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Sample records for bulbar muscular atrophy

  1. Current Status of Treatment of Spinal and Bulbar Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Fumiaki Tanaka

    2012-01-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR, a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N and carboxy-terminal (C (N/C interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS, and autophagy could be applicable for all types of polyglutamine diseases.

  2. Bulbar and spinal muscular atrophy (Kennedy's disease): a review.

    Science.gov (United States)

    Finsterer, J

    2009-05-01

    Bulbar and spinal muscular atrophy (BSMA) is an adult-onset, X-linked recessive trinucleotide, polyglutamine disorder, caused by expansion of a polymorphic CAG tandem-repeat in exon 1 of the androgen-receptor (AR) gene on chromosome Xq11-12. Pathogenetically, mutated AR accumulates in nuclei and cytoplasm of motor neurons, resulting in their degeneration and loss. Phenotypically, patients present with amyotrophic, proximal or distal weakness and wasting of the facial, bulbar and limb muscles, occasionally sensory disturbances, and endocrinologic disturbances, such as androgen resistance, gynecomastia, elevated testosterone or progesterone, and reduced fertility. There may be mild hyper-CK-emia, abnormal motor and sensory nerve conduction studies, and neuropathic and myopathic alterations on muscle biopsy. The golden standard for diagnosing BSMA is genetic analysis, demonstrating a CAG-repeat number >40. No causal therapy is available, but symptomatic therapy should be provided for tremor, endocrinologic abnormalities, sensory disturbances, or muscle cramps. The course is slowly progressive, the ability to walk lost only late in life, only few patients require ventilatory support, and life expectancy only slightly reduced.

  3. Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy.

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    Guber, Robert D; Takyar, Varun; Kokkinis, Angela; Fox, Derrick A; Alao, Hawwa; Kats, Ilona; Bakar, Dara; Remaley, Alan T; Hewitt, Stephen M; Kleiner, David E; Liu, Chia-Ying; Hadigan, Colleen; Fischbeck, Kenneth H; Rotman, Yaron; Grunseich, Christopher

    2017-12-12

    To determine the prevalence and features of fatty liver disease in spinal and bulbar muscular atrophy (SBMA). Two groups of participants with SBMA were evaluated. In the first group, 22 participants with SBMA underwent laboratory analysis and liver imaging. In the second group, 14 participants with SBMA were compared to 13 female carriers and 23 controls. Liver biopsies were done in 4 participants with SBMA. Evidence of fatty liver disease was detected by magnetic resonance spectroscopy in all participants with SBMA in the first group, with an average dome intrahepatic triacylglycerol of 27% (range 6%-66%, ref ≤5.5%). Liver dome magnetic resonance spectroscopy measurements were significantly increased in participants with SBMA in the second group relative to age- and sex-matched controls, with average disease and male control measurements of 17% and 3%, respectively. Liver biopsies were consistent with simple steatosis in 2 participants and nonalcoholic steatohepatitis in 2 others. We observed evidence of nonalcoholic liver disease in nearly all of the participants with SBMA evaluated. These observations expand the phenotypic spectrum of the disease and provide a potential biomarker that can be monitored in future studies. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  4. Rapidly worsening bulbar symptoms in a patient with spinobulbar muscular atrophy

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    Montserrat Diaz-Abad

    2013-12-01

    Full Text Available X-linked spinobulbar muscular atrophy (Kennedy’s disease affects muscles and motor neurons, manifesting as weakness and wasting of bulbar, facial, and proximal limb muscles due to loss of anterior horn cells in the brain and spinal cord. We present the case of a patient with X-linked spinobulbar muscular atrophy with rapidly worsening bulbar symptoms caused by laryngopharyngeal irritation associated with a viral upper respiratory tract infection, seasonal allergies and laryngopharyngeal reflux, who dramatically improved with multimodality therapy.

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

    DEFF Research Database (Denmark)

    Pareyson, Davide; Fratta, Pietro; Pradat, Pierre-François

    2016-01-01

    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...

  6. [A mother and her son with autosomal dominant bulbar spinal muscular atrophy].

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    Ibi, T; Suoh, H; Igarashi, S; Tsuji, S; Sahashi, K

    1992-09-01

    We reported a 49-year-old mother and her 28-year-old son with autosomal dominantly inherited bulbar spinal muscular atrophy (AD-BSMA). They showed progressive bulbar paresis, muscle wasting and weakness dominant in the proximal groups of limb muscles, and finger tremor. Onset of illness was in adult life. In laboratory examinations, elevated creatine kinase in serum and neurogenic changes either in EMG or muscle biopsy were noted. The son had neither gynecomastia nor abnormal sexual hormone levels which were observed in the sex-linked recessive bulbar spinal muscular atrophy (SR-BSMA). Elongation due to the CAG repeats at the androgen receptor gene of the X chromosome in SR-BSMA was not detected. In conclusion, it is clear that AD-BSMA is different from SR-BSMA on the basis of clinical and genetical aspects.

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

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    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. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

  8. Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

    DEFF Research Database (Denmark)

    Preisler, N; Andersen, G; Thøgersen, F

    2009-01-01

    OBJECTIVE: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage...... in SBMA also occurs independently of motor neuron damage. METHODS: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo(2max)), maximal work capacity (W(max)), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength......) or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. CONCLUSIONS: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma...

  9. Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy

    NARCIS (Netherlands)

    Giorgetti, Elise; Rusmini, Paola; Crippa, Valeria; Cristofani, Riccardo; Boncoraglio, Alessandra; Cicardi, Maria E.; Galbiati, Mariarita; Poletti, Angelo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone

  10. A rapidly progressive defective spermatogenesis in a Mexican family affected by spino-bulbar muscular atrophy.

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    Piña-Aguilar, Raul Eduardo; Regalado-Hernández, Miguel Ángel; Moreno-García, Jesús Daniel; Buentello-Volante, Beatriz; Chacón-Camacho, Oscar Francisco; Gallegos-Rivas, Mayra Celina; Kazakova, Ekaterina; Santillán-Hernández, Yuritzi; Zenteno, Juan Carlos

    2016-01-01

    Spino-bulbar muscular atrophy (SBMA) is an X-linked recessive adult progressive disorder affecting motor neurons. It is caused by a poly-glutamine tract expansion in the androgen receptor (AR) which generates protein aggregates that cannot be processed by proteasomes. A secondary mild androgen resistance is developed by AR dysfunction and patients present endocrine abnormalities including gynecomastia and poor function of testosterone in tissues; however, normally they are fertile. In this report we describe a Mexican family with three affected brothers with primary infertility caused by a progressive impairment of spermatogenesis leading to azoospermia before 40 years of age. They presented common features associated to patients affected by SMBA, such as gynecomastia, high level of CPK, muscle cramps, fasciculations, muscle wastage, and impaired swallowing. Two intracytoplasmic sperm injection (ICSI) cycles were performed in one of the patients resulting in fertilization failure. Molecular analysis of AR gene exon 1 revealed 54 CAG repeats in DNA extracted from leukocytes in affected patients and 22 repeats in the fertile non-affected brother. Severe impaired spermatogenesis of rapid progression has not been associated before to SBMA. This is the first report of assisted reproduction techniques indicated by male infertility in patients with this rare disorder. Further studies are required to confirm the unusual result of intracytoplasmic sperm injection cycles. We discuss the implications and possible pathogenesis of these unique features of SBMA in this family.

  11. A randomised, placebo-controlled trial of dutasteride in spinal and bulbar muscular atrophy

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    Fernández-Rhodes, Lindsay E; Kokkinis, Angela D; White, Michelle J; Watts, Charlotte A; Auh, Sungyoung; Jeffries, Neal O; Shrader, Joseph A; Lehky, Tanya J; Li, Li; Ryder, Jennifer E; Levy, Ellen W; Solomon, Beth I; Harris-Love, Michael O; La Pean, Alison; Schindler, Alice B; Chen, CheunJu; Di Prospero, Nicholas A; Fischbeck, Kenneth H

    2011-01-01

    Summary Background Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. Methods We explored the efficacy and safety of the 5-alpha-reductase inhibitor, dutasteride, in a single-site, two-year, double-blind, placebo-controlled clinical trial. Physical, neurophysiological, quality of life, and biochemical outcomes were assessed in 50 ambulatory, symptomatic, genetically confirmed, male SBMA subjects randomised to receive dutasteride or placebo (25 in each group). Findings At 24 months, the placebo group showed a decrease of 5% (−0.30 kg/kg) in the primary outcome measure, change in weight-scaled muscle strength as indicated by quantitative muscle assessment (QMA), and the dutasteride group showed an increase in strength of 1% (+0.14 kg/kg); the difference between the groups (6%; CI 18%, −6%) was not significant. Secondary measures of creatine kinase, muscle strength and function, motor and sensory nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. However, quality of life as measured by the SF-36v2 physical component summary favored dutasteride, while the mental component summary favored placebo. The dutasteride group had fewer falls; there were no other significant differences in reported adverse events. Interpretation This study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of benefit. A longer trial duration or larger number of subjects may be needed to show an effect on the disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials. Funding National Institutes of Health PMID:21216197

  12. Generation of sibling-matched induced pluripotent stem cell lines from spinal and bulbar muscular atrophy patients

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    Gunaseelan Narayanan

    2017-04-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is a neurodegenerative disease caused by the expansion of CAG repeats in the Androgen Receptor gene (AR. We report the generation of induced pluripotent stem cell (iPSC lines from two SBMA patients and their healthy siblings. The SBMA and healthy iPSC lines retain the number of AR CAG repeats, express pluripotency markers and are able to differentiate into the three germ layers. The iPSC lines are also free of Sendai virus transgenes and have normal karyotypes. The SBMA iPSC lines with their sibling-matched controls would serve as useful tools to study SBMA disease mechanism.

  13. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

    NARCIS (Netherlands)

    Bailey, CK; Andriola, IFM; Kampinga, HH; Merry, DE

    2002-01-01

    Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is

  14. Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy's disease

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    Francisco A. Dias

    2011-01-01

    Full Text Available OBJECTIVE: To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy's disease. METHODS: Ten patients (from 7 families with a genetic diagnosis of Kennedy's disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene. RESULTS: Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53. Tremor was present in 8 (80% patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88% patients with tremor, who all responded well to treatment with a β-blocker (propranolol. CONCLUSION: Tremor is a common feature in patients with Kennedy's disease and has characteristics similar to those of essential tremor.

  15. Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy.

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    Shinichiro Yamada

    Full Text Available The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA, and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS. We enrolled male subjects with SBMA (n = 40 and ALS (n = 25 along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

  16. Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy.

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    Marta Dossena

    Full Text Available 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.

  17. Long-term follow-up of spinal and bulbar muscular atrophy in Taiwan

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    Ser-Chen Fu

    2013-06-01

    Conclusion: Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness.

  18. Spinal muscular atrophy

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    D'Amico Adele

    2011-11-01

    Full Text Available Abstract 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

  19. Muscular atrophy in diabetic neuropathy

    DEFF Research Database (Denmark)

    Andersen, H; Gadeberg, P C; Brock, B

    1997-01-01

    Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non......-neuropathic patients and in 16 individually matched control subjects. In the neuropathic patients the muscle strength of the ankle dorsal and plantar flexors was reduced by 41 % as compared to the non-neuropathic patients (p ... confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains...

  20. Spinal Muscular Atrophy (SMA)

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    ... encouraging progress. The Muscular Dystrophy Association is the leading sponsor of SMA research. The Association also provides a full program of services for individuals and families coping with SMA, and up-to-date informa- tion ...

  1. Carrier testing for spinal muscular atrophy

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    Gitlin, Jonathan M.; Fischbeck, Kenneth; Crawford, Thomas O.; Cwik, Valerie; Fleischman, Alan; Gonye, Karla; Heine, Deborah; Hobby, Kenneth; Kaufmann, Petra; Keiles, Steven; MacKenzie, Alex; Musci, Thomas; Prior, Thomas; Lloyd-Puryear, Michele; Sugarman, Elaine A.; Terry, Sharon F.; Urv, Tiina; Wang, Ching; Watson, Michael; Yaron, Yuval; Frosst, Phyllis; Howell, R. Rodney

    2014-01-01

    Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general. PMID:20808230

  2. Hypospadias as a novel feature in spinal bulbar muscle atrophy.

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    Nordenvall, Anna Skarin; Paucar, Martin; Almqvist, Catarina; Nordenström, Anna; Frisén, Louise; Nordenskjöld, Agneta

    2016-04-01

    Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis; it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.

  3. [Spinal muscular atrophies in the adult].

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    Camu, W

    2004-02-01

    Spinal muscular atrophies are heterogeneous group. The diagnostic process should be careful to uncover the main differential diagnoses and to identify familial cases. Clinical phenotype is highly variable. In familial ALS cases with SOD1 mutation, the clinical scene may mimic spinal muscular atrophy. A careful questionning and a complete electroneuromyographic exam are warranted to allow the neurologist to choose among more invasive investigations for differential and positive diagnosis such as MRI, nerve or muscle biopsy, genetic analysis.

  4. Preimplantation genetic diagnosis of spinal muscular atrophy

    NARCIS (Netherlands)

    Dreesen, JCFM; Bras, M; de Die-Smulders, C; Dumoulin, JCM; Cobben, JM; Evers, JLH; Smeets, HJM; Geraedts, JPM

    After Duchenne muscular dystrophy, spinal muscular atrophy (SMA) is the most common severe neuromuscular disease in childhood. Since 1995, homozygous deletions in exon 7 of the survival motor neuron (SMN) gene have been described in >90-95% of SMA patients. However, the presence of a highly

  5. Spinal Muscular Atrophy: A Short Review Article

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    Farah Ashrafzadeh

    2014-07-01

    Full Text Available Spinal muscular atrophy (SMA is a genetic disorder which affect nervous system and is characterized with progressive distal motor neuron weakness. The survival motor neuron (SMN protein level reduces in patients with SMA. Two different genes code survival motor neuron protein in human genome. Skeletal and intercostal muscles denervation lead to weakness, hypotony, hyporeflexia, respiratory failure, symmetric muscle atrophy and paralysis in patients with SMA. Manifestations are prominent in proximal muscle of lower extremities. There is no curative treatment for spinal muscular atrophy, and supportive treatment should be considered to improve patients’ quality of life and independency. New treatment strategies focus on gene therapy or invent method to increase survival motor neuron protein level. The aim of this study is to review Spinal muscular atrophy (SMA clinical and molecular manifestations.

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

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    ... myoclonic epilepsy Spinal muscular atrophy with progressive myoclonic epilepsy Printable PDF Open All Close All Enable Javascript ... boxes. Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  7. Neuronal involvement in muscular atrophy

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    Bruno Alejandro Cisterna

    2014-12-01

    Full Text Available 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 formed by connexins and other none selective channels, including P2X7 receptors, TRPV2 channels were demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically prevented in denervated muscles deficient in connexins 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned none selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., BDNF, agrin/Lrp4/MuSK and acetylcholine are among the possible perpetrators of 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.

  8. Proximal spinal muscular atrophy: current orthopedic perspective

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    Haaker G

    2013-11-01

    Full Text Available Gerrit Haaker, Albert Fujak Department of Orthopaedic Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Abstract: 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. Keywords: spinal muscular atrophy, scoliosis, contractures, fractures, lung function, treatment, rehabilitation, surgery, ventilation, nutrition, perioperative management

  9. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy

    DEFF Research Database (Denmark)

    Witting, N; Mensah, A; Køber, L

    2014-01-01

    OBJECTIVES: To assess skeletal muscle weakness and progression as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). MATERIALS AND METHODS: Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical...

  10. Genetics Home Reference: spinal and bulbar muscular atrophy

    Science.gov (United States)

    ... affected, which causes progressive problems with swallowing and speech. Additionally, muscle twitches (fasciculations) are common. Some males with the disorder experience unusual breast development (gynecomastia) and may be unable to father a child (infertile). Related Information What does it mean if ...

  11. New therapeutic approaches to spinal muscular atrophy.

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    Lewelt, Aga; Newcomb, Tara M; Swoboda, Kathryn J

    2012-02-01

    Bench to bedside progress has been widely anticipated for a growing number of neurodegenerative disorders. Of these, spinal muscular atrophy (SMA) is perhaps the best poised to capitalize on advances in targeted therapeutics development over the next few years. Several laboratories have achieved compelling success in SMA animal models using sophisticated methods for targeted delivery, repair, or increased expression of the survival motor neuron protein, SMN. The clinical community is actively collaborating to identify, develop, and validate outcome measures and biomarkers in parallel with laboratory efforts. Innovative trial design and synergistic approaches to maximize proactive care in conjunction with treatment with one or more of the promising pharmacologic and biologic therapies currently in the pipeline will maximize our chances to achieve meaningful outcomes for patients. This review highlights recent promising scientific and clinical advances bringing us ever closer to effective treatment(s) for our patients with SMA.

  12. Valproate and spinal muscular atrophy (Review).

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    Natasha, Gemma; Brandom, Kevin G; Young, Elizabeth C; Young, Philip J

    2008-01-01

    Childhood spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neuron (SMN) gene. The severity of the disease is dictated by the copy number of a second copy of the gene, known as SMN2, with higher copy numbers associated with milder forms of SMA. This is because the level of SMN protein produced by patients dictates the severity of the disease. As all patients retain at least one copy of the SMN2 gene, therapeutic strategies are geared towards increasing full-length SMN protein expression from SMN2. One of the identified therapeutic compounds is valproic acid, or valproate (VPA), a histone deacetylase inhibitor (HDACI) that has been used since the 1970s as an anti-convulsant. Here, we discuss VPA's modes of action and potential side effects in the treatment of SMA.

  13. Mimic syndromes in sporadic cases of progressive spinal muscular atrophy

    NARCIS (Netherlands)

    Visser, J.; van den Berg-Vos, R. M.; Franssen, H.; van den Berg, L. H.; Vogels, O. J.; Wokke, J. H. J.; de Jong, J. M. B. V.; de Visser, M.

    2002-01-01

    Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded

  14. Perspectives on Clinical Trials in Spinal Muscular Atrophy

    Science.gov (United States)

    Swoboda, Kathryn J.; Kissel, John T.; Crawford, Thomas O.; Bromberg, Mark B.; Acsadi, Gyula; D'Anjou, Guy; Krosschell, Kristin J.; Reyna, Sandra P.; Schroth, Mary K.; Scott, Charles B.; Simard, Louise R.

    2011-01-01

    Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy. PMID:17761650

  15. Forced oscillation technique in spinal muscular atrophy.

    Science.gov (United States)

    Gauld, Leanne M; Keeling, Lucy A; Shackleton, Claire E; Sly, Peter D

    2014-09-01

    Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. Children with SMA aged resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P change +0.51, P .05) was found between clinical characteristics and FOT values. FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted.

  16. Carrier screening for spinal muscular atrophy in Italian population

    Indian Academy of Sciences (India)

    Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder characterized by motor neuron degeneration in the anterior horn of the spinal cord and brain stem, resulting in progressive muscle weakness and atrophy. The responsible survival motor neuron gene (SMN1; HGNC: 11117) is localized in ...

  17. Clinico-epidemiologic characteristics of spinal muscular atrophy ...

    African Journals Online (AJOL)

    Rabah M. Shawky

    Abstract Spinal muscular atrophy (SMA) is characterized by progressive hypotonia and muscular weakness because of progressive degeneration of alpha motor neuron from anterior horn cells in the spinal cord. It is inherited by an autosomal recessive pattern. The precise frequency of SMA in Egypt has not been ...

  18. Clinico-epidemiologic characteristics of spinal muscular atrophy ...

    African Journals Online (AJOL)

    Spinal muscular atrophy (SMA) is characterized by progressive hypotonia and muscular weakness because of progressive degeneration of alpha motor neuron from anterior horn cells in the spinal cord. It is inherited by an autosomal recessive pattern. The precise frequency of SMA in Egypt has not been determined.

  19. Spinal Muscular Atrophy and Its Molecular Genetics

    Directory of Open Access Journals (Sweden)

    Sabriye Kocaturk Sel

    2012-02-01

    Full Text Available Spinal muscular atrophy (SMA is one of the most common autosomal recessive diseases, affecting aproximately 1 in 6,000 - 10,000 live births, and with a carrier frequency of aproximately 1 in 40- 60. The childhood SMAs can be classified clinically into three groups. Type I (Werdnig-Hoffmann is the most severe form, with onset at ‹ 6 months of age and with death typically at ‹2 years of age. Type II SMA patients display an intermediate severity, with onset at ‹18 months of age and with an inability to walk. Type III (Kugelberg –Walender individuals are able to walk independently and have a relatively mild phenotype, with onset at ›18 months of age. The gene involved in type I–III SMA has been mapped to 5q12-q13 by linkage analysis, and refined to a region of about 500 kb. The region contains a large inverted duplication consisting of at least four genes, which are present in a telomeric (t and a centromeric (c copy: survival motor neuron gene (SMN1 or SMNt and SMN2 or SMNc; neuronal apoptosis inhibitory protein gene (NAIP; basal transcription factor subunit p44 (BTFp44t and BTFp44c; and a novel protein with unknown function H4F5. Although homozygous deletions encompassing all these genes are found in SMA patients, it is now well established that mutations or deletions of SMN1 (MIM#600354 cause the disease. SMN2 (MIM# 601627 gene, however, does not prevent the disease but attenuates disease severity. Therefore, upregulating functional SMN protein level via inducing gene expression and/or restoring splicing is an important therapeutic approach such as use of histone deacetylase (HDAC inhibitors. [Archives Medical Review Journal 2012; 21(1.000: 1-26

  20. [Anatomoclinical correlations of spinal muscular atrophy in infancy].

    Science.gov (United States)

    Rufo Campos, M; Chinchón Lara, I; Arias León, E; Martínez López, A; Gómez de Terreros, I

    1993-03-01

    Forty-three cases of infantile spinal muscular atrophy diagnosed in our department between 1977 to 1991 are presented. Following clinical-pathologic evaluation, 27 cases were included in type I, 7 in type II and 9 cases in type III. The most frequent pathologic finding was the presence of large groups of atrophic fibers and hypertrophy of isolated fibers in muscle biopsy. Enzyme study showed higher mean levels of CPK and aldolase in type I with respect to the other two. Likewise, a significant statistical difference was found in the age of onset of the different groups. Finally, the clinical classification of spinal muscular atrophies in infancy is discussed.

  1. Skeletal muscle training for spinal muscular atrophy type 3 (Protocol).

    NARCIS (Netherlands)

    Bartels, B.; Montes, J.; Pol, W.L. van der; Groot, J.F. de

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by a genetic mutation in the survival motor neuron 1 (SMN1) gene (5q11.2-q13.3) (Lefebvre 1995). With an incidence of one in 10,000 live births, it is the leading genetic cause of infant death (Lunn 2008;

  2. Physical complaints in ageing persons with spinal muscular atrophy.

    NARCIS (Netherlands)

    Groot, I.J.M. de; Witte, L.P de

    2005-01-01

    OBJECTIVE: While life expectancy is improving for persons with spinal muscular atrophy, new physical complaints may arise. To investigate this, we studied persons with a long duration and severe course (high functional limitations) of the disease. DESIGN: Cross-sectional descriptive study.

  3. Carrier screening for spinal muscular atrophy in Italian population

    Indian Academy of Sciences (India)

    Carrier screening for spinal muscular atrophy in Italian population. Francesco Calì Giuseppa Ruggeri Valeria Chiavetta Carmela Scuderi Sebastiano Bianca Chiara Barone Alda Ragalmuto Pietro Schinocca Girolamo Aurelio Vitello Valentino Romano Sebastiano Musumeci. Research Note Volume 93 Issue 1 April 2014 pp ...

  4. Cardiac pathology in spinal muscular atrophy : a systematic review

    NARCIS (Netherlands)

    Wijngaarde, C A|info:eu-repo/dai/nl/413993779; Blank, A C|info:eu-repo/dai/nl/304821578; Stam, M; Wadman, R I|info:eu-repo/dai/nl/341753637; van den Berg, L H|info:eu-repo/dai/nl/288255216; van der Pol, W L|info:eu-repo/dai/nl/203721721

    2017-01-01

    BACKGROUND: Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual

  5. Anaesthetic Management of Spinal Muscular Atrophy For Laparoscopic Cholecystectomy

    Directory of Open Access Journals (Sweden)

    Dr. E. Argyra / Dr. C. Staikou / Dr. G. Polymeneas / Dr. C. M. Markatou

    2006-01-01

    Full Text Available We report the anaesthetic management of a female patient with Spinal Muscular Atrophy (SMA presented for laparoscopic cholecystectomy. In order to avoid prolonged recovery; we chose to use total intravenous anaesthesia (TIVA with propofol and remifentanil. No neuromuscular blocking agent was used.

  6. Epidural anaesthesia in a child with possible spinal muscular atrophy

    NARCIS (Netherlands)

    Veen, A; Molenbuur, B; Richardson, FJ

    Spinal muscular atrophy (SMA) is a rare lower motor neurone disease in which anaesthetic management is often difficult as a result of muscle weakness and hypersensitivity to neuromuscular blocking agents. Neuraxial anaesthesia is controversial in these patients; however, some cases have been

  7. Best practice guidelines for molecular analysis in spinal muscular atrophy

    NARCIS (Netherlands)

    Scheffer, H; Cobben, JM; Matthijs, G; Wirth, B

    With a prevalence of approximately 1/10 000, and a carrier frequency of 1/40-1/60 the proximal spinal muscular atrophies (SMAs) are among the most frequent autosomal recessive hereditary disorders. Patients can be classified clinically into four groups: acute, intermediate, mild, and adult (SMA

  8. Vascular perfusion abnormalities in infants with spinal muscular atrophy.

    Science.gov (United States)

    Araujo, Alexandra prufer de Queiroz Campos; Araujo, Mario; Swoboda, Kathryn J

    2009-08-01

    Spinal muscular atrophy (SMA) is an important cause of death in children and SMA type I, also known as Werdnig-Hoffman disease, is the most severe form of this disease. We report 2 cases of infants with SMA I in whom a distal necrosis developed, a feature not previously reported. Poor perfusion, autonomic dysfunction, and position-dependent factors may all play a role in the development of this complication.

  9. The research progress of clinical diagnosis of spinal muscular atrophy

    Directory of Open Access Journals (Sweden)

    WANG Ning

    2012-06-01

    Full Text Available Spinal muscular atrophy (SMA is a common autosomal recessive neuromuscular disease caused by degeneration of anterior horn cell in spinal cord. The clinical feature is characterized by progressive symmetrical myasthenia and amyotrophia. The disease is caused by mutation of survival motor neuron (SMN1 gene. Four clinical types are defined for SMA: type Ⅰ, Ⅱ, Ⅲ and Ⅳ. The diagnosis depends on clinical manifestation, inherited history, laboratory test and genetic analysis. To date, there is no effective treatment for SMA, so prenatal diagnosis and carrier screening are important for the prevention of this disease.

  10. Exercise Therapy in Spinobulbar Muscular Atrophy and Other Neuromuscular Disorders

    DEFF Research Database (Denmark)

    Dahlqvist, Julia Rebecka; Vissing, John

    2016-01-01

    There is no curative treatment for most neuromuscular disorders. Exercise, as a treatment for these diseases, has therefore received growing attention. When executed properly, exercise can maintain and improve health and reduce the risk of cardiovascular disease, obesity, and diabetes. In persons...... in patients with neuromuscular diseases associated with weakness and wasting. We review studies that have investigated different types of exercise in both myopathies and motor neuron diseases, with particular emphasis on training of persons affected by spinobulbar muscular atrophy (SBMA). Finally, we provide...

  11. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

    Science.gov (United States)

    Liew, Wendy K. M.

    2013-01-01

    Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID:23634188

  12. Management of scoliosis in patients with Duchenne muscular dystrophy and spinal muscular atrophy: A literature review.

    Science.gov (United States)

    Garg, Sumeet

    2016-01-01

    Scoliosis occurs in nearly all non-ambulatory children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Non-operative treatments have not been shown to be effective at preventing progression of scoliosis. Progressive scoliosis can impact the ability of patients to sit comfortably, be cosmetically unappealing, and in severe cases exacerbate pulmonary disease. The main goal of operative treatment is to improve sitting balance and prevent progression of scoliosis. Complication rates are high and there is little data on effect of operative treatment on quality of life in children with SMA and DMD. Comprehensive multi-disciplinary pre-operative evaluations are vital to reduce the risks of operative treatment.

  13. Adult-onset spinal muscular atrophy: An update.

    Science.gov (United States)

    Juntas Morales, R; Pageot, N; Taieb, G; Camu, W

    2017-05-01

    Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials. This report provides a general overview of the clinical features and pathophysiological mechanisms in adult-onset genetic SMA disorders in which the causative gene has been identified (SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2). Sporadic lower motor neuron disease, also known as progressive muscular atrophy (PMA), is also discussed. The finding of TDP-43 aggregates in immunohistochemical studies of PMA strongly supports the idea that it is a phenotypic variant of amyotrophic lateral sclerosis (ALS). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

    Science.gov (United States)

    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-06-01

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Splice-Switching Therapy for Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Katharina E. Meijboom

    2017-06-01

    Full Text Available Spinal muscular atrophy (SMA is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA. Whilst approval of oligonucleotide-based therapies for SMA should be celebrated, we also discuss some of the limitations of this approach and alternate genetic strategies that are currently underway in clinical trials.

  16. Computed tomography of the skeletal musculature in Becker-type muscular dystrophy and benign infantile spinal muscular atrophy

    NARCIS (Netherlands)

    de Visser, M.; Verbeeten, B.

    1985-01-01

    Results of computed tomographic (CT) examination of the skeletal musculature in 26 patients with Becker-type muscular dystrophy (BMD) and 12 patients with benign infantile spinal muscular atrophy (BISMA) are presented. Both disorders revealed strikingly different changes that may have important

  17. Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

    Science.gov (United States)

    Sampaio, Hugo; Mowat, David; Roscioli, Tony

    2017-01-01

    Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID:28634552

  18. Development and Translation of Therapies for Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Hannah K. Shorrock

    2016-07-01

    Full Text Available Spinal muscular atrophy (SMA is an autosomal recessive neuromuscular disorder characterised by widespread loss of lower motor neurons from the spinal cord, leading to progressive weakness and muscle atrophy. SMA is largely caused by homozygous loss of the survival motor neuron (SMN 1 gene, resulting in reduced levels of full-length SMN protein. Although no approved treatment is currently available for SMA, several clinical trials investigating different approaches to increase SMN levels are showing promising early results. Trials investigating the use of therapies targeting muscle strength and neuroprotective pathways are also in progress, generating the possibility of delivering combination therapies utilising both SMN-dependent and SMN-independent targets. Due to an increased understanding of the cellular and molecular consequences of SMN depletion, a second wave of therapies targeted at pathways downstream of SMN are currently undergoing preclinical development. As these therapies move forward towards the clinic, new treatment options are likely to become available, raising the potential to generate an effective ‘cure’ for SMA.

  19. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Saif Ahmad

    2016-01-01

    Full Text Available 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.

  20. Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets

    Directory of Open Access Journals (Sweden)

    Li-Kai Tsai

    2012-01-01

    Full Text Available Spinal muscular atrophy (SMA is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1 gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

  1. Congenital Bone Fractures in Spinal Muscular Atrophy: Functional Role for SMN Protein in Bone Remodeling

    Science.gov (United States)

    Shanmugarajan, Srinivasan; Swoboda, Kathryn J.; Iannaccone, Susan T.; Ries, William L.; Maria, Bernard L.; Reddy, Sakamuri V.

    2009-01-01

    Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in bone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell-specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy. Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity. PMID:17761651

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

    Science.gov (United States)

    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.

  3. Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy

    Directory of Open Access Journals (Sweden)

    Millino Caterina

    2009-04-01

    Full Text Available Abstract Background Spinal muscular atrophy (SMA is a neurodegenerative disorder associated with mutations of the survival motor neuron gene SMN and is characterized by muscle weakness and atrophy caused by degeneration of spinal motor neurons. SMN has a role in neurons but its deficiency may have a direct effect on muscle tissue. Methods We applied microarray and quantitative real-time PCR to study at transcriptional level the effects of a defective SMN gene in skeletal muscles affected by the two forms of SMA: the most severe type I and the mild type III. Results The two forms of SMA generated distinct expression signatures: the SMA III muscle transcriptome is close to that found under normal conditions, whereas in SMA I there is strong alteration of gene expression. Genes implicated in signal transduction were up-regulated in SMA III whereas those of energy metabolism and muscle contraction were consistently down-regulated in SMA I. The expression pattern of gene networks involved in atrophy signaling was completed by qRT-PCR, showing that specific pathways are involved, namely IGF/PI3K/Akt, TNF-α/p38 MAPK and Ras/ERK pathways. Conclusion Our study suggests a different picture of atrophy pathways in each of the two forms of SMA. In particular, p38 may be the regulator of protein synthesis in SMA I. The SMA III profile appears as the result of the concurrent presence of atrophic and hypertrophic fibers. This more favorable condition might be due to the over-expression of MTOR that, given its role in the activation of protein synthesis, could lead to compensatory hypertrophy in SMA III muscle fibers.

  4. Therapeutic strategies for spinal muscular atrophy: SMN and beyond

    Directory of Open Access Journals (Sweden)

    Melissa Bowerman

    2017-08-01

    Full Text Available Spinal muscular atrophy (SMA is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

  5. Resistance strength training exercise in children with spinal muscular atrophy.

    Science.gov (United States)

    Lewelt, Aga; Krosschell, Kristin J; Stoddard, Gregory J; Weng, Cindy; Xue, Mei; Marcus, Robin L; Gappmaier, Eduard; Viollet, Louis; Johnson, Barbara A; White, Andrea T; Viazzo-Trussell, Donata; Lopes, Philippe; Lane, Robert H; Carey, John C; Swoboda, Kathryn J

    2015-10-01

    Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed. A 12-week supervised, home-based, 3-day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. © 2015 Wiley Periodicals, Inc.

  6. Gait assessment with solesound instrumented footwear in spinal muscular atrophy.

    Science.gov (United States)

    Montes, Jacqueline; Zanotto, Damiano; Dunaway Young, Sally; Salazar, Rachel; De Vivo, Darryl C; Agrawal, Sunil

    2017-08-01

    Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 ± 9.1%, which corresponded to an average deceleration of 0.37 ± 0.28 mm/s2 . Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. Muscle Nerve 56: 230-236, 2017. © 2016 Wiley Periodicals, Inc.

  7. Spinal muscular atrophy due to double gene conversion event.

    Science.gov (United States)

    Maamouri, Wiéme; Hammer, Monia Benhamed; Bouhlel, Yosr; Souilem, Sihem; Khmiri, Najla; Nehdi, Houda; Hentati, Fayçal; Amouri, Rim

    2011-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord. The survival motor neuron (SMN) gene has been identified as an SMA-determining gene. SMN exists as two copies in 5q13, and deletions in exons 7 and 8 of the telomeric copy (SMN(T)) occur in 95% of patients, regardless of disease severity. In a minority of patients, exon 7 but not exon 8 of SMN(T) appears deleted. We now report a patient with typical features of SMA type II who carried homozygous deletions of SMN(T) exon 7 and centromeric SMN (SMN(C)) exon 8 but retained SMN(T) exon 8 and SMN(C) exon 7. Sequence analysis demonstrated that SMN(C) exon 7 was adjacent to SMN(T) exon 8 on both SMN copies, indicating a double conversion. We confirm that sequence conversion is a common event in SMA and is associated with the milder form of the disease. The severity, however, can be modified in either positive or negative direction by other factors.

  8. Biomarkers in Rare Disorders: The Experience with Spinal Muscular Atrophy

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    Christina Brahe

    2010-12-01

    Full Text Available Spinal muscular atrophy (SMA is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Based on clinical severity, three forms of SMA are recognized (type I–III. All patients have at least one (usually 2–4 copies of a highly homologous gene (SMN2 which produces insufficient levels of functional SMN protein, due to alternative splicing of exon7. Recently, evidence has been provided that SMN2 expression can be enhanced by different strategies. The availability of potential candidates to treat SMA has raised a number of issues, including the availability of data on the natural history of the disease, the reliability and sensitivity of outcome measures, the duration of the studies, and the number and clinical homogeneity of participating patients. Equally critical is the availability of reliable biomarkers. So far, different tools have been proposed as biomarkers in SMA, classifiable into two groups: instrumental (the Compound Motor Action Potential, the Motor Unit Number Estimation, and the Dual-energy X-ray absorptiometry and molecular (SMN gene products dosage, either transcripts or protein. However, none of the biomarkers available so far can be considered the gold standard. Preclinical studies on SMA animal models and double-blind, placebo-controlled studies are crucial to evaluate the appropriateness of biomarkers, on the basis of correlations with clinical outcome.

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

    Science.gov (United States)

    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.

  10. GEMINs: Potential Therapeutic Targets for Spinal Muscular Atrophy?

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    Rebecca eBorg

    2014-10-01

    Full Text Available 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 homologue 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.

  11. Neuropsychological investigation in Chinese patients with progressive muscular atrophy.

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    Bo Cui

    Full Text Available 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.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.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.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.

  12. Bulbar muscle MRI changes in patients with SMA with reduced mouth opening and dysphagia.

    NARCIS (Netherlands)

    Wadman, R.I.; Bruggen, H.W. van; Witkamp, T.D.; Kalaykova, S.I.; Stam, M.; Berg, L.H. van den; Steenks, M.H.; Pol, W.L. van der

    2014-01-01

    OBJECTIVE: We performed a study in patients with proximal spinal muscular atrophy (SMA) to determine the prevalence of reduced maximal mouth opening (MMO) and its association with dysphagia as a reflection of bulbar dysfunction and visualized the underlying mechanisms using MRI. METHODS: We

  13. Spinal Muscular Atrophy Genetic Counseling Access and Genetic Knowledge: Parents’ Perspectives

    Science.gov (United States)

    Meldrum, Candice; Scott, Charles; Swoboda, Kathryn J.

    2012-01-01

    Spinal muscular atrophy is characterized by degeneration of α motor neurons in the anterior horns of the spinal cord, which leads to progressive symmetrical muscle weakness and atrophy. Spinal muscular atrophy is the leading fatal autosomal recessive disorder in infancy, and genetic counseling is an essential component of the care of families of these patients. However, little guidance is available in the published literature regarding the process and benefit of genetic counseling for families. Accordingly, the authors designed a questionnaire to assess parents’ knowledge of the disease, gauge their access to genetic counseling, and determine how parents use information gained from counseling to guide choices for future pregnancies. The questionnaire specifically targeted when genetic counseling was received, from whom, parental knowledge regarding spinal muscular atrophy genetics, parental choices regarding spinal muscular atrophy and their child, frequency of prenatal testing, perceived relevance of newborn screening, and opinions regarding the disease. Most families clearly received some type of genetic counseling. Yet how and from whom they received the information varied greatly, as did their genetic knowledge of spinal muscular atrophy. The highest percentage of families received counseling from neurologists, who may not be appropriately prepared to provide formal genetic counseling. Many respondents reported having a negative experience with genetic counseling, possibly because it occurred at the time of diagnosis or shortly afterward, a period of great emotional turmoil. These data suggest that a consistent approach for facilitating how and when genetic counseling is received is greatly needed. PMID:17761658

  14. SMN1 and NAIP Genes Deletions in Different Types of Spinal Muscular Atrophy in Khuzestan Province, Iran

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    Gholamreza Mohamadian

    2011-12-01

    Full Text Available Background: Spinal muscular atrophy (SMA is the second most common lethal autosomal recessive disease. It is a neuromuscular disorder caused by degenerative of lower motor neurons and occasionally bulbar neurons leading to progressive limb paralysis and muscular atrophy. The SMN1 gene is recognized as a SMA causing gene while NAIP has been characterized as a modifying factor for the clinical severity and age at disease onset in SMA patients (SMA subtypes. The relationship between NAIP deletion and type of SMA remains to be clarified; we investigated this gene alteration in all types of SMA patients. Methods: Molecular analysis was performed on fifty patients with a clinical diagnosis of SMA in Khuzestan province. In addition to common PCR-RFLP analysis for exon 7 and 8 of SMN1 gene, as an internal control we analysed NAIP deletion with PCR of exon 5 of this gene in a multiplex PCR with exon 13 of it. Results: Homozygous-deletion frequency rate for the telomeric copy of SMN (SMN1 exon 7 in all types (type I, II, Ш of SMA was approximately 90% and the frequency of deletion in exon 7 and 8 together in all types estimated about 70%. Moreover NAIP gene was deleted in about 60% of these patients and this shows deletion in 91% of type I SMA patients. The correlation between NAIP-deletion and SMN1 mutation showed a high frequency rate. Conclusion: In this study, high frequency of NAIP gene deletion in all type of disease shows the importance role of it in disease pathogenesis. High frequency of NAIP deletion in SMA type I, also shows the importance of the gene in type and severity of disease so it may be a modifier factor in severity of disease.

