    Koschate, J; Drescher, U; Baum, K; Eichberg, S; Schiffer, T; Latsch, J; Brixius, K; Hoffmann, U

    2016-06-01

    Pulmonary oxygen uptake (V˙O2) kinetics and heart rate kinetics are influenced by age and fitness. Muscular V˙O2 kinetics can be estimated from heart rate and pulmonary V˙O2. In this study the applicability of a test using pseudo-random binary sequences in combination with a model to estimate muscular V˙O2 kinetics was tested. Muscular V˙O2 kinetics were expected to be faster than pulmonary V˙O2 kinetics, slowed in aged subjects and correlated with maximum V˙O2 and heart rate kinetics. 27 elderly subjects (73±3 years; 81.1±8.2 kg; 175±4.7 cm) participated. Cardiorespiratory kinetics were assessed using the maximum of cross-correlation functions, higher maxima implying faster kinetics. Muscular V˙O2 kinetics were faster than pulmonary V˙O2 kinetics (0.31±0.1 vs. 0.29±0.1 s; p=0.004). Heart rate kinetics were not correlated with muscular or pulmonary V˙O2 kinetics or maximum V˙O2. Muscular V˙O2 kinetics correlated with maximum V˙O2 (r=0.35; p=0.033). This suggests, that muscular V˙O2 kinetics are faster than estimates from pulmonary V˙O2 and related to maximum V˙O2 in aged subjects. In the future this experimental approach may help to characterize alterations in muscular V˙O2 under various conditions independent of motivation and maximal effort. PMID:27116341

  10. A working group classification of focal prostate atrophy lesions.

    PubMed

    De Marzo, Angelo M; Platz, Elizabeth A; Epstein, Jonathan I; Ali, Tehmina; Billis, Anthanase; Chan, Teresa Y; Cheng, Liang; Datta, Milton; Egevad, Lars; Ertoy-Baydar, Dilek; Farre, Xavier; Farree, Xavier; Fine, Samson W; Iczkowski, Kenneth A; Ittmann, Michael; Knudsen, Beatrice S; Loda, Massimo; Lopez-Beltran, Antonio; Magi-Galluzzi, Cristina; Mikuz, Gregor; Montironi, Roldolfo; Pikarsky, Eli; Pizov, Galina; Rubin, Mark A; Samaratunga, Hema; Sebo, Thomas; Sesterhenn, Isabel A; Shah, Rajal B; Shah, Rajiv B; Signoretti, Sabina; Simko, Jeffery; Thomas, George; Troncoso, Patricia; Tsuzuki, Toyonori T; van Leenders, Geert J; Yang, Ximing J; Zhou, Ming; Figg, William D; Hoque, Ashraful; Hoque, Ashrafal; Lucia, M S

    2006-10-01

    Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was

  11. Brain atrophy in Alzheimer's Disease and aging.

    PubMed

    Pini, Lorenzo; Pievani, Michela; Bocchetta, Martina; Altomare, Daniele; Bosco, Paolo; Cavedo, Enrica; Galluzzi, Samantha; Marizzoni, Moira; Frisoni, Giovanni B

    2016-09-01

    Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression. PMID:26827786

  12. Effects of muscle atrophy on motor control

    NASA Technical Reports Server (NTRS)

    Stuart, D. G.

    1985-01-01

    As a biological tissue, muscle adapts to the demands of usage. One traditional way of assessing the extent of this adaptation has been to examine the effects of an altered-activity protocol on the physiological properties of muscles. However, in order to accurately interpret the changes associated with an activity pattern, it is necessary to employ an appropriate control model. A substantial literature exists which reports altered-use effects by comparing experimental observations with those from animals raised in small laboratory cages. Some evidence suggests that small-cage-reared animals actually represent a model of reduced use. For example, laboratory animals subjected to limited physical activity have shown resistance to insulin-induced glucose uptake which can be altered by exercise training. This project concerned itself with the basic mechanisms underlying muscle atrophy. Specifically, the project addressed the issue of the appropriateness of rats raised in conventional-sized cages as experimental models to examine this phenomenon. The project hypothesis was that rats raised in small cages are inappropriate models for the study of muscle atrophy. The experimental protocol involved: 1) raising two populations of rats, one group in conventional (small)-sized cages and the other group in a much larger (133x) cage, from weanling age (21 days) through to young adulthood (125 days); 2) comparison of size- and force-related characteristics of selected test muscles in an acute terminal paradigm.

  13. [Multiple system atrophy - synuclein and neuronal degeneration].

    PubMed

    Yoshida, Mari

    2011-11-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are α-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurties. Reviewing the pathological features of 102 MSA cases, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, which suggested different phenotypic pattern of MSA might exist between races, compared to the relatively high frequency of SND-type in western countries. In early stage of MSA, NNIs, NCIs and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic cord, lower motor neurons and cortical pyramidal neurons, in additions to GCIs. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA. PMID:22277386

  14. Treatment of facioscapulohumeral muscular dystrophy with Denosumab

    PubMed Central

    Lefkowitz, Stanley S.; Lefkowitz, Doris L.; Kethley, Jeremy

    2012-01-01

    Summary Background: Facioscapulohumeral muscular dystrophy (FSHD) is the 3rd most common form of muscular dystrophy. Effective treatments for any of the muscular dystrophies have yet to be realized. This report describes such a treatment. Case Report: A 66 year old female was diagnosed with osteoporosis. She had been diagnosed with FSHD muscular dystrophy a number of years previously by both genetic and clinical studies. Following a 2 year course with Forteo for osteoporosis, she was given an injection of Denosumab (Prolia) to maintain her bone density. By 24 hours, she exhibited increased strength and a dramatic reduction of her dystrophic symptoms e.g. she could walk unassisted in high heels. She was able to accomplish other things that had not been possible for a number of years. After approximately 5 weeks she gradually lost the newfound strength with a complete loss by about 6 weeks. A second injection of Denosumab resulted in the same effect, i.e. reversal of symptoms and increased functionality. A number of measurements and videos were taken to establish the beneficial effects of Prolia for future studies. This was repeated with a 3rd and 4th injection in order to establish the unequivocal beneficial effects on muscular dystrophy. Conclusions: Further studies will be required to establish Denosumab as a major “front line” treatment for this disease and possibly other muscular dystrophies. PMID:23569491

  15. Cerebellar atrophy and prognosis after temporal lobe resection.

    PubMed Central

    Specht, U; May, T; Schulz, R; Rohde, M; Ebner, A; Schmidt, R C; Schütz, M; Wolf, P

    1997-01-01

    OBJECTIVE: Experimental data indicate inhibitory effects of the cerebellum on seizure activity. Structural damage such as cerebellar atrophy, which is a common finding in patients with chronic epilepsy, may reduce these effects. METHODS: Outcome after temporal lobectomy was studied in 78 consecutive patients, with or without cerebellar atrophy diagnosed by MRI. RESULTS: Thirty five patients (45%) showed cerebellar atrophy. At a mean follow up of 14.6 (range, 6-40) months, 50 patients (64%) had no postoperative seizures. In these patients, the frequency of cerebellar atrophy was significantly lower (34%) than in patients who relapsed (64%, p < 0.01). Occurrence of generalised tonic-clonic seizures (GTCS) within two years before surgery, occurrence of GTCS at any time preoperatively, long duration of epilepsy, and older age at surgery were also associated with recurrence of seizures. Multiple logistic regression analysis suggested occurrence of GTCS within two years before surgery and cerebellar atrophy as the main predictive indicators. When both factors were present, the percentage of patients remaining seizure free since surgery fell to 30%, compared with 60% when only GTCS were present, 78.6% when only cerebellar atrophy was present, and 87.5% when both factors were absent. CONCLUSIONS: Cerebellar atrophy shown by MRI was a frequent finding in surgically treated patients with temporal lobe epilepsy. The presence of cerebellar atrophy seems to worsen the prognosis after temporal lobe resection. Images PMID:9153610

  16. Molecular events in skeletal muscle during disuse atrophy

    NASA Technical Reports Server (NTRS)

    Kandarian, Susan C.; Stevenson, Eric J.