  15. Clinical and biochemical polymorphism of spinal muscular atrophy

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    M. G. Sokolova

    2017-01-01

    Full Text Available Objective: to conduct clinical laboratory studies of spinal muscular atrophy (SMA for the clarification of the pathogenetic features and role of neurotrophic factors in the formation of polymorphism of this diseasePatients and methods. Thirty-five patients aged 9 months to 53 years (mean age, 14.5 years with different inherited forms of SMA were examined. Clinical, genealogical, and laboratory tests were carried out. A control group consisted of 40 healthy individuals aged 7–45 years (mean age, 16.5 years. The levels of neurotrophins, such as brain-derived growth factor (BDGF, nerve growth factor (NGF, and ciliary neurotrophic factor (CNTF in serum samples were determined by enzyme immunoassay.Results. Changes in the expression of the neurotrophic factors were found in patients with SMA. The enzyme immunoassay data suggest that the serum concentrations of BDGF, NGF, and CNTF in patients with SMA were significantly higher than those in healthy controls. The group of SMA patients aged under 18 years showed a statistically significant (p<0.001 increase in NGF concentrations (3680±936 ng/ml versus the control group of the same age (625±444 pg/ml.Conclusion. In our opinion, the clinical polymorphism of SMA can be explained by the polymorphism of various pathogenic factors: genetic, morphofunctional, and biochemical ones. Overexpression of neurotrophins was first noticed to play a role in the development of more severe clinical types of SMA (proximal SMA, which may be related to both the ontogenetic features of children's age and disease duration. The study results can be further used to choose pathogenetic personalized therapy for SMA.

  16. Natural History of Infantile-Onset Spinal Muscular Atrophy.

    Science.gov (United States)

    Kolb, Stephen J; Coffey, Christopher S; Yankey, Jon W; Krosschell, Kristin; Arnold, W David; Rutkove, Seward B; Swoboda, Kathryn J; Reyna, Sandra P; Sakonju, Ai; Darras, Basil T; Shell, Richard; Kuntz, Nancy; Castro, Diana; Parsons, Julie; Connolly, Anne M; Chiriboga, Claudia A; McDonald, Craig; Burnette, W Bryan; Werner, Klaus; Thangarajh, Mathula; Shieh, Perry B; Finanger, Erika; Cudkowicz, Merit E; McGovern, Michelle M; McNeil, D Elizabeth; Finkel, Richard; Iannaccone, Susan T; Kaye, Edward; Kingsley, Allison; Renusch, Samantha R; McGovern, Vicki L; Wang, Xueqian; Zaworski, Phillip G; Prior, Thomas W; Burghes, Arthur H M; Bartlett, Amy; Kissel, John T

    2017-11-17

    Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17). These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world", prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved. © 2017 American Neurological Association.

  17. Atrofia muscular progressiva: estudo clínico e laboratorial em onze pacientes Progressive muscular atrophy: clinical and laboratory study in eleven patients

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    Maria Elisabeth Matta de Rezende Ferraz

    2004-03-01

    Full Text Available A atrofia muscular progressiva (AMP é um tipo raro de doença do neurônio motor (DNM com acometimento exclusivo do neurônio motor inferior (NMI e com características clínicas bem definidas. A eletroneuromiografia é o principal exame subsidiário para a realização do diagnóstico, com demonstração de alterações neurogênicas generalizadas, agudas e crônicas. Outras doenças que mimetizam comprometimento do NMI devem ser excluídas através de investigação laboratorial ampla. Neste estudo são apresentados 11 casos de AMP (5,9% de todos os nossos casos de DNM, sendo 9 homens e 2 mulheres. O início dos sintomas ocorreu preferencialmente abaixo dos 50 anos, com média de idade de 45,5 anos. A cãibra foi o sintoma que mais comumente precedeu a fraqueza muscular. Outras queixas preliminares foram dor, fadiga muscular e fasciculações. O padrão mais freqüente de inauguração dos sintomas foi fraqueza muscular assimétrica, preferencialmente nos membros superiores. Com a evolução da doença, todos os pacientes apresentaram comprometimento bulbar. Não foi identificado nenhum fator predisponente para a doença, nem tampouco as evoluções foram distintas entre os casos. Oftalmoparesia e acometimento dos esfíncteres, sinais pouco comuns nas DNMs, foram observados em dois pacientes que se mantiveram por longo tempo em respiração artificial. As terapêuticas imunossupressoras / imunomodulatórias utilizadas (ciclofosfamida, gamaglobulina hiperimune, plasmaferese não tiveram resultado favorável. A doença teve caráter progressivo em todos os casos. Todos os pacientes faleceram, com tempo médio de sobrevida de 44 meses.Progressive muscular atrophy (PMA, an infrequent type of motor neuron disease (MND, is a predominantly lower motor neuron degeneration, causing muscle wasting and weakness with loss of weight and fasciculations. The diagnosis is based on rigid criteria, considering clinical aspects and eletroneuromyography findings

  18. Dificuldades diagnósticas na atrofia muscular espinhal Spinal muscular atrophy diagnostic difficulties

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    Alexandra Prufer de Q-C. Araújo

    2005-03-01

    Full Text Available OBJETIVO: Descrever o perfil clínico e laboratorial de pacientes com atrofia muscular espinhal (AME com deleção no gene da proteína sobrevivência do neurônio motor (SMN. MÉTODO: Estudo descritivo de uma série de casos confirmados pela presença da deleção no gene SMN. Determinação da freqüência da positividade dos critérios clínicos e laboratoriais revisados. RESULTADOS: Foram incluídos no estudo 22 casos. Em todos havia paresia simétrica, sendo a localização difusa predominante nos casos de início antes de 6 meses (75 %, enquanto nos demais havia predominância de localização proximal e/ou em membros inferiores (67 %. Fasciculações e atrofia foram freqüentes (82 %. Os exames complementares tiveram resultados variáveis, sendo a positividade da eletroneuromiografia (ENMG de 57 % e da biopsia muscular de 58 %. CONCLUSÃO: A presença de deleção no gene SMN pode ajudar a confirmar o diagnóstico de casos indefinidos .OBJECTIVE: To describe the clinical findings of patients with spinal muscular atrophy (SMA with survival motor neuron (SMN gene deletion. METHOD: Descriptive study of SMA cases confirmed with the deletion of the SMN gene. Frequency determination of positive clinical and laboratory revised diagnostic criteria. RESULTS: All of the 22 included patients had symmetrical muscle weakness, which was diffuse in those with onset of symptoms up to 6 months of age (75 %, and either proximal or predominant in lower limbs in the remaining group (67 %. Fasciculations and atrophy were both frequent findings (82 %. Laboratory tests findings were variable, with a positivity of 57 % for electrophysiology and of 58 % for muscle biopsy. CONCLUSION: The presence of a deletion in the SMN gene can help to confirm this diagnosis in unclear presentations.

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

    Science.gov (United States)

    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. © The Author(s) 2013.

  20. Differential diagnosis in spinal and bulbar muscular atrophy clinical and molecular aspects

    NARCIS (Netherlands)

    G.J. Jöbsis (G.); I. Louwerse (Ilse); J.M.B.V. de Jong (Vianney); M. de Visser (Marianne); R.A. Wolterman (Ruud); P.A. Bolhuis (P.); H.F.M. Busch (Herman); H.T. Brüggenwirth (Hennie); F. Baas (Frank); W.M. Wiersinga (Wilmar); J.H.T.M. Koelman (Johannes )

    1995-01-01

    textabstractKennedy disease is caused by an enlarged trinucleotide repeat sequence within the androgen receptor gene. We report here seven male patients with a benign motor neuron syndrome highly analogous to Kennedy disease but with a normal trinucleotide repeat.

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

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    Lee Kelvin H

    2011-03-01

    Full Text Available Abstract 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

  2. [Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

    Science.gov (United States)

    Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

    2016-08-16

    Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions. To describe the development of a scale to evaluate upper limb function (UL) in patients with DMD and SMA, and describe its validation process, which includes self-training for evaluators. The development of the scale included a review of published scales, an exploratory application of a pilot scale in healthy children and those with DMD, self-training of evaluators in applying the scale using a handbook and video tutorial, and assessment of a group of children with DMD and SMA using the final scale. Reliability was assessed using Cronbach and Kendall concordance and with intra and inter-rater test-retest, and validity with concordance and factorial analysis. A high level of reliability was observed, with high internal consistency (Cronbach α=0.97), and inter-rater (Kendall W=0.96) and intra-rater concordance (r=0.97 to 0.99). The validity was demonstrated by the absence of significant differences between results by different evaluators with an expert evaluator (F=0.023, P>.5), and by the factor analysis that showed that four factors account for 85.44% of total variance. This scale is a reliable and valid tool for assessing UL functionality in children with DMD and SMA. It is also easily implementable due to the possibility of self-training and the use of simple and inexpensive materials. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Electromyographic and computed tomographic findings in five patients with monomelic spinal muscular atrophy

    NARCIS (Netherlands)

    de Visser, M.; Ongerboer de Visser, B. W.; Verbeeten, B.

    1988-01-01

    Five patients with monomelic spinal muscular atrophy are described. Clinical features included insidious onset of wasting and weakness of one limb, lack of involvement of the cranial nerves, brain stem, pyramidal tracts and sensory system, and a stable condition over a period of 4-20 years. Clinical

  4. A PROVISIONAL TRANSCRIPT MAP OF THE SPINAL MUSCULAR-ATROPHY (SMA) CRITICAL REGION

    NARCIS (Netherlands)

    VANDERSTEEGE, G; DRAAIJERS, TG; GROOTSCHOLTEN, PM; OSINGA, J; ANZEVINO, R; VELONA, [No Value; DENDUNNEN, JT; SCHEFFER, H; BRAHE, C; VANOMMEN, GJB; BUYS, CHCM

    1995-01-01

    YACs from the region containing the spinal muscular atrophy (SMA) locus at 5q12 have been used as probes in a direct screening of cDNA libraries to isolate 8 cDNAs, mapped to different YAC fragments. Three clones showed complete identity to the genes for cyclin B1 (CCNB1), the p44 subunit of the

  5. Studies on spinal muscular atrophy : Exploring clinical variability, genetics, biomarkers and treatment

    NARCIS (Netherlands)

    Wadman, R.I.|info:eu-repo/dai/nl/341753637

    2017-01-01

    In this thesis, I describe the natural history and clinical variability of spinal muscular atrophy (SMA) in the Dutch SMA population, have explored various (epi)genetic factors in search for predictors of disease severity and systematically investigated different treatment strategies in SMA. All of

  6. Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

    NARCIS (Netherlands)

    Simic, G.; Mladinov, M.; Seso Simic, D.; Jovanov Milosevic, N.; Islam, A.; Pajtak, A.; Barisic, N.; Sertic, J.; Lucassen, P.J.; Hof, P.R.; Kruslin, B.

    2008-01-01

    The role of heterotopic (migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) is still controversial. We examined the occurrence and amount of HMN in spinal cord tissue from eight children with SMA (six with SMA-I and two with SMA-II). All affected subjects were carrying

  7. A natural history study of late onset spinal muscular atrophy types 3b and 4

    NARCIS (Netherlands)

    Piepers, S.; van den Berg, L. H.; Brugman, F.; Scheffer, H.; Ruiterkamp-Versteeg, M.; van Engelen, B. G.; Faber, C. G.; de Visser, M.; van der Pol, W.-L.; Wokke, J. H. J.

    2008-01-01

    Background Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron (SMN) 1 gene. The nearly identical SMN2 gene plays a disease modifying role. SMA is classified into four different subtypes based on age of onset and clinical course (SMA types 1-4). The natural

  8. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy

    NARCIS (Netherlands)

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

    1995-01-01

    DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type I. SMN deletions

  9. Muscular atrophy in severe cases of cubital tunnel syndrome: prognostic factors and outcome after surgical treatment.

    Science.gov (United States)

    Bruder, Markus; Dützmann, Stephan; Rekkab, Nourdin; Quick, Johanna; Seifert, Volker; Marquardt, Gerhard

    2017-03-01

    Cubital tunnel syndrome (CuTS) is a frequent neuropathy, leading to sensor-motoric dysfunction. Many patients even present with muscular atrophy as a sign for severe and long-lasting nerve impairment, usually suggesting unfavourable outcome. We analysed if those patients benefit from surgical treatment on a long-term basis. Between January 2010 and March 2015, 42 consecutive cases of CuTS with atrophy of the intrinsic hand muscles were surgically treated in our department. Clinical data of the treatment course and postoperative results were collected. Follow-up was prospectively assessed according to McGowen grading and Bishop outcome score. Mean follow-up time was 39.8 (±17.0) months. All patients were treated with in situ decompression; in 33%, submuscular transposition was performed. Forty-five percent showed improvement of sensory deficits and 57% showed improvement of motor deficits 6 months after the operation. Atrophy improved in 76%. At the time of follow-up, 79% were satisfied with the postoperative result and 77% of patients reached good or excellent outcome according to modified Bishop rating scale. Patients with improvement of atrophy had significantly shorter symptom duration period (7 ± 10 months vs 26 ± 33 months; p < 0.05). In the case of intraoperative pseudoneuroma observation, atrophy improvement was less likely (p < 0.05). In severe cases of CuTS with atrophy of the intrinsic hand muscles, surgical treatment enables improvement of sensory function, motor function and atrophy even in cases with muscular atrophy. Atrophy improvement was more likely in cases of short symptom duration and less likely in cases with pseudoneuroma.

  10. Training improves oxidative capacity, but not function, in spinal muscular atrophy type III

    DEFF Research Database (Denmark)

    Madsen, Karen Lindhardt; Hansen, Regitze Sølling; Preisler, Nicolai

    2015-01-01

    INTRODUCTION: In this study we investigated the effect of 12 weeks of cycle ergometer training in patients with spinal muscular atrophy type III (SMA III), a hereditary motor neuron disease with progressive muscle weakness and atrophy. METHODS: Six SMA III patients and 9 healthy subjects completed......max (17 ± 2 to 21 ± 2 ml/kg/min, P SMA III without causing muscle...... damage, but it also induces significant fatigue. This warrants study into alternative training methods to improve exercise capacity in SMA III patients....

  11. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

    OpenAIRE

    Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Leykekhman, Olga; Lutz, Cathleen; Arkovitz, Marc S.; Landmesser, Lynn T.; Monani, Umrao R.

    2008-01-01

    Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe- and mild-SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of ...

  12. Vitamin D intake is inadequate in spinal muscular atrophy type I cohort: correlations with bone health.

    Science.gov (United States)

    Aton, Jennifer; Davis, Rebecca Hurst; Jordan, Kristine C; Scott, Charles B; Swoboda, Kathryn J

    2014-03-01

    Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.

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

    Science.gov (United States)

    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). Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  14. Nutritional Status and Nutrient Intake Challenges in Children With Spinal Muscular Atrophy.

    Science.gov (United States)

    Mehta, Nilesh M; Newman, Haley; Tarrant, Stacey; Graham, Robert J

    2016-04-01

    Nutrition is recognized as a core component of multidisciplinary care for patients with spinal muscular atrophy, but specific nutritional challenges in this population are not well described. We aimed to describe the nutritional status and nutrient intake in children with spinal muscular atrophy. We performed a retrospective medical record review of prospectively collected data from children with spinal muscular atrophy followed at a multidisciplinary clinic at a tertiary referral center. We collected data including clinical parameters; anthropometrics, including weight, height, and body mass index (BMI); and 24-hour dietary intake records in all children followed in the clinic. Available data were found in records from the dietitian as part of a standard evaluation process, and additional clinical data were acquired from patient medical records. Subjects were classified based on spinal muscular atrophy type, and nutritional intake data were compared with dietary reference intakes for gender and age. Z-scores were calculated for weight for age (WAZ), height for age, and BMI (BMIZ) using the World Health Organization AnthroPlus software with appropriate World Health Organization reference growth standards. Subjects were classified as malnourished if their WAZ was +2. Anthropometric measurements were obtained at first visit and at a follow-up visit at an average of a 3-year interval between the clinic visits. A decline of more than 0.5 WAZ over this period was defined a priori as significant nutritional deterioration. We analyzed data from 60 subjects, 26 (43%) female, with median age 5.5 years (interquartile range 2 years to 12 years). The cohort consisted of children with spinal muscular atrophy type 1 (28 %), type 2 (45 %), and type 3 (27 %). At the first clinic visit, nine (15%) patients were malnourished. Thirteen (23%) subjects had a significant decline in WAZ from -0.35 (-1.31 to 0.58) to -1.04 (-2.15 to 0.02) at follow-up after approximately 3 years. A

  15. Deletion analysis of SMN and NAIP genes in Tunisian patients with spinal muscular atrophy

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    Imen Rekik

    2013-01-01

    Full Text Available Background: Spinal muscular atrophy (SMA is an autosomal recessive neuromuscular disorder involving degeneration of anterior horn cells of spinal cord, resulting in progressive muscle weakness and atrophy. Aims: The purpose of our study was to determine the frequency of SMN and NAIP deletions in Tunisian SMA patients. Materials and Methods: Polymerase chain reaction (PCR combined with restriction fragment length polymorphism (RFLP was used to detect the deletion of exon 7 and exon 8 of SMN1 gene, as well as multiplex PCR for exon 5 and 13 of NAIP gene. Results: Fifteen (45.4% out of 33 SMA patients were homozygously deleted for exons 7 and/or 8 of SMN1. Homozygous deletion of NAIP gene was observed in 20% (3 / 15 of patients. Conclusions: The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis, and pre-implantation genetic diagnosis of SMA.

  16. Kinesio taping application in a pediatric patient with spinal muscular atrophy

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    Bayram Kelle

    2016-06-01

    Full Text Available Kinesio taping is one of the elastic bandage methods which has been quite popular in the last 20 years and has been applied in various musculoskeletal conditions. Although the mechanism of action is not clear, many theories have been suggested so far. In this case report, we aimed to present the results of kinesiotape application for back pain of the patient with spinal muscular atrophy which is one of the progressive muscular disorders. It was performed for three times with four days interval. Fascial technique B (Space technique was applied. Reduce of pain was also observed during the subsequent applications. The application of kinesio taping could be beneficial on reducing the pain in patients with progressive muscle diseases. [Cukurova Med J 2016; 41(2.000: 386-389

  17. Catastrophic autonomic crisis with cardiovascular collapse in spinal muscular atrophy with respiratory distress type 1.

    Science.gov (United States)

    Nomura, Toshihiro; Takenouchi, Toshiki; Fukushima, Hiroyuki; Shimozato, Sachiko; Kosaki, Kenjiro; Takahashi, Takao

    2013-07-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare motor neuron disease that can result in dysautonomia but is usually only mildly symptomatic. We report a young girl with SMARD1 who had a catastrophic autonomic crisis with resultant permanent brain damage during an interhospital transfer. Although she was only mildly symptomatic prior to the transfer, in retrospect, her baseline autonomic function analysis had sympathetic hyperactivity without a typical circadian rhythm, indicating the presence of severe underlying dysautonomia. Because this underlying dysautonomia seemed markedly aggravated by the psychological stress, careful autonomic evaluation and management are warranted in patients with SMARD1.

  18. Very severe spinal muscular atrophy: Type 0 with Dandy-Walker variant.

    Science.gov (United States)

    Gathwala, Geeta; Silayach, Joginder; Bhakhari, Bhanu Kiran; Narwal, Varun

    2014-01-01

    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. In addition to the three classical SMA types, a new form known as type 0 with intrauterine onset, profound hypotonia and a progressive and early fatal course has been described. Herein we report a case of type 0 SMA with a Dandy Walker variant anomaly, which has not hitherto been reported in the world literature.

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

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    Daniel Flunt

    2009-01-01

    Full Text Available 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.

  20. Perioperative complications of scoliosis surgery in patients with Duchenne muscular dystrophy and spinal muscular atrophy, focussing on wound healing disorders.

    Science.gov (United States)

    Burow, Mareike; Forst, Raimund; Forst, Jürgen; Hofner, Benjamin; Fujak, Albert

    2017-06-01

    Patients with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA), both neuromuscular diseases, sustain spinal scoliosis in the course of their disease. To reduce the concomitant major morbidity and to improve their quality of life, patients require surgical spine stabilization. This can lead to complications like respiratory, cardiac or neurological complications or wound healing disorders (WHD). To find out the different complexities and risk factors increasing the chance to develop a WHD, the inpatient database was analyzed. We performed a retrospective statistical study. Therefore, we analyzed the inpatient database of 180 patients (142 DMD and 38 SMA patients). The focus was on WHD. To figure out the risk factors leading to WHD, we conducted a logistic regression. Cardiac complications occurred most frequently, followed by pulmonary complications and neurological lesions. Fifty-seven out of 180 patients developed a WHD. In 23 cases the WHD was aseptic, in the other 34 cases dermal organisms, Pseudomonas species and intestinal organisms were responsible. By means of the logistic regression, we were able to identify two more risk factors, in addition to diagnosis and gender, for developing a WHD in our patients: the year of surgery and the direction of pelvic tilt. Most common complications following scoliosis surgery are respiratory and cardiac complications. WHD is a severe complication that implies a prolonged therapy. Some risk factors for developing WHD could be identified in this analysis. Specifically, these were the date of surgery and the direction of pelvic tilt.

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

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    Tanyse Bahia Carvalho Marques

    2014-10-01

    Full Text Available 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.

  2. Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective.

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    Gama-Carvalho, Margarida; L Garcia-Vaquero, Marina; R Pinto, Francisco; Besse, Florence; Weis, Joachim; Voigt, Aaron; Schulz, Jörg B; De Las Rivas, Javier

    2017-04-01

    In this review, we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, amyotrophic lateral sclerosis, and spinal muscular atrophy. We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP-43, FUS, SMN, and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration. We review reported functional and physical interactions between these four proteins, highlighting their common association with nuclear bodies and small nuclear ribonucleoprotein particle biogenesis and function. We discuss how these interactions are turning out to be particularly relevant for the control of transcription and chromatin homeostasis, including the recent identification of an association between SMN and Senataxin required to ensure the resolution of DNA-RNA hybrid formation and proper termination by RNA polymerase II. These connections strongly support the existence of common pathways underlying the spinal muscular atrophy and amyotrophic lateral sclerosis phenotype. We also discuss the potential of genome-wide expression profiling, in particular RNA sequencing derived data, to contribute to unravelling the underlying mechanisms. We provide a review of publicly available datasets that have addressed both diseases using these approaches, and highlight the value of investing in cross-disease studies to promote our understanding of the pathways leading to neurodegeneration. © 2017 International Society for Neurochemistry.

  3. Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

    Science.gov (United States)

    Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

    2013-03-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

  4. Automated analysis of whole skeletal muscle for muscular atrophy detection of ALS in whole-body CT images: preliminary study

    Science.gov (United States)

    Kamiya, Naoki; Ieda, Kosuke; Zhou, Xiangrong; Yamada, Megumi; Kato, Hiroki; Muramatsu, Chisako; Hara, Takeshi; Miyoshi, Toshiharu; Inuzuka, Takashi; Matsuo, Masayuki; Fujita, Hiroshi

    2017-03-01

    Amyotrophic lateral sclerosis (ALS) causes functional disorders such as difficulty in breathing and swallowing through the atrophy of voluntary muscles. ALS in its early stages is difficult to diagnose because of the difficulty in differentiating it from other muscular diseases. In addition, image inspection methods for aggressive diagnosis for ALS have not yet been established. The purpose of this study is to develop an automatic analysis system of the whole skeletal muscle to support the early differential diagnosis of ALS using whole-body CT images. In this study, the muscular atrophy parts including ALS patients are automatically identified by recognizing and segmenting whole skeletal muscle in the preliminary steps. First, the skeleton is identified by its gray value information. Second, the initial area of the body cavity is recognized by the deformation of the thoracic cavity based on the anatomical segmented skeleton. Third, the abdominal cavity boundary is recognized using ABM for precisely recognizing the body cavity. The body cavity is precisely recognized by non-rigid registration method based on the reference points of the abdominal cavity boundary. Fourth, the whole skeletal muscle is recognized by excluding the skeleton, the body cavity, and the subcutaneous fat. Additionally, the areas of muscular atrophy including ALS patients are automatically identified by comparison of the muscle mass. The experiments were carried out for ten cases with abnormality in the skeletal muscle. Global recognition and segmentation of the whole skeletal muscle were well realized in eight cases. Moreover, the areas of muscular atrophy including ALS patients were well identified in the lower limbs. As a result, this study indicated the basic technology to detect the muscle atrophy including ALS. In the future, it will be necessary to consider methods to differentiate other kinds of muscular atrophy as well as the clinical application of this detection method for early ALS

  5. Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy

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    Bowerman Melissa

    2012-03-01

    Full Text Available Abstract Background Spinal muscular atrophy (SMA is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1 gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil. Methods Fasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at P t test for paired variables and one-way analysis of variance (ANOVA were used to test for differences between samples and data were considered significantly different at P Results Fasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific. Conclusions Our work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA

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

    NARCIS (Netherlands)

    vanderSteege, G; Grootscholten, PM; Cobben, JM; Zappata, S; Scheffer, H; denDunnen, JT; vanOmmen, GJB; Brahe, C; Buys, CHCM

    1996-01-01

    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 ((C)BCD541). Gene and copy gene can be discriminated by sequence differences in exons 7 and 8. The large majority of SMA patients show

  7. Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

    NARCIS (Netherlands)

    Riessland, M.; Kaczmarek, A.; Schneider, S.; Swoboda, K.J.; Lohr, H.; Bradler, C.; Grysko, V.; Dimitriadi, M.; Hosseinibarkooie, S.; Torres-Benito, L.; Peters, M.; Upadhyay, A.; Biglari, N.; Krober, S.; Holker, I.; Garbes, L.; Gilissen, C.; Hoischen, A.; Nurnberg, G.; Nurnberg, P.; Walter, M.; Rigo, F.; Bennett, C.F.; Kye, M.J.; Hart, A.C.; Hammerschmidt, M.; Kloppenburg, P.; Wirth, B.

    2017-01-01

    Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN

  8. Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid

    NARCIS (Netherlands)

    Piepers, Sanne; Cobben, Jan-Maarten; Sodaar, Peter; Jansen, Marc D.; Wadman, Renske I.; Meester-Delver, Ann; Poll-The, Bwee Tien; Lemmink, Henny H.; Wokke, John H. J.; van der Pol, W.-Ludo; van den Berg, Leonard H.

    2011-01-01

    Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by

  9. DELETIONS OF THE SURVIVAL MOTOR-NEURON GENE IN UNAFFECTED SIBLINGS OF PATIENTS WITH SPINAL MUSCULAR-ATROPHY

    NARCIS (Netherlands)

    COBBEN, JM; VANDERSTEEGE, G; GROOTSCHOLTEN, P; DEVISSER, M; SCHEFFER, H; BUYS, CHCM

    1995-01-01

    DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type I. SMN deletions

  10. Unusual pedigree patterns in seven families with spinal muscular atrophy; further evidence for the allelic model hypothesis

    NARCIS (Netherlands)

    Bouwsma, G.; Leschot, N. J.

    1986-01-01

    Clinical and genetic findings are presented in 18 patients, from 7 pedigrees with different types of spinal muscular atrophy (SMA). The SMA diagnosis was based on EMG and muscle biopsy findings. All 7 pedigrees show an unusual genetic pattern, not consistent with simple autosomal recessive

  11. Prenatal prediction of spinal muscular atrophy - Experience with linkage studies and consequences of present SMN deletion analysis

    NARCIS (Netherlands)

    Cobben, JM; Scheffer, H; DeVisser, M; VanderSteege, G; Verhey, JBBM; Osinga, J; Mensink, RGJ; Grootscholten, PM; TenKate, LP; Buys, CHCM; Burton, M.

    1996-01-01

    With the localisation of the gene for the autosomal recessive forms of proximal spinal muscular atrophies (SMA) to the chromosomal region 5q13 and the later detection of homozygous deletions of the SMN gene located in this region, prenatal prediction of SMA has become feasible and is widely applied

  12. Quantification of SMN protein in leucocytes from spinal muscular atrophy patients : effects of treatment with valproic acid

    NARCIS (Netherlands)

    Piepers, Sanne; Cobben, Jan-Maarten; Sodaar, Peter; Jansen, Marc D.; Wadman, Renske I.; Meester-Delver, Ann; Poll-The, Bwee Tien; Lemmink, Henny H.; Wokke, John H. J.; van der Pol, W-Ludo; van den Berg, Leonard H.

    Background Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein

  13. Familial adult spinal muscular atrophy associated with the VAPB gene: report of 42 cases in Brazil

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    Victor Kosac

    2013-10-01

    Full Text Available Familial spinal muscular atrophy (FSMA associated with the vesicle-associated membrane protein-associated protein B (VAPB gene is a rare autosomal dominant disease with late onset and slow progression. We studied 10 of 42 patients from 5 families by taking clinical histories and performing physical exams, electrophysiological studies, and genetic tests. All patients presented late onset disease with slow progression characterized by fasciculations, proximal weakness, amyotrophy, and hypoactive deep tendon reflex, except two who exhibited brisk reflex. Two patients showed tongue fasciculations and respiratory insufficiency. Electrophysiological studies revealed patterns of lower motor neuron disease, and genetic testing identified a P56S mutation of the VAPB gene. Although it is a rare motor neuron disease, FSMA with this mutation might be much more prevalent in Brazil than expected, and many cases may be undiagnosed. Genetic exams should be performed whenever it is suspected in Brazil.

  14. Fatigue in patients with spinal muscular atrophy type II and congenital myopathies

    DEFF Research Database (Denmark)

    Werlauff, Ulla; Højberg, A; Firla-Holme, R

    2014-01-01

    PURPOSE: The aim of this study was to evaluate whether the fatigue severity scale (FSS) is an appropriate instrument to assess fatigue in patients with spinal muscular atrophy type II (SMA II) and congenital myopathies (CM). METHODS: FSS and visual analog scale (VAS) were administered to 33 SMA II...... II patients, but very frequent in patients with CM. The cut-off score designating abnormal fatigue (FSS score ≥ 4) was exceeded by 10% of the SMA II patients in contrast to 76% of the CM patients, of whom 52% suffered from severe fatigue (FSS score ≥ 5). Focus group interviews demonstrated...... in CM and SMA II can be captured by FSS, omitting the first two items of the scale will improve its properties and content validity, along with comprehension of the scale itself....

  15. Perceptions of equine-assisted activities and therapies by parents and children with spinal muscular atrophy.

    Science.gov (United States)

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

    2014-01-01

    To identify the physical and psychosocial effects of equine-assisted activities and therapies (EAATs) on children with spinal muscular atrophy (SMA) from the perspective of the children and their parents. 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, semistructured interviews of children with SMA and their parents. 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. The data suggest that 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.

  16. SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?

    Science.gov (United States)

    Swoboda, Kathryn J

    2014-02-01

    Spinal muscular atrophy (SMA) remains one of the most common and lethal autosomal recessive diseases. Homozygous deletion of survival of motor neuron 1 (SMN1) and resulting SMN protein deficiency manifests predominantly with motor neuron degeneration; however, a wealth of emerging data supports a broader influence of SMN deficiency in disease pathogenesis. In this issue of the JCI, Kariya and colleagues demonstrate the relatively selective impact of SMN depletion on the distal motor unit using a series of SMN2-expressing transgenic mice in which constitutive SMN knockdown follows variable periods of normal development. Their observations provide further insights regarding the temporal requirements for SMN in mice, renewing speculation about when and where repletion of SMN is necessary for optimal outcomes in SMA patients.

  17. CT muscle scanning in the evaluation of patients with spinal muscular atrophy (SMA)

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    Sambrook, P.; Rickards, D.; Cumming, W.J.K.

    1988-12-01

    One hundred with spinal muscular atrophy (SMA) were assessed by CT scanning using a standardised technique. The spectrum of CT abnormality occurring in SMA was observed and by overall analysis the patients were divided into 4 groups. While the CT appearances of these groups correlated well with clinical assessment of severity of disease, the disease process was usually much more widespread than clinical examination suggested. CT abnormality was first observed in the leg and gluteal muscles, progressing to the posterior spinal, thigh, shoulder girdle and sternomastoid muscles. Hypertrophy of sartorius and gracilis was observed in a significant number of patients. Fascial planes were preserved in involved muscles in over half of the patients, even in late-stage disease. Asymmetrical muscle involvement was seen with increasing frequency as the disease process increased in extent as evaluated by CT scanning. There was no discernible difference in the CT appearances in those patients who clinically had limb-girdle, facioscapulohumeral or scapuloperoneal distribution of weakness.

  18. Segmental Spinal Muscular Atrophy Localised to the Lower Limbs : First case from Oman

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    Roshan Koul

    2017-08-01

    Full Text Available Spinal muscular atrophy (SMA is a genetic lower motor neuron disease. It usually involves all of the skeletal muscles innervated by the anterior horn cells of the spinal cord. In rare cases, there is also localised involvement of the spinal cord. We report a 10-year-old boy who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2015 with muscle weakness restricted to the lower limbs. The presence of a homozygous deletion within the survival of motor neuron 1 gene confirmed the diagnosis of SMA. To the best of the authors’ knowledge, this is the first report of an Omani patient with segmental SMA involving only the lower limbs. Treatment for this rare and relatively benign form of SMA is symptomatic and includes physiotherapy.

  19. NEUROMUSCULAR JUNCTIONS AS KEY CONTRIBUTORS AND THERAPEUTIC TARGETS IN SPINAL MUSCULAR ATROPHY

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    Marina eBoido

    2016-02-01

    Full Text Available Spinal muscular atrophy (SMA is a recessive autosomal neuromuscular disease, representing the most common fatal paediatric 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 and pathological (SMA conditions, 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.

  20. Social support network to family caregiver of a patient with Spinal Muscular Atrophy I and II.

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    Rafael Barreto de Mesquita

    2010-06-01

    Full Text Available Objective: To assess the formal and informal support given to the family caregiver of a patient with Spinal Muscular Atrophy I and II. Method: This was a study with a qualitative approach developed in 2008 in the homes of informants and in the premises of the Hospital Infantil Albert Sabin in Fortaleza, Ceara, conducted with 13 mothers, primary caregivers for their ill children. For data collection we used both the interview and the instrument generator of the names and qualifier of the relations, adapted for this study. Quantitative data were processed using the programs UCINET NetDraw 6.123 and 2.38, while the qualitative data were organized based on the technique of the Collective Subject Discourse. The analyses were conducted by means of network maps and collective discourses raised by central ideas. Results: The formal social network of family caregivers was composed of 72 actors, among professionals in the areas of health, education and others, linked to 12 institutions. The informal network was comprised of 83 actors. It was found that the management of care, even when the caregiver has support from other people is a cause of stress and overload. Conclusion: It is evident the importance of applying Social Network Analysis as a tool for understanding structural features and the dynamics of social relations of family caregiver. Of a patient with spinal muscular atrophy. The analysis suggests the need for intervention in thestudy group as a way to contribute to the recognition and use of existing services, increasing the significance of the help provided by network interactions.

  1. Training improves oxidative capacity, but not function, in spinal muscular atrophy type III.

    Science.gov (United States)

    Madsen, Karen Lindhardt; Hansen, Regitze Sølling; Preisler, Nicolai; Thøgersen, Frank; Berthelsen, Martin Peter; Vissing, John

    2015-08-01

    In this study we investigated the effect of 12 weeks of cycle ergometer training in patients with spinal muscular atrophy type III (SMA III), a hereditary motor neuron disease with progressive muscle weakness and atrophy. Six SMA III patients and 9 healthy subjects completed a 12-week training program, performing 42 30-minute sessions exercising at 65-70% of maximal oxygen uptake (VO2max ). VO2max , muscle strength, functional tests, and self-reported activities of daily living were assessed before and after the training. Training induced a 27 ± 3% increase in VO2max (17 ± 2 to 21 ± 2 ml/kg/min, P sleep in 3 patients, and led to training modifications in 2 patients. Cycle exercise improves VO2max in SMA III without causing muscle damage, but it also induces significant fatigue. This warrants study into alternative training methods to improve exercise capacity in SMA III patients. © 2014 Wiley Periodicals, Inc.

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

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    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. (New York State Psychiatric Institute, NY (United States)); Lien, L.L.; Kunkel, L.M. (Howard Hughes Medical Institute, Boston, MA (United States))

    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.

  3. Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent

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    Funanage Vicky L

    2009-05-01

    Full Text Available Abstract Background Deletion or mutation(s of the survival motor neuron 1 (SMN1 gene causes spinal muscular atrophy (SMA. The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts. Results Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, β-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that β-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts. Conclusion Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.

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

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    Ansorge Olaf

    2008-10-01

    Full Text Available Abstract 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.

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

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    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

  6. Muscle magnetic resonance imaging in spinal muscular atrophy type 3: Selective and progressive involvement.

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    Durmus, Hacer; Yilmaz, Ravza; Gulsen-Parman, Yesim; Oflazer-Serdaroglu, Piraye; Cuttini, Marina; Dursun, Memduh; Deymeer, Feza

    2017-05-01

    In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b). Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner. MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression. This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017. © 2016 Wiley Periodicals, Inc.

  7. A qualitative study of perceptions of meaningful change in spinal muscular atrophy.

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    McGraw, Sarah; Qian, Ying; Henne, Jeff; Jarecki, Jill; Hobby, Kenneth; Yeh, Wei-Shi

    2017-04-04

    This qualitative study examined how individuals with Spinal Muscular Atrophy (SMA), their caregivers, and clinicians defined meaningful change, primarily in the Type II and non-ambulant type III patient populations, associated with treatment of this condition. In addition, we explored participants' views about two measures of motor function routinely used in clinical trials for these SMA subtypes, namely the expanded version of the Hammersmith Functional Motor Scale (HFMSE) and the Upper Limb Module (ULM). The 123 participants (21 with SMA, 64 parents, and 11 clinicians), recruited through SMA advocacy organizations, participated in one of 16 focus groups or 37 interviews. The sessions were audio-recorded, and verbatim transcripts were analyzed using a grounded theory approach. For the participants, meaningful change was relative to functional ability, and small changes in motor function could have an important impact on quality of life. Because patients and families feared progressive loss of functional ability, the participants saw maintenance of abilities as a meaningful outcome. They believed that measures of motor function covered important items, but worried that the HFMSE and ULM might not be sensitive enough to capture small changes. In addition, they felt that outcome measures should assess other important features of life with SMA, including the ability to perform daily activities, respiratory function, swallowing, fatigue, and endurance. Given the heterogeneity of SMA, it is important to expand the assessment of treatment effects to a broader range of outcomes using measures sensitive enough to detect small changes.

  8. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2.

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    Mailman, Matthew D; Heinz, John W; Papp, Audrey C; Snyder, Pamela J; Sedra, Mary S; Wirth, Brunhilde; Burghes, Arthur H M; Prior, Thomas W

    2002-01-01

    This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing. From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients. Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients. SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing. Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information.

  9. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

    Science.gov (United States)

    Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Leykekhman, Olga; Lutz, Cathleen; Arkovitz, Marc S.; Landmesser, Lynn T.; Monani, Umrao R.

    2008-01-01

    Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe- and mild-SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of neurodegeneration in the human disease. We show that the earliest structural defects appear distally and involve the neuromuscular synapse. Insufficient SMN protein arrests the post-natal development of the neuromuscular junction (NMJ), impairing the maturation of acetylcholine receptor (AChR) clusters into ‘pretzels’. Pre-synaptic defects include poor terminal arborization and intermediate filament aggregates which may serve as a useful biomarker of the disease. These defects are reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. We suggest that SMA might best be described as a NMJ synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ. PMID:18492800

  10. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy.

    Science.gov (United States)

    Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Leykekhman, Olga; Lutz, Cathleen; Arkovitz, Marc S; Landmesser, Lynn T; Monani, Umrao R

    2008-08-15

    Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe- and mild-SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of neurodegeneration in the human disease. We show that the earliest structural defects appear distally and involve the neuromuscular synapse. Insufficient SMN protein arrests the post-natal development of the neuromuscular junction (NMJ), impairing the maturation of acetylcholine receptor (AChR) clusters into 'pretzels'. Pre-synaptic defects include poor terminal arborization and intermediate filament aggregates which may serve as a useful biomarker of the disease. These defects are reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. We suggest that SMA might best be described as a NMJ synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ.

  11. Glossopharyngeal pistoning for lung insufflation in children with spinal muscular atrophy type II.

    Science.gov (United States)

    Nygren-Bonnier, Malin; Markström, Agneta; Lindholm, Peter; Mattsson, Eva; Klefbeck, Brita

    2009-08-01

    To evaluate whether children with spinal muscular atrophy (SMA) type II were able to learn glossopharyngeal pistoning for lung insufflation (GI), and to evaluate the effects of GI on pulmonary function and chest expansion. Eleven children with SMA type II were recruited. They performed 10 cycles of GI, four times per week, for 8 weeks. Lung function and chest expansion were measured before and after the 8-week period. Five of the 11 children learned the technique. The median GI volume was 0.28 (range 0.15-0.98) L. Four of the children who completed the study showed a mean increase in inspiratory vital capacity (IVC) of 0.13 L (95% confidence interval (CI) 0.03-0.23) and peak expiratory flow (PEF) of 116 L/min (95% CI 60-173). They also had an increased chest expansion with GI at the level of the xiphoid process of 1.50 cm (95% CI 0.16-2.84) and at the level of the fourth costa of 1.79 cm (95% CI 0.85-2.73). The children reported temporary symptoms of dizziness and tension in the chest. Five of the 11 children were able to learn the technique of GI and for the four who fulfilled the training, it had positive effects on IVC, PEF and chest expansion. GI did not cause major discomfort.

  12. ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

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    Ottesen Eric W.

    2017-01-01

    Full Text Available Spinal muscular atrophy (SMA is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1 gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1 has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX, an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

  13. Clinical trial of L-carnitine and valproic acid in spinal muscular atrophy type I.

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    Krosschell, Kristin J; Kissel, John T; Townsend, Elise L; Simeone, Sarah D; Zhang, Ren Zhe; Reyna, Sandra P; Crawford, Thomas O; Schroth, Mary K; Acsadi, Gyula; Kishnani, Priya S; Von Kleist-Retzow, Jürgen-Christoph; Hero, Barbara; D'Anjou, Guy; Smith, Edward C; Elsheikh, Bakri; Simard, Louise R; Prior, Thomas W; Scott, Charles B; Lasalle, Bernard; Sakonju, Ai; Wirth, Brunhilde; Swoboda, Kathryn J

    2017-08-18

    The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  14. Reliability and validity of the TIMPSI for infants with spinal muscular atrophy type I.