    2002-01-01

    This review summarizes the current knowledge of the molecular processes underlying skeletal muscle atrophy due to disuse. Because the processes involved with muscle wasting due to illness are similar to disuse, this literature is used for comparison. Areas that are ripe for further study and that will advance our understanding of muscle atrophy are suggested.

  17. [The heartache of muscular dystrophy].

    PubMed

    Hoogerwaard, E M; Ginjaar, H B; Wilde, A A; Leschot, N J; de Voogt, W G; de Visser, M

    2000-11-11

    Duchenne and Becker muscular dystrophy are caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome. Three so called dystrophinopathy patients, a women aged 54 and two men aged 23 and 21 years, suffered from a severe dilated cardiomyopathy. Such a cardiomyopathy can develop in both carriers and patients. In addition, it is often more important for prognosis than muscle weakness. For these two reasons it is important to screen both groups for (early) cardiological abnormalities. If these are present, regular follow-up is necessary to start timely therapy. When cardiological investigations yield normal results, it is advised to screen carriers with a five-year interval. Dystrophinopathy patients should be checked every year, because the cardiomyopathy sometimes develops and deteriorates over a short period of time. Patients with dilated cardiomyopathy and with a positive family history for dilated cardiomyopathy, muscle weakness or high serum creatine kinase activity should be screened for a mutation in the dystrophin gene. PMID:11103252

  18. Simulation of tissue atrophy using a topology preserving transformation model.

    PubMed

    Karaçali, Bilge; Davatzikos, Christos

    2006-05-01

    We propose a method to simulate atrophy and other similar volumetric change effects on medical images. Given a desired level of atrophy, we find a dense warping deformation that produces the corresponding levels of volumetric loss on the labeled tissue using an energy minimization strategy. Simulated results on a real brain image indicate that the method generates realistic images of tissue loss. The method does not make assumptions regarding the mechanics of tissue deformation, and provides a framework where a pre-specified pattern of atrophy can readily be simulated. Furthermore, it provides exact correspondences between images prior and posterior to the atrophy that can be used to evaluate provisional image registration and atrophy quantification algorithms. PMID:16689268

  19. Bone and muscle atrophy with suspension of the rat

    NASA Technical Reports Server (NTRS)

    Leblanc, A.; Marsh, C.; Evans, H.; Johnson, P.; Schneider, V.; Jhingran, S.

    1985-01-01

    In order to identify a suitable model for the study of muscle atrophy due to suspension in space, a modified version of the Morey tail suspension model was used to measure the atrophic responses of rat bone and muscle to 14-30 days of unloading of the hindlimbs. The progress of atrophy was measured by increases in methylene diphosphonate (MDP) uptake. It is found that bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in the bone formation rate of immobilized dogs and cats. Increased MDP uptake after a period of 60 days indicated an accelerated bone metabolism. Maximum muscle atrophy in the suspended rats was distinctly different from immobilization atrophy. On the basis of the experimental results, it is concluded that the tail suspension model is an adequate simulation of bone atrophy due to suspension.

  20. Indices of Regional Brain Atrophy: Formulae and Nomenclature

    PubMed Central

    Arias-Carrión, Oscar

    2015-01-01

    The pattern of brain atrophy helps to discriminate normal age-related changes from neurodegenerative diseases. Albeit indices of regional brain atrophy have proven to be a parameter useful in the early diagnosis and differential diagnosis of some neurodegenerative diseases, indices of absolute regional atrophy still have some important limitations. We propose using indices of relative atrophy for representing how the volume of a given region of interest (ROI) changes over time in comparison to changes in global brain measures over the same time. A second problem in morphometric studies is terminology. There is a lack of systematization naming indices and the same measure can be named with different terms by different research groups or imaging softwares. This limits the understanding and discussion of studies. In this technological report, we provide a general description on how to compute indices of absolute and relative regional brain atrophy and propose a standardized nomenclature. PMID:26261753

  1. Simulated and Experimental Damping Properties of a SMA/Fiber Glass Laminated Composite

    NASA Astrophysics Data System (ADS)

    Arnaboldi, S.; Bassani, P.; Biffi, C. A.; Tuissi, A.; Carnevale, M.; Lecis, N.; Loconte, A.; Previtali, B.

    2011-07-01

    In this article, an advanced laminated composite is developed, combining the high damping properties of shape memory alloy (SMA) with mechanical properties and light weight of a glass-fiber reinforced polymer. The composite is formed by stacking a glass-fiber reinforced epoxy core between two thin patterned strips of SMA alloy, and two further layers of fiber-glass reinforced epoxy. The bars of the laminated composite were assembled and cured in autoclave. The patterning was designed to enhance the interface adhesion between matrix and SMA inserts and optimally exploit the damping capacity of the SMA thin ribbons. The patterned ribbons of the SMA alloy were cut by means of a pulsed fiber laser source. Damping properties at different amplitudes on full scale samples were investigated at room temperature with a universal testing machine through dynamic tension tests, while temperature dependence was investigated by dynamic mechanical analyses (DMA) on smaller samples. Experimental results were used in conjunction with FEM analysis to optimize the geometry of the inserts. Experimental decay tests on the laminated composite have been carried out to identify the adimensional damping value related to their first flexural mode.

  2. SMA actuators for vibration control and experimental determination of model parameters dependent on ambient airflow velocity

    NASA Astrophysics Data System (ADS)

    Suzuki, Y.

    2016-05-01

    This article demonstrates the practical applicability of a method of modelling shape memory alloys (SMAs) as actuators. For this study, a pair of SMA wires was installed in an antagonistic manner to form an actuator, and a linear differential equation that describes the behaviour of the actuator’s generated force relative to its input voltage was derived for the limited range below the austenite onset temperature. In this range, hysteresis need not be considered, and the proposed SMA actuator can therefore be practically applied in linear control systems, which is significant because large deformations accompanied by hysteresis do not necessarily occur in most vibration control cases. When specific values of the parameters used in the differential equation were identified experimentally, it became clear that one of the parameters was dependent on ambient airflow velocity. The values of this dependent parameter were obtained using an additional SMA wire as a sensor. In these experiments, while the airflow distribution around the SMA wires was varied by changing the rotational speed of the fans in the wind tunnels, an input voltage was conveyed to the SMA actuator circuit, and the generated force was measured. In this way, the parameter dependent on airflow velocity was estimated in real time, and it was validated that the calculated force was consistent with the measured one.

  3. Experimental research on strain monitoring in composite plates using embedded SMA wires

    NASA Astrophysics Data System (ADS)

    Qiu, Zi-xue; Yao, Xing-tian; Yuan, Jiang; Soutis, Costas

    2006-08-01

    Shape memory alloy (SMA) materials possess complete superelasticity or pseudoelasticity above the austenite finish temperature (Af) and many unique mechanical, thermal, thermal-mechanical and electrical properties compared with other conventional materials. Many studies have reported that the superelastic and hysteresis properties of SMA materials can absorb energies coming from external excitations or sudden impacts. In addition, due to the special electrical properties of NiTi superelastic wires, they can also be used as a strain-sensing element to monitor structural health conditions. In this paper, composite laminated specimens embedded with SMA wire sensors were fabricated and a detailed testing system was designed, for example for multi-parameter measuring for impact and weak signal processing for SMA sensors. A low-velocity impact test shows that SMA wire sensors embedded in fibre-reinforced plastic (FRP) laminate can be used to monitor impact responses, such as the location of impact damage, impact degree, and strain distribution. Experimental results and theoretical predictions reveal almost the same results. Compared with other methods, the research provides a simple, economic and reliable technique for monitoring important engineering structures online.