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    Krosschell, Kristin J; Maczulski, Jo Anne; Scott, Charles; King, Wendy; Hartman, Jill T; Case, Laura E; Viazzo-Trussell, Donata; Wood, Janine; Roman, Carolyn A; Hecker, Eva; Meffert, Marianne; Léveillé, Maude; Kienitz, Krista; Swoboda, Kathryn J

    2013-01-01

    This study examined the reliability and validity of the Test of Infant Motor Performance Screening Items (TIMPSI) in infants with type I spinal muscular atrophy (SMA). After training, 12 evaluators scored 4 videos of infants with type I SMA to assess interrater reliability. Intrarater and test-retest reliability was further assessed for 9 evaluators during a SMA type I clinical trial, with 9 evaluators testing a total of 38 infants twice. Relatedness of the TIMPSI score to ability to reach and ventilatory support was also examined. Excellent interrater video score reliability was noted (intraclass correlation coefficient, 0.97-0.98). Intrarater reliability was excellent (intraclass correlation coefficient, 0.91-0.98) and test-retest reliability ranged from r = 0.82 to r = 0.95. The TIMPSI score was related to the ability to reach (P ≤ .05). The TIMPSI can reliably be used to assess motor function in infants with type I SMA. In addition, the TIMPSI scores are related to the ability to reach, an important functional skill in children with type I SMA.

  15. Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy.

    Science.gov (United States)

    Krosschell, Kristin J; Scott, Charles B; Maczulski, Jo Anne; Lewelt, Aga J; Reyna, Sandra P; Swoboda, Kathryn J

    2011-08-01

    The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up. Copyright © 2011 Wiley Periodicals, Inc.

  16. Current Aspects in the Molecular Genetics and Diagnostics of Spinal Muscular Atrophy

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    Shu-Chin Chien

    2005-09-01

    Full Text Available Proximal spinal muscular atrophy (SMA is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene on 5q13. It leads to progressive muscle wasting and paralysis as a result of degeneration of anterior horn cells of the spinal cord. The most frequent mutation is biallelic deletion of exon 7 of the SMN1 gene. About 5-6% of SMA patients present compound heterozygosity with a point mutation on one allele and deletion on the other; the remaining cases are likely to be related to non-5q-linked defects. Introduction of a quantitative polymerase chain reaction-based test further enhances the diagnostic potential by increasing the detection rate of cases with the biallelic exon 7 deletion in SMN1 and point mutations. Due to the higher prevalence of SMA than other autosomal recessive disorders and lack of efficient medical treatment, accurate identification of SMA carriers in general populations is much more important to reduce the social and financial burden of SMA.

  17. Clinical and molecular analysis of spinal muscular atrophy in Brazilian patients

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    Kim C.A.

    1999-01-01

    Full Text Available Spinal muscular atrophy (SMA, the second most common lethal autosomal recessive disorder, has an incidence of 1:10,000 newborns. SMA is divided into acute (Werdnig-Hoffmann disease, type I, intermediate (type II and juvenile forms (Kugelberg-Welander disease, type III. The gene of all three forms of SMA maps to chromosome 5q 11.2-13.3. Two candidate genes, the survival motor neuron (SMN gene and the neuronal apoptosis inhibitory protein (NAIP gene, have been identified; SMN is deleted in most SMA patients. We studied both genes in 87 Brazilian SMA patients (20 type I, 14 type II and 53 type III from 74 unrelated families, by using PCR and single strand conformation polymorphism (SSCP. Deletions of exons 7 and/or 8 of the SMN gene were found in 69% of the families: 16/20 in type I, 9/12 in type II and 26/42 in type III. Among 51 families with deletions, 44 had both exons deleted while seven had deletions only of exon 7. Deletions of exon 5 of the NAIP gene were found in 7/20 of type I, 2/12 of type II and 1/42 of type III patients. No deletion of SMN and NAIP genes was found in 112 parents, 26 unaffected sibs and 104 normal controls. No correlation between deletions of one or both genes and phenotype severity was found.

  18. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy.

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    Karen K Y Ling

    2010-11-01

    Full Text Available Spinal muscular atrophy (SMA is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7. In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3-5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.

  19. Denosumab Treatment of Severe Disuse Osteoporosis in a Boy With Spinal Muscular Atrophy

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    Stepan Kutilek

    2017-12-01

    Full Text Available Denosumab is a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-κB ligand. Denosumab is used in the treatment of postmenopausal osteoporosis and cancer-related bone disorders. There are only very scarce data on denosumab treatment in children. 14-year-old boy with spinal muscular atrophy (SMA and severe disuse osteoporosis (spinal bone mineral density L1-L4 BMD-6.2SD Z-score and two prevalent fragility fractures was treated with denosumab. He received 60 mg  subcutaneous injection at the baseline and seven months later. Six months after the initial injection there was a 19% increase in L1-L4 BMD. The injections were well tolerated without any adverse reactions. Calcemia remained stable (2.3-2.4 mmol/L. He was scheduled for the third denosumab injection six months later. Prior to this date, he acquired pneumonia and died due to respiratory failure, which is a frequent cause of death in patients with SMA. There was no relation to the denosumab treatment. In conclusion, one dose of denosumab significantly increased BMD in a child with severe osteoporosis.

  20. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

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    Penelope J Boyd

    2017-04-01

    Full Text Available Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA, resulting from low levels of ubiquitously-expressed survival motor neuron (SMN protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant, gastrocnemius (intermediate vulnerability, and tibialis anterior (vulnerable muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1, was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1, rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

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

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    Y. Sifi

    2013-01-01

    Full Text Available 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.

  2. Proximal spinal muscular atrophy types I-IV: Specific features of molecular genetic diagnosis

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    V. V. Zabnenkova

    2013-01-01

    Full Text Available Proximal spinal muscular atrophy (SMA types I-IV is the most common autosomal recessive neuromuscular disease caused by mutations in the SMN1 gene encoding the survival motor neuron protein. It is characterized by progressive muscle weakness due to injury of the motor neurons of the anterior horns of the spinal cord. The classification of the disease is based on the time of its onset, severity, and survival. The detection of the major mutation of exon 7 and/or 8 deletion in the SMN1 gene is a qualitative reliable and sensitive diagnostic test. The SMN1 gene has the almost complete homolog SMN2 gene, which hampers the analysis of heterozygous carriage of the disease. So the determination of the carriage status is based on the quantitative analysis of the number of SMN1 gene copies. The paper covers problems and new possibilities in themolecular genetic diagnosis of proximal SMA.

  3. [Excitability of cervical lower motoneuron in juvenile muscular atrophy of the distal upper limb].

    Science.gov (United States)

    Kuwabara, S; Nakajima, M; Tokumaru, Y; Hirayama, K

    1994-11-01

    We investigated excitability of cervical lower motoneurons in 18 patients with juvenile muscular atrophy of the distal upper limb (Hirayama's disease), by F wave analysis and electrophysiological estimation of the number of motor units in the abductor pollicis brevis muscles of the affected side. In all the 18 patients, F wave persistencies and numbers of motor units were decreased, whereas amplitudes of single motor unit potentials were increased, compared to those of age-matched normal controls. Patients in a progressive phase showed markedly decreased F wave persistencies, overwhelming the degree of decreases in numbers of motor units. In half of them, F waves were significantly increased in number during neck flexion. On the other hand, patients treated with neck brace and patients having stabilized symptoms with longer duration showed F wave persistence reduction corresponded to the degree of the motor unit loss, and no changes in F wave persistencies in a posture of neck flexion. These results suggest that the disorder is characterized by decreased excitabilities of survived cervical anterior horn cells, as well as denervation and reinnervation, presumably resulting from local compression or circulatory failure by anterior shift of the posterior dural wall during neck flexion.

  4. X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.

    Science.gov (United States)

    Dressman, Devin; Ahearn, Mary Ellen; Yariz, Kemal O; Basterrecha, Hugo; Martínez, Francisco; Palau, Francesc; Barmada, M Michael; Clark, Robin Dawn; Meindl, Alfons; Wirth, Brunhilde; Hoffman, Eric P; Baumbach-Reardon, Lisa

    2007-01-01

    X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. We first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. Linkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. The addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).

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

    Energy Technology Data Exchange (ETDEWEB)

    Merette, C.; Gilliam, T.C.; Brzustowicz, L.M. (Columbia Univ., New York, NY (United States)); Daniels, R.J.; Davies, K.E. (Institute of Molecular Medicine, Oxford (United Kingdom)); Melki, J.; Munnich, A. (Hopital des Enfants-Malades, Paris (France)); Pericak-Vance, M.A. (Duke Univ Medical Center, Durham, NC (United States)); Siddique, T. (Northwestern Univ., Chicago, IL (United States)); Voosen, B. (Institute fuer Humangenetik der Universitaet, Bonn (Germany)) (and others)

    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.

  6. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

    Science.gov (United States)

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice. PMID:25221469

  7. SMA-MAP: a plasma protein panel for spinal muscular atrophy.

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    Dione T Kobayashi

    Full Text Available OBJECTIVES: Spinal Muscular Atrophy (SMA presents challenges in (i monitoring disease activity and predicting progression, (ii designing trials that allow rapid assessment of candidate therapies, and (iii understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i to discover additional markers from the Biomarkers for SMA (BforSMA study using an immunoassay platform, and (ii to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS. METHODS: BforSMA study plasma samples (N = 129 were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158 from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. RESULTS: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05 with motor function, with a 13(th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP for association with motor and other functional measures. CONCLUSIONS: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other

  8. Newborn screening for spinal muscular atrophy by calibrated short-amplicon melt profiling.

    Science.gov (United States)

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

    2012-06-01

    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. 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. 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. 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.

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

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    Vicki L McGovern

    Full Text Available 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.

  10. New multiplex real-time PCR approach to detect gene mutations for spinal muscular atrophy.

    Science.gov (United States)

    Liu, Zhidai; Zhang, Penghui; He, Xiaoyan; Liu, Shan; Tang, Shi; Zhang, Rong; Wang, Xinbin; Tan, Junjie; Peng, Bin; Jiang, Li; Hong, Siqi; Zou, Lin

    2016-08-17

    Spinal muscular atrophy (SMA) is the most common autosomal recessive disease in children, and the diagnosis is complicated and difficult, especially at early stage. Early diagnosis of SMA is able to improve the outcome of SMA patients. In our study, Real-time PCR was developed to measure the gene mutation or deletion of key genes for SMA and to further analyse genotype-phenotype correlation. The multiple real-time PCR for detecting the mutations of survival of motor neuron (SMN), apoptosis inhibitory protein (NAIP) and general transcription factor IIH, polypeptide 2 gene (GTF2H2) was established and confirmed by DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). The diagnosis and prognosis of 141 hospitalized children, 100 normal children and further 2000 cases of dry blood spot (DBS) samples were analysed by this multiple real-time PCR. The multiple real-time PCR was established and the accuracy of it to detect the mutations of SMN, NAIP and GTF2H2 was at least 98.8 % comparing with DNA sequencing and MLPA. Among 141 limb movement disorders children, 75 cases were SMA. 71 cases of SMA (94.67 %) were with SMN c.840 mutation, 9 cases (12 %) with NAIP deletion and 3 cases (4 %) with GTF2H2 deletion. The multiple real-time PCR was able to diagnose and predict the prognosis of SMA patients. Simultaneously, the real-time PCR was applied to detect trace DNA from DBS and able to make an early diagnosis of SMA. The clinical and molecular characteristics of SMA in Southwest of China were presented. Our work provides a novel way for detecting SMA in children by using real-time PCR and the potential usage in newborn screening for early diagnosis of SMA.

  11. Transcriptome profiling of spinal muscular atrophy motor neurons derived from mouse embryonic stem cells.

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    Miho Maeda

    Full Text Available Proximal spinal muscular atrophy (SMA is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1. Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC model for severe SMA, the RNA transcript profiles (transcriptomes between control and severe SMA (SMN2+/+;mSmn-/- mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq. The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3,094 upregulated and 6,964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs.

  12. Targeting SR proteins improves SMN expression in spinal muscular atrophy cells.

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    Claribel D Wee

    Full Text Available 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.

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

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    James N. Sleigh

    2011-07-01

    Full Text Available 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.

  14. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy

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    Chong-Chong Xu

    2016-01-01

    Full Text Available Spinal muscular atrophy (SMA, characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1 gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

  15. [Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1].

    Science.gov (United States)

    Agra Tuñas, María Carmen; Hernández Rastrollo, Ramón; Hernández González, Arturo; Ramil Fraga, Carmen; Cambra Lasaosa, Francisco José; Quintero Otero, Sebastián; Ruiz Extremera, Angela; Rodríguez Núñez, Antonio

    2017-03-01

    Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  16. [Spinal muscular atrophy and respiratory failure. How do primary care pediatricians act in a simulated scenario?].

    Science.gov (United States)

    Agra Tuñas, M C; Sánchez Santos, L; Busto Cuiñas, M; Rodríguez Núñez, A

    2015-11-01

    Spinal muscular atrophy type 1 (SMA-1) tends to be fatal in the first year of life if there is no ventilatory support. The decision whether to start such support is an ethical conflict for healthcare professionals. A scenario of acute respiratory failure in an infant with SMA-1 has been included in a training program using advanced simulation for Primary Care pediatricians (PCP). The performances of 34 groups of 4 pediatricians, who participated in 17 courses, were systematically analyzed. Clinical, ethical and communication aspects with parents were evaluated. The initial technical assistance (Administration of oxygen and immediate ventilatory support) was correctly performed by 94% of the teams. However, the PCP had problems in dealing with the ethical aspects of the case. Of the 85% of the teams that raised the ethical conflict with parents, 29% did so on their own initiative, 23% actively excluded them, and only 6% involved them and took their opinion into account in making decisions. Only 11.7% asked about the quality of life of children and 12% for their knowledge of the prognosis of the disease. None explained treatment alternatives, nor tried to contact the pediatrician responsible for the child. When faced with a simulated SMA-1 infant with respiratory failure, PCP have difficulties in interacting with the family, and to involve it in the decision making process. Practical training of all pediatricians should include case scenarios with an ethical clinical problem. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  17. Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III.

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    Heike Kölbel

    Full Text Available Autosomal-recessive proximal spinal muscular atrophies (SMA are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking.In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III, aged 0.6-21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 -MFM32 as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined.Hyperleptinemia was found in 15/35 (43% of our patients; 9/15 (60% of the hyperleptinemic patients were underweight, whereas 1/15 (7% was obese. Hyperleptinemia was associated with SMA type (p = 0.018. There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946-0.992. In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found.Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia.

  18. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

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    Emmanuelle eCoque

    2014-08-01

    Full Text Available Spinal muscular atrophy (SMA is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the surviving motor neuron 1 (SMN1 gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK, which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myocytes, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

  19. Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

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    Maia Lanfranco

    2017-06-01

    Full Text Available Spinal Muscular Atrophy (SMA is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5 complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs to generate small nuclear ribonucleoproteins (snRNPs, which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

  20. Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy.

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    Dhruv Sareen

    Full Text Available Spinal muscular atrophy (SMA is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients.

  1. Use of Genetic and Physical Mapping to Locate the Spinal Muscular Atrophy Locus between Two New Highly Polymorphic DNA Markers

    OpenAIRE

    Clermont, Olivier; Burlet, Philippe; Burglen, Lydie; Lefebvre, Suzie; Pascal, Fabrice; McPherson, John; Wasmuth, John J.; Cohen, Daniel; Le Paslier, Denis; Weissenbach, Jean; Lathrop, Mark; Munnich, Arnold; Melki, Judith

    1994-01-01

    The gene for autosomal recessive forms of spinal muscular atrophy (SMA) has recently been mapped to chromosome 5ql3, within a 4-cM region between the blocks D5S465/D5S125 and MAP-1B/D5S112. We 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. Our data suggest that the ...

  2. High incidence of spinal muscular atrophy type I (Werdnig - Hoffmann disease) in the Karaite community in Israel.

    Science.gov (United States)

    Fried, K; Mundel, G

    1977-10-01

    Spinal muscular atrophy (S.M.A.) type I (Infantile werdnig - Hoffmann Disease) was found in 4:1,600 (1:400) infants of the Egyptian Karaite community. This group constitutes a representative sample of the Egyptian Karaite community in Israel, which numbers at present somewhat more than 7,000. The community existed as a religious and reproductive isolate for over 10 centuries. The very high gene frequency, 0.05 for the autosomal recessive gene of S.M.A. type I, is probably the result of genetic drift.

  3. Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

    Science.gov (United States)

    Swoboda, Kathryn J.; Scott, Charles B.; Reyna, Sandra P.; Prior, Thomas W.; LaSalle, Bernard; Sorenson, Susan L.; Wood, Janine; Acsadi, Gyula; Crawford, Thomas O.; Kissel, John T.; Krosschell, Kristin J.; D'Anjou, Guy; Bromberg, Mark B.; Schroth, Mary K.; Chan, Gary M.; Elsheikh, Bakri; Simard, Louise R.

    2009-01-01

    Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly. Conclusions While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various

  4. Phase II open label study of valproic acid in spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Kathryn J Swoboda

    Full Text Available Preliminary in vitro and in vivo studies with valproic acid (VPA in cell lines and patients with spinal muscular atrophy (SMA demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS, electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP amplitudes and motor unit number estimation (MUNE, body composition and bone density via dual-energy X-ray absorptiometry (DEXA, and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

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

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    Matthew E R Butchbach

    2016-03-01

    Full Text Available 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.

  6. Congenital muscular dystrophy and severe central nervous system atrophy in two siblings

    NARCIS (Netherlands)

    Leyten, Q. H.; Barth, P. G.; Gabreëls, F. J.; Renkawek, K.; Renier, W. O.; Gabreëls-Festen, A. A.; ter Laak, H. J.; Smits, M. G.

    1995-01-01

    Severe degenerative features of the nervous system of a hitherto unknown kind, associated with a neuromuscular disorder with histopathological features of congenital muscular dystrophy, are reported in two female siblings. The clinical profile was characterized by generalized hypotonia followed by

  7. Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy

    DEFF Research Database (Denmark)

    Schwartz, M; Sørensen, N; Hansen, F J

    1997-01-01

    In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes...

  8. A SUBLOCUS OF THE MULTICOPY MICROSATELLITE MARKER CMS1 MAPS PROXIMAL TO SPINAL MUSCULAR-ATROPHY (SMA) AS SHOWN BY RECOMBINANT ANALYSIS

    NARCIS (Netherlands)

    VANDERSTEEGE, G; COBBEN, JM; OSINGA, J; SCHEFFER, H; VANOMMEN, GJB; BUYS, CHCM

    1995-01-01

    The critical region containing the spinal muscular atrophy (SMA) gene is flanked by the 5q11-q13 markers, D5S435 and D5S557, as determined by linkage analysis. Here we present the results of an analysis of a Dutch SMA family with the multicopy microsatellite marker CMS1. A crossover is revealed in

  9. A Comparative Study of SMN Protein and mRNA in Blood and Fibroblasts in Patients with Spinal Muscular Atrophy and Healthy Controls

    NARCIS (Netherlands)

    Wadman, Renske I.|info:eu-repo/dai/nl/341753637; Stam, Marloes; Jansen, Marc D.|info:eu-repo/dai/nl/311460577; van der Weegen, Yana; Wijngaarde, Camiel A.; Harschnitz, Oliver; Sodaar, Peter; Braun, Kees P J|info:eu-repo/dai/nl/207237239; Dooijes, Dennis; Lemmink, Henny H.; Van Den Berg, Leonard H.|info:eu-repo/dai/nl/288255216; van der Pol, W. Ludo|info:eu-repo/dai/nl/203721721

    2016-01-01

    BACKGROUND: Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack

  10. Congenital heart defects in spinal muscular atrophy type I : A clinical report of two siblings and a review of the literature

    NARCIS (Netherlands)

    Menke, Leonie A.; Poll-The, Bwee Tien; Clur, Sally-Ann; Bilardo, Catia M.; van der Wal, Allard C.; Lenunink, Henny H.; Cobben, Jan Maarten

    2008-01-01

    A newborn girl presented with asphyxia, joint contractures and diminished spontaneous movements. Echocardiography showed hypoplastic left heart. Spinal muscular atrophy type I (SMA I) was diagnosed by detecting a homozygous deletion in the survival motor neuron 1 gene (SMN1). In the first trimester

  11. In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

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    Paola Bernabò

    2017-10-01

    Full Text Available Genetic alterations impacting ubiquitously expressed proteins involved in RNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translation defects can contribute to disease. Spinal muscular atrophy (SMA is a neuromuscular disease caused by low levels of SMN protein, whose role in pathogenesis remains unclear. Here, we identified in vivo and in vitro translation defects that are cell autonomous and SMN dependent. By determining in parallel the in vivo transcriptome and translatome in SMA mice, we observed a robust decrease in translation efficiency arising during early stages of disease. We provide a catalogue of RNAs with altered translation efficiency, identifying ribosome biology and translation as central processes affected by SMN depletion. This was further supported by a decrease in the number of ribosomes in SMA motor neurons in vivo. Overall, our findings suggest ribosome biology as an important, yet largely overlooked, factor in motor neuron degeneration.

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

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    Christian Czech

    Full Text Available 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.

  13. Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients.

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    Xing Chen

    Full Text Available Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA, sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials.

  14. Magnetic resonance imaging in a juvenile type of distal and segmental muscular atrophy of the upper extremities

    Energy Technology Data Exchange (ETDEWEB)

    Hasuo, K. [Dept. of Radiology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan); Uchino, A. [Dept. of Radiology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan); Matsumoto, S. [Dept. of Radiology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan); Yoshida, K. [Dept. of Radiology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan); Kira, J. [Dept. of Neurology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan); Masuda, K. [Dept. of Radiology, Faculty of Medicine, Kyushu Univ., Fukuoka (Japan)

    1994-04-01

    Eight patients with a juvenile type of distal and segmental muscular atrophy of the upper extremities (DSMA), a type of cervical flexion myelopathy, were evaluated using MR imaging. In the neutral position there was no spinal cord compression, but in flexion the spinal cord was displaced anteriorly and was compressed by the posterior surfaces or margins of the vertebrae and/or any herniated disks in all cases. In flexion, compression of the cord was exaggerated in seven patients by the anterior displacement of the posterior margin of the thecal sac, which was accompanied by dilated posterior internal vertebral veins. In patients suspected of having DSMA, MR images made in flexion are regarded essential for verifying the diagnosis. (orig.)

  15. A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency.

    Science.gov (United States)

    Pronicki, Maciej; Kowalski, Paweł; Piekutowska-Abramczuk, Dorota; Taybert, Joanna; Karkucinska-Wieckowska, Agnieszka; Szymanska-Debinska, Tamara; Karczmarewicz, Elzbieta; Pajdowska, Magdalena; Migdal, Marek; Milewska-Bobula, Bogumila; Sykut-Cegielska, Jolanta; Popowska, Ewa

    2010-05-01

    Infants with deficiency of cytochrome c oxidase (COX) due to SCO2 mutations observed so far usually demonstrated early cardiomyopathy, encephalopathy and lactic acidosis. Milder spinal muscular atrophy-like (SMA-like) phenotype was also rarely reported. The aim is to present 18 Polish patients with SCO2 mutations. Molecular study revealed p.E140K mutation in all cases (on 32 alleles); p.Q53X mutation and novel p.M177T change were identified in single patients. In three families no second mutation was found. Thirteen p.E140K homozygotes presented in infancy with floppiness and remarkable stridor. Survival motor neuron (SMN) gene deletion was excluded. Mild to moderate lactic academia was found. Neurological involvement manifested as spasticity and psychomotor retardation. In some patients strabismus, ptosis and episodes of seizures were seen. During second half of the year chronic respiratory failure with artificial respiration dependency appeared in all homozygotes. Heart involvement was never present at the beginning. Rapidly progressive hypertrophic cardiomyopathy developed in several patients at the terminal stage. The stridor was constant and striking feature. Skeletal muscle biopsy was performed in 16 patients including 11 homozygotes. Four pathological patterns were discerned - from neurogenic muscle changes, including spinal muscular atrophy (SMA) to unspecific findings. Histochemical cytochrome c oxidase (COX) deficit was not a constant feature. Significant decrease in respiratory chain complex IV activity was detected in muscle homogenate by spectrophotometric method only in 7 out of 12 examined cases. 1/Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit; 2/Inspiratory stridor may be symptomatic of SCO2 gene mutation(s). Copyright 2009 European Paediatric Neurology Society. Published by Elsevier

  16. The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy.

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    Hong Liu

    Full Text Available 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.

  17. Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset.

    Science.gov (United States)

    Feng, Zhihua; Ling, Karen K Y; Zhao, Xin; Zhou, Chunyi; Karp, Gary; Welch, Ellen M; Naryshkin, Nikolai; Ratni, Hasane; Chen, Karen S; Metzger, Friedrich; Paushkin, Sergey; Weetall, Marla; Ko, Chien-Ping

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that Δ7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult Δ7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1-follistatin ameliorates muscle atrophy in suboptimally dosed Δ7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy.

    Science.gov (United States)

    Dachs, E; Piedrafita, L; Hereu, M; Esquerda, J E; Calderó, J

    2013-10-10

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by defective levels of the survival motor neuron (SMN) protein. SMA causes spinal motoneuron (MN) loss, and progressive muscle weakness and paralysis. Currently, there is no effective therapy to cure this disease. Although different strategies focused on increasing the expression of functional SMN protein have been assayed, numerous SMN-independent therapeutic approaches have been demonstrated to have potential effectiveness in improving the SMA phenotype in mouse models and clinical trials. Recent works have shown that compounds which inhibit GSK-3β activity are effective in promoting MN survival and ameliorating lifespan in models of MN diseases including SMA. Taking into account the reported neuroprotective actions of lithium (Li) through the inhibition of GSK-3β in different studies, we tested here its potential efficiency as a therapeutic agent in a mouse model of severe SMA (SMNΔ7 mice). We show that the chronic treatment with Li initiated before the appearance of disease symptoms, although inhibited GSK-3β, did not improve the median survival, motor behavior, and spinal MN loss linked to SMA. Li administration did not either ameliorate the microglial and astroglial reaction in the spinal cord or the depletion of glutamatergic synapses on MNs observed in SMNΔ7 animals. Moreover, Li treatment did not mitigate muscle atrophy or calcitonin gene-related peptide (CGRP) downregulation in the neuromuscular junctions linked to the disease. However, a significant reduction in apoptotic cell death found in the skeletal muscle of SMA mice was observed after Li treatment. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Survival of motor neuron protein downregulates miR-9 expression in patients with spinal muscular atrophy

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    Li-Ting Wang

    2014-05-01

    Full Text Available Spinal muscular atrophy (SMA is a lethal hereditary disease caused by homozygous absence of the survival of the motor neuron (SMN 1 gene (SMN1, and it is the leading genetic cause of infant mortality. The severity of SMA is directly correlated with SMN protein levels in affected patients; however, the cellular regulatory mechanisms for SMN protein expression are not completely understood. In this study, we investigated the regulatory effects between SMN expression and miR-9a, a downstream noncoding small RNA. Using an inducible SMN short hairpin RNA interference (shRNAi system in NSC 34 and human skin fibroblast cells, cellular miR-9 levels and SMN protein repression were time-dependently upregulated. Conversely, cellular miR-9 levels decreased when HeLa cells were transfected with SMN protein fused with green fluorescent protein. In SMA-like mice spinal cords and human primary skin fibroblasts isolated from patients with different degrees of SMA, human SMN exhibited a disease severity-dependent decrease, whereas cellular miR-9 levels increased. These results clearly suggested that cellular SMN proteins regulated miR-9 expression and that miR-9 expression was related to SMA severity. Thus, miR-9 may be a marker for SMA prognosis.

  20. Lysine-Less Variants of Spinal Muscular Atrophy SMN and SMNΔ7 Proteins Are Degraded by the Proteasome Pathway

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    Raúl Sánchez-Lanzas

    2017-12-01

    Full Text Available Spinal muscular atrophy is due to mutations affecting the SMN1 gene coding for the full-length protein (survival motor neuron; SMN and the SMN2 gene that preferentially generates an exon 7-deleted protein (SMNΔ7 by alternative splicing. To study SMN and SMNΔ7 degradation in the cell, we have used tagged versions at the N- (Flag or C-terminus (V5 of both proteins. Transfection of those constructs into HeLa cells and treatment with cycloheximide showed that those protein constructs were degraded. Proteasomal degradation usually requires prior lysine ubiquitylation. Surprisingly, lysine-less variants of both proteins tagged either at N- (Flag or C-terminus (V5 were also degraded. The degradation of the endogenous SMN protein, and the protein constructs mentioned above, was mediated by the proteasome, as it was blocked by lactacystin, a specific and irreversible proteasomal inhibitor. The results obtained allowed us to conclude that SMN and SMNΔ7 proteasomal degradation did not absolutely require internal ubiquitylation nor N-terminal ubiquitylation (prevented by N-terminal tagging. While the above conclusions are firmly supported by the experimental data presented, we discuss and justify the need of deep proteomic techniques for the study of SMN complex components (orphan and bound turn-over to understand the physiological relevant mechanisms of degradation of SMN and SMNΔ7 in the cell.

  1. Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients

    Science.gov (United States)

    Williams, Jason H.; Jayaraman, Bhuvaneswari; Swoboda, Kathryn J.; Barrett, Jeffrey S.

    2012-01-01

    Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2-compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), central volume (70%), and peripheral volume (42%) over the base model. The final model for clearance and volume parameters was clearance = 0.854 · (weight/70)0.75; central volume of distribution = 10.3 · (weight/70)1.0 · (age/8.5)−0.267; peripheral volume of distribution = 4.08 · (weight/70)1.0; and intercompartmental clearance = 5.34 · (weight/70)0.75. Application of the model to data from a clinical trial in SMA patients suggests altered kinetics, perhaps based on underlying physiologic differences such as alterations in lean body mass. Future studies in SMA should incorporate modeling and simulation techniques to support individualized dosing and further assess if additional patient-specific factors necessitate alternative dosing strategies. PMID:22167565

  2. Sensory Neurons Do Not Induce Motor Neuron Loss in a Human Stem Cell Model of Spinal Muscular Atrophy

    Science.gov (United States)

    Schwab, Andrew J.; Ebert, Allison D.

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system. PMID:25054590

  3. Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy.

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    Chalermchai Mitrpant

    Full Text Available Spinal muscular atrophy (SMA is caused by loss of the Survival Motor Neuron 1 (SMN1 gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.

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

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    Palittiya Sintusek

    Full Text Available 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.

  5. An Evaluation of a Continuing Education Program for Family Caregivers of Ventilator-Dependent Children with Spinal Muscular Atrophy (SMA

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    Deborah S. Boroughs

    2017-04-01

    Full Text Available Until 25 years ago, there were limited options for long-term mechanical ventilation of children, and the majority of children were cared for in hospitals. However, with improving technology, the pediatric intensive care unit has moved from the hospital to a home setting, as children with increasingly complex healthcare needs are now often cared for by family members. One of the most complex care conditions involves ventilator and tracheostomy support. Advanced respiratory technologies that augment natural respiratory function prolong the lives of children with respiratory compromise; however, this care often comes with serious risks, including respiratory muscle impairment, respiratory failure, and chronic pulmonary disease. Both non-invasive assisted ventilation and assisted ventilation via tracheostomy can prolong survival into adulthood in many cases; however, mechanical ventilation in the home is a high-stakes, high risk intervention. Increasing complexity of care over time requires perpetual skill training of family caregivers that is delivered and supported by professional caregivers; yet, opportunities for additional training outside of the hospital rarely exist. Recent data has confirmed that repetitive caregiver education is essential for retention of memory and skills in adult learners. This study analyzes the use of continued education and training in the community for family caregivers of ventilator-dependent children diagnosed with spinal muscular atrophy (SMA.

  6. Methylation levels of SLC23A2 and NCOR2 genes correlate with spinal muscular atrophy severity.

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    Galina Yu Zheleznyakova

    Full Text Available Spinal muscular atrophy (SMA is a monogenic neurodegenerative disorder subdivided into four different types. Whole genome methylation analysis revealed 40 CpG sites associated with genes that are significantly differentially methylated between SMA patients and healthy individuals of the same age. To investigate the contribution of methylation changes to SMA severity, we compared the methylation level of found CpG sites, designed as "targets", as well as the nearest CpG sites in regulatory regions of ARHGAP22, CDK2AP1, CHML, NCOR2, SLC23A2 and RPL9 in three groups of SMA patients. Of notable interest, compared to type I SMA male patients, the methylation level of a target CpG site and one nearby CpG site belonging to the 5'UTR of SLC23A2 were significantly hypomethylated 19-22% in type III-IV patients. In contrast to type I SMA male patients, type III-IV patients demonstrated a 16% decrease in the methylation levels of a target CpG site, belonging to the 5'UTR of NCOR2. To conclude, this study validates the data of our previous study and confirms significant methylation changes in the SLC23A2 and NCOR2 regulatory regions correlates with SMA severity.

  7. Smn deficiency causes neuritogenesis and neurogenesis defects in the retinal neurons of a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Liu, Hong; Beauvais, Ariane; Baker, Adam N; Tsilfidis, Catherine; Kothary, Rashmi

    2011-02-01

    The eye is an excellent model for the study of neuronal development and pathogenesis of central nervous system disorders because of its relative ease of accessibility and the well-characterized cellular makeup. We have used this model to study spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 gene (SMN1). We have investigated the expression pattern of mouse Smn mRNA and protein in the neural retina and the optic nerve of wild type mice. Smn protein is present in retinal ganglion cells and amacrine cells within the neural retina as well as in glial cells in the optic nerve. Histopathological analysis in phenotype stage SMA mice revealed that Smn deficiency is associated with a reduction in ganglion cell axon and glial cell number in the optic nerve, as well as compromised cellular processes and altered organization of neurofilaments in the neural retina. Whole mount preparation and retinal neuron primary culture provided further evidence of abnormal synaptogenesis and neurofilament accumulation in the neurites of Smn-deficient retinal neurons. A subset of amacrine cells is absent, in a cell-autonomous fashion, in the retina of SMA mice. Finally, the retinas of SMA mice have altered electroretinograms. Altogether, our study has demonstrated defects in axodendritic outgrowth and cellular composition in Smn-depleted retinal neurons, indicating a role for Smn in neuritogenesis and neurogenesis, and providing us with an insight into pathogenesis of SMA. Copyright © 2010 Wiley Periodicals, Inc.

  8. Targeted sequencing of maternal plasma for haplotype-based non-invasive prenatal testing of spinal muscular atrophy.

    Science.gov (United States)

    Chen, M; Lu, S; Lai, Z F; Chen, C; Luo, K; Yuan, Y; Wang, Y S; Li, S Q; Gao, Y; Chen, F; Asan; Chen, D J

    2017-06-01

    Five pregnant women with a child affected by spinal muscular atrophy (SMA) were recruited between November 2014 and March 2015. Deletion of exons 7 and/or 8 in the SMN1 gene were identified by multiplex ligation-dependent probe amplification (MLPA), the current standard diagnostic test for SMA. Parental and fetal haplotypes of the SMN1 gene were determined in each family from haplotype-based non-invasive testing of blood samples and maternal plasma, respectively. Fetal haplotype was compared with the results of MLPA of fetal DNA obtained from amniotic fluid or chorionic villi. Parental haplotypes were constructed successfully in the five families. Assisted by the information on parental haplotype, non-invasive testing of maternal plasma identified one fetus with homozygous deletion of exons 7 and 8, two fetuses with heterozygous deletion of exons 7 and 8 and two normal fetuses. These results were consistent with the diagnosis by MLPA. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

  9. Small molecule suppressors of Drosophila kinesin deficiency rescue motor axon development in a zebrafish model of spinal muscular atrophy.

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    Andrew Gassman

    Full Text Available Proximal spinal muscular atrophy (SMA is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP. In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease.

  10. A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds

    NARCIS (Netherlands)

    Sleigh, J.N.; Buckingham, S.D.; Esmaeili, B.; Viswanathan, M.; Cuppen, E.; Westlund, B.M.; Sattelle, D.B.

    2010-01-01

    Spinal muscular atrophy (SMA), an autosomal recessive genetic disorder, is characterized by the selective degeneration of lower motor neurons, leading to muscle atrophy and, in the most severe cases, paralysis and death. Deletions and point mutations cause reduced levels of the widely expressed

  11. Management of neuromuscular diseases and spinal muscular atrophy in Latin America.

    Science.gov (United States)

    Monges, S; Rosa, A L

    2017-09-01

    Latin America (LA) has a population of ~645 million people distributed over 33 countries with marked political, cultural and economic differences. In LA, patients with inherited neuromuscular diseases (NMDs) often do not have access to specialized medical centers and many of them go undiagnosed. General management and care of spinal muscular dystrophy (SMA) patients in the region varies due to heterogeneous health care. An active generation of young clinical neurologists is being trained for the specialized care of SMA and other neuromuscular (NM) patients, both in the private and public sectors. The Euro-Latin-American Summer School of Myology (EVELAM) as well as efforts of professionals at large public centers in the major cities of LA have a leading role in this development. Different regional academic-scientific organizations as well as the expanding number of telethon centers and the creation of parent organizations, mostly concerning SMA, all together are contributing to the increased quality of the management of NMD patients. Over the past years, academic and clinical research, as well as the establishment of qualified centers for the molecular testing of NMD are pushing forward the creation of patient registries and the development of specific clinical trials, with Argentina and Brazil having a major role in this field. Nevertheless, increased awareness and further training of specialized health professionals are necessary to reach patients that are currently lacking care throughout the region.

  12. Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis.

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    Delle Vedove, Andrea; Storbeck, Markus; Heller, Raoul; Hölker, Irmgard; Hebbar, Malavika; Shukla, Anju; Magnusson, Olafur; Cirak, Sebahattin; Girisha, Katta M; O'Driscoll, Mary; Loeys, Bart; Wirth, Brunhilde

    2016-11-03

    We report ten individuals of four independent consanguineous families from Turkey, India, Libya, and Pakistan with a variable clinical phenotype that comprises arthrogryposis, spontaneously resolving respiratory insufficiency at birth, muscular atrophy predominantly of the distal lower limbs, scoliosis, and mild distal sensory involvement. Using whole-exome sequencing, SNPchip-based linkage analysis, DNA microarray, and Sanger sequencing, we identified three independent homozygous frameshift mutations and a homozygous deletion of two exons in PIEZO2 that segregated in all affected individuals of the respective family. The mutations are localized in the N-terminal and central region of the gene, leading to nonsense-mediated transcript decay and consequently to lack of PIEZO2 protein. In contrast, heterozygous gain-of-function missense mutations, mainly localized at the C terminus, cause dominant distal arthrogryposis 3 (DA3), distal arthrogryposis 5 (DA5), or Marden-Walker syndrome (MWKS), which encompass contractures of hands and feet, scoliosis, ophthalmoplegia, and ptosis. PIEZO2 encodes a mechanosensitive ion channel that plays a major role in light-touch mechanosensation and has recently been identified as the principal mechanotransduction channel for proprioception. Mice ubiquitously depleted of PIEZO2 are postnatally lethal. However, individuals lacking PIEZO2 develop a not life-threatening, slowly progressive disorder, which is likely due to loss of PIEZO2 protein in afferent neurons leading to disturbed proprioception causing aberrant muscle development and function. Here we report a recessively inherited PIEZO2-related disease and demonstrate that depending on the type of mutation and the mode of inheritance, PIEZO2 causes clinically distinguishable phenotypes. Copyright © 2016 American Society of Human Genetics. All rights reserved.

  13. Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy

    Science.gov (United States)

    Ramser, Juliane; Ahearn, Mary Ellen; Lenski, Claus; Yariz, Kemal O.; Hellebrand, Heide; von Rhein, Michael; Clark, Robin D.; Schmutzler, Rita K.; Lichtner, Peter; Hoffman, Eric P.; Meindl, Alfons; Baumbach-Reardon, Lisa

    2008-01-01

    X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3–Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G→T, p.Met539Ile; c.1639 A→G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C→T substitution (c.1731 C→T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 × 10−10, p = 0.001815). We also demonstrated that the synonymous C→T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C→T transitions might have the potential to affect gene expression. PMID:18179898

  14. Motoneuron development influences dorsal root ganglia survival and Schwann cell development in a vertebrate model of spinal muscular atrophy.

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    Hao, Le Thi; Duy, Phan Q; Jontes, James D; Beattie, Christine E

    2015-01-15

    Low levels of the survival motor neuron protein (SMN) cause the disease spinal muscular atrophy. A primary characteristic of this disease is motoneuron dysfunction and paralysis. Understanding why motoneurons are affected by low levels of SMN will lend insight into this disease and to motoneuron biology in general. Motoneurons in zebrafish smn mutants develop abnormally; however, it is unclear where Smn is needed for motoneuron development since it is a ubiquitously expressed protein. We have addressed this issue by expressing human SMN in motoneurons in zebrafish maternal-zygotic (mz) smn mutants. First, we demonstrate that SMN is present in axons, but only during the period of robust motor axon outgrowth. We also conclusively demonstrate that SMN acts cell autonomously in motoneurons for proper motoneuron development. This includes the formation of both axonal and dendritic branches. Analysis of the peripheral nervous system revealed that Schwann cells and dorsal root ganglia (DRG) neurons developed abnormally in mz-smn mutants. Schwann cells did not wrap axons tightly and had expanded nodes of Ranvier. The majority of DRG neurons had abnormally short peripheral axons and later many of them failed to divide and died. Expressing SMN just in motoneurons rescued both of these cell types showing that their failure to develop was secondary to the developmental defects in motoneurons. Driving SMN just in motoneurons did not increase survival of the animal, suggesting that SMN is needed for motoneuron development and motor circuitry, but that SMN in other cells types factors into survival. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

    Science.gov (United States)

    Crawford, Thomas O.; Paushkin, Sergey V.; Kobayashi, Dione T.; Forrest, Suzanne J.; Joyce, Cynthia L.; Finkel, Richard S.; Kaufmann, Petra; Swoboda, Kathryn J.; Tiziano, Danilo; Lomastro, Rosa; Li, Rebecca H.; Trachtenberg, Felicia L.; Plasterer, Thomas; Chen, Karen S.

    2012-01-01

    Background The universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early “biomarker” of treatment effect. Methods A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age. Results SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other. Conclusion This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an “early look” for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number. Trial Registry Clinicaltrials.gov NCT00756821 PMID:22558076

  16. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA clinical study.

    Directory of Open Access Journals (Sweden)

    Thomas O Crawford

    Full Text Available BACKGROUND: The universal presence of a gene (SMN2 nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early "biomarker" of treatment effect. METHODS: A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS. Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age. RESULTS: SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other. CONCLUSION: This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an "early look" for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number. TRIAL REGISTRY: Clinicaltrials.gov NCT00756821.

  17. Electrophysiological properties of motor neurons in a mouse model of severe spinal muscular atrophy: in vitro versus in vivo development.

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    Hongmei Zhang

    2010-07-01

    Full Text Available We examined the electrophysiological activity of motor neurons from the mouse model of severe spinal muscular atrophy (SMA using two different methods: whole cell patch clamp of neurons cultured from day 13 embryos; and multi-electrode recording of ventral horns in spinal cord slices from pups on post-natal days 5 and 6. We used the MED64 multi-electrode array to record electrophysiological activity from motor neurons in slices from the lumbar spinal cord of SMA pups and their unaffected littermates. Recording simultaneously from up to 32 sites across the ventral horn, we observed a significant decrease in the number of active neurons in 5-6 day-old SMA pups compared to littermates. Ventral horn activity in control pups is significantly activated by serotonin and depressed by GABA, while these agents had much less effect on SMA slices. In contrast to the large differences observed in spinal cord, neurons cultured from SMA embryos for up to 21 days showed no significant differences in electrophysiological activity compared to littermates. No differences were observed in membrane potential, frequency of spiking and synaptic activity in cells from SMA embryos compared to controls. In addition, we observed no difference in cell survival between cells from SMA embryos and their unaffected littermates. Our results represent the first report on the electrophysiology of SMN-deficient motor neurons, and suggest that motor neuron development in vitro follows a different path than in vivo development, a path in which loss of SMN expression has little effect on motor neuron function and survival.

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

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    Chung-Wei Yang

    Full Text Available 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.

  19. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA.

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    Saniya Fayzullina

    Full Text Available Spinal Muscular Atrophy (SMA is a hereditary childhood disease that causes paralysis by 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. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0 exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA.

  20. Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III

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    Schiöth Helgi B

    2011-07-01

    Full Text Available Abstract Background Spinal muscular atrophy (SMA type I, II and III is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (SMN1. SMN2 is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two SMN2 copies while most SMA type II patients carry three SMN2 copies and SMA III patients have three or four SMN2 copies. The SMN1 gene produces a full-length transcript (FL-SMN while SMN2 is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMNΔ7 mRNA. Methods In this study we performed quantification of the SMN2 gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the SMN1 gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMNΔ7 mRNA ratio as SMA biomarker. Results Comparison of the SMN2 copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III and presence of four copies of the SMN2 gene. In both asymptomatic cases we found an increased number of SMN2 copies in the healthy carriers and a biallelic SMN1 absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls. Conclusions We suggest that the SMN2 gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMNΔ7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.

  1. Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy.

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    Dirk Bäumer

    2009-12-01

    Full Text Available Spinal muscular atrophy is a severe motor neuron disease caused by inactivating mutations in the SMN1 gene leading to reduced levels of full-length functional SMN protein. SMN is a critical mediator of spliceosomal protein assembly, and complete loss or drastic reduction in protein leads to loss of cell viability. However, the reason for selective motor neuron degeneration when SMN is reduced to levels which are tolerated by all other cell types is not currently understood. Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death. However, it remains unclear whether splicing abnormalities are present during early stages of the disease, which would be a requirement for a direct role in disease pathogenesis. We performed exon-array analysis of RNA from SMN deficient mouse spinal cord at 3 time points, pre-symptomatic (P1, early symptomatic (P7, and late-symptomatic (P13. Compared to littermate control mice, SMA mice showed a time-dependent increase in the number of exons showing differential expression, with minimal differences between genotypes at P1 and P7, but substantial variation in late-symptomatic (P13 mice. Gene ontology analysis revealed differences in pathways associated with neuronal development as well as cellular injury. Validation of selected targets by RT-PCR confirmed the array findings and was in keeping with a shift between physiologically occurring mRNA isoforms. We conclude that the majority of splicing changes occur late in SMA and may represent a secondary effect of cell injury, though we cannot rule out significant early changes in a small number of transcripts crucial to motor neuron survival.

  2. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs.

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    Francesca Gabanella

    2007-09-01

    Full Text Available Spinal muscular atrophy (SMA is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defective SMN complex function in snRNP assembly causes a significant decrease in the levels of a subset of snRNPs and preferentially affects the accumulation of U11 snRNP--a component of the minor spliceosome--in tissues of severe SMA mice. Thus, impairment of a ubiquitous function of SMN changes the snRNP profile of SMA tissues by unevenly altering the normal proportion of endogenous snRNPs. These findings are consistent with the hypothesis that SMN deficiency affects the splicing machinery and in particular the minor splicing pathway of a rare class of introns in SMA.

  3. Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.

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    Sean G Mack

    Full Text Available 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.

  4. Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis.

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    Riessland, Markus; Kaczmarek, Anna; Schneider, Svenja; Swoboda, Kathryn J; Löhr, Heiko; Bradler, Cathleen; Grysko, Vanessa; Dimitriadi, Maria; Hosseinibarkooie, Seyyedmohsen; Torres-Benito, Laura; Peters, Miriam; Upadhyay, Aaradhita; Biglari, Nasim; Kröber, Sandra; Hölker, Irmgard; Garbes, Lutz; Gilissen, Christian; Hoischen, Alexander; Nürnberg, Gudrun; Nürnberg, Peter; Walter, Michael; Rigo, Frank; Bennett, C Frank; Kye, Min Jeong; Hart, Anne C; Hammerschmidt, Matthias; Kloppenburg, Peter; Wirth, Brunhilde

    2017-02-02

    Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca 2+ -dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. Social/economic costs and health-related quality of life in patients with spinal muscular atrophy (SMA) in Spain.

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    López-Bastida, Julio; Peña-Longobardo, Luz María; Aranda-Reneo, Isaac; Tizzano, Eduardo; Sefton, Mark; Oliva-Moreno, Juan

    2017-08-18

    The aim of this study was to determine the economic burden and health-related quality of life (HRQOL) of patients with Spinal Muscular Atrophy (SMA) and their caregivers in Spain. This was a cross-sectional and retrospective study of patients diagnosed with SMA in Spain. We adopted a bottom up, prevalence approach design to study patients with SMA. The patient's caregivers completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and non-healthcare services. Costs were estimated from a societal perspective (including healthcare costs and non-healthcare costs), and health-related quality of life (HRQOL) was assessed using the EQ-5D questionnaire. The main caregivers also answered a questionnaire on their characteristics and on their HRQOL. A total of 81 caregivers of patients with different subtypes of SMA completed the questionnaire. Based on the reference unitary prices for 2014, the average annual costs per patient were € 33,721. Direct healthcare costs were € 10,882 (representing around 32.3% of the total cost) and the direct non-healthcare costs were € 22,839 (67.7% of the total cost). The mean EQ-5D social tariff score for patients was 0.16, and the mean score of the EQ-5D visual analogue scale was 54. The mean EQ-5D social tariff score for caregivers was 0.49 and their mean score on the EQ-5D visual analogue scale was 69. The results highlight the burden that SMA has in terms of costs and decreased HRQOL, not only for patients but also for their caregivers. In particular, the substantial social/economic burden is mostly attributable to the high direct non-healthcare costs.

  6. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA clinical study.

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    Richard S Finkel

    Full Text Available Spinal Muscular Atrophy (SMA is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1 gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS and to a number of secondary clinical measures.A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites and 44 urine metabolites. No transcripts correlated with MHFMS.In this cross-sectional study, "BforSMA" (Biomarkers for SMA, candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with

  7. Neuroprotective effect of non-viral gene therapy treatment based on tetanus toxin C-fragment in a severe mouse model of Spinal Muscular Atrophy.

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    Sara Olivan Garcia

    2016-08-01

    Full Text Available 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.

  8. Moving ahead in language: observations on a report of precocious language development in 3-4 year old children with spinal muscular atrophy type II.

    Science.gov (United States)

    Sieratzki, Jechil S; Woll, Bencie

    2005-01-01

    Benony and Benony in a recent issue of this Journal have presented new data on the precocity of language acquisition in children with type II spinal muscular atrophy (SMA), at age 36-47 months. They refer to our interim report of advanced early language development in these motor-impaired children, which covers the age period 18-35 months. Here, we provide more details of our findings and discuss them in relation to their report and our theory of the role of the procedural system in language learning.

  9. Change in muscle strength over time in spinal muscular atrophy types II and III. A long-term follow-up study

    DEFF Research Database (Denmark)

    Werlauff, U; Vissing, J; Steffensen, B F

    2012-01-01

    Whether muscle strength deteriorates with time in spinal muscular atrophy (SMA) types II and III is still debated. We present a long-term follow-up study on muscle strength in 30 patients with SMA types II and III. Median follow-up time was 17 years. Median number of assessments was four. All...... patients were assessed by Manual Muscle Testing (MMT), Brooke upper limb scale and EK scale. There was a difference in muscle strength of the upper limbs from first to last assessment in SMA II (p...

  10. Familial bulbar urethral strictures

    Science.gov (United States)

    Jindal, Tarun; Pal, Partha; Sinha, Rajan Kumar; Karmakar, Dilip

    2014-01-01

    Strictures are commonly encountered in the urological practice. The most common aetiologies are infection, trauma and iatrogenic events. Familial occurrence of urethral stricture is exceptionally rare. We present a case in which bulbar urethral strictures developed in a father and his two sons. PMID:24591388

  11. Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    ... early, it can cause children to miss certain developmental milestones, such as rolling over, sitting up without support, ... has SMA only after the child misses certain developmental milestones, such as being able to support his or ...

  12. Spinal Muscular Atrophy

    Science.gov (United States)

    ... females inherit an X chromosome from each parent. Daughters have a 50 percent chance of inheriting their mother's faulty X chromosome and a safe X chromosome from their father, which would make them asymptomatic carriers of the ...

  13. Spinal Muscular Atrophy

    Science.gov (United States)

    ... Page NINDS Cephalic Disorders Information Page NINDS Cerebral Cavernous Malformation Information Page NINDS Chronic Pain Information Page ... Information Page Adrenoleukodystrophy Information Page Agenesis of the Corpus Callosum Information Page Agnosia Information Page Aicardi-Goutieres ...

  14. SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy.

    Science.gov (United States)

    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

    2014-02-01

    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. 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. 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. 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.

  15. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns

    DEFF Research Database (Denmark)

    Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity...... is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely...... unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show...

  16. Social support network to family caregiver of a patient with Spinal Muscular Atrophy I and II - doi:10.5020/18061230.2010.p126

    Directory of Open Access Journals (Sweden)

    Cláudia Viot de Albuquerque Moura

    2012-01-01

    Full Text Available Objective: To assess the formal and informal support given to the family caregiver of a patient with Spinal Muscular Atrophy I and II. Method: This was a study with a qualitative approach developed in 2008 in the homes of informants and in the premises of the Hospital Infantil Albert Sabin in Fortaleza, Ceara, conducted with 13 mothers, primary caregivers for their ill children. For data collection we used both the interview and the instrument generator of the names and qualifier of the relations, adapted for this study. Quantitative data were processed using the programs UCINET NetDraw 6.123 and 2.38, while the qualitative data were organized based on the technique of the Collective Subject Discourse. The analyses were conducted by means of network maps and collective discourses raised by central ideas. Results: The formal social network of family caregivers was composed of 72 actors, among professionals in the areas of health, education and others, linked to 12 institutions. The informal network was comprised of 83 actors. It was found that the management of care, even when the caregiver has support from other people is a cause of stress and overload. Conclusion: It is evident the importance of applying Social Network Analysis as a tool for understanding structural features and the dynamics of social relations of family caregiver. Of a patient with spinal muscular atrophy. The analysis suggests the need for intervention in the study group as a way to contribute to the recognition and use of existing services, increasing the significance of the help provided by network interactions.

  17. Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.

    Science.gov (United States)

    Shababi, Monir; Feng, Zhihua; Villalon, Eric; Sibigtroth, Christine M; Osman, Erkan Y; Miller, Madeline R; Williams-Simon, Patricka A; Lombardi, Abby; Sass, Thalia H; Atkinson, Arleigh K; Garcia, Michael L; Ko, Chien-Ping; Lorson, Christian L

    2016-05-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of α-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

  18. 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

    Science.gov (United States)

    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.

  19. Estimulação elétrica neuromuscular em cães com atrofia muscular induzida Neuromuscular electric stimulation in dogs with induced muscle atrophy

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    C. Pelizzari

    2008-02-01

    Full Text Available Empregou-se a estimulação elétrica neuromuscular (EENM de baixa freqüência no músculo quadríceps femoral de cães com atrofia induzida e avaliou-se a ocorrência de ganho de massa nessa musculatura. Foram utilizados oito cães com pesos entre 15 e 30kg, distribuídos aleatoriamente em dois grupos denominados de I ou controle e II ou tratado. A articulação femorotibiopatelar esquerda foi imobilizada por 30 dias pelo método de transfixação percutânea tipo II, com retirada de aparelho de imobilização após esse período. Decorridas 48 horas da remoção, foi realizada a EENM nos cães do grupo II, cinco vezes por semana, com intervalo de 24 horas cada sessão, pelo período de 60 dias. Foram avaliadas a circunferência da coxa, a goniometria do joelho, a análise clínica da marcha, as enzimas creatina-quinase (CK e aspartato-amino-transferase (AST e a morfometria das fibras musculares em cortes transversais do músculo vasto lateral colhido mediante biópsia muscular. A EENM foi empregada no músculo quadríceps femoral na freqüência de 50Hz, duração de pulso de 300 milisegundos e relação de tempo on/off de 1:2. Quanto à morfometria das fibras do músculo vasto lateral, no grupo tratado houve aumento significativo (PLow frequency neuromuscular electrical stimulation (NMES was used on the femoral quadriceps of dogs with induced muscular atrophy and the occurrence of gain in mass in these muscles was evaluated. Eight dogs from 15 to 30kg were randomly distributed in two groups named I, or control; and II, or treated. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days by percutaneous transfixation type II. After 30 days, the immobilization device was removed. The NMES treatment began 48 hours after the removal of the immobilization device of the dogs of group II, and it was carried out five times per week with an interval of 24 hours between each session, for 60 days. The

  20. TRACHEOTOMY IN BULBAR POLIOMYELITIS

    Science.gov (United States)

    Miller, Alden H.; Buck, Leonard S.

    1950-01-01

    Tracheotomy was performed on 181 of 351 patients with bulbar poliomyelitis. The essential indication for tracheotomy was secretional obstruction of the respiratory tract that could not be relieved by postural drainage and aspiration. Comparison of mortality rates in this series with those of previous series in which tracheotomy was not done in the presence of similar indications, suggests that the procedure may be life-saving in a considerable percentage of cases. Outside the respirator the tracheotomy can be done with or without the aid of the bronchoscope or endotracheal anesthesia tube. When done inside the opened respirator the Bennett flow-sensitive positive pressure machine should be used to supply oxygen to the patient while the respirator is not operating. PMID:15398892

  1. Association between the SMN2 gene copy number and clinical characteristics of patients with spinal muscular atrophy with homozygous deletion of exon 7 of the SMN1 gene

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    Žarkov Marija

    2015-01-01

    Full Text Available Background/Aim. Spinal muscular atrophy (SMA is an autosomal recessive disease characterized by degeneration of alpha motor neurons in the spinal cord and the medulla oblongata, causing progressive muscle weakness and atrophy. The aim of this study was to determine association between the SMN2 gene copy number and disease phenotype in Serbian patients with SMA with homozygous deletion of exon 7 of the SMN1 gene. Methods. The patients were identified using regional Serbian hospital databases. Investigated clinical characteristics of the disease were: patients’ gender, age at disease onset, achieved and current developmental milestones, disease duration, current age, and the presence of the spinal deformities and joint contractures. The number of SMN1 and SMN2 gene copies was determined using real-time polymerase chain reaction (PCR. Results. Among 43 identified patients, 37 (86.0% showed homozygous deletion of SMN1 exon 7. One (2.7% of 37 patients had SMA type I with 3 SMN2 copies, 11 (29.7% patients had SMA type II with 3.1 ± 0.7 copies, 17 (45.9% patients had SMA type III with 3.7 ± 0.9 copies, while 8 (21.6% patients had SMA type IV with 4.2 ± 0.9 copies. There was a progressive increase in the SMN2 gene copy number from type II towards type IV (p < 0.05. A higher SMN2 gene copy number was associated with better current motor performance (p < 0.05. Conclusion. In the Serbian patients with SMA, a higher SMN2 gene copy number correlated with less severe disease phenotype. A possible effect of other phenotype modifiers should not be neglected.

  2. New, Improved Version of the mCOP-PCR Screening System for Detection of Spinal Muscular Atrophy Gene (SMN1) Deletion.

    Science.gov (United States)

    Shinohara, Masakazu; Ar Rochmah, Mawaddah; Nakanishi, Kenta; Harahap, Nur Imma Fatimah; Niba, Emma Tabe Eko; Saito, Toshio; Saito, Kayoko; Takeuchi, Atsuko; Bouike, Yoshihiro; Nishio, Hisahide

    2017-09-07

    Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder, characterized by lower motor neuron loss in the spinal cord. More than 95% of SMA patients show homozygous survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique. However, non-specific amplification products were observed with mCOP-PCR, which might lead to erroneous interpretation of the screening results. To establish an improved version of the mCOP-PCR screening system without non-specific amplification. DNA samples were assayed using a new version of the mCOP-PCR screening system. DNA samples had already been genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP), showing the presence or absence of SMN1 exon 7. The new mCOP-PCR method contained a targeted pre-amplification step of the region, including an SMN1-specific nucleotide, prior to the mCOP-PCR step. mCOP-PCR products were electrophoresed on agarose gels. No non-specific amplification products were detected in electrophoresis gels with the new mCOP-PCR screening system. An additional targeted pre-amplification step eliminated non-specific amplification from mCOP-PCR screening.

  3. Juvenile muscular atrophy of the distal upper extremities associated with x-linked periventricular heterotopia with features of Ehlers-Danlos syndrome.

    Science.gov (United States)

    Hommel, Alyson L; Jewett, Tamison; Mortenson, Megan; Caress, James B

    2016-10-01

    Juvenile muscular atrophy of the distal upper extremities (JMADUE) is a rare, sporadic disorder that affects adolescent males and is characterized by progressive but self-limited weakness of the distal upper extremities. The etiology is unknown, but cervical hyperflexion has been hypothesized. We report a case of an adolescent male who presented with typical JMADUE but also had joint hypermobility and multiple congenital anomalies, including periventricular heterotopias, suggesting a multisystem syndrome. Subsequent diagnostic testing confirmed a diagnosis of JMADUE, and sequencing of the filamin-A gene showed a novel, pathogenic mutation that confirmed an additional diagnosis of X-linked periventricular heterotopias with features of Ehlers-Danlos syndrome (XLPH-EDS). The concurrent diagnosis of these 2 rare conditions suggests a pathogenic connection. It is likely that the joint hypermobility from XLPH-EDS predisposed this patient to developing JMADUE. This supports the cervical hyperflexion theory of pathogenesis. This case also expands the phenotype associated with FLNA mutations. Muscle Nerve 54: 794-797, 2016. © 2016 Wiley Periodicals, Inc.

  4. Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome.

    Science.gov (United States)

    Mailman, M D; Hemingway, T; Darsey, R L; Glasure, C E; Huang, Y; Chadwick, R B; Heinz, J W; Papp, A C; Snyder, P J; Sedra, M S; Schafer, R W; Abuelo, D N; Reich, E W; Theil, K S; Burghes, A H; de la Chapelle, A; Prior, T W

    2001-02-01

    We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage. The presence of two intact SMN1 genes in the parent of an affected child indicates either the occurrence of a de novo mutation event or a situation in which one chromosome has two copies of SMN1, whereas the other is null. We have separated individual chromosomes from two of these parents with two-copy SMN1 dosage by somatic cell hybridization and have employed a modified quantitative dosage assay to provide direct evidence that one parent is a two-copy/ zero-copy SMN1 carrier, whereas the other parent had an affected child as the result of a de novo mutation. These findings are important for assessing the recurrence risk of parents of children with spinal muscular atrophy and for providing accurate family counseling.

  5. Observational study of caloric and nutrient intake, bone density, and body composition in infants and children with spinal muscular atrophy type I.

    Science.gov (United States)

    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

    2012-11-01

    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 1month to 13years (median 9.8months) 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 1-3years old was 68.8±15.8kcal/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. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. A Drosophila Model of Spinal Muscular Atrophy Uncouples snRNP Biogenesis Functions of Survival Motor Neuron from Locomotion and Viability Defects

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    Kavita Praveen

    2012-06-01

    Full Text Available The spinal muscular atrophy (SMA protein, survival motor neuron (SMN, functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs. SMN has also been implicated in tissue-specific functions; however, it remains unclear which of these is important for the etiology of SMA. Smn null mutants display larval lethality and show significant locomotion defects as well as reductions in minor-class spliceosomal snRNAs. Despite these reductions, we found no appreciable defects in the splicing of mRNAs containing minor-class introns. Transgenic expression of low levels of either wild-type or an SMA patient-derived form of SMN rescued the larval lethality and locomotor defects; however, snRNA levels were not restored. Thus, the snRNP biogenesis function of SMN is not a major contributor to the phenotype of Smn null mutants. These findings have major implications for SMA etiology because they show that SMN's role in snRNP biogenesis can be uncoupled from the organismal viability and locomotor defects.

  7. 3′ Splice Site Sequences of Spinal Muscular Atrophy Related SMN2 Pre-mRNA Include Enhancers for Nearby Exons

    Directory of Open Access Journals (Sweden)

    Sunghee Cho

    2014-01-01

    Full Text Available Spinal muscular atrophy (SMA is a human genetic disease which occurs because of the deletion or mutation of SMN1 gene. SMN1 gene encodes the SMN protein which plays a key role in spliceosome assembly. Although human patients contain SMN2, a duplicate of SMN1, splicing of SMN2 produces predominantly exon 7 skipped isoform. In order to understand the functions of splice site sequences on exon 7 and 8, we analyzed the effects of conserved splice site sequences on exon 7 skipping of SMN2 and SMN1 pre-mRNA. We show here that conserved 5′ splice site sequence of exon 7 promoted splicing of nearby exons and subsequently reduced splicing of distant exons. However, to our surprise, conserved 3′ splice site sequence of exon 7 and 8 did not promote splicing of nearby exons. By contrast, the mutation inhibited splicing of nearby exons and subsequently promoted splicing of distant exons. Our study shows that 3′ splice sites of exon 7 and 8 contain enhancer for their splice site selection, in addition to providing cleavage sites.

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

    Directory of Open Access Journals (Sweden)

    Andrea Luchetti

    2015-08-01

    Full Text Available 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.

  9. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Armbruster, Nicole; Lattanzi, Annalisa; Jeavons, Matthieu; Van Wittenberghe, Laetitia; Gjata, Bernard; Marais, Thibaut; Martin, Samia; Vignaud, Alban; Voit, Thomas; Mavilio, Fulvio; Barkats, Martine; Buj-Bello, Ana

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.

  10. Mandibular dysfunction as a reflection of bulbar involvement in SMA type 2 and 3.

    Science.gov (United States)

    van Bruggen, H Willemijn; Wadman, Renske I; Bronkhorst, Ewald M; Leeuw, Maureen; Creugers, Nico; Kalaykova, Stanimira I; van der Pol, W Ludo; Steenks, Michel H

    2016-02-09

    In a cross-sectional study, we aimed to determine (1) the effect of spinal muscular atrophy (SMA) type 2 and 3 on mandibular function reflected as masticatory performance, mandibular range of motion, and bite force and (2) the predictors of mandibular dysfunction. Sixty patients with SMA type 2 and 3 (mean age 32.3 years, SD 17.4 years) and 60 age-matched controls filled out questionnaires about impairments of mandibular function. All participants underwent detailed clinical examination to document the mandibular range of motion including maximal mouth opening, bite force, and masticatory function. All mandibular movements, including mouth opening, lateral range of motion, and protrusion of the mandible, were reduced in patients with SMA type 2 and 3 compared to healthy controls (p mandibular range of motion (R(2) = 0.82) and weakness of neck muscles for bite force (R(2) = 0.47). Reduced mandibular mobility and bite force are common complications in SMA. SMA type and neck muscle strength are important correlates of these complications. We provide further evidence for clinically relevant bulbar involvement in patients with SMA. © 2016 American Academy of Neurology.

  11. MRI findings of nonprogressive juvenile spinal muscular atrophy of the distal upper limbs (Hirayama's disease)

    Energy Technology Data Exchange (ETDEWEB)

    Lee, In Sook; Lee, Tae Hong; Kim, Hak Jin; Song, Jong Woon; Lee, Suk Hong; Choi, Kwang Dong; Park, Kyoung Pil; Choi, Ki Bok [Pusan National University College of Medicine, Pusan (Korea, Republic of)

    2003-05-01

    The aim of this study was to describe the dynamic changes of the cervical dural sac and the spinal cord during neck flexion in patients suffering from Hirayama's disease and to present the usefulness of flexion MR study for the diagnosis. Seven consecutive male patients (age ranging 17-43 years, mean age 23.7 years) with the clinical diagnosis of Hirayama's disease and 5 healthy subjects (aged 25-32 years) for controls had done cervical MRI from January 2001 through June 2002. Cervical MRI was done in neutral and neck flexed positions using 1.5T system (Sonata, Siemens, Germany) and obtained images were reviewed by two radiologists. We compared the cervical MRI findings of 7 patients with those of 5 healthy controls regarding neck flexion induced changes in the lower cervical segments. Neutral positioned cervical sagittal MR images revealed subtle or mild cord atrophy in only 2 patients. On maximal neck flexion, AP diameter of the cresent posterior epidural space was increased and also cord flattening with anterior shifting of posterior wall of the lower cervical dural canal was noted in all 7 patients. In all 7 cases, the level and side of spinal cord changes corresponded to the clinical phenotype. All control subjects showed neither cord flattening nor widening of posterior epidural space on neck flexion. In patients with the clinical diagnosis of Hirayama's disease, MRI scans obtained on maximal neck flexion showed characteristically dynamic flattening of lower cervical cord and widening of posterior epidural space. Therefore, a flexion MR study is needed to prove the diagnosis.

  12. MRI findings of nonprogressive juvenile spinal muscular atrophy of the distal upper limbs(Hirayama's disease)

    Energy Technology Data Exchange (ETDEWEB)

    Lee, In Sook; Lee, Tae Hong; Kim, Hak Jin; Song, Jong Woon; Lee, Suk Hong; Choi, Kwang Dong; Park, Kyoung Pil [Pusan National University College of Medicine, Pusan (Korea, Republic of); Choi, Ki Bok [Inje University College of Medicine, Pusan (Korea, Republic of)

    2003-05-01

    The aim of this study was to describe the dynamic changes of the cervical dural sac and the spinal cord during neck flexion in patients suffering from Hirayama's disease and to present the usefulness of flexion MR study for the diagnosis. Seven consecutive male patients (age ranging 17-43 years, mean age 23.7 years) with the clinical diagnosis of Hirayama's disease and 5 healthy subjects (aged 25-32 years) for controls had done cervical MRI from January 2001 through June 2002. Cervical MRI was done in neutral and neck flexed positions using 1.5 T system (Sonata, Siemens, Germany) and obtained images were reviewed by two radiologists. We compared the cervical MRI findings of 7 patients with those of 5 healthy controls regarding neck flexion induced changes in the lower cervical segments. Neutral positioned cervical sagittal MR images revealed subtle or mild cord atrophy in only 2 patients. On maximal neck flexion, AP diameter of the cresent posterior epidural space was increased and also cord flattening with anterior shifting of posterior wall of the lower cervical dural canal was noted in all 7 patients. In all 7 cases, the level and side of spinal cord changes corresponded to the clinical phenotype. All control subjects showed neither cord flattening nor widening of posterior epidural space on neck flexion. In patients with the clinical diagnosis of Hirayama's disease, MRI scans obtained on maximal neck flexion showed characteristically dynamic flattening of lower cervical cord and widening of posterior epidural space. Therefore, a flexion MR study is needed to prove the diagnosis.

  13. Genetic screening of spinal muscular atrophy using a real-time modified COP-PCR technique with dried blood-spot DNA.

    Science.gov (United States)

    Ar Rochmah, Mawaddah; Harahap, Nur Imma Fatimah; Niba, Emma Tabe Eko; Nakanishi, Kenta; Awano, Hiroyuki; Morioka, Ichiro; Iijima, Kazumoto; Saito, Toshio; Saito, Kayoko; Lai, Poh San; Takeshima, Yasuhiro; Takeuchi, Atsuko; Bouike, Yoshihiro; Okamoto, Maya; Nishio, Hisahide; Shinohara, Masakazu

    2017-10-01

    Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in SMN1. More than 95% of SMA patients carry homozygous SMN1 deletion. SMA is the leading genetic cause of infant death, and has been considered an incurable disease. However, a recent clinical trial with an antisense oligonucleotide drug has shown encouraging clinical efficacy. Thus, early and accurate detection of SMN1 deletion may improve prognosis of many infantile SMA patients. A total of 88 DNA samples (37 SMA patients, 12 carriers and 39 controls) from dried blood spots (DBS) on filter paper were analyzed. All participants had previously been screened for SMN genes by PCR restriction fragment length polymorphism (PCR-RFLP) using DNA extracted from freshly collected blood. DNA was extracted from DBS that had been stored at room temperature (20-25°C) for 1week to 5years. To ensure sufficient quality and quantity of DNA samples, target sequences were pre-amplified by conventional PCR. Real-time modified competitive oligonucleotide priming-PCR (mCOP-PCR) with the pre-amplified PCR products was performed for the gene-specific amplification of SMN1 and SMN2 exon 7. Compared with PCR-RFLP using DNA from freshly collected blood, results from real-time mCOP-PCR using DBS-DNA for detection of SMN1 exon 7 deletion showed a sensitivity of 1.00 (CI [0.87, 1.00])] and specificity of 1.00 (CI [0.90, 1.00]), respectively. We combined DNA extraction from DBS on filter paper, pre-amplification of target DNA, and real-time mCOP-PCR to specifically detect SMN1 and SMN2 genes, thereby establishing a rapid, accurate, and high-throughput system for detecting SMN1-deletion with practical applications for newborn screening. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  14. Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.

    Science.gov (United States)

    Comley, Laura H; Nijssen, Jik; Frost-Nylen, Johanna; Hedlund, Eva

    2016-05-01

    Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind-paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. J. Comp. Neurol. 524:1424-1442, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

  15. Carrier screening for spinal muscular atrophy (SMA in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study.

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    Yi-Ning Su

    Full Text Available BACKGROUND: Spinal muscular atrophy (SMA is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50 as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program. METHODS AND FINDINGS: This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1 pregnant women were tested for SMA heterozygosity; (2 if the mother was determined to be heterozygous for SMA (carrier status, the paternal partner was then tested; (3 if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%. The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49% and SMA was diagnosed in 12 (27.91% fetuses. The prevalence of SMA in our population was 1 in 8,968. CONCLUSION: The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.

  16. Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

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    Ximena Paez-Colasante

    Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

  17. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

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    John T Kissel

    Full Text Available BACKGROUND: Multiple lines of evidence have suggested that valproic acid (VPA might benefit patients with spinal muscular atrophy (SMA. The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. METHODS: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend, timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP, handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. RESULTS: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. CONCLUSIONS: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

  18. Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

    Science.gov (United States)

    Baasch, Anna-Lena; Hüning, Irina; Gilissen, Christian; Klepper, Joerg; Veltman, Joris A; Gillessen-Kaesbach, Gabriele; Hoischen, Alexander; Lohmann, Katja

    2014-04-01

    Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

  19. Muscle atrophy

    Science.gov (United States)

    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 ...

  20. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

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    Kathryn J Swoboda

    2010-08-01

    Full Text Available Valproic acid (VPA has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1 and an ambulatory group of "walkers" (cohort 2. Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51. Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409. Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03 compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007.This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that

  1. Learning about Spinal Muscular Atrophy

    Science.gov (United States)

    ... in terms of medical and in particular respiratory, nutritional and rehabilitation care. In addition, several drugs have been identified in ... research program developed by NINDS to accelerate the process of developing a safe and effective treatment for ...

  2. Multifocal motor neuropathy and progressive atrophy : Pathophysiological similarities and differences

    NARCIS (Netherlands)

    Vlam, L.

    2015-01-01

    Progressive muscular atrophy (PMA) and multifocal motor neuropathy (MMN) share many clinical similarities. They are both characterized by progressive asymmetric muscle weakness with atrophy and fasciculations. Tendon reflexes are normally low or absent, although in some patients with MMN normal

  3. Autologous adipose-derived stem cells attenuate muscular atrophy and protect spinal cord ventral horn motor neurons in an animal model of burn injury.

    Science.gov (United States)

    Wu, Sheng-Hua; Huang, Shu-Hung; Lo, Yi-Ching; Chai, Chee-Yin; Lee, Su-Shin; Chang, Kao-Ping; Lin, Sin-Daw; Lai, Chung-Sheng; Yeh, Jwu-Lai; Kwan, Aij-Lie

    2015-08-01

    Burn injuries might increase muscle mass loss, but the mechanisms are still unclear. In this study, we demonstrated that burn injury induced spinal cord ventral horn motor neuron (VHMN) apoptosis and subsequently caused muscle atrophy and revealed the potential protection of autologous adipose-derived stem cells (ASCs) transplantation on spinal cord VHMNs and muscle against burn injury. Third-degree hind-paw burns were established by contact with a 75°C metal surface for 10 seconds. Adipose tissues were harvested from the groin fat pad, expanded in culture and labeled with chloromethyl-benzamido/1,1'-dioctadecyl-3,3,3',3'- tetramethyl indocarbocyanine perchlorate. The ASCs were transplanted into the injured hind paw at 4 weeks after burn injury. The lumbar spinal cord, sciatic nerve, gastrocnemius muscle and hind-paw skin were processed for immunofluorescent staining at 4 weeks after transplantation, including terminal deoxynucleotidyl transferase (TUNEL) assay, caspase-3, caspase-9, CD 90 and S100, and the gastrocnemius muscle was evaluated through the use of hematoxylin and eosin staining. Caspase-3-positive, caspase-9-positive and TUNEL-positive cells were significantly increased in the corresponding dermatome spinal cord VHMNs after burn injury. Moreover, the decrease of Schwann cells in sciatic nerve and the increase of denervation atrophy in gastrocnemius muscle were observed. Furthermore, ASCs transplantation significantly attenuated apoptotic death of VHMNs and the area of muscle denervation atrophy in the gastrocnemius muscle fibers. The animal model of third-degree burns in the hind paw showed significant apoptosis in the corresponding spinal cord VHMNs, which suggests that neuroprotection might be the potentially therapeutic target in burn-induced muscle atrophy. ASCs have potential neuroprotection against burn injuries through its anti-apoptotic effects. Copyright © 2015. Published by Elsevier Inc.

  4. Adrenomyeloneuropathy with bulbar palsy: A rare association

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    Vishal Annaji Chafale

    2014-01-01

    Full Text Available Adrenomyeloneuropathy (AMN is a variant of adrenoleukodystrophy (ALD, an X-linked recessive peroxisomal disorder associated with accumulation of very long chain fatty acids (VLCFA. Mutations of this gene lead to abnormal peroxisomal β-oxidation, which results in the harmful accumulation of VLCFAs in affected cells. Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. Bulbar palsy in a case of AMN is very unusual. We report a case of a 22-year-old male with AMN who developed adrenal insufficiency at the age of 4 years successfully treated by gluco- and mineralocorticoids followed by features of myeloneuropathy with bulbar palsy. AMN with prominent bulbar symptoms emphasizes the diverse clinical manifestation of this disease.

  5. Spinal muscular atrophy type II (intermediary and III (Kugelberg-Welander: evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool Atrofia muscular espinhal tipo II (intermediária e III (Kugelberg-Welander: evolução de 50 pacientes com fisioterapia e hidroterapia em piscina

    Directory of Open Access Journals (Sweden)

    Márcia C. B. Cunha

    1996-09-01

    Full Text Available We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA who were being treated with individual conventional physiotherapy. Hydrotherapy was performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and for forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test, and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.A hidroterapia foi realizada em SO pacientes com atrofia muscular espinhal, os quais foram também tratados com fisioterapia individual convencional. O tratamento hidroterápico foi realizado em piscina aquecida numa temperatura de aproximadamente 30° Celsius, duas vezes por semana, durante 30 minutos em crianças e 45 minutos em adultos num período de dois anos. Os benefícios deste tipo de tratamento foram avaliados de acordo com a evolução clínica, o MMT(Teste de Força Muscular e a Escala de Barthel. Os pacientes foram reavaliados a cada dois meses. Após dois anos de tratamento nós observamos que as deformidades nos quadris, joelhos e pés foram progressivas em todos os pacientes do Tipo II e em alguns do Tipo III. Houve estabilização da força muscular na maioria dos pacientes com SMA Tipo III, e melhora da força em alguns; nos

  6. Buccal Mucosa Urethroplasty for Bulbar Urethral Strictures ...

    African Journals Online (AJOL)

    After the bulbar urethra is exposed, we perform a dorsal endoscopic cold knife urethrotomy until the urethra is fully opened. After measurement of the defect, the graft is harvested from the lower lip and sutured to the urethra and to the corpora cavernosa. A transurethral grooved catheter and suprapubic drainage are left for 7 ...

  7. Estimulação elétrica neuromuscular de média freqüência (russa em cães com atrofia muscular induzida Medium frequency neuromuscular electrical stimulation (russian in dogs with induced muscle atrophy

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    Charles Pelizzari

    2008-06-01

    Full Text Available A estimulação elétrica neuromuscular (EENM de média freqüência (Russa ou de Kotz pode ser empregada para a recuperação de massa muscular em animais apresentando atrofia muscular por desuso. Assim, o objetivo deste trabalho foi empregar a EENM de média freqüência no quadríceps femoral de cães com atrofia muscular induzida, avaliando-se a ocorrência de ganho de massa. Foram utilizados oito cães em dois grupos denominados de GI ou controle e de GII ou tratado. Para a indução da atrofia muscular, a articulação fêmoro-tíbio-patelar esquerda foi imobilizada por 30 dias. Após 48 horas da remoção, foi realizada a EENM nos cães do grupo II, três vezes por semana, com intervalo de 48 horas cada sessão, pelo período de 60 dias. Foram avaliadas a mensuração da perimetria da coxa, da goniometria do joelho, as enzimas creatina-quinase (CK e morfometria das fibras musculares em cortes transversais do músculo vasto lateral, colhido mediante a biópsia muscular. A EENM foi empregada no músculo quadríceps femoral numa freqüência de 2.500Hz, largura de pulso de 50% e relação de tempo on/off de 1:2. Não houve diferença significativa quanto aos valores de perimetria da coxa e a atividade da enzima CK entre os grupos I e II. Na goniometria, houve diminuição significativa (PThe medium frequency neuromuscular electrical stimulation (NMES (Russa or Kotz is designed for recuperation of muscle mass in dogs with muscular atrophy in disuse. This study aims to utilize medium frequency NMES on the femoral quadriceps of dogs with induced muscular atrophy and evaluate the occurrence of gain in mass. Eight dogs in two groups denominated GI, or control, and GII, or treated were used. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days. NMES treatment began 48 hours after the removal of the immobilization device on dogs from group II and was carried out three times per week, with an

  8. Avaliação dos resultados do tratamento cirúrgico da escoliose na atrofia muscular espinhal tipo 2 Evaluación de los resultados del tratamiento quirúrgico de la escoliosis en la atrofia muscular espinal tipo 2 Results evaluation of surgical treatment of scoliosis in spinal muscular atrophy type 2

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    Luiz Eduardo Munhoz da Rocha

    2011-01-01

    evaluaron el grado y el porcentaje de corrección de la deformidad y la oblicuidad pélvica después de la operación y la pérdida, además de las complicaciones y el impacto del tratamiento sobre la función respiratoria. RESULTADOS: El promedio de seguimiento fue 77,5 meses (6,4 años ± 58,9 meses (4,9 años, el ángulo de Cobb antes de la cirugía en promedio 76,1° ± 31,7° (35° a 144° y el postoperatorio fue 29,5° ± 23,2° (5° a 90°, con un promedio de corrección de 46,6° (61,29%. La oblicuidad pélvica promedio en el preoperatorio fue 15,1 ° ± 13,3° (variación de 0 ° a 37 ° y después de la operación 8,5° ± 9,9° (variación de 0° a 30°, con una corrección promedio de 6,5 ° (43,37%. Cinco pacientes presentaron complicaciones (41,6%. La Capacidad Ventilatoria Forzada (CVF preoperatoria promedio fue 62,9% ± 38,6% (variación de 23,3% a 89%, y 45,9% ± 25,0% (variación de 15% a 86,2% en la última evaluación. La disminución fue de 17% de la capacidad vital, con una reducción de 2,4% por año de seguimiento. CONCLUSIONES: El tratamiento quirúrgico de la escoliosis, en pacientes con AME, permite la corrección de la oblicuidad pélvica y restaurar el equilibrio sagital y coronal, liberando las manos para las actividades de la vida diaria. La función pulmonar se vio afectada positivamente por el tratamiento.OBJECTIVE: To evaluate the outcome of surgical treatment of scoliosis in patients with spinal muscular atrophy (SMA type 2. METHODS: A retrospective study with 12 patients with SMA type 2 who underwent arthrodesis and instrumentation for scoliosis correction with more than two years of follow-up. The degree and rate of correction of deformity and pelvic obliquity postoperatively and loss in the last evaluation were evaluated, in addition to the complications and the impact of treatment on respiratory function. RESULTS: Mean follow-up was 77.5 months (6.4 years ± 58.9 months (4.9 years, Cobb angle before surgery averaged 76.1° ± 31.7

  9. Mandibular dysfunction as a reflection of bulbar involvement in SMA type 2 and 3.

    NARCIS (Netherlands)

    Bruggen, H.W. van; Wadman, R.I.; Bronkhorst, E.M.; Leeuw, M. de; Creugers, N.H.; Kalaykova, S.I.; Pol, W.L. van der; Steenks, M.H.