  4. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

    PubMed

    Cash, David M; Frost, Chris; Iheme, Leonardo O; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B; Pennec, Xavier; Pierson, Ronald K; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Guizard, Nicolas; Fonov, Vladimir S; Collins, D Louis; Modat, Marc; Cardoso, M Jorge; Leung, Kelvin K; Wang, Hongzhi; Das, Sandhitsu R; Yushkevich, Paul A; Malone, Ian B; Fox, Nick C; Schott, Jonathan M; Ourselin, Sebastien

    2015-12-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  5. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

    PubMed Central

    Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

    2015-01-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  6. Prestressing effect of cold-drawn short NiTi SMA fibres in steel reinforced mortar beams

    NASA Astrophysics Data System (ADS)

    Choi, Eunsoo; Kim, Dong Joo; Hwang, Jin-Ha; Kim, Woo Jin

    2016-08-01

    This study investigated the prestressing effect of cold-drawn short NiTi shape memory alloy (SMA) fibres in steel reinforced mortar beams. The SMA fibres were mixed with 1.5% volume content in a mortar matrix with the compressive strength of 50 MPa. The SMA fibres had an average length of 34 mm, and they were manufactured with a dog-bone shape: the diameters of the end- and middle-parts were 1.024 and 1.0 mm, respectively. Twenty mortar beams with the dimensions of 40 mm × 40 mm × 160 mm (B × H × L) were prepared. Two types of tests were conducted. One was to investigate the prestressing effect of the SMA fibres, and the beams with the SMA fibres were heated at the bottom. The other was to assess the bending behaviour of the beams prestressed by the SMA fibres. The SMA fibres induced upward deflection and cracking at the top surface by heating at the bottom; thus, they achieved an obvious prestressing effect. The beams that were prestressed by the SMA fibres did not show a significant difference in bending behaviour from that of the SMA fibre reinforced beams that were not subjected to heating. Stress analysis of the beams indicated that the prestressing effect decreased in relation to the cooling temperature.

  7. Seismic vulnerability assessment of a steel-girder highway bridge equipped with different SMA wire-based smart elastomeric isolators

    NASA Astrophysics Data System (ADS)

    Hedayati Dezfuli, Farshad; Shahria Alam, M.

    2016-07-01

    Shape memory alloy wire-based rubber bearings (SMA-RBs) possess enhanced energy dissipation capacity and self-centering property compared to conventional RBs. The performance of different types of SMA-RBs with different wire configurations has been studied in detail. However, their reliability in isolating structures has not been thoroughly investigated. The objective of this study is to analytically explore the effect of SMA-RBs on the seismic fragility of a highway bridge. Steel-reinforced elastomeric isolators are equipped with SMA wires and used to isolate the bridge. Results revealed that SMA wires with a superelastic behavior and re-centering capability can increase the reliability of the bearing and the bridge structure. It was observed that at the collapse level of damage, the bridge isolated by SMA-HDRB has the lowest fragility. Findings also showed that equipping NRB with SMA wires decreases the possibility of damage in the bridge while, replacing HDRB with SMA-HDRB; or LRB with SMA-LRB increases the failure probability of the system at slight, moderate, and extensive limit states.

  8. The neuropsychiatric profile of posterior cortical atrophy.

    PubMed

    Isella, Valeria; Villa, Giulia; Mapelli, Cristina; Ferri, Francesca; Appollonio, Ildebrando Marco; Ferrarese, Carlo

    2015-06-01

    We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement with anecdotal reports, anxiety seems particularly relevant in PCA. PMID:25330926

  9. Cardiac atrophy in women following bed rest.

    PubMed

    Dorfman, Todd A; Levine, Benjamin D; Tillery, Tommy; Peshock, Ronald M; Hastings, Jeff L; Schneider, Suzanne M; Macias, Brandon R; Biolo, Gianni; Hargens, Alan R