    2016-01-01

    OBJECTIVE: In a cross-sectional study, we aimed to determine (1) the effect of spinal muscular atrophy (SMA) type 2 and 3 on mandibular function reflected as masticatory performance, mandibular range of motion, and bite force and (2) the predictors of mandibular dysfunction. METHODS: Sixty patients

  10. Muscular Dystrophy

    Science.gov (United States)

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

  11. Dorsal onlay graft bulbar urethroplasty using buccal mucosa ...

    African Journals Online (AJOL)

    It can be used for penile urethral stricture repair and different types of dorsal onlay graft urethroplasty for bulbar urethral stricture repair. The current paper describes, step by step, Barbagli technique of dorsal onlay graft bulbar urethroplasty using buccal mucosa. The preoperative patient evaluation and postoperative course ...

  12. Multiple System Atrophy

    Science.gov (United States)

    ... Home » Disorders » Patient & Caregiver Education » Fact Sheets Multiple System Atrophy Fact Sheet What is multiple system atrophy? ... can I get more information? What is multiple system atrophy? Multiple system atrophy (MSA) is a progressive ...

  13. Genetics Home Reference: spinal muscular atrophy

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    ... within cells are impaired. A decrease in chemical messaging between neurons that control muscle movement is thought ... API Site Map Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & Players U.S. Department of Health & ...

  14. Types of SMA (Spinal Muscular Atrophy)

    Science.gov (United States)

    ... Research Publications Spinraza Support & Care For Newly Diagnosed Care Packages Information Packets Equipment Pool Living With SMA Medical Issues Palliative Breathing Orthopedics Nutrition Equipment Daily Life At School At Home Adults With SMA Play Travel Grief & Loss Community & ...

  15. Bulbar dysfunction in normal pressure hydrocephalus: a prospective study.

    Science.gov (United States)

    Chankaew, Ekawut; Srirabheebhat, Prajak; Manochiopinig, Sriwimon; Witthiwej, Theerapol; Benjamin, Itsara

    2016-09-01

    OBJECTIVE Normal pressure hydrocephalus (NPH) is clinically characterized by gait disturbance, cognitive impairment, and urinary incontinence, as well as enlargement of the ventricles. To the best of the authors' knowledge, there have been no previous publications regarding the correlation between bulbar dysfunction and NPH. The primary objective of this study was to compare preoperative and postoperative prevalence of bulbar dysfunction in patients with NPH. Secondary objectives included assessing the results of surgery for swallowing, speech, gait, cognition, and urination, and evaluating the correlation between bulbar dysfunction and triad symptoms. METHODS Fifty-three patients with NPH who underwent shunt placement surgery at Siriraj Hospital were included in the study. Patients were evaluated for gait, cognition, urination, swallowing, and speech before and 6 months after shunt placement. Triad symptoms were assessed using standard methods. Bulbar dysfunctions were assessed using the Swallowing Problem Questionnaire, Thai Articulation Test, Resonation Screening Test (RST), and Thai Nasality Test. The Thai Speech Assessment Program and nasometer were used for objective speech measurement. RESULTS Preoperatively, 86% (43/50) of patients had swallowing problems and 75% (37/49) had speech problems, as measured by the RST. Postoperatively, there was significant improvement in swallowing (p nasometer test. All triad symptoms were improved. There were significant correlations between swallowing impairment and gait disturbance (r = 0.358, p = 0.009), and RST and cognitive impairment (r = -0.502, p < 0.001). CONCLUSIONS This is the first study of bulbar dysfunction in patients with NPH. The results showed that the prevalence of bulbar dysfunction is very high. The correlation between bulbar dysfunction and the classic NPH triad has been documented and published. These bulbar symptoms also significantly improved after surgery. As such, bulbar dysfunction should be

  16. Muscular Dystrophy

    Science.gov (United States)

    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 ...

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

    Science.gov (United States)

    Wirth, B; Pick, E; Leutner, A; Dadze, A; Voosen, B; Knapp, M; Piechaczek-Wappenschmidt, B; Rudnik-Schöneborn, S; Schönling, J; Cox, S

    1994-03-01

    The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we 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-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). 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 (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), 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-q13.3. 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- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained

  18. Slow saccades in bulbar-onset motor neurone disease.

    Science.gov (United States)

    Donaghy, Colette; Pinnock, Ralph; Abrahams, Sharon; Cardwell, Chris; Hardiman, Orla; Patterson, Victor; McGivern, R Canice; Gibson, J Mark

    2010-07-01

    Historical studies of eye movements in motor neurone disease (MND) have been conflicting although current findings suggest that eye movement abnormalities relate to frontal lobe impairment. Numerous case reports, however, describe slow saccades and supranuclear gaze palsies in patients with MND often associated with bulbar-onset disease. We performed a study of saccades and smooth pursuit in a large group of patients with MND to examine for any differences between bulbar-onset and spinal-onset patients. Forty-four patients (14 bulbar-onset and 30 spinal-onset patients) and 45 controls were recruited. Reflexive saccades, antisaccades and smooth pursuit were examined using infra-red oculography and all subjects then underwent neuropsychological evaluation. Reflexive saccades were found to be slower in bulbar-onset compared to spinal-onset patients and controls (p = 0.03, p = 0.05). Antisaccade latency (p = 0.01) and antisaccade type 1 errors (p = 0.03, p = 0.04) were increased in patients compared to controls. 'Proportion of time spent in smooth pursuit' and smooth pursuit 'velocity gain' were reduced in patients compared to controls (p = 0.000, p = 0.001). Antisaccade errors and velocity gain correlated with neuropsychological measures sensitive to lesions of the frontal lobes. This is the first study to highlight the presence of slow saccades in bulbar-onset MND. These findings suggest that slow saccades may be due to increased brainstem pathology in bulbar-onset disease that involves burst cell neurons. Furthermore these observations highlight the potential for overlap between bulbar-onset MND and progressive supranuclear palsy (PSP) as both can have a bulbar palsy and slowed saccades.

  19. Muscular Dystrophy

    Science.gov (United States)

    ... Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy . Muscle Nerve. Jul 2006;34(1):1-15. Congenital ( ... affected? Throat References: 1. Emery AEH. The muscular ... V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of ...

  20. A sphenoid sinus mucocele simulating as retro bulbar optic neuritis

    Directory of Open Access Journals (Sweden)

    Anoop Kishore Gupta

    2012-01-01

    Full Text Available A 25-year-old male presented with complaints of sudden diminution of vision with pain on eye movement in the left eye which was diagnosed clinically as retro bulbar optic neuritis. However, magnetic resonance imaging (MRI showed lesion consistent with sphenoid sinus mucocele. Early surgical removal of mucocele led to complete recovery of vision, contrast and visual field. A high index of suspicion is necessary for intracranial lesions in all cases of retro bulbar neuritis, especially those with atypical symptoms.

  1. Atrophy of sacrospinal muscle groups in patients with chronic, diffusely radiating lumbar back pain

    Energy Technology Data Exchange (ETDEWEB)

    Laasonen, E.M.

    1984-01-01

    After surgery necessitated by lumbar back pain syndromes, radiolucency verified by CT may appear in the sacrospinal muscle group on the operate side. This radiolucency represents muscular atrophy and is in its most severe form a result of the replacement of muscle tissue with adipose tissue. Such muscular atrophy appeared in the present series in 31 out of all 156 patients (19.9%) and in 29 out of 94 patients operated on because of radiating lumbar back pain (30.9%). The radiological appearance, extent, and HU values of this muscular atrophy are presented in detail. Only weak correlations with the multitude of clinical symptoms and signs were found in this retrospective study. The effects of irreversible muscular atrophy on the indications for surgery and physiotherapy are discussed.

  2. Muscular Dystrophy

    Science.gov (United States)

    ... Inheritance patterns Muscular dystrophy Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  3. Anatomy of cerebellar nucleo-bulbar projections in the rat

    NARCIS (Netherlands)

    T.M. Teune (Thea)

    1999-01-01

    textabstractThe cerebellum is located caudal to the cerebral hemispheres and is connected to the rest of the brain by way of three "peduncles", that convey its afferent and efferent information. The cerebellum is functionally related to spinal, bulbar and cerebral motor systems. Its role in the

  4. Ventral onlay graft bulbar urethroplasty using buccal mucosa

    African Journals Online (AJOL)

    H. Wessells

    2016-01-21

    Jan 21, 2016 ... web page of the journal www.ees.elsevier.com/afju · www.sciencedirect.com. Review. Ventral onlay graft bulbar urethroplasty using ..... use and increase probability of long term success in patients with compromised urethras. Conflict of interest. No conflict of interest. References. [1] Santucci RA, Joyce GF, ...

  5. Review: Non-transecting bulbar urethroplasty using buccal mucosa ...

    African Journals Online (AJOL)

    Augmentation urethroplasty using oral mucosal graft has become the standard surgical treatment of long bulbar strictures. In very tight strictures the urethral plate is narrowed to the extent that an almost circumferential substitution with oral graft is necessary, with suboptimal results. If the obliterative segment within a longer ...

  6. Ventral onlay graft bulbar urethroplasty using buccal mucosa ...

    African Journals Online (AJOL)

    Objective: To assess the ongoing role of ventral onlay oral mucosa free graft in the treatment of bulbar urethral stricture. Methods: Detailed review of technical consideration and outcomes from the author's institution along with review of other peer reviewed literature. Results: Of 62 patients undergoing ventral onlay buccal ...

  7. Non-transecting bulbar urethroplasty using buccal mucosa

    African Journals Online (AJOL)

    S. Bugeja

    2015-12-02

    Dec 2, 2015 ... Augmentation urethroplasty using oral mucosal graft has become the standard surgical treatment of long bulbar strictures. .... complications [14]. The legs are supported in Allen® Yellofin® stir- rups. Anti-thromboembolic stockings and pneumatic intermittent calf compression devices are used routinely.

  8. Optic nerve atrophy

    Science.gov (United States)

    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. ...

  9. Multiple System Atrophy (MSA)

    Science.gov (United States)

    Multiple system atrophy (MSA) Overview Multiple system atrophy (MSA) is a rare, degenerative neurological disorder affecting your body's involuntary (autonomic) functions, including blood pressure, breathing, bladder function and muscle ...

  10. Influência da adequação postural em cadeira de rodas na função respiratória de pacientes com amiotrofia espinhal tipo II Influence of wheelchair positioning aids on the respiratory function of patients with type II spinal muscular atrophy

    Directory of Open Access Journals (Sweden)

    Luanda André Collange

    2009-09-01

    Full Text Available Este estudo visou determinar a influência da adequação postural em cadeira de rodas na função respiratória de pacientes com amiotrofia espinhal tipo II (AME. Doze pacientes (idades entre 7 e 24 anos com diagnóstico de AME II, confirmado por achados clínicos e análise genética, participaram do estudo. Os parâmetros respiratórios - volume minuto (VM, volume corrente (VC, capacidade vital forçada (CVF, pressões inspiratória (PImáx e expiratória (PEmáx máximas e pico de fluxo expiratório (PFE - na cadeira de rodas individual, com adaptações, e em uma cadeira de rodas padrão, isto é, sem reclinação ou inclinação. Os resultados mostram valores melhores estatisticamente significativos de todos os parâmetros respiratórios (VM, p=0,002; VC, p=0,003; CVF, p=0,017; PImáx, p=0,002; PEmáx, p=0,006; e PFE, p=0,007 nas medidas tomadas na cadeira adaptada para a postura adequada. Os resultados permitem concluir que a adequação postural em cadeira de rodas influencia positivamente a função respiratória de pacientes com AME tipo II.This study aimed at determining the influence of adequate wheelchair positioning aids on the respiratory function in spinal muscular atrophy (SMA type II patients. Twelve patients (aged 7 to 24 with SMA diagnosed by clinical findings and confirmed by genetic analysis, who owned wheelchairs with positioning aids, underwent spirometric assessment - as to minute volume (MV, tidal volume (TV, forced vital capacity (FVC, maximum inspiratory (IPmax and expiratory (EPmax pressures, and peak expiratory flow (PEF - both on their own wheelchair and on a standard wheelchair with no recline or tilt. Results show significantly better values in all assessed parameters (MV, p=0.002; TV, p=0.003; FVC, p=0.017; IPmax, p=0.002, EPmax, p=0.006; and PEF, p=0.007 of measures taken at the patient's own chair, with positioning aids. These results allow for concluding that wheelchair positioning aids may positively

  11. Aspectos clínicos e concentração sérica da creatina-quinase e lactato-desidrogenase em cães submetidos à fisioterapia após atrofia muscular induzida Clinical aspects and serum concentration creatina kinase and lactate dehydrogenase in dogs submitted to physiotherapy after induced muscle atrophy

    Directory of Open Access Journals (Sweden)

    Soraia Figueiredo de Souza

    2011-07-01

    Full Text Available Avaliou-se a resposta de diferentes protocolos fisioterapêuticos em cães após a indução de atrofia muscular por meio da imobilização do joelho por 30 dias. Os grupos foram denominados grupo C ou controle, grupo E (massagem, movimentação passiva e eletroterapia, grupo H (massagem, movimentação passiva e hidroterapia em esteira aquática e grupo EH (massagem, movimentação passiva, eletroterapia e hidroterapia em esteira aquática. Foram mensurados os graus de claudicação, arco do movimento, circunferência da coxa e a variação sérica das enzimas creatina-quinase e lactato-desidrogenase. De acordo com os resultados encontrados, foi possível concluir que as modalidades terapêuticas de massagem, movimentação passiva da articulação, estimulação elétrica neuromuscular e hidroterapia por caminhada em esteira aquática aceleram a recuperação clínica em cães com atrofia muscular induzida.The response of different physiotherapeutic treatment protocols was evaluated in dogs after muscle atrophy induced by joint immobilization for 30 days. Groups were named C group or control, E group (massage, passive range of motion and neuromuscular electrical stimulation, H group (massage, passive range of motion and aquatic therapy in underwater treadmill and EH group (massage, passive range of motion, neuromuscular electrical stimulation and aquatic therapy in underwater treadmill. It was measured the degree of lameness, range motion, thigh circumference and range of serum creatine kinase (CK and lactate dehydrogenase (LDH. According to the results, it was possible to conclude that associated therapeutics modalities such as massage, passive range of motion of the joint, neuromuscular electrical stimulation and aquatic therapy by walking on underwater treadmill accelerate clinical recovery in dogs with induced muscle atrophy.

  12. Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

    Science.gov (United States)

    Caress, James B; Johnson, Janel O; Abramzon, Yevgeniya A; Hawkins, Gregory A; Gibbs, J Raphael; Sullivan, Elizabeth A; Chahal, Chamanpreet S; Traynor, Bryan J

    2017-11-01

    Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017. © 2016 Wiley Periodicals, Inc.

  13. Bulbar and speech motor assessment in ALS: challenges and future directions.

    Science.gov (United States)

    Green, Jordan R; Yunusova, Yana; Kuruvilla, Mili S; Wang, Jun; Pattee, Gary L; Synhorst, Lori; Zinman, Lorne; Berry, James D

    2013-12-01

    Bulbar motor deterioration due to amyotrophic lateral sclerosis (ALS) leads to the eventual impairment of speech and swallowing functions. Despite these devastating consequences, no standardized diagnostic procedure for assessing bulbar dysfunction in ALS exists and adequate objective markers of bulbar deterioration have not been identified. In this paper, we consider objective measures of speech motor function, which show promise for forming the basis of a comprehensive, quantitative bulbar motor assessment in ALS. These measures are based on the assessment of four speech subsystems: respiratory, phonatory, articulatory, and resonatory. The goal of this research is to design a non-invasive, comprehensive bulbar motor assessment instrument intended for early detection, monitoring of disease progression, and clinical trial application. Preliminary data from an ongoing study of bulbar motor decline are presented, which demonstrate the potential clinical efficacy of the speech subsystem approach.

  14. A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

    OpenAIRE

    Yunusova, Yana; Green, Jordan R.; Wang, Jun; Pattee, Gary; Zinman, Lorne

    2011-01-01

    Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression across speech subsystems, and for addressing the critical need for sensitive outcome measures for ongoing experimental treatment trials. To address this need, we are obtaining longitudinal profiles of bulbar impairment in 100 individuals based on a comprehensive instrumentation-based assessment that yield objective measures. Using instrumenta...

  15. Central nervous system involvement in progressive muscular dystrophy.

    Science.gov (United States)

    Yoshioka, M; Okuno, T; Honda, Y; Nakano, Y

    1980-01-01

    Several abnormalities in the central nervous system were shown in patients with progressive muscular dystrophy using computerised tomography (CT) scans, electroencephalograms, psychometry, and ophthalmological methods. In congenital muscular dystrophy, the most characteristic finding in the CT scan was a low density area in the white matter, seen in 14 (56%) out of 25 cases. In Duchenne dystrophy, slight cerebral atrophy was observed in 20 (67%) out of 30 cases. It was interesting that in the case of Duchenne dystrophy the older the patient, the more severe were the CT findings. In congenital muscular dystrophy half the patients with a low density area showed a spike or a spike-and-wave complex in the electroencephalogram, and optic atrophy was evident in several cases. It is concluded that progressive muscular dystrophy is not only a myogenic disorder but also one which affects the central nervous system. Images Fig. 1 Fig. 2 PMID:7436514

  16. Associations with Meibomian Gland Atrophy in Daily Contact Lens Wearers.

    Science.gov (United States)

    Pucker, Andrew D; Jones-Jordan, Lisa A; Li, Wing; Kwan, Justin T; Lin, Meng C; Sickenberger, Wolfgang; Marx, Sebastian; Srinivasan, Sruthi; Jones, Lyndon W

    2015-09-01

    To determine associations for contact lenses (CLs) and meibomian gland atrophy in a matched-pair study. Contact lens wearers (case) and age- and sex-matched non-contact lens (NCL) wearers with no history of CL use (control) were recruited for a multicenter study. All subjects were administered the Ocular Surface Disease Index questionnaire and a comprehensive battery of clinical tests (e.g., tear breakup time, bulbar and limbal redness, meibography, etc.) were performed. Upper and lower eyelid meibomian gland atrophy were graded with both digital meibography (percent gland atrophy) and visual meiboscore methods. Conditional logistic regression analyses were then used to determine relationships among CL use, meibomian gland atrophy, and ocular surface signs and symptoms. A total of 70 matched pairs were analyzed. The mean (± SD) age of the CL group was 30.6 (± 12.4) years, and that of the NCL group was 30.1 (± 12.2) years. The subjects were 63% female. The association between CL wear and meiboscore was not significant univariately, but the best-fitting multivariate regression model showed that higher meiboscores were associated with being a CL wearer (odds ratio [OR], 2.45) in a model that included eyelid margin erythema (OR, 0.25) and lissamine green staining (OR, 1.25). Percent gland atrophy was not associated with CL wear in regression analysis (p = 0.31). This study determined inconclusive associations with CLs and meibomian gland atrophy. This study also provided a comprehensive assessment of differences between CL and NCL wearers.

  17. Distrofia muscular progressiva: alguns aspectos do diagnõstico diferencial

    Directory of Open Access Journals (Sweden)

    Sylvio Saraiva

    1960-09-01

    Full Text Available The authors call attention to some clinical entities which are less known and more difficult to recognize and with which differential diagnosis of progressive muscular dystrophy should be made (infantile spinal muscular atrophy, amyotonia congenita, congenital acute anterior poliomyelitis, anthro-griposis multiplex, von Gierke's disease, central core disease, chronical polymyositis and dermatomyositis, thyrotoxic myopathy and menopausal dys- trophy. The importance of muscle biopsy in the differential diagnosis is emphasized.

  18. Ventral free oral mucous membrane graft for bulbar urethral stricture.

    Science.gov (United States)

    Haque, M E; Rahman, M A; Islam, M F; Siddique, F H; Uddin, M M; Khondoker, M I; Kaiser, I; Siddiqui, O; Karim, M M; Saha, P; Salam, M A

    2012-10-01

    The use of oral mucous membrane graft onlay urethroplasty represents the most widespread method of bulbar urethral stricture repair. We investigated the short term result of oral mucous membrane graft placed on the ventral surface for management of bulbar urethral stricture. Patients with Bulbar urethral stricture of any length, infection free urinary tract and informed consent for oral mucosa harvesting and urethroplasty were selected for study. We enrolled 108 cases of bulbar urethral stricture patients from January 2004 to July 2009. The mean ± SD preoperative maximum flow rate of 5.2 ± 2.6 ml/sec and mean ± SD PVR 87 ± 58.3 ml were treated by substitution urethroplasty with oral mucous membrane by a single surgical team in a private hospital. Causes of stricture were trauma 26(24.1%), infection 58(53.7%), catheter induced 8(7.4%), post TURP 11(10.2%) and unknown 5(4.6%). Oral mucous membrane was harvested from the cheek or from the inner side of lower lip. Defect of the urethra displayed by longitudinal ventral urethrotomy and the graft was sutured over the edges of the incised urethral mucosa over a 14 Fr latex Foley's catheter. Spongiosum tissue was closed over the graft. Pericatheter urethrogram was performed in all cases to check for the anastomotic leakage and the Catheter was removed after 2 weeks of the procedure. After removal of catheter uroflowmetry & ultrasound scan of bladder were performed to estimate the maximum flow rate and post voidal residue. The patient was followed-up every 3 months with uroflowmetry & ultrasonography. The median (range) age of the patients was 32(21-72) years. Mean follow up period was 36 months (range 12-54). Mean ± SD stricture length was 3.7 ± 2.6 cm. The overall success rate was 91.7%. Mean ± SD flow rate was 23 ± 4.2 ml/sec, mean ± SD post void residue was 25 ± 15.5 ml and patient quality of life (QOL) was excellent in almost all patients. Overall complications were seen in 9(8.3%) cases. Of which

  19. Disease: H00062 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00062 Spinal and bulbar muscular atrophy (SBMA); Kennedy's disease Spinal and bulb...:898-910 (2009) PMID:18775514 Jordan CL, Lieberman AP Spinal and bulbar muscular ...t Med 13:348-53 (2007) PMID:15133611 Katsuno M, Adachi H, Tanaka F, Sobue G Spinal

  20. CABLES MUSCULARES

    Directory of Open Access Journals (Sweden)

    Alejandro Gómez

    Full Text Available Los cables musculares o fibras de nitinol presentan una excelente alternativa a los actuadores convencionales, con una fuerza de actuación muy alta, equivalente a la de los actuadores hidráulicos, proporcionalmente a su peso, además de su acción silenciosa. Este material, inventado en 1963, aún no es muy conocido y de ahí que se haya realizado una recopilación de sus propiedades. Entre ellas, la temperatura de transición es la más importante, por ser la que activa la aleación. Muchos sistemas se han creado para alcanzar adecuadamente la temperatura de transición, y también se continúa en la investigación de métodos que ayuden a lograr un control preciso del movimiento de la aleación con memoria de forma (SMA.

  1. Optic Nerve Atrophy

    Science.gov (United States)

    ... cord (hydrocephalus) may prevent further optic nerve damage. Spectacles may be prescribed to correct refractive error. When optic atrophy is unilateral protection of the good eye is essential and wearing of protective lenses should ...

  2. Muscle Atrophy Reversed by Growth Factor Activation of Satellite Cells in a Mouse Muscle Atrophy Model

    DEFF Research Database (Denmark)

    Hauerslev, Simon; Vissing, John; Krag, Thomas O

    2014-01-01

    Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory...... factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth...... control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we...

  3. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

    Full Text Available Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

  4. Osteoprotegerin protects against muscular dystrophy.

    Science.gov (United States)

    Dufresne, Sébastien S; Dumont, Nicolas A; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M; Frenette, Jérôme

    2015-04-01

    Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Developmental milestones in type I spinal muscular atrophy.

    Science.gov (United States)

    De Sanctis, Roberto; Coratti, Giorgia; Pasternak, Amy; Montes, Jacqueline; Pane, Marika; Mazzone, Elena S; Young, Sally Dunaway; Salazar, Rachel; Quigley, Janet; Pera, Maria C; Antonaci, Laura; Lapenta, Leonardo; Glanzman, Allan M; Tiziano, Danilo; Muntoni, Francesco; Darras, Basil T; De Vivo, Darryl C; Finkel, Richard; Mercuri, Eugenio

    2016-11-01

    The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Muscle MRI findings in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Gerevini, Simonetta; Scarlato, Marina; Maggi, Lorenzo; Cava, Mariangela; Caliendo, Giandomenico; Pasanisi, Barbara; Falini, Andrea; Previtali, Stefano Carlo; Morandi, Lucia

    2016-03-01

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

  7. Mitochondrial respiratory chain disease presenting as progressive bulbar paralysis of childhood

    NARCIS (Netherlands)

    Roeleveld-Versteegh, ABC; Braun, KPJ; Smeitink, JAM; Dorland, L; de Koning, TJ

    2004-01-01

    We report two siblings with a mitochondrial respiratory chain defect who presented with progressive bulbar paralysis of childhood ( Fazio-Londe disease). Mitochondrial respiratory chain defects should be considered in the differential diagnosis of this rare clinical entity.

  8. Mitochondrial respiratory chain disease presenting as progressive bulbar paralysis of childhood.

    NARCIS (Netherlands)

    Roeleveld-Versteegh, A.B.; Braun, K.P.; Smeitink, J.A.M.; Dorland, L.; Koning, T.J.

    2004-01-01

    We report two siblings with a mitochondrial respiratory chain defect who presented with progressive bulbar paralysis of childhood (Fazio-Londe disease). Mitochondrial respiratory chain defects should be considered in differential diagnosis of this rare clinical entity.

  9. Bulbar Paralysis and Facial Paralysis due to Metastatic Hepatocellular Carcinoma: A Case Report and Literature Review

    National Research Council Canada - National Science Library

    Liu, Min; Liu, Shixin; Liu, Bailong; Liu, Bin; Guo, Liang; Wang, Xu; Wang, Qiang; Yang, Shuo; Dong, Lihua

    2016-01-01

    .... We report a case of bulbar and facial paralysis due to SBM from HCC. A 46-year-old Chinese man presented with a hepatic right lobe lesion that was detected during a routine physical examination...

  10. Clinical Features of Isolated Bulbar Palsy of Amyotrophic Lateral Sclerosis in Chinese Population

    Directory of Open Access Journals (Sweden)

    Hua-Gang Zhang

    2017-01-01

    Conclusions: IBP was evidently different from PBP, which was characterized with the predominance of female, pure LMN bulbar signs, an older onset age, a relative preservation of respiratory function, and a better prognosis.

  11. Agraphia in Bulbar-Onset Amyotrophic Lateral Sclerosis: Not Merely a Consequence of Dementia or Aphasia

    OpenAIRE

    Hiroo Ichikawa; Nobuyoshi Takahashi; Soutaro Hieda; Hideki Ohno; Mitsuru Kawamura

    2008-01-01

    The clinical significance and characteristics of writing errors in bulbar-onset amyotrophic lateral sclerosis (ALS) are not clear. We retrospectively investigated writing samples in 19 patients with bulbar-onset ALS without preceding extra-motor symptoms. Co-development of dementia and/or aphasia was also explored and single photon emission computed tomography (SPECT) images of the brain were reviewed. As a result, a high prevalence of writing errors (15 of the 19 patients) was found. Of note...

  12. Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model.

    Directory of Open Access Journals (Sweden)

    Simon Hauerslev

    Full Text Available Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.

  13. Duchenne muscular dystrophy

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000705.htm Duchenne muscular dystrophy To use the sharing features on this page, please enable JavaScript. Duchenne muscular dystrophy is an inherited disorder. It involves muscle weakness , ...

  14. Six-month effects of a thermodynamic treatment for MGD and implications of meibomian gland atrophy.

    Science.gov (United States)

    Finis, David; König, Claudia; Hayajneh, Jasmin; Borrelli, Maria; Schrader, Stefan; Geerling, Gerd

    2014-12-01

    The aim of this study was to evaluate the 6-month effect of a single automated thermodynamic treatment (LipiFlow) and implications of meibomian gland atrophy on treatment efficacy 6 months after application. We analyzed the data of 26 subjects with meibomian gland dysfunction before and 6 months after treatment. Investigated parameters included subjective symptoms, lipid layer thickness, meibomian gland assessment, tear osmolarity, corneal and conjunctival staining, lid margin parallel conjunctival folds, Schirmer test values, bulbar redness, tear meniscus height, meibomian gland atrophy, and noninvasive tear break-up time. Subjective symptoms (mean Ocular Surface Disease Index, 42 ± 19 to 33 ± 21; P = 0.004, mean Standard Patient Evaluation of Eye Dryness 16 ± 7 to 12 ± 7; P = 0.0001), lipid layer thickness (44.0 ± 15.6 to 51.3 ± 20.4; P = 0.014), number of expressible glands (2.9 ± 1.6 to 6.4 ± 4.6; P < 0.0001), lid margin parallel conjunctival folds (2.3 ± 1.0 to 2.0 ± 0.9; P = 0.04), and bulbar redness (1.4 ± 0.5 to 1.2 ± 0.5; P = 0.0001) were all improved 6 months after treatment. Symptomatic improvement was higher in patients with less severe meibomian gland atrophy compared with patients with more dropout at treatment. There was no change of meibomian gland atrophy 6 months after treatment. In summary, the results showed that a single thermodynamic treatment is effective in the treatment of meibomian gland dysfunction and that the effects last for at least 6 months. We suggest performing meibography in every patient before treatment for better prediction of therapeutic effects.

  15. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... MD Living With MD en español Qué significa distrofia muscular What Is Muscular Dystrophy? Muscular dystrophy (say: MUS- ... blood test if a kid has Becker or Duchenne MD. Or the doctor might take a small piece of the muscle and look at it under a microscope to ...

  16. Perspectives of stem cell therapy in Duchenne muscular dystrophy.

    Science.gov (United States)

    Meregalli, Mirella; Farini, Andrea; Belicchi, Marzia; Parolini, Daniele; Cassinelli, Letizia; Razini, Paola; Sitzia, Clementina; Torrente, Yvan

    2013-09-01

    Muscular dystrophies are heritable and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle, usually caused by mutations in the proteins forming the link between the cytoskeleton and the basal lamina. As a result of mutations in the dystrophin gene, Duchenne muscular dystrophy patients suffer from progressive muscle atrophy and an exhaustion of muscular regenerative capacity. No efficient therapies are available. The evidence that adult stem cells were capable of participating in the regeneration of more than their resident organ led to the development of potential stem cell treatments for degenerative disorder. In the present review, we describe the different types of myogenic stem cells and their possible use for the progression of cell therapy in Duchenne muscular dystrophy. © 2012 The Authors Journal compilation © 2012 FEBS.

  17. Limb Girdle Muscular Dystrophy (LGMD): Case Report.

    Science.gov (United States)

    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.

  18. Bulbar urethroplasty using the dorsal approach: current techniques

    Directory of Open Access Journals (Sweden)

    Barbagli Guido

    2003-01-01

    Full Text Available INTRODUCTION: The use of flaps or grafts is mandatory in patients with longer and complex strictures. In 1995-96 we described a new dorsal onlay graft urethroplasty. Over time, our original technique was better defined and changed. Now this procedure (also named Barbagli technique has been greeted with a fair amount of enthusiasm in Europe and in the United States. SURGICAL TECHNIQUE: The patient is placed in normal lithotomy position, and a midline perineo-scrotal incision is made. The bulbar urethra is then free from the bulbo-cavernous muscles, and is dissected from the corpora cavernosa. The urethra is completely mobilized from the corpora cavernosa, it is rotated 180 degrees, and is incised along its dorsal surface. The graft (preputial skin or buccal mucosa or the flap is fixed and quilted to the tunica albuginea of the corporal bodies. The right mucosal margin of the opened urethra is sutured to the right side of the patch-graft. The urethra is rotated back into its original position. The left urethral margin is sutured to the left side of the patch graft and to the corporal bodies, and the grafted area is entirely covered by the urethral plate. The bulbo-cavernous muscles are approximated over the grafted area. A 16F silicone Foley catheter is left in place. COMMENTS: Dorsal onlay graft urethroplasty is a versatile procedure that may be combined with various substitute materials like preputial skin, buccal mucosa grafts or pedicled flaps.

  19. Microcirculation changes of bulbar conjunctiva at primary pterygium

    Directory of Open Access Journals (Sweden)

    A. V. Petrayevsky

    2014-07-01

    Full Text Available Purpose. To reveal microcirculation changes in nasal part of bulbar conjunctiva at various stages of primary pterygium formation using fluorescent angiography.Methods. 10 eyes (10 patients with pinguecula, 15 eyes (14 patients with primary pterygium were investigated. As a control group 10 eyes (10 patients without pathological changes in nasal part of conjunctiva were investigated. Biomicroscopy and anterior segment fluorescent angiography were performed for all patients.Results. Severe changes of microcirculation in nasal part of conjunctiva in patients with pinguecula and pterygium were revealed in comparison with a control group. The defect of terminal limbal arcades confirmed by fluorescent angiography can be a sign of transformation of pinguecula into pterygium. Primary pterygium gets blood supply from posterior conjunctival arteries, capillary network of a semilunar fold and also from returnable branches of anterior ciliary arteries. Neovascularization going from a semilunar fold to a body of pterygium is one of possible components in pathogenesis of pterygium.Conclusion. The obtained data testify about sign of transformation of pinguecula into pterygium, blood supply sources of pterygium and a role of neogenic vessels from a capillary network of a semilunar fold in pathogenesis of this disease.

  20. Olfaction and Pheromones: Uncanonical Sensory Influences and Bulbar Interactions

    Directory of Open Access Journals (Sweden)

    Víctor Vargas-Barroso

    2017-11-01

    Full Text Available The rodent main and accessory olfactory systems (AOS are considered functionally and anatomically segregated information-processing pathways. Each system is devoted to the detection of volatile odorants and pheromones, respectively. However, a growing number of evidences supports a cooperative interaction between them. For instance, at least four non-canonical receptor families (i.e., different from olfactory and vomeronasal receptor families have been recently discovered. These atypical receptor families are expressed in the sensory organs of the nasal cavity and furnish parallel processing-pathways that detect specific stimuli and mediate specific behaviors as well. Aside from the receptor and functional diversity of these sensory modalities, they converge into a poorly understood bulbar area at the intersection of the main- main olfactory bulb (MOB and accessory olfactory bulb (AOB that has been termed olfactory limbus (OL. Given the intimate association the OL with specialized glomeruli (i.e., necklace and modified glomeruli receiving uncanonical sensory afferences and its interactions with the MOB and AOB, the possibility that OL is a site of non-olfactory and atypical vomeronasal sensory decoding is discussed.

  1. In vivo oximetry of human bulbar conjunctival and episcleral microvasculature using snapshot multispectral imaging.

    Science.gov (United States)

    MacKenzie, L E; Choudhary, T R; McNaught, A I; Harvey, A R

    2016-08-01

    Multispectral imaging (MSI) is a well-established technique for non-invasive oximetry of retinal blood vessels, which has contributed to the understanding of a variety of retinal conditions, including glaucoma, diabetes, vessel occlusion, and retinal auto-regulation. We report the first study to use snapshot multi-spectral imaging (SMSI) for oximetry of the bulbar conjunctival and episcleral microvasculature in the anterior segment of the eye. We report the oxygen dynamics of the bulbar conjunctival and episcleral microvasculature at normoxia and at acute mild hypoxia conditions. A retinal-fundus camera fitted with a custom Image-Replicating Imaging Spectrometer was used to image the bulbar conjunctival and episcleral microvasculature in ten healthy human subjects at normoxia (21% Fraction of Inspired Oxygen [FiO2]) and acute mild hypoxia (15% FiO2) conditions. Eyelid closure was used to control oxygen diffusion between ambient air and the sclera surface. Four subjects were imaged for 30 seconds immediately following eyelid opening. Vessel diameter and Optical Density Ratio (ODR: a direct proxy for oxygen saturation) of vessels was computed automatically. Oximetry capability was validated using a simple phantom that mimicked the scleral vasculature. Acute mild hypoxia resulted in a decrease in blood oxygen saturation (SO2) (i.e. an increase in ODR) when compared with normoxia in both bulbar conjunctival (p microvasculature, and consequently, the first study to directly observe the rapid reoxygenation of hypoxic bulbar conjunctival vessels when exposed to ambient air. Oximetry of bulbar conjunctival vessels could potentially provide insight into conditions where oxygen dynamics of the microvasculature are not fully understood, such as diabetes, sickle-cell diseases, and dry-eye syndrome. Oximetry in the bulbar conjunctival and episcleral microvasculature could be complimentary or alternative to retinal oximetry. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Dominant optic atrophy

    DEFF Research Database (Denmark)

    Lenaers, Guy; Hamel, Christian; Delettre, Cécile

    2012-01-01

    DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC......) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain....

  3. [Muscle fiber atrophy].

    Science.gov (United States)

    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.

  4. Progressive hemifacial atrophy with ciliary body atrophy and ocular hypotony

    Directory of Open Access Journals (Sweden)

    T Ashwini Kini

    2015-01-01

    Full Text Available Progressive hemifacial atrophy (PHA is a disease of unknown etiology affecting one-half of the face. Ocular involvement is uncommon. Atrophy of iris is rare, with only a few cases of partial atrophy being reported in the literature. We report a case of total atrophy of iris and ciliary body with associated ocular hypotony in a 16-year-old girl with PHA. We believe this is the first reported case of complete atrophy of iris and ciliary body in PHA. Ocular hypotony in PHA was thought to be due to intra-ocular inflammation. However in our case it appears to be secondary to severe atrophy of the ciliary body.

  5. Case report of optic atrophy in Dentatorubropallidoluysian Atrophy (DRPLA).

    Science.gov (United States)

    Silver, Michael R; Sethi, Kapil D; Mehta, Shyamal H; Nichols, Fenwick T; Morgan, John C

    2015-12-18

    Dentatorubropallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease that is associated with numerous movement disorders. Ocular problems also occur with DRPLA with reports of corneal endothelial degeneration in some patients living with the disease. We report a new visual problem associated with DRPLA, optic atrophy. A 47 year-old man presented complaining of progressive visual loss associated with optic atrophy on ophthalmological evaluation. He gradually developed a progressive ataxia with dystonia. Brain MRI revealed a diffuse leukoencephalopathy. Genetic analysis revealed 62 CAG repeats in one allele of the DRPLA gene and he was diagnosed with DRPLA. Optic atrophy should be included in the clinical spectrum of DRPLA.

  6. Isolated dysphagia unmasking bulbar neurosarcoidosis and pulmonary sarcoidosis.

    Science.gov (United States)

    Abdallah, Tarek; Abdallah, Mokhtar; Elsayegh, Dany; Chalhoub, Michel; Khoueiry, Georges; Glatman, Alex; Maniatis, Theodore

    2014-06-01

    Dysphagia is a rare manifestation of sarcoidosis. It is more commonly the result of esophageal compression by enlarged mediastinal lymph nodes rather than direct esophageal involvement and rarely secondary to neurosarcoidosis and oropharyngeal dysphagia. We report a 54 year old female presenting with a six month history of worsening dysphagia. She denied respiratory symptoms. Physical exam was normal. ESR was 61 mm/hr. Serum ACE level was 65 mcg/L. Chest X-ray was normal. Esophagram revealed a large amount of contrast pooling in pharyngeal recesses with intermittent laryngeal aspiration. Swallow videofluorography showed a decreased retraction of the base of the tongue, limited laryngeal elevation, and a large amount of contrast pooling in pharyngeal recesses with intermittent laryngeal aspiration. EGD showed a normal opening of the upper esophageal sphincter and the cricopharyngeus appeared normal. Proximal esophageal biopsies were normal. Brain MRI with gadolinium was normal. Lumbar puncture was performed. CSF showed a moderate pleocytosis, a WBC count of 19 with 97% lymphocytes, an elevated total protein level of 85 mg/dl (15-60). Neck CT scan showed no oropharyngeal tissue thickening or infiltration, no masses or enlarged lymph nodes. Chest CT scan showed enlarged intrathoracic lymph nodes and no esophageal compression. Bronchoscopy showed the vocal cords to be intact, and the CD4/CD8 ratio in BAL was 5.3. Subcarinal lymph node EBUS biopsy revealed non caseating granulomas. The patient was started on IV methylprednisolone. Three days later, the swallow videofluorography showed a near complete response to steroids. The patient tolerated regular consistency diet with thin liquids, and she was discharged on a slow taper of prednisone over a period of three months. A unique case of isolated dysphagia unmasking bulbar neurosarcoidosis and pulmonary sarcoidosis is herein reported. Copyright © 2014 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All

  7. Analysis of cardiac exams: electrocardiogram and echocardiogram use In Duchenne muscular dystrophies

    OpenAIRE

    Bachur, Cynthia Kallás; Garcia, Marlon Hermógenes; Bernardino, Camila Araújo; Requel, Rogério Camillo; Bachur, José Alexandre

    2014-01-01

    Introduction Duchenne Muscular Dystrophies (DMD) is a genetic muscle disorder that causes degeneration and atrophy of skeletal muscle and heart. Objective The aim of this survey is accomplish an evaluation electrocardiographic and echocardiography in the patients bearers of Duchene Muscular Dystrophies (DMD), to observe which alterations, which the degree of cardiac compromising these patient present and the effectiveness of these exams in the evaluation cardiologic. Methods Nine patients of ...