    2007-07-01

    Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 +/- 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6 degrees head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training (n = 8), or 2) protein (0.45 g x kg(-1) x day(-1) increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation (n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 +/- 26 to 77 +/- 25 ml; P = 0.03) and RV volumes (104 +/- 33 to 86 +/- 25 ml; P = 0.02), LV (2.2 +/- 0.2 to 2.0 +/- 0.2 g/kg; P = 0.003) and RV masses (0.8 +/- 0.1 to 0.6 +/- 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 +/- 6 to 84 +/- 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645-653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in

  10. Asymptomatic cerebellar atrophy after acute enteroviral encephalitis.

    PubMed

    Vitaszil, Edina; Kamondi, Anita; Csillik, Anita; Velkey, Imre; Szirmai, Imre

    2005-07-01

    We report on a 13-year-old male who had acute enteroviral encephalitis causing cerebellar symptoms at the age of 10 years. Magnetic resonance imaging (MRI) showed no abnormalities. Clinically he appeared to be recovered completely after 6 months. Twenty-three months after the recovery, MRI was performed because he presented with slight lower-limb and truncal ataxia experienced as lack of foot coordination while playing football or riding a bicycle. MRI demonstrated severe cerebellar atrophy. Clinically he recovered completely in 10 days. Only sophisticated electrophysiological methods revealed cerebellar dysfunction. The case provides evidence for the plasticity of cerebellar regulatory structures involved in the coordination of fine movements. It seems that in childhood the slow, isolated disintegration of cerebellar systems can be compensated for by upper thalamic or telencephalic connections, in a similar way to a congenital deficit of the cerebellum. PMID:15991870

  11. [Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].

    PubMed

    Kamauchi, Shinya; Urade, Yoshihiro

    2011-11-01

    Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD. PMID:22068479

  12. Note: A component-level frequency tunable isolator for vibration-sensitive chips using SMA beams

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaoyong; Ding, Xin; Wu, Di; Qi, Junlei; Wang, Ruixin; Lu, Siwei; Yan, Xiaojun

    2016-06-01

    This note presents a component-level frequency tunable isolator for vibration-sensitive chips. The isolator employed 8 U-shaped shape memory alloy (SMA) beams to support an isolation island (used for mounting chips). Due to the temperature-induced Young's modulus variation of SMA, the system stiffness of the isolator can be controlled through heating the SMA beams. In such a way, the natural frequency of the isolator can be tuned. A prototype was fabricated to evaluate the concept. The test results show that the natural frequency of the isolator can be tuned in the range of 64 Hz-97 Hz by applying different heating strategies. Moreover, resonant vibration can be suppressed significantly (the transmissibility decreases about 65% near the resonant frequency) using a real-time tuning method.

  13. Note: A component-level frequency tunable isolator for vibration-sensitive chips using SMA beams.

    PubMed

    Zhang, Xiaoyong; Ding, Xin; Wu, Di; Qi, Junlei; Wang, Ruixin; Lu, Siwei; Yan, Xiaojun

    2016-06-01

    This note presents a component-level frequency tunable isolator for vibration-sensitive chips. The isolator employed 8 U-shaped shape memory alloy (SMA) beams to support an isolation island (used for mounting chips). Due to the temperature-induced Young's modulus variation of SMA, the system stiffness of the isolator can be controlled through heating the SMA beams. In such a way, the natural frequency of the isolator can be tuned. A prototype was fabricated to evaluate the concept. The test results show that the natural frequency of the isolator can be tuned in the range of 64 Hz-97 Hz by applying different heating strategies. Moreover, resonant vibration can be suppressed significantly (the transmissibility decreases about 65% near the resonant frequency) using a real-time tuning method. PMID:27370507