  8. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-03-15

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

  9. Atrofia muscular proximal familiar

    Directory of Open Access Journals (Sweden)

    José Antonio Levy

    1962-09-01

    Full Text Available Os autores relatam dois casos de atrofia muscular proximal familiar, moléstia caracterizada por déficit motor e atrofias musculares de distribuição proximal, secundárias a lesão de neurônios periféricos. Assim, como em outros casos descritos na literatura, foi feito inicialmente o diagnóstico de distrofia muscular progressiva. O diagnóstico correto foi conseguido com auxílio da eletromiografia e da biopsia muscular.

  10. ALS Regional Variants (Brachial Amyotrophic Diplpegia, Leg Amyotrophic Diplegia, and Isolated Bulbar ALS)

    Science.gov (United States)

    Jawdat, Omar; Statland, Jeffrey M.; Barohn, Richard J.; Katz, Jonathan; Dimachkie, Mazen M.

    2015-01-01

    Synopsis Amyotrophic lateral sclerosis is a rapidly progressive, invariably fatal disease, comprised of mixed upper and lower motor neuron involvement in different spinal cord regions. Characteristic initial presentations have implications for prognosis. Bulbar onset patients progress more rapidly than limb-onset patients, or patients with a pure lower motor neuron presentation. Other regional variants have been described where disease is restricted to one spinal region at presentation, including a flail arm or flail leg, and restricted respiratory or bulbar disease. More recent descriptions of regional variants suggest some ALS patients have disease isolated to a single spinal region for many years, including: brachial amyotrophic diplegia; leg amyotrophic diplegia; and isolated bulbar palsy. More clearly defining regional variants will have implications for prognosis, but also for understanding the pathophysiology of ALS, for identifying genetic factors related to slower disease progression, and for future clinical trial planning. PMID:26515621

  11. Reconstruction of the bulbar urethra using dorsal onlay buccal mucosal grafts: New concepts and surgical tricks

    Directory of Open Access Journals (Sweden)

    Guido Barbagli

    2006-01-01

    Full Text Available Buccal mucosa onlay graft urethroplasty represents one of the most widespread methods for the repair of strictures in the bulbar urethra, because of its thick and highly vascular spongiosum tissue. Recently the location of the patch has become a contentious issue, since we described our original techniques of dorsal onlay graft urethroplasty. The design rationale for this approach was based on the concept that the corporeal body remains a healthy host for receiving a free transplanted tissues. Moreover, graft fixation onto a defined surface may decrease graft shrinkage and sacculation. The success rate using buccal mucosa grafts for the repair of bulbar urethral strictures has generally been high with dorsal or ventral onlay grafts or using an augmented roof-strip anastomotic urethroplasty. We describe here the fundamental concepts of the bulbar urethra reconstruction using buccal mucosal grafts, presenting a new surgical technique of dorsal onlay buccal mucosa graft urethroplasty using fibrin glue.

  12. Late results of bulbar trigeminal tractotomy. Some remarks on recovery of sensibility.

    Science.gov (United States)

    Moffie, D

    1971-06-01

    Re-examination of eight patients in whom bulbar trigeminal tractotomy had been performed 13 to 15 years previously showed that four had no complaints, and the other four had only very slight complaints about pain. In two patients a Spiller-Frazier operation had been performed after tractotomy, in two patients exairesis of the infraorbital or supraorbital nerve had been done. As bulbar trigeminal tractotomy is a major operation and the risk of recurrence is substantial, the indications for this type of operation have to remain very restricted. Theories to explain the recovery of sensation are discussed. It is possible that regeneration of transected fibres is responsible for the loss of analgesia.

  13. A unique case of isolated sebaceous adenoma of the bulbar conjunctiva

    Directory of Open Access Journals (Sweden)

    Hatice Deniz Ilhan

    Full Text Available ABSTRACT Our patient was a 34 year-old male who presented with a painless conjunctival mass that had developed 3 months before his first visit. On performing slit-lamp biomicroscopy, a lobulated pink-yellowish solid mobile mass was observed on the nasal bulbar conjunctival surface of his left eye. The tumor was excised, and histopathologic examination of the tumor revealed a sebaceous adenoma. Systemic examination was normal. No recurrence was observed during the 24-month follow-up period. Sebaceous adenoma of the bulbar conjunctiva is an extremely rare benign tumor, which may be observed to be isolated in the absence of malignancy.

  14. Facioscapulohumeral muscular dystrophy

    Science.gov (United States)

    ... on this page, please enable JavaScript. Facioscapulohumeral muscular dystrophy is muscle weakness and loss of muscle tissue that gets ... to have children. Alternative Names Landouzy-Dejerine muscular dystrophy Images ... Superficial anterior muscles References Preston DC, Shapiro BE. Proximal, distal, and ...

  15. Paralisia bulbar progressiva juvenil doença de Fazio-Londe: relato de caso Progressive bulbar palsy (Fazio-Londe disease: case report

    Directory of Open Access Journals (Sweden)

    Bianca Helena Brum Batista

    2002-09-01

    Full Text Available A paralisia bulbar progressiva, também denominada doença de Fazio-Londe, caracteriza-se pelo acometimento degenerativo progressivo de nervos cranianos bulbares em crianças. Foi descrita primeiramente por Fazio em 1892 e até a presente data somente 30 casos foram relatados na literatura. Acomete ambos os sexos, assumindo dois padrões clínicos, um de início precoce (idade Progressive bulbar palsy, also called Fazio -Londe disease, is characterized by progressive impairment of cranial nerves in children. It was first reported by Fazio in 1892 and until now only 30 cases have been published in the literature. Both sexes can be affected and clinical course can be divided on early (< 6 years age, predominance of respiratory symptoms and late course (6-20 years of age, predominance of motor symptoms on superior limbs. We report a 4 years old boy that started with intense stridor and respiratory distress, initially being diagnosed as an acute asthma attack. Clinical signs worsened and 12 months latter he already had impairment of cranial nerves V, VII, VIII, IX and X confirmed by clinical examination and neurophysiological evaluation.

  16. 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

    Directory of Open Access Journals (Sweden)

    Meng Wang

    2016-01-01

    Full Text Available 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.

  17. Dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Lenaers Guy

    2012-07-01

    Full Text Available Abstract Definition of the disease Dominant Optic Atrophy (DOA is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3 encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8 are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7 are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of

  18. Dominant optic atrophy.

    Science.gov (United States)

    Lenaers, Guy; Hamel, Christian; Delettre, Cécile; Amati-Bonneau, Patrizia; Procaccio, Vincent; Bonneau, Dominique; Reynier, Pascal; Milea, Dan

    2012-07-09

    DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs

  19. Predicting Early Bulbar Decline in Amyotrophic Lateral Sclerosis: A Speech Subsystem Approach

    Science.gov (United States)

    2015-01-01

    Purpose. To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS) based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach. Method. Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory) functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss. Results. For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate. Conclusions. The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS. PMID:26136624

  20. Predicting Early Bulbar Decline in Amyotrophic Lateral Sclerosis: A Speech Subsystem Approach

    Directory of Open Access Journals (Sweden)

    Panying Rong

    2015-01-01

    Full Text Available Purpose. To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach. Method. Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss. Results. For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate. Conclusions. The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS.

  1. Acute Thyrotoxic Bulbar Myopathy with Encephalopathic Behaviour: An Uncommon Complication of Hyperthyroidism

    Directory of Open Access Journals (Sweden)

    Neeraja J. Boddu

    2013-01-01

    Full Text Available Objective. Acute thyrotoxic bulbar palsy is rare, severe, and rapidly progressive. We describe a case of thyrotoxicosis with bulbar palsy, encephalopathy, and pyramidal tract dysfunction. Case Report. 64-year-old white male with toxic multinodular goiter presented with rapid atrial fibrillation. He had mild tremor, normal cranial nerve examination, 4/5 strength in all extremities, normal reflexes, and down going plantars. TSH was low at 0.09 (normal: 0.34–5.6 uIU/mL, and free T4 was high at 5.22 (normal: 0.47–1.41 ng/dL. Despite optimal AV nodal blockade, he had persistent rapid atrial fibrillation. He later developed cervical dystonia, rigidity, clonus, dysarthria, dysphagia, vocal cord palsy, and absent gag reflex. Thyroid storm was suspected. Neuroimaging and cerebrospinal fluid cultures were nondiagnostic. Acetylcholine receptor antibodies were negative. Swallow ability was impaired with heavy secretions. Remarkable improvement in symptoms was noted after initiation of treatment for thyroid storm. Conclusion. Pyramidal tract symptoms and bulbar palsy may occur with thyrotoxicosis. Cranial nerve involvement and encephalopathy raise a question of primary brain mechanism causing bulbar palsy. This is reversible with prompt treatment of thyroid storm.

  2. Speech Movement Measures as Markers of Bulbar Disease in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Shellikeri, Sanjana; Green, Jordan R.; Kulkarni, Madhura; Rong, Panying; Martino, Rosemary; Zinman, Lorne; Yunusova, Yana

    2016-01-01

    Purpose: The goal of this study was to identify the effects of amyotrophic lateral sclerosis (ALS) on tongue and jaw control, both cross-sectionally and longitudinally. The data were examined in the context of their utility as a diagnostic marker of bulbar disease. Method: Tongue and jaw movements were recorded cross-sectionally (n = 33…

  3. Speech deterioration in amyotrophic lateral sclerosis (ALS) after manifestation of bulbar symptoms.

    Science.gov (United States)

    Makkonen, Tanja; Ruottinen, Hanna; Puhto, Riitta; Helminen, Mika; Palmio, Johanna

    2017-11-21

    The symptoms and their progression in amyotrophic lateral sclerosis (ALS) are typically studied after the diagnosis has been confirmed. However, many people with ALS already have severe dysarthria and loss of adequate speech at the time of diagnosis. Speech-and-language therapy interventions should be targeted timely based on communicative need in ALS. To investigate how long natural speech will remain functional and to identify the changes in the speech of persons with ALS. Altogether 30 consecutive participants were studied and divided into two groups based on the initial type of ALS, bulbar or spinal. Their speech disorder was evaluated on severity, articulation rate and intelligibility during the 2-year follow-up. The ability to speak deteriorated to poor and necessitated augmentative and alternative communication (AAC) methods with 60% of the participants. Their speech remained adequate on average for 18 months from the first bulbar symptom. Severity, articulation rate and intelligibility declined with nearly all participants during the study. To begin with speech deteriorated more in the bulbar group than in the spinal group and the difference remained during the whole follow-up with some exceptions. The onset of bulbar symptoms indicated the time to loss of speech better than when assessed from ALS diagnosis or the first speech therapy evaluation. In clinical work, it is important to take the initial type of ALS into consideration when determining the urgency of AAC measures as people with bulbar-onset ALS are more susceptible to delayed evaluation and AAC intervention. © 2017 Royal College of Speech and Language Therapists.

  4. Advantage of CT scan in muscular pathology. Personal cases and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Laroche, M.; Rousseau, H.; Mazieres, B.; Bonafe, A.; Joffre, F.; Arlet, J.

    1989-05-01

    The advantage of CT scans in muscular pathology is studied. The scan, in addition to the diagnosis of tumors and muscular abscesses, permits to differentiate primary myopathies from neurogenic atrophies: in the course of myopathies, the muscle volume is preserved and they appear as a hypodensity; in neurogenic atrophies, the muscle volume is reduced with preserved density. The CT scan permits to determine the extension of these lesions. In the course of polymyositis, certain forms of rheumatid arthritis, the scan discloses a trabecular and 'worm-eaten' aspect of the muscles. This is also observed after long-term steroid therapy and other endocrine diseases (hyperthyroidism, osteomalacia) indicating an infra-clinical myopathy. In vertebral osteoporosis with fractures and patients with chronic lumbalgia, very ofter, an atrophy of the spinal muscle is observed. Finally, in the course of acquired kyphosis of the adult patient (camptocormia), the CT scan suggest an isolated myopathy, with late manifestations, of the paravertebral muscles.

  5. Multiple system atrophy.

    Science.gov (United States)

    Peeraully, Tasneem

    2014-04-01

    Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the "hot cross bun sign"), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  6. Posterior cortical atrophy.

    Science.gov (United States)

    Zakzanis, K K; Boulos, M I

    2001-11-01

    The term posterior cortical atrophy (PCA) was introduced in 1988 to describe five patients with fairly homogeneous, but otherwise unclassified, symptoms. These patients showed signs of a slowly progressive dementia bearing behavioral and physiologic similarities to Alzheimer's disease, but with notable distinctions. Specifically, PCA is characterized by an early onset of visual agnosia, followed by some or all components of Balint's syndrome, Gerstmann's syndrome, and transcortical sensory aphasia. In this review, the history, epidemiology, pathophysiology, neurobehavioral aspects, assessment (including neurologic and neuropsychologic), differential diagnosis, and treatment recommendations for this disorder are reviewed. As originally defined, PCA appears to be a clinically homogeneous syndrome. The cluster of symptoms that are common to virtually all examined cases evidences this. Although the behavioral and cognitive properties of the disorder are well established, many aspects of PCA remain unclear. Specifically, available research and understanding of PCA epidemiology and treatment are highly inadequate. In fact, the majority of such information regarding PCA is derived from studies of Alzheimer's disease. To a lesser extent, Pick's disease and Creutzfeldt-Jakob disease research have also provided insight into the underpinnings of PCA. Until PCA is categorically defined as a variant or subgroup of these other neurodegenerative disorders, however, such derivations are merely speculations.

  7. [Macular atrophy in Terson's syndrome].

    Science.gov (United States)

    Sánchez-Vicente, J L; Frau-Aguilera, L; Sánchez-Vicente, P; Herrador-Montiel, A; Rueda-Rueda, T; Castilla-Lázpita, A; Romera-Piñero, A; Medina-Tapia, A

    2015-01-01

    The case is presented on a 63-year-old patient with Terson's syndrome who complained of loss of visual acuity. The optical coherence tomography showed macular atrophy. The patient developed macular atrophy probably secondary to macular hemorrhage caused by the rupture of a cerebral aneurysm. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  8. CUG-BP1 regulates RyR1 ASI alternative splicing in skeletal muscle atrophy.

    Science.gov (United States)

    Tang, Yinglong; Wang, Huiwen; Wei, Bin; Guo, Yuting; Gu, Lei; Yang, Zhiguang; Zhang, Qing; Wu, Yanyun; Yuan, Qi; Zhao, Gang; Ji, Guangju

    2015-11-04

    RNA binding protein is identified as an important mediator of aberrant alternative splicing in muscle atrophy. The altered splicing of calcium channels, such as ryanodine receptors (RyRs), plays an important role in impaired excitation-contraction (E-C) coupling in muscle atrophy; however, the regulatory mechanisms of ryanodine receptor 1 (RyR1) alternative splicing leading to skeletal muscle atrophy remains to be investigated. In this study we demonstrated that CUG binding protein 1 (CUG-BP1) was up-regulated and the alternative splicing of RyR1 ASI (exon70) was aberrant during the process of neurogenic muscle atrophy both in human patients and mouse models. The gain and loss of function experiments in vivo demonstrated that altered splicing pattern of RyR1 ASI was directly mediated by an up-regulated CUG-BP1 function. Furthermore, we found that CUG-BP1 affected the calcium release activity in single myofibers and the extent of atrophy was significantly reduced upon gene silencing of CUG-BP1 in atrophic muscle. These findings improve our understanding of calcium signaling related biological function of CUG-BP1 in muscle atrophy. Thus, we provide an intriguing perspective of involvement of mis-regulated RyR1 splicing in muscular disease.

  9. Acute deterioration of bulbar function after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Meijer, Jan-Willem G; van Kuijk, Annet A; Geurts, Alexander C H; Schelhaas, H Jurgen; Zwarts, Machiel J

    2008-04-01

    Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.

  10. Acute bulbar palsy plus syndrome: A rare variant of Guillain-Barre syndrome.

    Science.gov (United States)

    Ray, Sanghamitra; Jain, Prakash Chand

    2016-01-01

    Guillain-Barre syndrome (GBS) is the most common cause of acute flaccid paralysis worldwide both in adult and pediatric population. Although flaccid paralysis is the hallmark of this disease, there are some rare variants which may be easily missed unless suspected. Here, we present a very rare variant of GBS - acute bulbar palsy plus syndrome in a pediatric patient. A 13-year-old female child presented with right-sided lower motor neuron type of facial palsy and palsy of bilateral glossopharyngeal and vagus nerve of 2 weeks duration. On detailed neurological examination, motor and sensory system were normal, but the deep tendon reflexes were absent universally. Nerve conduction study showed demyelinating motor neuropathy. Based on typical clinical course and electrophysiological studies, the diagnosis was made. To the best of our knowledge, this is the first pediatric case of unilateral facial palsy with bulbar involvement without any motor abnormality.

  11. Dismorfia muscular Muscle dysmorphia

    Directory of Open Access Journals (Sweden)

    Sheila Seleri Marques Assunção

    2002-12-01

    Full Text Available Preocupações mórbidas com a imagem corporal eram tidas até recentemente como problemas eminentemente femininos. Atualmente estas preocupações também têm sido encontradas no sexo masculino. A dismorfia muscular é um subtipo do transtorno dismórfico corporal que ocorre principalmente em homens que, apesar da grande hipertrofia muscular, consideram-se pequenos e fracos. Além de estar associada a prejuízos sociais, ocupacionais, recreativos e em outras áreas do funcionamento do indivíduo, a dismorfia muscular é também um fator de risco para o abuso de esteróides anabolizantes. Este artigo aborda aspectos epidemiológicos, etiológicos e padrões clínicos da dismorfia muscular, além de tecer comentários sobre estratégias de tratamento para este transtorno.Morbid concern over body image was considered, until recently, a female issue. Nowadays, it has been viewed as a common male disorder. Muscle dysmorphia, a subtype of a body dysmorphic disorder, affects men who, despite having clear muscular hypertroph,y see themselves as frail and small. Besides being associated to major social, leisure and occupational dysfunction, muscle dysmorphia is also a risk factor for the abuse of steroids. This article describes epidemiological, etiological and clinical characteristics of muscle dysmorphia and comments on its treatment strategy.

  12. Evaluation of Limb-Girdle Muscular Dystrophy

    Science.gov (United States)

    2014-03-06

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

  13. MicroRNA in skeletal muscle development, growth, atrophy, and disease.

    Science.gov (United States)

    Kovanda, Anja; Režen, Tadeja; Rogelj, Boris

    2014-01-01

    MicroRNAs (miRNAs) are short noncoding RNAs that are important global- as well as tissue- and cell-type-specific regulators of gene expression. Muscle-specific miRNAs or myomirs have been shown to control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli, such as exercise. Importantly, myomirs are also involved in the development of muscle atrophy arising from aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. Additionally, muscle atrophy is both induced by and exacerbates many important chronic and infectious diseases. As global yet specific muscle regulators, myomirs are also good candidates for therapeutic use. Understanding the dynamics of myomirs expression and their role in the development of disease is necessary to determine their potential for muscle atrophy prevention. © 2014 John Wiley & Sons, Ltd.

  14. Agraphia in Bulbar-Onset Amyotrophic Lateral Sclerosis: Not Merely a Consequence of Dementia or Aphasia

    Directory of Open Access Journals (Sweden)

    Hiroo Ichikawa

    2008-01-01

    Full Text Available The clinical significance and characteristics of writing errors in bulbar-onset amyotrophic lateral sclerosis (ALS are not clear. We retrospectively investigated writing samples in 19 patients with bulbar-onset ALS without preceding extra-motor symptoms. Co-development of dementia and/or aphasia was also explored and single photon emission computed tomography (SPECT images of the brain were reviewed. As a result, a high prevalence of writing errors (15 of the 19 patients was found. Of note were isolated writing errors with neither dementia nor aphasia verified in 2 patients whose dysarthria was mild enough to evaluate spoken language. The remaining 13 patients also showed agraphia, but either dysarthria was too severe to evaluate aphasia or frontotemporal dementia (FTD-like features co-existed. Of these patients, one who initially lacked dementia subsequently developed FTD-like features. The frequent writing errors were omission or substitution of kana letters and syntactic errors. SPECT images showed bilateral or left-side dominant hypoperfusion in the frontotemporal lobes as a consistent feature. These results show that patients with bulbar-onset ALS frequently exhibit agraphic writing errors and that these are not merely consequences of dementia or aphasia. However, these writing errors may indicate the involvement of frontotemporal language-related areas beyond the primary motor cortex.

  15. Agraphia in bulbar-onset amyotrophic lateral sclerosis: not merely a consequence of dementia or aphasia.

    Science.gov (United States)

    Ichikawa, Hiroo; Takahashi, Nobuyoshi; Hieda, Soutaro; Ohno, Hideki; Kawamura, Mitsuru

    2008-01-01

    The clinical significance and characteristics of writing errors in bulbar-onset amyotrophic lateral sclerosis (ALS) are not clear. We retrospectively investigated writing samples in 19 patients with bulbar-onset ALS without preceding extra-motor symptoms. Co-development of dementia and/or aphasia was also explored and single photon emission computed tomography (SPECT) images of the brain were reviewed. As a result, a high prevalence of writing errors (15 of the 19 patients) was found. Of note were isolated writing errors with neither dementia nor aphasia verified in 2 patients whose dysarthria was mild enough to evaluate spoken language. The remaining 13 patients also showed agraphia, but either dysarthria was too severe to evaluate aphasia or frontotemporal dementia (FTD)-like features co-existed. Of these patients, one who initially lacked dementia subsequently developed FTD-like features. The frequent writing errors were omission or substitution of kana letters and syntactic errors. SPECT images showed bilateral or left-side dominant hypoperfusion in the frontotemporal lobes as a consistent feature. These results show that patients with bulbar-onset ALS frequently exhibit agraphic writing errors and that these are not merely consequences of dementia or aphasia. However, these writing errors may indicate the involvement of frontotemporal language-related areas beyond the primary motor cortex.

  16. Duchenne and Becker Muscular Dystrophies

    Science.gov (United States)

    ... that our son Mike, then age 4, has Duchenne muscular dystrophy, we were devastated. Immediately, our hopes and dreams ... over time, the per- son’s muscle strength declines. Duchenne muscular dystrophy (DMD) was first described by the French neurologist ...

  17. Tratamento cirúrgico da escoliose em pacientes com amiotrofia espinhal com parafusos pediculares (instrumental de 3ª geração e complicações precoces Tratamiento quirúrgico de la escoliosis en pacientes con amiotrofia espinal con tornillos pediculares (instrumental de 3ª generación y complicaciones precoces Surgical treatment of scoliosis in spinal muscular atrophy with pedicle screws (third generation instrumentation and early complications

    Directory of Open Access Journals (Sweden)

    Daniel Cantarelli dos Santos

    2010-06-01

    pacientes tuvieron complicaciones precoces (31.2% con buena resolución. CONCLUSIÓN: el tratamiento quirúrgico de la escoliosis en pacientes con amiotrofia espinal, con artrodesis vía posterior utilizando tornillos pediculares, tiene gran potencial de corrección de la deformidad coronal y de la oblicuidad pélvica, sin grandes complicaciones en el postoperatorio precoz.OBJECTIVES: to report the results on the treatment of scoliosis in spinal muscular atrophy, using posterior arthrodesis with pedicle screws. METHODS: a retrospective study was carried out with 16 patients who underwent posterior spinal fusion with pedicle screws. The general status of the patients, correction of the Cobb angle, correction of pelvic obliquity and early complications were analyzed. RESULTS: the initial Cobb angle mean was 94.6º (65 to 132º turning into 40,4º (2 to 20º after the surgery, correction of 57.2%. The initial pelvic obliquity mean was 34.7º(25 to 56º turning into 11.3º (0 to 20º, correction of 67.4%. CONCLUSIONS: the treatment of scoliosis in spinal muscular atrophy using posterior arthrodesis with pedicle screws presents a great potential of correction for the coronal deformity and pelvic obliquity, without serious early complications.

  18. Therapeutic advances in muscular dystrophy

    OpenAIRE

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystr...

  19. Limb girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Vissing, John

    2016-01-01

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

  20. [Nocturnal stridor in multiple system atrophy

    NARCIS (Netherlands)

    Louter, M.; Pelleboer, R.H.; Broek, G.B. van den; Post, B.; Pevernagie, D.A.; Overeem, S.

    2011-01-01

    BACKGROUND: Multiple system atrophy is a neurodegenerative disorder with parkinsonism, cerebellar ataxia and autonomic dysfunction. The occurrence of nocturnal stridor in patients with multiple system atrophy is associated with a decreased life expectancy. This is what makes adequate treatment so

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

    Directory of Open Access Journals (Sweden)

    Mohamed-Mounir El Mendili

    Full Text Available 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.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.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.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.

  2. [Infantile spinal atrophy: our experience in the last 25 years].

    Science.gov (United States)

    Madrid Rodríguez, A; Martínez Martínez, P L; Ramos Fernández, J M; Urda Cardona, A; Martínez Antón, J

    2015-03-01

    To determine the incidence of spinal muscular atrophy (SMA) in our study population and genetic distribution and epidemiological and clinical characteristics and to analyze the level of care and development. Retrospective descriptive study of patients treated in our hospital in the past 25 years (from 1987 to early 2013), with a clinical and neurophysiological diagnosis of SMA. A total of 37 patients were found, representing an incidence for our reference population and year of 1 case per 10,000 live births. Males predominated (male/female ratio: 1.6/1). The type of SMA diagnosed more frequently was, type i (26 cases), followed by type ii (9 cases), one case with SMA type iii, and one case of spinal muscular atrophy with respiratory distress type 1 (SMARD1). The most frequent genetic alteration was homozygous deletion of exons 7 and 8 of SMN1 gene in 31 cases, while five patients had atypical genetics. The median survival for type i was 8.0 months and 15.8 years for type ii. The incidence in our population remains stable at around 1/10.000. Most cases presented with, predominantly male, typical genetics. In approximately 1/10 patients the genetic alteration was different from the classical one to the SMN gene. The prevalence of AME unrelated SMN gene was 1/37. The level of care has increased in line with social and welfare demands in recent years. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  3. Duchenne muscular dystrophy.

    Science.gov (United States)

    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. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  4. Becker Muscular Dystrophy-Like Myopathy Regarded as So-Called “Fatty Muscular Dystrophy” in a Pig: A Case Report and Its Diagnostic Method

    Science.gov (United States)

    HORIUCHI, Noriyuki; AIHARA, Naoyuki; MIZUTANI, Hiroshi; KOUSAKA, Shinichi; NAGAFUCHI, Tsuneyuki; OCHIAI, Mariko; OCHIAI, Kazuhiko; KOBAYASHI, Yoshiyasu; FURUOKA, Hidefumi; ASAI, Tetsuo; OISHI, Koji

    2013-01-01

    ABSTRACT We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin-embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called “fatty muscular dystrophy”. Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig. PMID:24162004

  5. Acute bulbar palsy plus syndrome: A rare variant of Guillain–Barre syndrome

    OpenAIRE

    Sanghamitra Ray; Prakash Chand Jain

    2016-01-01

    Guillain?Barre syndrome (GBS) is the most common cause of acute flaccid paralysis worldwide both in adult and pediatric population. Although flaccid paralysis is the hallmark of this disease, there are some rare variants which may be easily missed unless suspected. Here, we present a very rare variant of GBS - acute bulbar palsy plus syndrome in a pediatric patient. A 13-year-old female child presented with right-sided lower motor neuron type of facial palsy and palsy of bilateral glossophary...

  6. Atrofia muscular espinhal tipo II (intermediária) e III (Kugelberg-Welander): evolução de 50 pacientes com fisioterapia e hidroterapia em piscina

    OpenAIRE

    Cunha, Márcia C. B. [UNIFESP; Oliveira, Acary Souza Bulle [UNIFESP; Labronici, Rita Helena D. D. [UNIFESP; Gabbai, Alberto Alain [UNIFESP

    1996-01-01

    We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy was performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and for forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. P...

  7. Lobar atrophy without Pick bodies.

    Science.gov (United States)

    Hulette, C M; Crain, B J

    1992-01-01

    Four patients from the Kathleen Price Bryan Brain Bank with clinical Pick's syndrome are presented. Thorough neurological evaluation revealed no evidence of a movement disorder. The brains showed marked knife-blade type atrophy of the frontal and temporal lobes with relative sparing of the superior temporal gyrus and parietal and occipital lobes. There was marked caudate atrophy in all four. Histologically there was severe neuronal loss and gemistocytic astrocytosis in the involved areas with marked myelin pallor in the deep white matter and subcortical gliosis. There was sometimes marked spongiform change in cortical layer 2. There was severe neuronal loss and gliosis of the caudate nucleus. The gross and microscopic features were characteristic of Pick's disease except that careful search failed to uncover either Pick's bodies or Pick's cells. Review of the literature revealed that fronto-temporal cortical and caudate atrophy with clinical features of Pick's disease has received many different names including Pick's disease type C, Pick's disease type II, progressive subcortical gliosis, presenile glial dystrophy, long duration Creutzfeldt-Jakob disease, frontal lobe degeneration, dysphasic dementia, and dementia lacking distinctive histologic features. Nevertheless, the morphologic findings in the present cases so closely resemble Pick's disease that they may well represent endstage Pick's disease. In our experience, such cases account for a significant proportion of non-Alzheimer disease dementia.

  8. Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).

    Science.gov (United States)

    Jawdat, Omar; Statland, Jeffrey M; Barohn, Richard J; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Conjunctival Impression Cytology and Bulbar Surface Epithelium Changes in Patients with Psoriasis

    Directory of Open Access Journals (Sweden)

    Sevda Söker

    2007-01-01

    Full Text Available In this study, we evaluated bulbar surface epithelium changes with conjunctival impression cytology (IC in patients with psoriasis. Our study group consisted of 32 psoriatic patients (64 eyes, who were followed up at Dermatology Department of Dicle University Hospital. Control group comprised 32 healthy volunteers (64 eyes who had no abnormality on routine ophthalmological examination and were in the same age and sex distribution. Specimens for conjunctival IC were obtained with a cellulose acetate filter paper from the upper bulbar conjunctiva and fixed with 70 % ethyl alcohol, 37 % formaldehyde and 20:1:1 glicial asetic acid solution. Specimens were stained with periodic acid Schiff’s and Hematoxylin-eosin. The grades of Nelson system were evaluated with light microscopy. Of the patients with psoriasis, 39 % had grade 0, 36 % grade I, and 25 % grade II conjunctival IC differentiation compared with 78, 22, and 0 %, respectively in the control group (p< 0.001. Snake-like appearance of nuclear chromatin in conjunctival epithelial cells was demonstrated in 3 % of eyes in group I but in no eyes in group II. In conclusion, we showed that there could be early conjunctival changes and squamose metaplasia as well as increased goblet cell density in patients with psoriasis when compared with control group.

  10. Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

    Science.gov (United States)

    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

  11. Limb-Girdle Muscular Dystrophy (LGMD)

    Science.gov (United States)

    ... Blog Donate Search MDA.org Close Limb-Girdle Muscular Dystrophy (LGMD) Share print email share facebook twitter google plus linkedin Limb-Girdle Muscular Dystrophy (LGMD) What is limb-girdle muscular dystrophy? Limb- ...

  12. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    Science.gov (United States)

    ... Health Conditions Fukuyama congenital muscular dystrophy Fukuyama congenital muscular dystrophy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Fukuyama congenital muscular dystrophy is an inherited condition that predominantly affects the ...

  13. Genetics Home Reference: tibial muscular dystrophy

    Science.gov (United States)

    ... Twitter Home Health Conditions Tibial muscular dystrophy Tibial muscular dystrophy Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Tibial muscular dystrophy is a condition that affects the muscles at ...

  14. Cardio-Muscular Conditioner

    Science.gov (United States)

    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.

  15. Microvillous inclusion disease (microvillous atrophy

    Directory of Open Access Journals (Sweden)

    Goulet Olivier

    2006-06-01

    Full Text Available Abstract Microvillous inclusion disease (MVID or microvillous atrophy is a congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea and is characterized by morphological enterocyte abnormalities. MVID manifests either in the first days of life (early-onset form or in the first two months (late-onset form of life. MVID is a very rare disorder of unknown origin, probably transmitted as an autosomal recessive trait. To date, no prevalence data are available. Ultrastructural analyses reveal: 1 a partial to total atrophy of microvilli on mature enterocytes with apical accumulation of numerous secretory granules in immature enterocytes; 2 the highly characteristic inclusion bodies containing rudimentary or fully differentiated microvilli in mature enterocytes. Light microscopy shows accumulation of PAS-positive granules at the apical pole of immature enterocytes, together with atrophic band indicating microvillus atrophy and, in parallel, an intracellular PAS or CD10 positive line (marking the microvillous inclusion bodies seen on electron microscopy. Intestinal failure secondary to diarrhea is definitive. To date, no curative therapy exists and children with MVID are totally dependent on parenteral nutrition. Long-term outcome is generally poor, due to metabolic decompensation, repeated states of dehydration, infectious and liver complications related to the parenteral nutrition. As MVID is a very rare disorder, which is extremely difficult to diagnose and manage, children with MVID should be transferred to specialized pediatric gastro-intestinal centers, if possible, a center equipped to perform small bowel transplantation. Early small bowel transplantation resulting in intestinal autonomy gives new hope for disease management and outcome.

  16. Vessel Sampling and Blood Flow Velocity Distribution With Vessel Diameter for Characterizing the Human Bulbar Conjunctival Microvasculature.

    Science.gov (United States)

    Wang, Liang; Yuan, Jin; Jiang, Hong; Yan, Wentao; Cintrón-Colón, Hector R; Perez, Victor L; DeBuc, Delia C; Feuer, William J; Wang, Jianhua

    2016-03-01

    This study determined (1) how many vessels (i.e., the vessel sampling) are needed to reliably characterize the bulbar conjunctival microvasculature and (2) if characteristic information can be obtained from the distribution histogram of the blood flow velocity and vessel diameter. Functional slitlamp biomicroscope was used to image hundreds of venules per subject. The bulbar conjunctiva in five healthy human subjects was imaged on six different locations in the temporal bulbar conjunctiva. The histograms of the diameter and velocity were plotted to examine whether the distribution was normal. Standard errors were calculated from the standard deviation and vessel sample size. The ratio of the standard error of the mean over the population mean was used to determine the sample size cutoff. The velocity was plotted as a function of the vessel diameter to display the distribution of the diameter and velocity. The results showed that the sampling size was approximately 15 vessels, which generated a standard error equivalent to 15% of the population mean from the total vessel population. The distributions of the diameter and velocity were not only unimodal, but also somewhat positively skewed and not normal. The blood flow velocity was related to the vessel diameter (r=0.23, P<0.05). This was the first study to determine the sampling size of the vessels and the distribution histogram of the blood flow velocity and vessel diameter, which may lead to a better understanding of the human microvascular system of the bulbar conjunctiva.

  17. The response of apoptotic and proteolytic systems to repeated heat stress in atrophied rat skeletal muscle.

    Science.gov (United States)

    Yoshihara, Toshinori; Sugiura, Takao; Yamamoto, Yuki; Shibaguchi, Tsubasa; Kakigi, Ryo; Naito, Hisashi

    2015-10-01

    We examined the effect of repeated heat stress on muscle atrophy, and apoptotic and proteolytic regulation in unloaded rat slow- and fast-type skeletal muscles. Forty male Wistar rats (11 week-old) were divided into control (CT), hindlimb unweighting (HU), intermittent weight-bearing during HU (HU + IWB), and intermittent weight-bearing with heat stress during HU (41-41.5°C for 30 min; HU + IWB + HS) groups. The HU + IWB + HS and HU + IWB groups were released from unloading for 1 h every second day, during which the HU + IWB + HS group underwent the heating. Our results revealed that repeated bouts of heat stress resulted in protection against disuse muscle atrophy in both soleus and plantaris muscles. This heat stress-induced protection against disuse-induced muscular atrophy may be partially due to reduced apoptotic activation in both muscles, and decreased ubiquitination in only the soleus muscle. We concluded that repeated heat stress attenuated skeletal muscle atrophy via suppressing apoptosis but the response to proteolytic systems depend on the muscle phenotype. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  18. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset

    Energy Technology Data Exchange (ETDEWEB)

    Cistaro, Angelina; Fania, Piercarlo [Positron Emission Tomography Center IRMET S.p.A, Turin (Italy); Consuelo Valentini, Maria; Carrara, Giovanna [CTO Hospital, Department of Neuroradiology, Turin (Italy); Chio, Adriano; Calvo, Andrea; Moglia, Cristina; Montuschi, Anna [University of Turin, Department of Neuroscience, ALS Center, Turin (Italy); Nobili, Flavio [University of Genoa, Department of Neurosciences, Clinical Neurophysiology Unit, Ophthalmology and Genetics, Genoa (Italy); Morbelli, Silvia [University of Genoa, Department of Internal Medicine, Nuclear Medicine Unit, Genoa (Italy); Salmaso, Dario [Institute of Cognitive Sciences and Technologies, CNR, Padua (Italy); Institute of Cognitive Sciences and Technologies, CNR, Rome (Italy); Pagani, Marco [Institute of Cognitive Sciences and Technologies, CNR, Padua (Italy); Karolinska Hospital, Department of Nuclear Medicine, Stockholm (Sweden); Institute of Cognitive Sciences and Technologies, CNR, Rome (Italy)

    2012-02-15

    To identify the neurobiological traits of amyotrophic lateral sclerosis (ALS) and to elucidate functional differences between ALS of spinal and bulbar onset. We hypothesized that glucose metabolism distribution might vary between groups. The study groups comprised 32 patients with ALS of either bulbar (n = 13) or spinal (n=19) onset and 22 subjects as controls. They were investigated by [{sup 18}F]fluorodeoxyglucose (FDG) positron emission tomography (FDG PET), comparing the patient groups with each other and with the controls by statistical parametric mapping. Highly significant relative increases in glucose metabolism distribution were found in the group comprising all 32 ALS patients as compared with the controls in the bilateral amygdalae, midbrain, pons and cerebellum. Relative hypermetabolism was also found in patients with spinal onset as compared with the controls in the right midbrain. In patients with bulbar onset compared with the controls and with patients with spinal onset, large relatively hypometabolic areas were found in the bilateral frontal cortex, right insula, anterior cingulate, precuneus and inferior parietal lobe. Patients with spinal onset had significantly higher scores in a neuropsychological test assessing verbal fluency compared with patients with bulbar onset. This large FDG PET investigation provided unprecedented evidence of relatively increased metabolism in the amygdalae, midbrain and pons in ALS patients as compared with control subjects, possibly due to local activation of astrocytes and microglia. Highly significant relative decreases in metabolism were found in large frontal and parietal regions in the bulbar onset patients as compared with the spinal onset patients and the controls, suggesting a differential metabolic and neuropsychological state between the two conditions. (orig.)

  19. Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

    Science.gov (United States)

    Kudryashova, Elena; Kramerova, Irina; Spencer, Melissa J.

    2012-01-01

    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

  20. A case of bulbar type cerebral palsy: representative symptoms of dorsal brainstem syndrome.

    Science.gov (United States)

    Hiyane, Masato; Saito, Yoshiaki; Saito, Takashi; Komaki, Hirofumi; Nakagawa, Eiji; Sugai, Kenji; Sasaki, Masayuki; Sato, Noriko; Yamamoto, Toshiyuki; Imai, Yoko

    2012-10-01

    In this study, we present the case of a 2-year-old boy who exhibited facial and bulbar paralysis since birth, severe dysphagia, signs of oculomotor disturbance, jaw jerks, pyramidal signs on both toes, intellectual disability, and severe gastroesophageal reflux. His blink reflex and auditory/somatosensory evoked potentials suggested abnormalities in the lower brainstem, and magnetic resonance imaging showed a T2 hyperintense area in the pontine tegmentum. These findings combined with the patient's symptoms suggested "dorsal brainstem syndrome" and indicated a possibility of prenatal asphyxia in this patient. Nosologic issues regarding this subgroup of cerebral palsy are discussed here. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  1. Short term general anesthesia for retro-bulbar block in ophthalmic surgery generates no significant hypercapnia.

    Science.gov (United States)

    Baulig, Werner; Weber, Monica; Beck-Schimmer, Beatrice; Theusinger, Oliver M; Biro, Peter

    2017-03-11

    To assess the impact of short time hypnosis for retro-bulbar anesthesia on ventilation in patients undergoing ophthalmic surgery of the anterior eye chamber. In all patients, a combined continuous transcutaneous carbon dioxide tension (PtcCO2) and partial oxygen saturation (SpO2) measurement was applied in addition to routine monitoring. To enable unconscious application of retro-bulbar anesthesia, intravenous thiopental was given in one to multiple bolus doses. Transient breathing support included chin lift, Esmarch maneuver and manual hand-bag ventilation via face mask. Main endpoints were apnea time, recovery time according to the Richmond Agitation Sedation Scale, as well as SpO2 and PtcCO2 readings at predefined time points. Fifty-two patients with a mean age of 68 ± 13 years were included. Average thiopental dose was 2.7 ± 0.6 mg/kg. In seven (13.5%) patients repeated doses of thiopental were necessary to a total of 3.3 ± 1.1 mg/kg. Except one patient, no severe, significant or clinical relevant hypercapnia or desaturation periods were observed, and the occurring elevation of PtcCO2 values did not correlate with the application of repeated doses of thiopental or the need for the Esmarch maneuver. Higher PtcCO2 values were associated with the presence of hypertension and smoking. Apnea (p < 0.001) and recovery (p = 0.003) time were significantly prolonged in the patients needing the Esmarch maneuver. Short term anesthesia with thiopental in ophthalmic surgery is associated with a mild but not clinically relevant hypercapnia.

  2. Amyotrophic Lateral Sclerosis and Multiple Sclerosis Overlap: A Case Report

    OpenAIRE

    Francesca Trojsi; Anna Sagnelli; Giovanni Cirillo; Giovanni Piccirillo; Cinzia Femiano; Francesco Izzo; Maria Rosaria Monsurrò; Gioacchino Tedeschi

    2012-01-01

    The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resona...

  3. Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge

    Directory of Open Access Journals (Sweden)

    Cláudio Martins

    2016-01-01

    Full Text Available Celiac disease is the most important cause of intestinal villous atrophy. Seronegative intestinal villous atrophy, including those that are nonresponsive to a gluten-free diet, is a diagnostic challenge. In these cases, before establishing the diagnosis of seronegative celiac disease, alternative etiologies of atrophic enteropathy should be considered. Recently, a new clinical entity responsible for seronegative villous atrophy was described—olmesartan-induced sprue-like enteropathy. Herein, we report two uncommon cases of atrophic enteropathy in patients with arterial hypertension under olmesartan, who presented with severe chronic diarrhea and significant involuntary weight loss. Further investigation revealed intestinal villous atrophy and intraepithelial lymphocytosis. Celiac disease and other causes of villous atrophy were ruled out. Drug-induced enteropathy was suspected and clinical improvement and histologic recovery were verified after olmesartan withdrawal. These cases highlight the importance for clinicians to maintain a high index of suspicion for olmesartan as a precipitant of sprue-like enteropathy.

  4. Muscular Dystrophy: Data and Statistics

    Science.gov (United States)

    ... listing of Medicaid or Children’s Health Insurance Program (CHIP) insurance in the medical record. Age in Years ( ... Oleszek J; Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STAR net ). Trends with corticosteroid use in ...

  5. Wasting Mechanisms in Muscular Dystrophy

    Science.gov (United States)

    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

  6. Learning about Duchenne Muscular Dystrophy

    Science.gov (United States)

    Skip to main content Learning About Duchenne Muscular Dystrophy Enter Search Term(s): Español Research Funding An Overview Bioinformatics Current Grants Education and Training Funding Extramural Research News Features Funding Divisions Funding ...

  7. Preventive effects of Chlorella on skeletal muscle atrophy in muscle-specific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice.

    Science.gov (United States)

    Nakashima, Yuya; Ohsawa, Ikuroh; Nishimaki, Kiyomi; Kumamoto, Shoichiro; Maruyama, Isao; Suzuki, Yoshihiko; Ohta, Shigeo

    2014-10-11

    Oxidative stress is involved in age-related muscle atrophy, such as sarcopenia. Since Chlorella, a unicellular green alga, contains various antioxidant substances, we used a mouse model of enhanced oxidative stress to investigate whether Chlorella could prevent muscle atrophy. Aldehyde dehydrogenase 2 (ALDH2) is an anti-oxidative enzyme that detoxifies reactive aldehydes derived from lipid peroxides such as 4-hydroxy-2-nonenal (4-HNE). We therefore used transgenic mice expressing a dominant-negative form of ALDH2 (ALDH2*2 Tg mice) to selectively decrease ALDH2 activity in the muscles. To evaluate the effect of Chlorella, the mice were fed a Chlorella-supplemented diet (CSD) for 6 months. ALDH2*2 Tg mice exhibited small body size, muscle atrophy, decreased fat content, osteopenia, and kyphosis, accompanied by increased muscular 4-HNE levels. The CSD helped in recovery of body weight, enhanced oxidative stress, and increased levels of a muscle impairment marker, creatine phosphokinase (CPK) induced by ALDH2*2. Furthermore, histological and histochemical analyses revealed that the consumption of the CSD improved skeletal muscle atrophy and the activity of the mitochondrial cytochrome c oxidase. This study suggests that long-term consumption of Chlorella has the potential to prevent age-related muscle atrophy.

  8. Ageing with Muscular Disease.

    Science.gov (United States)

    Martinsen, Bente; Dreyer, Pia

    2016-01-01

    The demographic development with an ageing population is predicted to be the next global public health challenge. Advances in medicine and the socioeconomic development have reduced mortality and morbidity due to infectious conditions and non-communicable diseases. The increase in longevity will not be restricted to healthy people. To understand how people with muscular diseases experience ageing. A literature review was conducted using the Matrix Method developed by Garrard (2007). This systematic method was used to identify, describe and interpret studies, irrespective of the methods applied. To avoid the exclusion of important sources, experiences and topics, we chose an integrative approach that accommodates the inclusion of studies with different methodologies. People with MD have gradually extended their life expectancy during the last 30 years. Thus, we reviewed the literature regarding MD and ageing without time limit. We identified three themes: 1) Slowing down early 2) Accepting lifelong deterioration and 3) Striving for normality. People with MD live in a field of tension between a feeling of autonomy and normality and difficulties coping with reduced physical abilities. Getting older accentuates this tension since the physical strength diminishes and it is harder to maintain autonomy. The bodily challenges may coincide with the end of the rehabilitation people living with MD have received. Seemingly, no age-related rehabilitation is offered, and people living with MD are thus at risk of an unnecessarily passive life.

  9. A Case of Myasthenia Gravis Presenting Solely With Bulbar Palsy Not Associated With Easy Fatigability.

    Directory of Open Access Journals (Sweden)

    Pinank R. Mer

    2015-12-01

    Full Text Available Introduction: Myesthenia Gravis (MG is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in number of available acetylcholine receptors (AChRs at neuromuscular junction due to an antibody-mediated autoimmune attack. Case Report: A 26 year old male patient from Dhar (M.P., a tribal district, presented to civil hospital Ahmedabad (CHA with complaints of unable to drink water since 5 months. Patient complained of water coming out from nose. Gradually he developed inability to eat also, with no evidence of vomiting.2 months later patient developed slurring of speech which was followed by total inability to speak. Along with that he developed diplopia on binocular vision. No such symptoms in siblings were there. On examination general examination was normal. On CNS examination he was conscious oriented with normal planter and deep tendon reflexes. On cranial nerve examination 3, 7, 9, 10th nerve palsies seen in the form of absence of medial & upward movement of left eye (3rd, inability to close eyes completely (3rd, reduced power and tone of buccinators muscle (7th, gag reflex absent (9th, presence of dysphagia (10th. Rest of the CNS findings were normal. He was given ryle’s tube feeding and investigated.CBC, LFT, RFT, urine routine-micro were normal.CSF examination showed mild increase of protein.MRI brain was normal. Vitamin B12, TSH, Calcium, HbA1c, ESR, RA factor were normal.ANA was (+ with nuclear speckled pattern. Fundus examination was normal with abnormal ocular movement as described.VEP study was normal.EMG NCV showed reduced amplitude of bilateral facial nerve, involvement of right oculomotor nerve suggesting bulbar myasthenia >generalized myasthenia. Then we did AChR antibody test which came highly positive. He was started T.Pyridostigmine 60mg TDS and T. Prednisolone 5mg/kg and discharged. On follow up we found marked improvement of symptoms. Conclusion: The

  10. Coexistence of amyotrophic lateral sclerosis and argyrophilic grain disease: a non-demented autopsy case showing circumscribed temporal atrophy and involvement of the amygdala.

    Science.gov (United States)

    Yokota, Osamu; Tsuchiya, Kuniaki; Noguchi, Yoshimasa; Akabane, Hisamasa; Ishizu, Hideki; Saito, Yukinobu; Akiyama, Haruhiko

    2007-12-01

    We report a case of a 68-year-old right-handed man with sporadic amyotrophic lateral sclerosis (ALS) and argyrophilic grain disease (AGD) having a 22-month duration. His initial symptoms were dysarthria and swallowing difficulty at the age of 67. Subsequently bulbar palsy and pyramidal signs developed. His cognitive functions including face recognition, personality, and behavior were not changed compared with that of before the disease onset. However, magnetic resonance imaging disclosed severe right side-predominant temporal atrophy. The neurological diagnosis was bulbar type ALS. Pathological examination disclosed histological evidence of ALS, including loss of Betz cells and lower motor neurons, corticospinal tract degeneration, and Bunina bodies. In addition, severe neuronal loss in the bilateral temporal cortex with an anterior gradient was found. Ubiquitin-positive inclusions were encountered in the spinal anterior horn cells and hippocampal dentate gyrus, while few ubiquitin-positive inclusions were noted in the affected temporal cortex. The amygdala, especially the basolateral nuclear group, was severely affected by neuronal loss with tissue rarefaction. Moderate neuronal loss was encountered in the parahippocampal gyrus, and to a lesser degree, in the ambient gyrus. Unexpectedly, many argyrophilic grains, coiled bodies, tau-positive bush-like astrocytes, pretangles, and ballooned neurons were found in the limbic system and temporal cortex. In the hippocampus, selective tau accumulation with minor neurofibrillary changes was observed in CA2 neurons. The present case suggests that (i) ALS and AGD do rarely coexist, and (ii) when ALS patients have severe temporal atrophy, not only ALS with dementia but also concurrent AGD should be considered in the differential diagnosis.

  11. Lesiones musculares en el deporte. Muscular injuries in sport.

    OpenAIRE

    Jiménez Díaz, José Fernando

    2006-01-01

    ResumenDurante la práctica de la actividad física hay una gran incidencia de lesiones musculares, si bien se han llevado a cabo pocos estudios clínicos sobre el tratamiento y la resolución de las mismas. Desde el punto de vista etiopatogénico, hay que señalar que la incidencia de lesión es mayor en aquellos músculos poliarticulares en condiciones de acumulación de fatiga y con condiciones ambientales desfavorables. La clasificación de las lesiones musculares permite distinguir entre aquellas ...

  12. The neuropathological signature of bulbar-onset ALS: A systematic review.

    Science.gov (United States)

    Shellikeri, S; Karthikeyan, V; Martino, R; Black, S E; Zinman, L; Keith, J; Yunusova, Y

    2017-04-01

    ALS is a multisystem disorder affecting motor and cognitive functions. Bulbar-onset ALS (bALS) may be preferentially associated with cognitive and language impairments, compared with spinal-onset ALS (sALS), stemming from a potentially unique neuropathology. The objective of this systematic review was to compare neuropathology findings reported for bALS and sALS subtypes in studies of cadaveric brains. Using Cochrane guidelines, we reviewed articles in MEDLINE, Embase, and PsycINFO databases using standardized search terms for ALS and neuropathology, from inception until July 16th 2016. 17 studies were accepted for analysis. The analysis revealed that both subtypes presented with involvement in motor and frontotemporal cortices, deep cortical structures, and cerebellum and were characterized by neuronal loss, spongiosis, myelin pallor, and ubiquitin+ and TDP43+ inclusion bodies. Changes in Broca and Wernicke areas - regions associated with speech and language processing - were noted exclusively in bALS. Further, some bALS cases presented with atypical pathology such as neurofibrillary tangles and basophilic inclusions, which were not found in sALS cases. Given the limited number of studies, all with methodological biases, further work is required to better understand neuropathology of ALS subtypes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Dysfunction of bulbar central pattern generator in ALS patients with dysphagia during sequential deglutition.

    Science.gov (United States)

    Aydogdu, Ibrahim; Tanriverdi, Zeynep; Ertekin, Cumhur

    2011-06-01

    The aim of this study is to investigate a probable dysfunction of the central pattern generator (CPG) in dysphagic patients with ALS. We investigated 58 patients with ALS, 23 patients with PD, and 33 normal subjects. The laryngeal movements and EMG of the submental muscles were recorded during sequential water swallowing (SWS) of 100ml of water. The coordination of SWS and respiration was also studied in some normal cases and ALS patients. Normal subjects could complete the SWS optimally within 10s using 7 swallows, while in dysphagic ALS patients, the total duration and the number of swallows were significantly increased. The novel finding was that the regularity and rhythmicity of the swallowing pattern during SWS was disorganized to irregular and arhythmic pattern in 43% of the ALS patients. The duration and speed of swallowing were the most sensitive parameters for the disturbed oropharyngeal motility during SWS. The corticobulbar control of swallowing is insufficient in ALS, and the swallowing CPG cannot work very well to produce segmental muscle activation and sequential swallowing. CPG dysfunction can result in irregular and arhythmical sequential swallowing in ALS patients with bulbar plus pseudobulbar types. The arhythmical SWS pattern can be considered as a kind of dysfunction of CPG in human ALS cases with dysphagia. Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  14. [Ambulatory intensive therapy in the bulbar form of amyotrophic lateral sclerosis].

    Science.gov (United States)

    Kirisits, H; Reisecker, F

    1996-01-01

    Due to the instability of their respiratory functions, patients suffering from ALS are potentially patients for permanent intensive care. The desire to provide care in the familiar environment at home on the one hand, and qualified professional support on the other hand, gives rise to the concept of ambulatory intensive care. This concept might be successfully implemented if one proceeds according to the motto: it is not the patient who is committed to technical facilities, but rather that the technical facilities ought to be committed to the patient. Home care, gastrostomy, tracheostomy, mobile suction drainage and the feasibility of home ventilation provide the groundwork for competent palliative medical care even in the bulbar form of ALS. Home care of such patients would be enhanced in terms of both security and quality if it were possible to have regular ambulatory check of the vital functions at intensive care units. In emergency cases, once their respiratory functions are stabilized patients could be discharged into home nursing after a short-term stay at the intensive care unit. Ambulatory intensive therapy would both serve to ease the burden of intensive care units in terms of costs and personnel, and to improve the life quality of patients.

  15. Calpain 3 Expression Pattern during Gastrocnemius Muscle Atrophy and Regeneration Following Sciatic Nerve Injury in Rats

    Directory of Open Access Journals (Sweden)

    Ronghua Wu

    2015-11-01

    Full Text Available 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.

  16. Immunoproteasome in animal models of Duchenne muscular dystrophy.

    Science.gov (United States)

    Chen, Chiao-Nan Joyce; Graber, Ted G; Bratten, Wendy M; Ferrington, Deborah A; Thompson, LaDora V

    2014-04-01

    Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.

  17. How Do People Cope with Muscular Dystrophy?

    Science.gov (United States)

    ... Other FAQs Share Facebook Twitter Pinterest Email Print Muscular Dystrophy: Other FAQs Basic information for topics, such as “ ... in this section. How do people cope with muscular dystrophy (MD)? Although MD presents many challenges in many ...

  18. What Are the Treatments for Muscular Dystrophy?

    Science.gov (United States)

    ... Pinterest Email Print What are the treatments for muscular dystrophy? No treatment is currently available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  19. Metabolismo muscular en el ejercicio

    OpenAIRE

    Martín Martín, Laura

    2017-01-01

    Fundamentos: Cada vez son más las personas que realizan algún tipo de actividad física, pero pocas son las que poseen un verdadero conocimiento de los procesos que se desencadenan a nivel muscular y la influencia de la alimentación en la misma. El objetivo de este trabajo es ofrecer información de manera general sobre el metabolismo muscular. Métodos: Revisión bibliográfica de artículos y documentos consultando bases de datos y libros. La mayor parte del análisis ha sido ext...

  20. FIBROSIS MUSCULAR ESQUELETICA: PAPEL DE LOS FIBROBLASTOS EN LA DISTROFIA MUSCULAR

    OpenAIRE

    MEZZANO ROBINSON, VALERIA; MEZZANO ROBINSON, VALERIA

    2007-01-01

    La distrofia muscular de Duchenne (DMD) es la distrofia muscular más frecuente en niños. Se caracteriza por degeneración muscular progresiva que lleva a atrofia muscular, invalidez y muerte alrededor de la 2da década de vida. El ratón mdx ha sido ampliame 97p.

  1. Genetics Home Reference: spinal muscular atrophy with respiratory distress type 1

    Science.gov (United States)

    ... and CRISPR-Cas9? What is direct-to-consumer genetic testing? What is precision medicine? What is newborn screening? New Pages Leprosy Polycystic ovary syndrome Gorlin-Chaudhry-Moss syndrome All New & Updated Pages ...

  2. Compound muscle action potential and motor function in children with spinal muscular atrophy.

    Science.gov (United States)

    Lewelt, Aga; Krosschell, Kristin J; Scott, Charles; Sakonju, Ai; Kissel, John T; Crawford, Thomas O; Acsadi, Gyula; D'anjou, Guy; Elsheikh, Bakri; Reyna, Sandra P; Schroth, Mary K; Maczulski, Jo Anne; Stoddard, Gregory J; Elovic, Elie; Swoboda, Kathryn J

    2010-11-01

    Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action potential (CMAP) data were collected at two visits over a 4-6-week period in children with SMA types II and III, 2-17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non-ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test-retest reliability (ICC = 0.96-0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS-Extend (r = 0.61-0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status.

  3. Sensory changes in pediatric patients with spinal muscular atrophy: an electrophysiologic study

    Directory of Open Access Journals (Sweden)

    Hussien E Sultan

    2016-01-01

    Conclusion Sensory neuron and/or axonal affection have been demonstrated in the studied series of pediatric SMA patients suggesting that the pathological changes in SMA may also involve the sensory system.

  4. Derivation of human embryonic stem cell from spinal muscular atrophy patient

    Directory of Open Access Journals (Sweden)

    Pingyuan Xie

    2016-03-01

    Full Text Available 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.

  5. Six minute walk test in type III spinal muscular atrophy: a 12month longitudinal study

    NARCIS (Netherlands)

    Mazzone, E.; Bianco, F.; Main, M.; van den Hauwe, M.; Ash, M.; de Vries, R.; Fagoaga Mata, J.; Stein, S.; de Sanctis, R.; D'Amico, A.; Palermo, C.; Fanelli, L.; Scoto, M. C.; Mayhew, A.; Eagle, M.; Vigo, M.; Febrer, A.; Korinthenberg, R.; de Visser, M.; Bushby, K.; Muntoni, F.; Goemans, N.; Sormani, M. P.; Bertini, E.; Pane, M.; Mercuri, E.

    2013-01-01

    The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in

  6. Triplet repeat sequences in human DNA can be detected by hybridization to a synthetic (5'-CGG-3')17 oligodeoxyribonucleotide

    DEFF Research Database (Denmark)

    Behn-Krappa, A; Mollenhauer, J; Doerfler, W

    1993-01-01

    The seemingly autonomous amplification of naturally occurring triplet repeat sequences in the human genome has been implicated in the causation of human genetic disease, such as the fragile X (Martin-Bell) syndrome, myotonic dystrophy (Curshmann-Steinert), spinal and bulbar muscular atrophy...

  7. Disease: H00062 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 1/j.1468-1331.2009.02591.x ... PMID:18775514 ... AUTHORS ... Jordan CL, Lieberman AP ... TITLE ... Spinal and bulbar muscular atrophy: a moton...euron or muscle disease? ... JOURNAL ... Curr Opin Pharmacol 8:752-8 (2008) DOI:10.1016

  8. Untitled

    African Journals Online (AJOL)

    sclerosis (ALS), Primary lateral sclerosis, progressive bulbar palsy, and spinal muscular atrophy (1,2). Although several putative agents(3), which include neurotoxins, glutamate toxicity (4), oxidative stress, and trauma (5.6,) have been implicated in the causation of motor neurone disease, mutations ot'superoxide dismutase ...

  9. Porcine models of muscular dystrophy

    Science.gov (United States)

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

  10. Glucocorticoids for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-07-01

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

  11. Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Acary S. Bulle Oliveira

    1992-12-01

    Full Text Available To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

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

    Directory of Open Access Journals (Sweden)

    Uluç Yis

    2016-01-01

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

  13. Research progress of motor function assessments and their clinical applications in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Wei SHI

    2015-07-01

    Full Text Available Duchenne muscular dystrophy (DMD, clinically featured as progressive skeletal muscle atrophy with gradual loss of muscle strength and activity abilities, is the most common genetic muscular disease in children throughout the world. The core and continuous characteristic of DMD is motor dysfunction. Motor function assessments of DMD are now focusing on muscle strength, walking ability, range of motion and ability of activities, still without unified standards. Confirming the comprehensive, scientific, reasonable and accurate evaluation tools for DMD assessment is the premise of research in motor developmental rules of DMD, which will help to better understand the motor progress of DMD and to supply evidences for choosing treatment methods, confirming timing of intervention, assessing effect of treatments and designing rehabilitation plans. DOI: 10.3969/j.issn.1672-6731.2015.06.002

  14. Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

    Directory of Open Access Journals (Sweden)

    Franziska Lang

    2017-07-01

    Full Text Available Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.

  15. Bulbar paralysis associated with Miller-Fisher syndrome and its overlaps in Chinese patients.

    Science.gov (United States)

    Hu, Qiaoxia; Li, Hongfu; Tian, Jun; Zhang, Baorong

    2017-11-09

    The study aimed to determine the incidence and the onset time of bulbar paralysis (BP) associated with Miller-Fisher syndrome (MFS) and its overlaps, to better understand the clinical characteristics among patients with MFS and its overlaps. Medical records from 48 patients with MFS and its overlaps were divided into two groups based on the presence (MFS-BP+) or absence (MFS-BP-) of BP. Their clinical features, laboratory and electrophysiological findings, neuroimaging data, and treatment plan were analyzed and compared between two groups. The incidence of BP associated with MFS and its overlaps was 48%. Eighty-two percent of the patients developed BP within 1 week after the onset of MFS and its overlaps. The cerebrospinal fluid (CSF) protein level in patients was higher in MFS-BP+ than in MFS-BP- group (67.69 ± 26.59 vs. 50.15 ± 20.44 mg/dl; P < 0.05). Frequencies of severe limb weakness, hypoglossal paralysis, disturbance of consciousness, and tracheal intubation required were also significantly higher in MFS-BP+ than in MFS-BP- group. Positive results of anti-GQ1b and anti-GT1b antibodies were all found in MFS-BP+ group. The prevalence of BP in MFS and its overlap was higher, the majority of BP occurred within 7 days after the onset of the disease, and early diagnosis of BP concurrence is helpful to decide the treatment plan.

  16. Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.

    Directory of Open Access Journals (Sweden)

    Aditya Gilra

    Full Text Available Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells linearize the input-output transformation of the principal neurons (mitral cells, unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells. Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.

  17. Toxic myopathies: muscle biopsy features Miopatia tóxica: biópsia muscular

    Directory of Open Access Journals (Sweden)

    Rosana Herminia Scola

    2007-03-01

    Full Text Available Several drugs and toxic substances can cause muscular abnormalities and are frequent causes of acquired myopathies. We present a series of 32 patients, predominance of young adult patients, diagnosed with toxic myopathy. The most common substances inducing myopathy were corticosteroids (56.2% followed by the propoxyphene, neuroleptics, zidovudine and drug-induced hypokalemia. The investigation showed normal serum creatine kinase levels in 65.4%, myopathic pattern of the needle electromyography in 40% and the more frequent histological diagnosis of the muscle biopsy was type 2 fiber atrophy (59.3%. Clinical features, etiology, course of the disease, serum levels of muscular enzymes, electromyographic features and, especially, muscle biopsy features are discussed.Diversos medicamentos e substâncias tóxicas podem causar alterações musculares e são causas freqüentes de miopatia adquirida. Apresentamos uma série de 32 pacientes, predomínio de pacientes adulto jovens, com miopatia tóxica. As substâncias mais relacionadas com a miopatia foram os corticosteróides (56,2% seguidos pelo propoxifeno, neurolépticos, zidovudina e drogas indutoras de hipocalemia. A investigação mostrou níveis normais de creatino quinase sérica em 65,4%, eletromiografia de agulha com padrão miopático em 40% e o mais freqüente diagnóstico histológico da biópsia muscular foi atrofia de fibras do tipo 2 (59,3%. As manifestações clínicas, etiologia, tempo de evolução, nível sérico das enzimas musculares, alterações da eletroneuromiografia e, especialmente, da biópsia muscular são discutidos.

  18. Geographic atrophy phenotype identification by cluster analysis.

    Science.gov (United States)

    Monés, Jordi; Biarnés, Marc

    2017-07-20

    To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm(2)/year, respectively, p=0.0005). Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Mirror movements in progressive hemifacial atrophy

    Directory of Open Access Journals (Sweden)

    Rajesh Verma

    2015-01-01

    Full Text Available Mirror movements are simultaneous, involuntary, identical movements occurring during contralateral voluntary movements. These movements are considered as soft neurologic signs seen uncommonly in clinical practice. The mirror movements are described in various neurological disorders which include parkinsonism, cranio veretebral junction anamolies, and hemiplegic cerebral palsy. These movements are intriguing and can pose significant disability. However, no such observation regarding mirror movements in progressive hemifacial atrophy have been reported previously. We are reporting a teenage girl suffering from progressive hemifacial atrophy and epilepsy with demonstrable mirror movements in hand.

  20. CT features of olivopontocerebellar atrophy in children

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, S.D. [Sultan Qaboos Univ., Muscat (Oman). Dept. of Radiology; Chand, R.P. [Sultan Qaboos Univ., Muscat (Oman). Dept. of Medicine (Neurology); Gururaj, A.K. [Sultan Qaboos Univ., Muscat (Oman). Dept. of Child Health; Jeans, W.D. [Sultan Qaboos Univ., Muscat (Oman). Dept. of Radiology

    1995-11-01

    Between 1990 and 1992, 14 children were seen in whom a clinical diagnosis of olivopontocerebellar atrophy (OPCA) had been made. The majority of patients presented with cerebellar ataxia and hypotonia. Five children had a family history of a similar illness in first-degree relatives. All cases had undergone clinical and neurologic examinations, routine laboratory tests and cranial CT. CT features were graded to quantitative the degree of atrophy in each cerebellar hemisphere, vermis and brain stem. All patients had varying degrees of atrophic changes of cerebellum, brain stem and cerebrum. These CT features appear to be distinctive enough to enable the diagnosis of OPCA to be made. (orig.).

  1. Liver Atrophy Associated With Monolobar Caroli's Disease

    Science.gov (United States)

    Mohan, L. N.; Kilpadi, A. B.; D'Cunha, S.

    1991-01-01

    The association of the atrophy-hypertrophy complex in monolobar Caroli’s disease (Type I) is reported in a 30 year old male who presented with recurrent cholangitis. Ultrasound and CT scan showed localised, right sided, saccular biliary dilatation in a normal sized liver. Severe right lobar atrophy was detected at operation and the resected right lobe weighed only 140 gms. Distortion of the hilar vascular anatomy and posterior displacement of the right hepatic duct orifice were problems encountered at surgery. PMID:1931788

  2. Acute muscular weakness in children

    Directory of Open Access Journals (Sweden)

    Ricardo Pablo Javier Erazo Torricelli

    Full Text Available ABSTRACT Acute muscle weakness in children is a pediatric emergency. During the diagnostic approach, it is crucial to obtain a detailed case history, including: onset of weakness, history of associated febrile states, ingestion of toxic substances/toxins, immunizations, and family history. Neurological examination must be meticulous as well. In this review, we describe the most common diseases related to acute muscle weakness, grouped into the site of origin (from the upper motor neuron to the motor unit. Early detection of hyperCKemia may lead to a myositis diagnosis, and hypokalemia points to the diagnosis of periodic paralysis. Ophthalmoparesis, ptosis and bulbar signs are suggestive of myasthenia gravis or botulism. Distal weakness and hyporeflexia are clinical features of Guillain-Barré syndrome, the most frequent cause of acute muscle weakness. If all studies are normal, a psychogenic cause should be considered. Finding the etiology of acute muscle weakness is essential to execute treatment in a timely manner, improving the prognosis of affected children.

  3. Cyclosporine increases muscular force generation in Duchenne muscular dystrophy.

    Science.gov (United States)

    Sharma, K R; Mynhier, M A; Miller, R G

    1993-03-01

    We investigated the effect of cyclosporine (CsA) on force generation in 15 boys with Duchenne muscular dystrophy (DMD) by obtaining monthly measures of tetanic force and maximum voluntary contraction (MVC) of both anterior tibial muscles. During 4 months of a natural history phase, both tetanic force and MVC declined significantly. During 8 weeks of CsA treatment (5 mg/kg/day), significantly increased tetanic force (25.8 +/- 6.6%) and MVC (13.6 +/- 4.0%) occurred within 2 weeks. The maximum mean increase during treatment was 35.2 +/- 5.9% (tetanic force) and 19.0 +/- 4.6% (MVC). Side effects from CsA, gastrointestinal and flu-like symptoms, were transient and self-limiting. Thus, as previously reported with prednisone, CsA increases muscular force generation in the anterior tibial muscles of DMD patients.

  4. Protein Turnover and Cellular Stress in Mildly and Severely Affected Muscles from Patients with Limb Girdle Muscular Dystrophy Type 2I

    DEFF Research Database (Denmark)

    Hauerslev, Simon; Sveen, Marie-Louise; Vissing, John

    2013-01-01

    Patients with Limb girdle muscular dystrophy type 2I (LGMD2I) are characterized by progressive muscle weakness and wasting primarily in the proximal muscles, while distal muscles often are spared. Our aim was to investigate if wasting could be caused by impaired regeneration in the proximal...... highly increased in severely affected muscles compared to mildly affected muscles. Our results indicate that alterations in the protein turnover and myostatin levels could progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy....

  5. Cube propagation for focal brain atrophy estimation

    DEFF Research Database (Denmark)

    Pai, Akshay Sadananda Uppinakudru; Sørensen, Lauge; Darkner, Sune

    2013-01-01

    Precise and robust whole brain, ventricle, and hippocampal atrophy measurements are important as they serve as biomarkers for Alzheimer’s disease. They are used as secondary outcomes in drug trials, and they correlate with the cognitive scores. When two successive scans are non-linearly aligned...

  6. Corpus callosum atrophy in Wernicke's encephalopathy.

    Science.gov (United States)

    Lee, Soon-Tae; Jung, Young-Min; Na, Duk L; Park, Seong Ho; Kim, Manho

    2005-10-01

    Neuropathologic changes in Wernicke's encephalopathy (WE) involve variable brain structures. Corpus callosum involvement in WE, however, is largely unknown. The authors investigated the degree and the pattern of corpus callosum changes in WE according to the etiologies. Nineteen patients with WE (between 34 and 81 years) and 19 age- and sex-matched control participants were included. The total cross-sectional callosal area and 5 callosal subregions (C1-C5) were measured by tracing outer margins in the midsagittal sections. Subregions were determined by placing radial dividers with 10 rays. The pixel numbers for corpus callosums were calculated, and the values obtained were adjusted for head size variations. The causes of WE were alcoholism (10), intestinal surgery (5), anorexia (3), and hyperemesis gravidarum (1). The mean size of the total corpus callosum was significantly reduced in alcoholic WE (P< .001; 527.8 +/- 70.8 mm2 for alcoholic WE; 664.6 +/- 58.1 mm2 for the corresponding controls), but not in nonalcoholic WE. In subregion analysis, prefrontal callosum (C2) atrophy was the most prominent in alcoholic WE. In contrast, only splenium (C5) was atrophied in nonalcoholic WE. The degree of atrophy did not change throughout the follow-up period (mean 5.3 weeks). This study suggests that the extent and location of corpus callosum atrophy differs between alcoholic WE and nonalcoholic WE, implying separate contribution of alcohol neurotoxicity and nutritional deficiency.

  7. Hippocampal atrophy in subcortical vascular dementia

    NARCIS (Netherlands)

    van de Pol, L.A.; Gertz, H.J.; Scheltens, P.; Wolf, H

    2011-01-01

    Background and Purpose: New research criteria for subcortical vascular dementia (SVaD) have been suggested to define a more homogeneous subgroup of vascular dementia. Hippocampal (Hc) atrophy is a hallmark of Alzheimer's disease (AD), but it also occurs in other dementia disorders including vascular

  8. Sensorimotor gating deficits in multiple system atrophy

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Biernat, Heidi Bryde; Nikolic, Miki

    2014-01-01

    Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism's ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently...

  9. [Psoas muscular abscess in children].

    Science.gov (United States)

    Pires, A M; Reis, A G; Grisi, S J

    1996-01-01

    Symptoms of psoas muscular abscess in children are nonspecific and differential diagnosis is made among diseases included in childreńs acute hip pain syndrome, imaging tests being necessary for diagnostic confirmation. During the first semester of 1995, 48,550 children were examined in Pronto Socorro do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, four of them diagnosed as having psoas muscular abscess (2 females and 2 males, ages varying from 1 to 12 years). All of them had nonspecific clinical features and diagnosis was confirmed by abdominal ultrasound and/or computerized tomography. Staphylococcus aureus was isolated as the etiologic agent in 3 children, findings similar to the ones in literature.

  10. Congenital muscular dystrophy in Jordanian children.

    Science.gov (United States)

    Al-Qudah, A A; Tarawneh, M

    1998-08-01

    This is a consecutive study on 28 patients who have been diagnosed as having congenital muscular dystrophy at Jordan University Hospital in the period from January 1990 to February 1997. Of 75 patients diagnosed as having muscle disease, 55 (73.3%) had muscular dystrophy. Of 55 muscular dystrophy patients, 28 (50.9%) had congenital muscular dystrophy, 11 (20%) had Duchenne muscular dystrophy, 9 (16.4%) had Becker muscular dystrophy, 4 (7.3%) had myotonic dystrophy, 2 (3.6%) had limb-girdle dystrophy, and 1 (1.8%) patient had facioscapulohumeral dystrophy. Age of onset of symptoms of congenital muscular dystrophy (hypotonia and weakness) was documented antenatally or in the first few months in the majority (92.9%) of patients. Parental consanguinity was documented in 21 (75%) of congenital muscular dystrophy cases, and family history of possible similar cases in 15 (53.6%). Congenital muscular dystrophy patients with normal cognitive milestones (n = 16; 57.1%) were slightly more common than patients with cognitive delay. In contrast to previous reports, congenital muscular dystrophy is probably more common in communities with high rates of parental consanguinity than other dystrophies. Our study adds significant support to the most recent literature on this finding.

  11. An unusual cause of optic atrophy in a child

    Directory of Open Access Journals (Sweden)

    Nishant Kumar

    2014-01-01

    Full Text Available A 13-year-old child presenting with gross visual impairment was diagnosed as a case of optic atrophy. However, radiological investigations revealed osteopetrosis, which, though rare, can result in optic atrophy. The aim of this case report is to highlight this possibility while evaluating cases of optic atrophy in young patients.

  12. Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

    Directory of Open Access Journals (Sweden)

    Erika Hissong, M.D.

    2016-06-01

    Full Text Available Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

  13. Lesiones musculares en el deporte. Muscular injuries in sport.

    Directory of Open Access Journals (Sweden)

    Jiménez Díaz, José Fernando

    2006-04-01

    Full Text Available ResumenDurante la práctica de la actividad física hay una gran incidencia de lesiones musculares, si bien se han llevado a cabo pocos estudios clínicos sobre el tratamiento y la resolución de las mismas. Desde el punto de vista etiopatogénico, hay que señalar que la incidencia de lesión es mayor en aquellos músculos poliarticulares en condiciones de acumulación de fatiga y con condiciones ambientales desfavorables. La clasificación de las lesiones musculares permite distinguir entre aquellas que no afectan a la fascia produciéndose un sangrado dentro del mismo (intramuscular o bien si la fascia también se rompe, el sangrado se sitúa entre los diferentes músculos (intermuscular. El tratamiento de estas lesiones se realizará combinando reposo, compresión, aplicación de frío y elevación del área lesionada así como el desarrollo de un adecuado programa de readaptación funcional que permita al jugador incorporarse lo antes posible a la dinámica del equipo. En la actualidad se está llevando a cabo opciones terapéuticas con factores de crecimiento, terapia génica y células madre, si bien todavía no están lo suficientemente desarrolladas.AbstractDuring the practice of the physical activity there is a great effect of muscular injuries, though few clinical studies have been carried out on the treatment and the resolution of the same ones. Inside the reasons it is necessary to indicate that the effect of injury is major in those muscles you will polyarticulate in situation of fatigue and with environmental unfavorable conditions.The classification of the muscular injuries allows to distinguish between those that do not affect the fascia producing the bled intramuscular or if the fascia also breaks, the bled one places between the different muscles (intermuscular.The treatment will be realized combining rest, compression, application of cold and elevation of these injuries as well as the development of a program of functional

  14. Age-Related Differences in Muscular Strength and Muscular Endurance among Female Masters Swimmers.

    Science.gov (United States)

    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.…

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

    Science.gov (United States)

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

    2016-09-01

    : Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. ©AlphaMed Press.

  16. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    Science.gov (United States)

    ... Health Conditions Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Emery-Dreifuss muscular dystrophy is a condition that primarily affects muscles used ...

  17. Genetics Home Reference: limb-girdle muscular dystrophy

    Science.gov (United States)

    ... Health Conditions Limb-girdle muscular dystrophy Limb-girdle muscular dystrophy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Limb-girdle muscular dystrophy is a term for a group of diseases ...

  18. Genetics Home Reference: LAMA2-related muscular dystrophy

    Science.gov (United States)

    ... Health Conditions LAMA2-related muscular dystrophy LAMA2-related muscular dystrophy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description LAMA2 -related muscular dystrophy is a disorder that causes weakness and wasting ( ...

  19. Oxyntic atrophy, metaplasia and gastric cancer

    Science.gov (United States)

    Goldenring, James R.; Nam, Ki Taek

    2015-01-01

    The process of gastric carcinogenesis involves the loss of parietal cells (oxyntic atrophy) and subsequent replacement of the normal gastric lineages with metaplastic lineages. In humans, two metaplastic lineages develop as sequelae of chronic Helicobacter pylori infection: intestinal metaplasia and Spasmolytic Polypeptide-expressing Metaplasia (SPEM). Mouse models of both chronic Helicobacter infection and acute pharmacological oxyntic atrophy have led to the recognition that SPEM arises from transdifferentiation of mature chief cells. The presence of inflammation promotes the expansion of SPEM in mice. Furthermore, studies in Mongolian gerbils as well as increasing evidence from human studies indicates that SPEM likely represents a precursor for development of intestinal metaplasia. These findings indicate that loss of parietal cells, augmented by chronic inflammation, leads to a cascade of metaplastic events. Identification of specific biomarkers for SPEM and intestinal metaplasia hold promise for providing both early detection of pre-neoplasia as well as information on prognostic outcome following curative resection. PMID:21075342

  20. [Posterior cortical atrophy with progressive visual agnosia].

    Science.gov (United States)

    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.

  1. [Posterior cortical atrophy. Report of five cases].

    Science.gov (United States)

    Delgado D, Carolina; Donoso S, Archibaldo

    2009-11-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome, usually due to Alzheimer's disease. The first symptoms are progressive impairment of visuo spatial (Balint's and Gertsmann's syndromes) or visuo perceptive (visual agnosia, alexia) function. Episodic memory and executive function are spared until later stages. We report two males aged 51 and 55years and three females aged 50, 54 and 56 years, with posterior cortical atrophy. Ophthalmologic study was normal in all. Presenting signs and symptoms were visual ataxia, simultagnosia, agraphia, acalculia, spatial disorientation and unilateral neglect (Balint's and Gerstmann's syndromes). Apperceptive visual agnosia, aphasia, apraxia and alexia were also observed. One female had cortical blindness. Structural images were inconclusive, but PET scan and SPECT disclosed functional impairments in occipitotemporal or occipitoparietal areas.

  2. Rehabilitation of the muscular dystrophies.

    Science.gov (United States)

    Pangilinan, Percival H; Hornyak, Joseph E

    2013-01-01

    The muscular dystrophies (MD) are a heterogeneous group of inherited disorders characterized by findings on muscle biopsy. In general, they feature progressive muscle wasting and weakness. In addition to the musculoskeletal system, direct and indirect effects can be seen in a variety of organ systems. These issues create challenges in patients with MD for ambulation and mobility, self-care, pain, fatigue, and community involvement. Because of its progressive nature and wide variety of pathophysiological mechanisms, patients with MD require individualized rehabilitation care. This chapter reviews specific rehabilitation needs and treatment of patients with MD. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Space travel directly induces skeletal muscle atrophy

    Science.gov (United States)

    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.