  14. Large size superelastic SMA bars: heat treatment strategy, mechanical property and seismic application

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Fang, Cheng; Liu, Jia

    2016-07-01

    This paper reports a comprehensive study on the mechanical performance of large size superelastic shape memory alloy (SMA) bars, with the main focus given to their potential applications for seismic-resistant connections. A series of practical issues, including heat treatment, mechanical property assessment, and connection design/evaluation, were discussed aiming to benefit both material and civil engineering communities. The study commenced with a detailed discussion on the heat treatment strategy for SMA bars and the resulting mechanical properties including strength/stiffness, self-centring ability, energy dissipation, and fractural resistance. It was observed that the mechanical performance of the bars were quite sensitive to both annealing temperature and duration, and size effect was also evident, resulting in different appropriate heat treatment procedures for the bars with varying diameters. The optimally heat-treated SMA bars were machined to the bolt form and were then used for two types of practical self-centring connections, namely, connection with all SMA bars and that with combined angles and SMA bars. Through conducting full-scale tests, both connections were shown to have stable and controllable hysteretic responses till 5% loading drift. Up to 3% drift, the self-centring performance was satisfactory for both connection types, but beyond that the presence of the angles could lead to accumulated residual rotation. Importantly, for both connections, the deformation was accommodated by the SMA bolts or angles, whereas no plastic deformation was observed at any other structural members. This confirmed the feasibility of using such connections for highly resilient structures where minimal repair work is required after earthquakes.

  15. Damage behavior analysis of smart composites with embedded pre-strained SMA foils

    NASA Astrophysics Data System (ADS)

    Ogisu, Toshimichi; Shimanuki, Masakazu; Kiyoshima, Satoshi; Takaki, Junji; Taketa, Ichiro; Takeda, Nobuo

    2006-02-01

    This paper presents the results of experimental and analytical studies with respect to the damage onset/growth suppression behavior using quasi-isotropic CFRP laminates with embedded pre-strained SMA foils under quasi-static uniaxial tension load. In our previous studies, we conducted some preliminary quasi-static load-unload tests using CFRP laminates with embedded pre-strained SMA foils (smart composites). The results confirmed that these smart composites had excellent effects on damage onset/growth suppression, in comparison with the conventional CFRP laminates. In this study, systematic load-unload tests are conducted for quasi-isotropic laminates, with and without SMA foils and adhesive layers. Following this, a detailed observation of the damage onset/growth suppression behavior is conducted. This observation verified that the microcracks, which originated at the -45/90 interface, generally grow into transverse cracks in a 90° ply of the quasi-isotropic CFRP laminates ([45/0/-45/90]s). It has also been experimentally confirmed that the damage onset/growth suppression effects of smart composites are obtained by the suppression of crack opening displacement. Furthermore, the stress and strain distributions of all the composite systems with microcracks are calculated by FEM analysis at room temperature (RT) and at 80 °C for conventional composites ([45/0/-45/90]s) and smart composites ([45/0/-45/90/Ad/SMA/Ad/90/-45/0/45]), respectively. From the results of the FEM analysis, the strain energy release rate is calculated using the 'crack closure method' for the evaluation of the damage onset/growth suppression effect. It is confirmed that the damage onset/growth suppression effects of the CFRP laminates with embedded pre-strained SMA foils are obtained by the suppression of crack opening displacement in 90° layers, which is generated by the suppression of the strain energy release rate for smart composites by the recovery stress of SMA.

  16. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

    PubMed Central

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A.; Nordsborg, Nikolai; Russell, Aaron P.; MacRae, Calum A.; Gerber, Anthony N.; Jain, Mukesh K.; Haldar, Saptarsi M.

    2015-01-01

    Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC–KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming. PMID:26598680

  17. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.

    PubMed

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A; Lemieux, Madeleine E; Nordsborg, Nikolai; Russell, Aaron P; MacRae, Calum A; Gerber, Anthony N; Jain, Mukesh K; Haldar, Saptarsi M

    2015-12-01

    Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming. PMID:26598680

  18. Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

    PubMed

    Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E

    2016-04-01

    While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. PMID:26780946

  19. [Muscular Dystrophies Involving the Retinal Function].

    PubMed

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis. PMID:27011029

  20. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact.

    PubMed

    Rojas, Juan Ignacio; Patrucco, Liliana; Miguez, Jimena; Cristiano, Edgardo

    2016-03-01

    Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients. PMID:27050854