  4. Type-selective muscular degeneration promotes infiltrative growth of intramuscular lipoma

    Directory of Open Access Journals (Sweden)

    Ishizawa Michihito

    2004-06-01

    Full Text Available Abstract Background Intramuscular lipoma is a relatively common benign neoplasm that is occasionally described as an infiltrating lipoma. Typical benign tumors show a clear margin, however, the infiltrative growth pattern of this lipoma mimics that of a malignant tumor. Although its growth has an effect on muscle bundles and it is known to never metastasize, the mechanism of infiltrative growth is not well understood. Previously, little attention has been paid to pathogenic features of muscle fibers around an intramuscular lipoma. Methods In the present study, we focused on pathologic changes of the surrounding skeletal muscles especially to the degenerative features of involving muscular types, and evaluate the role of type-selective muscular degeneration for the infiltrative growth of intramuscular lipomas. Following a review of the medical records in our institute, 17 lesions containing muscle tissues in their specimens (15 infiltrating lipomas, 2 well-circumscribed lipomas were analyzed immunohistochemically. The tumor from the most recent case was also subjected to ultrastructural analysis. Two cases of the traumatic muscle damage were also evaluated as the control experiments. Results These analyses revealed type-selective muscle involution in 11 of 17 intramuscular lipomas and in 10 of 11 of the infiltrative type, with an involving pattern that resembled that of a neurogenic or myogenic disorder. Immunoreactivity to cathepsin-D, a lysosomal catabolic enzyme, was increased in the involved muscle fibers. Subsarcolemmal vacuoles in the muscle fibers of the peripheral areas were also positive for cathepsin-D, while degenerative findings were not visually apparent in these areas. Ultrastructural analysis revealed degenerative changes in those fibers. Neither positive staining for cathepsin-D nor type-selective atrophy was detected in the sections of traumatic muscle damage. Conclusions Our findings suggest that type-selective muscular

  5. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    Directory of Open Access Journals (Sweden)

    Alessandra Costa

    2014-01-01

    Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

  6. [The significance of Ulex europaeus agglutinin I lectin binding fibers in various muscular diseases].

    Science.gov (United States)

    Yatabe, K; Hiraguri, M; Sueishi, M; Takeuchi, M; Nonaka, I; Kawai, M

    1998-05-01

    In the present study, we have reported that Ulex europaeus agglutinin I (UEA I) lectin labeled muscle fibers in distal myopathy with rimmed vacuole formation (DMRV). UEA I binding to muscle fibers was also observed in a small number of biopsies with inflammatory myopathy, but not in other diseases, including neurogenic muscular atrophies and muscular dystrophies. In order to elucidate the relationship between this UEA I binding, rimmed vacuole formation and active autophagocytosis, we examined the UEA I binding fibers in other myopathies which frequently showed rimmed vacuoles, including adult onset acid maltase deficiency, oculo-pharyngo-distal type myopathy and oculopharyngeal muscular dystrophy. No UEA I lectin labeling fiber was observed in the diseases examined. We then studied UEA I binding behavior on 70 biopsies of inflammatory myopathy to characterize the clinical features of UEA I binding positive patients. UEA I binding fibers were observed in 3 of 28 patients (11%) with other collagen diseases, 11 of 36 (31%) without these disorders, and 2 of 6 (33%) with inclusion body myositis. There were no common clinical histories, complications or laboratory findings among the UEA I binding positive patients. In conclusion, a common process may exist between the muscle fiber degeneration in DMRV and subgroups of inflammatory myopathy patients, but the basic mechanism remains to be elucidated.

  7. Therapeutic potential of heat shock protein induction for muscular dystrophy and other muscle wasting conditions.

    Science.gov (United States)

    Thakur, Savant S; Swiderski, Kristy; Ryall, James G; Lynch, Gordon S

    2018-01-19

    Duchenne muscular dystrophy is the most common and severe of the muscular dystrophies, a group of inherited myopathies caused by different genetic mutations leading to aberrant expression or complete absence of cytoskeletal proteins. Dystrophic muscles are prone to injury, and regenerate poorly after damage. Remorseless cycles of muscle fibre breakdown and incomplete repair lead to progressive and severe muscle wasting, weakness and premature death. Many other conditions are similarly characterized by muscle wasting, including sarcopenia, cancer cachexia, sepsis, denervation, burns, and chronic obstructive pulmonary disease. Muscle trauma and loss of mass and physical capacity can significantly compromise quality of life for patients. Exercise and nutritional interventions are unlikely to halt or reverse the conditions, and strategies promoting muscle anabolism have limited clinical acceptance. Heat shock proteins (HSPs) are molecular chaperones that help proteins fold back to their original conformation and restore function. Since many muscle wasting conditions have pathophysiologies where inflammation, atrophy and weakness are indicated, increasing HSP expression in skeletal muscle may have therapeutic potential. This review will provide evidence supporting HSP induction for muscular dystrophy and other muscle wasting conditions.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'. © 2017 The Author(s).

  8. Assessment of Consistency in Assignment of Severe (Grade 3) Squamous Metaplasia to Human Bulbar Conjunctiva Impression Cytology Cell Samples.

    Science.gov (United States)

    Doughty, Michael J

    2015-10-01

    Nucleus-to-cytoplasm (N:C) characteristics of published images of human bulbar conjunctival cells designated as showing severe (grade 3) squamous metaplasia were retrospectively assessed. From publications over a 40-year period, measurements were made from images of cell and nucleus size (based on areas and dimensions) and four different calculations were made for nucleo-cytoplasmic (N:C) ratios. From 54 published images, the mean nucleus-to-cytoplasm area ratio (NU/CYT AREA ratio) was 0.145 +/- 0.077 (range 0.052 to 0.346), compared to two different reference set values of 0.069 +/- 0.017 and 0.080 +/- 0.021. Similarly, a nucleus-to-cytoplasm length ratio (as LNLONG) was 0.308 +/- 0.080 (range 0.191 to 0.475) compared to reference values of 0.226 +/- 0.032 and 0.236 +/- 0.034. Similar differences in reference values were obtained using two other N:C ratio calculations. A wide range of values was found for morphometric N:C indices from published images, especially those without a scale bar, indicating a high incidence of inconsistent grading assignments. Overall, only about 30% of the published images showed morphological features consistent with severe squamous metaplasia (i.e., with the rest neither enlarged nor showing substantially changed N:C ratios) with no substantial pictorial evidence indicating that cells from the human bulbar conjunctiva have pyknotic nuclei. Current evidence indicates that grade 3 squamous metaplasia cells should be substantially enlarged. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

    Science.gov (United States)

    Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

    2011-01-01

    Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall

  10. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale.

    Directory of Open Access Journals (Sweden)

    Christine A M Payan

    Full Text Available The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362 and Multiple System Atrophy (MSA, n = 398. To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study.Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116, validity (n = 760, and responsiveness (n = 642. Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70. Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94 and 9 dimensions (Intra-class coefficient = 0.80-0.93, and moderate (Intra-class coefficient = 0.54-0.77 for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70. The total score was significantly and linearly related to survival (p<0.0001. Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10, though higher in PSP (SRM = 1.25 than in MSA (SRM = 1.0, indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar.The NNIPPS-PPS has suitable validity, is

  11. Ocular features of multiple system atrophy.

    Science.gov (United States)

    Garcia, Maria D; Pulido, Jose S; Coon, Elizabeth A; Chen, John J

    2018-01-01

    The aim of this paper is to gain better understanding of the ocular manifestations of multiple system atrophy (MSA), a neurodegenerative disorder rarely studied in terms of its ophthalmologic features. We performed a retrospective case series (1/1/05-12/31/14) to search for patients seen at Mayo Clinic, Rochester, MN, who had mention of MSA in the medical record and an eye examination, which yielded 285 cases. Of the 285, we identified 39 cases of true MSA. Each of these 39 patients was further reviewed for ocular abnormalities potentially related to MSA. Ocular findings potentially attributable to MSA were found in 64% of patients. Most common were dry eye (N = 14), conjugate eye movement abnormalities (N = 13), and ocular misalignment (N = 7). One patient had dry eye and monocular diplopia from trichiasis due to cicatricial pemphigoid, one had bilateral optic atrophy, and one had Adie's tonic pupil. Conjugate eye movement abnormalities (33%) and ocular misalignment (18%) were more common in patients with MSA-C. Patients with ocular findings, excluding dry eye, had a significantly shorter lifespan from time of initial neurologic symptoms to death. Our study confirms conjugate eye movement abnormalities and misalignment are common ocular findings in patients with MSA. Bilateral optic atrophy and cicatricial pemphigoid are possibly attributable to the disease. Ocular manifestations in MSA predict a poor prognosis as these patients have a significantly shorter lifespan. Therefore, we recommend patients with MSA have a comprehensive neuro-ophthalmologic exam at time of diagnosis, and thereafter, to screen for eye findings that may indicate a shorter lifespan. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. [Homonymous hemianopia and posterior cortical atrophy].

    Science.gov (United States)

    Formaglio, M; Krolak-Salmon, P; Tilikete, C; Bernard, M; Croisile, B; Vighetto, A

    2009-03-01

    Posterior cortical atrophy (PCA) is a clinically and radiologically defined syndrome, in which predominant symptoms focus on higher visual dysfunction with progressive course and association with cortical atrophy or hypometabolism that predominates in the posterior part of the hemispheres. Homonymous hemianopia (HH) has rarely been described in this syndrome. We report on six patients (four females, two males, aged 63 to 80) referred for visual disorder which led to demonstration of HH using perimetry testing. These patients were followed for 1 to 5 years after discovery of HH. Brain imaging with MRI or CT scan was obtained in the six cases and a SPECT scan was performed in four cases. HH was left-sided in four cases and right-sided in two cases. Associated symptoms related to higher visual dysfunction were simultagnosia, alone or as part of a full Balint's syndrome, alexia, constructional apraxia, dressing apraxia, visual form agnosia, prosopagnosia and hemispatial neglect. These symptoms were mild at onset but invariably worsened with disease progression. Dementia eventually developed in all cases. The clinical diagnosis was probable Alzheimer's disease in five cases and corticobasal degeneration in one case. Radiology showed posterior cortex atrophy in all cases as well as reduced cerebral blood flow in the same region, with an asymmetrical pattern compatible with the side of HH. Elementary cortical lesions in PCA can develop mainly in the associative visual areas and even in the primary visual area, resulting in HH. HH has rarely been documented in PCA, but its prevalence would probably be higher if systematic search was conducted. Apparently isolated HH of insidious onset should suggest PCA and lead to neuropsychological testing and search for discrete atrophic changes of the posterior cortex on MRI as well as for metabolic alterations with SPECT or PET.

  13. [Myocardiopathy of progressive muscular dystrophy].

    Science.gov (United States)

    Ion, I C; Dumitriu, M; Nisipeanu, P; Cinteza, M

    1976-01-01

    The authors have effected a clinical, radiological, electrocardiographic and apexocardiographic survey in 13 patients with progressive muscular distrophy (PMD) and in 6 healthy subjects belonging to families affected by the disease, in parallel with a group of 11 patients with severe myasthenia and 23 healthy subjects. Comparing the results with those found in the literature lead to the following results: 1) The ECG modifications and above all the abnormalities of the ventricular complex develop precociously in the PMD and express the pleiotropism of the myopathic gene. 2) The myocardial dyssynergia represents a link in the physiopathological chain of the cardiac distress. 3) The precociousness of electro and apexocardiographic modifications and their presence in healthy parents recommend these investigations in the genetic enquiry. 4) Clinical, histological and haemodynamic data individualize the myocardial distress as a true myocardiopathy.

  14. Skin lightening cream induced dermatitis and atrophy.

    Science.gov (United States)

    Bremmer, Matthew; Gardner, James; Driscoll, Marcia

    2011-03-15

    We present the case of a Malian woman who had been using skin-lightening creams for an excess of 5 years. On presentation to our clinic she had multiple areas of atrophy and striae with erythema. She had been using a topical estrogen cream over all effected areas for two weeks. We present this case to draw attention to the serious problem of widespread and unregulated use of skin lightening creams in Africa. Herein we include a review of the literature on the prevalence of the problem as well as associated side effects of commonly implicated medications.

  15. Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach Distrofia muscular de Duchenne e Becker: abordagem molecular e imuno-histoquímica

    Directory of Open Access Journals (Sweden)

    Aline Andrade Freund

    2007-03-01

    Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains. The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.As distrofias musculares de Duchenne (DMD e de Becker (DMB são doenças causadas por mutação no gene da distrofina. Foram estudados 106 casos com a suspeita diagnóstica de DMD/BMD com a analise de 20 exons do gene da distrofina no sangue e biópsia muscular com imuno-histoquímica para distrofina em alguns casos. Em 71,7% dos casos foi encontrada deleção em pelo menos um dos exons, sendo que 68% das deleções localizam-se na região 3' hot spot. Foram encontradas deleções em 81,5% dos DMD e em todos os BMD, sendo que os sem deleção tinham deficiência de distrofina, incluindo a mulher com DMD. As portadoras sintomáticas não tinham deleções mas anormalidades na distribuição da distrofina no sarcolema. Os outros casos sem deleção, com auxilio da

  16. Duchenne muscular dystrophy: current cell therapies.

    Science.gov (United States)

    Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-07-01

    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.

  17. Abnormal pain perception in patients with Multiple System Atrophy.

    Science.gov (United States)

    Ory-Magne, F; Pellaprat, J; Harroch, E; Galitzsky, M; Rousseau, V; Pavy-Le Traon, A; Rascol, O; Gerdelat, A; Brefel-Courbon, C

    2018-03-01

    Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Effects of muscle atrophy on motor control

    Science.gov (United States)

    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.

  19. Bringing CLARITY to Gray Matter Atrophy

    Science.gov (United States)

    Spence, Rory D.; Kurth, Florian; Itoh, Noriko; Mongerson, Chandler R.L.; Wailes, Shannon H.; Peng, Mavis S.; MacKenzie-Graham, Allan J.

    2015-01-01

    Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5 mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross-modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI. PMID:25038439

  20. Oats induced villous atrophy in coeliac disease

    Science.gov (United States)

    Lundin, K E A; Nilsen, E M; Scott, H G; Løberg, E M; Gjøen, A; Bratlie, J; Skar, V; Mendez, E; Løvik, A; Kett, K

    2003-01-01

    The current trend is to allow coeliac disease (CD) patients to introduce oats to their gluten free diet. We sought further data from the clinical setting with regards to oats consumption by coeliac patients. Several oat products were tested for wheat contamination using a commercial enzyme linked immunoassay (ELISA) kit, and six samples were examined by an ELISA using a cocktail of monoclonal antibodies, mass spectrometry, and western blot analysis. Nineteen adult CD patients on a gluten free diet were challenged with 50 g of oats per day for 12 weeks. Serological testing and gastroduodenoscopy was performed before and after the challenge. Biopsies were scored histologically and levels of mRNA specific for interferon γ were determined by reverse transcription-polymerase chain reaction analysis. Oats were well tolerated by most patients but several reported initial abdominal discomfort and bloating. One of the patients developed partial villous atrophy and a rash during the first oats challenge. She subsequently improved on an oats free diet but developed subtotal villous atrophy and dramatic dermatitis during a second challenge. Five of the patients showed positive levels of interferon γ mRNA after challenge. Some concerns therefore remain with respect to the safety of oats for coeliacs. PMID:14570737

  1. Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome: a rare cause of acute bulbar dysfunction in children = Variante faringo-cérvico-braquial da síndrome de Guillain-Barré: uma causa rara de disfunção bulbar aguda em crianças

    Directory of Open Access Journals (Sweden)

    Coelho, Joana

    2014-01-01

    Conclusões: Apesar da variante faringo-cervico-braquial ser pouco frequente em idade pediátrica, é um diagnóstico que deve ser considerado perante uma criança com disfunção bulbar aguda, pois a identificação precoce permite instituir rapidamente medidas terapêuticas que podem evitar a morte

  2. What Are the Treatments for Muscular Dystrophy?

    Science.gov (United States)

    ... NICHD Research Information Find a Study More Information Preeclampsia and Eclampsia About NICHD Research Information Find a ... Facebook Twitter Pinterest Email Print What are the treatments for muscular dystrophy? No treatment is currently available ...

  3. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    Science.gov (United States)

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., ... expertise and patient preferences. The goals of any physical therapy plan of care are to assist patients to:  ...

  4. An unusual variant of Becker muscular dystrophy

    NARCIS (Netherlands)

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

    1990-01-01

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

  5. Brain MRI Findings in Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-03-01

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

  6. Anoctamin 5 muscular dystrophy in Denmark

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Petri, Helle

    2013-01-01

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

  7. Duchenne muscular dystrophy: Case report and review

    Directory of Open Access Journals (Sweden)

    Rupam Sinha

    2017-01-01

    Full Text Available Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  8. Duchenne muscular dystrophy: Case report and review.

    Science.gov (United States)

    Sinha, Rupam; Sarkar, Soumyabrata; Khaitan, Tanya; Dutta, Soumyajit

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  9. Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

    Science.gov (United States)

    Sadda, Srinivas R; Guymer, Robyn; Holz, Frank G; Schmitz-Valckenberg, Steffen; Curcio, Christine A; Bird, Alan C; Blodi, Barbara A; Bottoni, Ferdinando; Chakravarthy, Usha; Chew, Emily Y; Csaky, Karl; Danis, Ronald P; Fleckenstein, Monika; Freund, K Bailey; Grunwald, Juan; Hoyng, Carel B; Jaffe, Glenn J; Liakopoulos, Sandra; Monés, Jordi M; Pauleikhoff, Daniel; Rosenfeld, Philip J; Sarraf, David; Spaide, Richard F; Tadayoni, Ramin; Tufail, Adnan; Wolf, Sebastian; Staurenghi, Giovanni

    2017-11-02

    To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). Consensus meeting. Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. A consensus classification system for atrophy and OCT-based criteria to identify atrophy. OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete

  10. Corpus callosum atrophy in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Garde, Ellen; Skimminge, Arnold

    2011-01-01

    Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as ...

  11. A case of spinocerebellar ataxia type 6 mimicking olivopontocerebellar atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, N.; Katayama, T.; Makita, Y.; Kuroda, K.; Aizawa, H.; Kikuchi, K. [First Dept. of Internal Medicine, Asahikawa Medical Coll. (Japan)

    1999-07-01

    Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, slowly progressive cerebellar ataxia without multisystem involvement. We report a 57-year-old woman with genetically confirmed SCA6 who showed clinical features of olivopontocerebellar atrophy. Conventional T2-weighted and FLAIR MRI demonstrated high signal in the middle cerebellar peduncles, in addition to mild atrophy of the pons and cerebellum. (orig.)

  12. Duchenne muscular dystrophy: current cell therapies

    OpenAIRE

    Sienkiewicz, Dorota; Kulak, Wojciech; 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 cel...

  13. Duchenne muscular dystrophy: the management of scoliosis.

    Science.gov (United States)

    Archer, James E; Gardner, Adrian C; Roper, Helen P; Chikermane, Ashish A; Tatman, Andrew J

    2016-09-01

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

  14. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. © 2015 American Society for Parenteral and Enteral Nutrition.

  15. Quantitative assessment of gastric atrophy using the syntactic structure analysis.

    Science.gov (United States)

    Zaitoun, A M; al Mardini, H; Record, C O

    1998-12-01

    To assess the topographical relation between gastric glands, using the minimum spanning tree (MST), to derive both a model of neighbourhood and quantitative representation of the tissue's architecture, to assess the characteristic features of gastric atrophy, and to assess the grades of gastric atrophy. Haematoxylin and eosin stained sections from corporal and antral biopsy specimens (n = 139) from normal patients and from patients with nonatrophic gastritis and atrophic gastritis of grades 1, 2, and 3 (Sydney system) were assessed by image analysis system (Prodit 5.2) and 11 syntactic structure features were derived. These included both line and connectivity features. Syntactic structure analysis was correlated with the semiquantitative grading system of gastric atrophy. The study showed significant reductions in the number of points and the length of MST in both body and antrum. The standard deviation of the length of MST was significantly increased in all grades of atrophy. The connectivity to two glands was the highest and most affected by the increased grade of atrophy. The reciprocal values of the Wiener, Randic, and Balaban indices showed significant changes in the volume of gland, abnormality in the shape of glands, and changes in irregularity and branching of the glands in both types of gastric mucosa. There was a complete separation in the MST, connectivity, and index values between low grade and high grade gastric atrophy. (1) Gastric atrophy was characterised by loss of the gland, variation in the volume, reduction in the neighbourhood, irregularity in spacing, and abnormality in the shape of the glands. (2) Syntactic structure analysis significantly differentiated minor changes in gastric gland (low grade atrophy) from high grade atrophy of clinical significance. (3) Syntactic structure analysis is a simple, fast, and highly reproducible technique and appears a promising method for quantitative assessment of atrophy.

  16. Teres minor innervation in the context of isolated muscle atrophy.

    Science.gov (United States)

    Friend, Jikol; Francis, Sarah; McCulloch, Jane; Ecker, Jeff; Breidahl, William; McMenamin, Paul

    2010-03-01

    Teres minor atrophy occurs either in isolation, associated with other rotator cuff muscle pathologies or in quadrilateral space syndrome. In the latter condition, compression of the axillary nerve is the likely cause; however, the anatomy of the nerve to teres minor and how this may relate to isolated teres minor atrophy have not been extensively investigated. In light of the significance of teres minor atrophy in shoulder pathology, we performed a combined radiological and anatomical study of teres minor and its nerve supply. Cadaveric dissection of nine shoulder specimens from eight cadavers was performed to investigate the anatomical variability in course, length and branching pattern of both the teres minor nerve and the axillary nerve. Radiological imaging and reports were analysed on all shoulder magnetic resonance images performed over a 1-week period at four radiology clinic locations in an attempt to identify the incidence of isolated teres minor atrophy and review teres minor atrophy in association with other shoulder pathology. Finally, we studied a case of isolated teres minor atrophy identified during a routine undergraduate dissection class. Considerable anatomical variation was noticed in cadaver dissections in the nerve(s) supplying teres minor muscle revealing several various points where it may be vulnerable to impingement or injury at along its course. Analysis of 61 shoulder MR images revealed two patients with shoulder complaints that had isolated teres minor atrophy. Case-based study of these two male patients revealed other associated shoulder injury but the presentation was markedly different and clinically distinct from quadrilateral space syndrome. Isolated teres minor atrophy is a relatively common shoulder pathology which appears to be clinically distinct from other syndromes with rotator cuff muscle atrophy including quadrilateral space syndrome. The exact aetiology is unknown but cadaveric dissection in this study suggests the

  17. Muscular fatigue: considerations for dance.

    Science.gov (United States)

    Wyon, Matthew A; Koutedakis, Yiannis

    2013-01-01

    Muscular fatigue can be defined as the failure to maintain an expected power output. It is a multifaceted phenomenon that incorporates metabolic, neural and neuromuscular components, among others. Metabolic causes of fatigue are associated with the ability to maintain energy supply during exercise, the speed at which homeostasis is achieved post-exercise, and the effects of high intensity exercise by-products on the peripheral neuromuscular system. Research has indicated that the central nervous system plays a protective role in preventing catastrophic muscle damage by reducing the intensity and frequency of propagation founded on biofeedback from the muscle cells. The duration and particularly the type of physical activity play a role in the development of muscle fatigue, with impact or weightbearing exercises, such as dance, producing increased symptoms compared to non-impact or non-weightbearing equivalents. The effects of prolonged exercise and the associated increased levels of muscle fatigue that may lead to compromises in neuromuscular propagation need to be considered in dance.

  18. Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's disease

    NARCIS (Netherlands)

    Lehmann, M.; Koedam, E.L.G.E.; Barnes, J.; Bartlett, J.W.; Ryan, N.S.; Pijnenburg, Y.A.L.; Barkhof, F.; Wattjes, M.P.; Scheltens, P.; Fox, N.C.

    2012-01-01

    Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual

  19. Fluid biomarkers in multiple system atrophy

    DEFF Research Database (Denmark)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy

    2015-01-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target...... engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood...... and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results...

  20. Visual Dysfunction in Posterior Cortical Atrophy

    Science.gov (United States)

    Maia da Silva, Mari N.; Millington, Rebecca S.; Bridge, Holly; James-Galton, Merle; Plant, Gordon T.

    2017-01-01

    Posterior cortical atrophy (PCA) is a syndromic diagnosis. It is characterized by progressive impairment of higher (cortical) visual function with imaging evidence of degeneration affecting the occipital, parietal, and posterior temporal lobes bilaterally. Most cases will prove to have Alzheimer pathology. The aim of this review is to summarize the development of the concept of this disorder since it was first introduced. A critical discussion of the evolving diagnostic criteria is presented and the differential diagnosis with regard to the underlying pathology is reviewed. Emphasis is given to the visual dysfunction that defines the disorder, and the classical deficits, such as simultanagnosia and visual agnosia, as well as the more recently recognized visual field defects, are reviewed, along with the evidence on their neural correlates. The latest developments on the imaging of PCA are summarized, with special attention to its role on the differential diagnosis with related conditions. PMID:28861031

  1. Visual Dysfunction in Posterior Cortical Atrophy.

    Science.gov (United States)

    Maia da Silva, Mari N; Millington, Rebecca S; Bridge, Holly; James-Galton, Merle; Plant, Gordon T

    2017-01-01

    Posterior cortical atrophy (PCA) is a syndromic diagnosis. It is characterized by progressive impairment of higher (cortical) visual function with imaging evidence of degeneration affecting the occipital, parietal, and posterior temporal lobes bilaterally. Most cases will prove to have Alzheimer pathology. The aim of this review is to summarize the development of the concept of this disorder since it was first introduced. A critical discussion of the evolving diagnostic criteria is presented and the differential diagnosis with regard to the underlying pathology is reviewed. Emphasis is given to the visual dysfunction that defines the disorder, and the classical deficits, such as simultanagnosia and visual agnosia, as well as the more recently recognized visual field defects, are reviewed, along with the evidence on their neural correlates. The latest developments on the imaging of PCA are summarized, with special attention to its role on the differential diagnosis with related conditions.

  2. Visual Dysfunction in Posterior Cortical Atrophy

    Directory of Open Access Journals (Sweden)

    Mari N. Maia da Silva

    2017-08-01

    Full Text Available Posterior cortical atrophy (PCA is a syndromic diagnosis. It is characterized by progressive impairment of higher (cortical visual function with imaging evidence of degeneration affecting the occipital, parietal, and posterior temporal lobes bilaterally. Most cases will prove to have Alzheimer pathology. The aim of this review is to summarize the development of the concept of this disorder since it was first introduced. A critical discussion of the evolving diagnostic criteria is presented and the differential diagnosis with regard to the underlying pathology is reviewed. Emphasis is given to the visual dysfunction that defines the disorder, and the classical deficits, such as simultanagnosia and visual agnosia, as well as the more recently recognized visual field defects, are reviewed, along with the evidence on their neural correlates. The latest developments on the imaging of PCA are summarized, with special attention to its role on the differential diagnosis with related conditions.

  3. A new cholesterol biosynthesis and absorption disorder associated with epilepsy, hypogonadism, and cerebro-cerebello-bulbar degeneration.

    Science.gov (United States)

    Korematsu, Seigo; Uchiyama, Shin-ichi; Honda, Akira; Izumi, Tatsuro

    2014-06-01

    Cholesterol is one of the main components of human cell membranes and constitutes an essential substance in the central nervous system, endocrine system, and its hormones, including sex hormones. A 19-year-old male patient presented with failure to thrive, psychomotor deterioration, intractable epilepsy, hypogonadism, and cerebro-cerebello-bulbar degeneration. His serum level of cholesterol was low, ranging from 78.7 to 116.5 mg/dL. The serum concentrations of intermediates in the cholesterol biosynthesis pathway, such as 7-dehydrocholesterol, 8-dehydrocholesterol, desmosterol, lathosterol, and dihydrolanosterol, were not increased. In addition, the levels of the urinary cholesterol biosynthesis marker mevalonic acid, the serum cholesterol absorption markers, campesterol and sitosterol, and the serum cholesterol catabolism marker, 7α-hydroxycholesterol, were all low. A serum biomarker analysis indicated that the patient's basic abnormality differed from that of Smith-Lemli-Opitz syndrome and other known disorders of cholesterol metabolism. Therefore, this individual may have a new metabolic disorder with hypocholesterolemia because of decreased biosynthesis and absorption of cholesterol. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. The golden retriever model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N

    2017-05-19

    Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about

  5. Specific profiles of neurocognitive and reading functions in a sample of 42 Italian boys with Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Lorusso, Maria Luisa; Civati, Federica; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo; D'Angelo, Maria Grazia

    2013-01-01

    A group of 42 Italian boys with Duchenne Muscular Dystrophy was compared with a control group of 10 boys with Spinal Muscular Atrophy and Osteogenesis Imperfecta on tests assessing general intellectual ability, language, neuropsychological functions, and reading skills with the aim of describing a comprehensive profile of the various functions and investigating their interrelationships. The influence of general intellectual level on performance was analyzed. Further, correlations between various neuropsychological measures and language performances were computed for the group with Duchenne Muscular Dystrophy, as well as the correlations between reading scores and other cognitive and linguistic measures. A general lowering in VIQ, PIQ, and FSIQ scores was found to characterize the group with Duchenne Muscular Dystrophy. Expressive language skills were within the normal range, while syntactic and grammatical comprehension were significantly impaired. The presence of below-average reading performances was further confirmed. However, unlike previous studies on irregular orthographies, the present results show that (a) the mild reading difficulties found in the sample essentially concern speed rather than accuracy; (b) they concern word rather than nonword reading; (c) lower reading performances are related to lower scores in general IQ; (d) no correlations emerge with phonological abilities, verbal short-term memory, or working memory, but rather with long-term memory and lexical skills. This may suggest that language-specific effects modulate the cognitive expressions of Duchenne Muscular Dystrophy and raises the possibility that the dysfunctions underlying the reading difficulties observed in affected readers of regular orthographies involve different neurocognitive systems than the cortico-cerebellar circuits usually invoked.

  6. Orbital hydrocephalus: a proven cause for optic atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Towbin, R.; Garcia-Revillo, J.; Fitz, C. [Department of Radiology, Children`s Hospital of Pittsburgh, PA (United States)

    1998-12-01

    A 4-year-old boy with bilateral optic sheath enlargement and progressive optic atrophy and blindness is presented. Computed tomography demonstrated hydrocephalus and enlargement of the optic nerve sheath complex. The child died during an attempted repair of hypoplastic atrioventricular valves. Autopsy demonstrated a patulous perioptic subarachnoid space and optic atrophy. This condition has been described in the literature but has not had radiologic-pathologic correlation. With the availability of magnetic resonance imaging, this diagnosis may be made prospectively, thus, it is important for the radiologist to be aware of this entity because optic atrophy and blindness may be prevented by early diagnosis and surgery. (orig.) With 3 figs., 10 refs.

  7. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Rojas

    2016-03-01

    Full Text Available ABSTRACT 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.

  8. Deformation-Based Atrophy Estimation for Alzheimer’s Disease

    DEFF Research Database (Denmark)

    Pai, Akshay Sadananda Uppinakudru

    Alzheimer’s disease (AD) - the most common form of dementia, is a term used for accelerated memory loss and cognitive abilities enough to severely hamper day-to-day activities. One of the most globally accepted markers for AD is atrophy, in mainly the brain parenchyma. The goal of the PhD project...... and a new way to estimate atrophy from a deformation field. We demonstrate the performance of the proposed solution but applying it on the publicly available Alzheimer’s disease neuroimaging data (ADNI) initiative and compare to existing state-of-art atrophy estimation methods....

  9. Mechanisms of cisplatin-induced muscle atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  10. Effect of Lumbar Progressive Resistance Exercise on Lumbar Muscular Strength and Core Muscular Endurance in Soldiers.

    Science.gov (United States)

    Mayer, John M; Childs, John D; Neilson, Brett D; Chen, Henian; Koppenhaver, Shane L; Quillen, William S

    2016-11-01

    Low back pain is common, costly, and disabling for active duty military personnel and veterans. The evidence is unclear on which management approaches are most effective. The purpose of this study was to assess the effectiveness of lumbar extensor high-intensity progressive resistance exercise (HIPRE) training versus control on improving lumbar extension muscular strength and core muscular endurance in soldiers. A randomized controlled trial was conducted with active duty U.S. Army Soldiers (n = 582) in combat medic training at Fort Sam Houston, Texas. Soldiers were randomized by platoon to receive the experimental intervention (lumbar extensor HIPRE training, n = 298) or control intervention (core stabilization exercise training, n = 284) at one set, one time per week, for 11 weeks. Lumbar extension muscular strength and core muscular endurance were assessed before and after the intervention period. At 11-week follow-up, lumbar extension muscular strength was 9.7% greater (p = 0.001) for HIPRE compared with control. No improvements in core muscular endurance were observed for HIPRE or control. Lumbar extensor HIPRE training is effective to improve isometric lumbar extension muscular strength in U.S. Army Soldiers. Research is needed to explore the clinical relevance of these gains. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

  11. Mitochondrial disorders in progressive muscular dystrophies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

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

  12. Circulating Biomarkers for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-07-22

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

  13. Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.

    Science.gov (United States)

    Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

    2014-11-01

    Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. © 2014 Wiley Periodicals, Inc.

  14. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials.

    Science.gov (United States)

    Shimizu-Motohashi, Yuko; Miyatake, Shouta; Komaki, Hirofumi; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients. To date, exon skipping that targets exons 51, 44, 45, and 53 is being globally investigated including in USA, EU, and Japan. The latest announcement from Japan was made, demonstrating successful dystrophin production in muscles of patients with DMD after treating with exon 53 skipping antisense oligonucleotides (ASOs). However, the innovative therapeutic approaches have demonstrated limited efficacy. To address this issue in exon skipping, studies to unveil the mechanism underlying gymnotic delivery of ASO uptake in living cells have been conducted in an effort to improve in vivo delivery. Further, establishing the infrastructures to integrate multi-institutional clinical trials are needed to facilitate the development of successful therapies for DMD, which ultimately is applicable to other myopathies and neurodegenerative diseases, including spinal muscular atrophy and motor neuron diseases.

  15. Wilmington robotic exoskeleton: a novel device to maintain arm improvement in muscular disease.

    Science.gov (United States)

    Haumont, Thierry; Rahman, Tariq; Sample, Whitney; M King, Marilyn; Church, Chris; Henley, John; Jayakumar, Shanmuga

    2011-01-01

    Upper-extremity movement is limited in individuals with muscular weakness. This paper describes a novel, articulated upper-extremity orthosis, the Wilmington Robotic Exoskeleton (WREX), which helps people overcome this movement deficit. This prospective, case-controlled study involved an ambulatory patient with arthrogryposis multiplex congenita and 2 nonambulatory patients with spinal muscular atrophy type II. The WREX uses elastic bands to negate the effects of gravity; it allows a person with neuromuscular weakness to move their arm in 3 dimensions. The WREX can be fixed on a brace for ambulatory patients and on the wheelchair for nonambulatory patients. Assessment was performed through motion analysis (with and without the WREX), clinical examination, and qualitative questionnaire. Motion analysis showed a marked improvement in upper-extremity function with the WREX. The questionnaire illustrated enhanced functionality with the WREX including self-feeding, fine motor control, and use of a television remote control. Enhanced functionality resulted in improved quality of life by increasing participation in school, raising self-esteem, and increasing social interaction. Two unexpected outcomes were increased security with trunk inclination and amelioration of the effects of contractures. The WREX provided an increase in functionality and improved the quality of life of the patients. The device has become an integral part of the lives of the 3 patients. Level III in Therapeutic Studies-Investigating the Results of Treatment.

  16. Analysis of cardiac exams: electrocardiogram and echocardiogram use In Duchenne muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Cynthia Kallás Bachur

    Full Text Available Introduction Duchenne Muscular Dystrophies (DMD is a genetic muscle disorder that causes degeneration and atrophy of skeletal muscle and heart. Objective The aim of this survey is accomplish an evaluation electrocardiographic and echocardiography in the patients bearers of Duchene Muscular Dystrophies (DMD, to observe which alterations, which the degree of cardiac compromising these patient present and the effectiveness of these exams in the evaluation cardiologic. Methods Nine patients of the sex male bearers of DMD, with medium age of 14.12 ± 4.19 years, varying of 7 to 23 years were appraised. All were submitted to the evaluation physiotherapy and the cardiologic: electrocardiogram and echocardiogram. Results The experimental conditions of the present survey we propitiate the observation of the alterations echocardiography, as well as: significant increase in the diastolic diameter of the left ventricular (LV, increase in the systolic diameter of the left atrium (LA, and significant decrease of the ejection fraction of the LV, characterizing global systolic function reduced, and of the alterations electrocardiographic suggested possible overload of RV, septum hypertrophy, blockade of left previous fascicle and overload of atrium left. Compatible alterations of hypertrophy left ventricular were not observed. Conclusion The evidences corroborate with the data described in the literature in the characterization of an important heart compromising that these patient present, like this the evaluation cardiologic, through the complemented exams of the echocardiography and electrocardiography provide important information for the prognostic, the accompaniment, and the treatment of patient bearers of DMD.

  17. Redox homeostasis, oxidative stress and disuse muscle atrophy

    National Research Council Canada - National Science Library

    Pellegrino, Maria Antonietta; Desaphy, Jean‐François; Brocca, Lorenza; Pierno, Sabata; Camerino, Diana Conte; Bottinelli, Roberto

    2011-01-01

    Abstract  A pivotal role has been ascribed to oxidative stress in determining the imbalance between protein synthesis and degradation leading to muscle atrophy in many pathological conditions and in disuse...

  18. Acquired alopecia, mental retardation, short stature, microcephaly, and optic atrophy

    NARCIS (Netherlands)

    Hennekam, R. C.; Renckens-Wennen, E. G.

    1990-01-01

    We report on a female patient who had acquired total alopecia, short stature, microcephaly, optic atrophy, severe myopia, and mental retardation. A survey of published reports failed to show an identical patient, despite various similar cases

  19. Mechanisms of muscle growth and atrophy in mammals and Drosophila

    National Research Council Canada - National Science Library

    Piccirillo, Rosanna; Demontis, Fabio; Perrimon, Norbert; Goldberg, Alfred L

    2014-01-01

    .... Although the pathogenesis of this condition has been primarily studied in mammals, Drosophila is emerging as an attractive system to investigate some of the mechanisms involved in muscle growth and atrophy. Results...

  20. Biochemical adaptations of antigravity muscle fibers to disuse atrophy

    Science.gov (United States)

    Booth, F. W.

    1978-01-01

    Studies are presented in four parts of this report. The four parts include; (1) studies to gain information on the molecular basis of atrophy by antigravity muscle; (2) studies on the work capacity of antigravity muscles during atrophy and during recovery from atrophy; (3) studies on recovery of degenerated antigravity fibers after removal of hind-limb casts; and (4) studies on the atrophy and recovery of bone. The philosophy of these studies was to identify the time sequence of events in the soleus muscle of the rat following immobilization of the hind limbs, so that the length of the soleus muscle within the fixed limb is less than its resting length. In two separate studies, no decline in the weight of the soleus muscle could be detected during the first 72 hours of limb immobilization.

  1. Disease-Induced Skeletal Muscle Atrophy and Fatigue

    NARCIS (Netherlands)

    Powers, Scott K.; Lynch, Gordon S.; Murphy, Kate T.; Reid, Michael B.; Zijdewind, Inge

    2016-01-01

    Numerous health problems including acute critical illness, cancer, diseases associated with chronic inflammation, and neurological disorders often result in skeletal muscle weakness and fatigue. Disease-related muscle atrophy and fatigue is an important clinical problem because acquired skeletal

  2. Lesiones musculares en el mundo del deporte. [Muscular injuries in the world of the sport

    OpenAIRE

    María Ángeles Cardero Durán

    2009-01-01

    Resumen En el mundo del deporte y no solo en este, sino en toda la práctica de una actividad física, son muy frecuentes las lesiones musculares. Hay muchos tipos de lesiones musculares de los que hablaremos más adelante, como pueden ser desgarros musculares, calambres, contracturas etc., que tienen mayor incidencia en la musculatura poli-articular, por condiciones de acumulación de fatiga, trabajo no realizado correctamente, o condiciones ambientales desfavorables. Es importante el dia...

  3. Quantitative study of the physiological cerebral atrophy with aging. A statistical analysis of the normal range

    Energy Technology Data Exchange (ETDEWEB)

    Nagata, K.; Basugi, N.; Fukushima, T.; Tango, T.; Suzuki, I.; Kaminuma, T.; Kurashina, S.

    1987-07-01

    A new method of discriminating pathological cerebral atrophy from physiological atrophy during aging is reported. The authors advocate a pixel counting method using a minicomputer for the quantitative measurement of cerebral atrophy. Five hundred cases were studied with this quantitative method and the normal range of the physiological atrophy was determined statistically. In order to estimate the degree of cerebral atrophy easily, the conventional linear measurement methods were compared with the pixel counting method using multivariant analysis, and a simple formula for the calculation of the degree of cerebral atrophy is proposed. Using this formula and the normal range, pathological cerebral atrophy is easily detectable.

  4. Facilitating text reading in posterior cortical atrophy.

    Science.gov (United States)

    Yong, Keir X X; Rajdev, Kishan; Shakespeare, Timothy J; Leff, Alexander P; Crutch, Sebastian J

    2015-07-28

    We report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA. Reading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2). Mean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy (PCA mean reading accuracy: single-word reading aid = 96%; individual patient improvement range: 6%-270%) and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA. These findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities. This study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy. © 2015 American Academy of Neurology.

  5. Photoreceptor atrophy in acute zonal occult outer retinopathy

    DEFF Research Database (Denmark)

    Zibrandtsen, N.; Munch, I.C.; Klemp, K.

    2006-01-01

    Purpose: To assess retinal morphology in acute zonal occult outer retinopathy (AZOOR). Methods: Three patients with a normal ophthalmoscopic fundus appearance, a history of photopsia, and visual field loss compatible with AZOOR were examined using optical coherence tomography, automated perimetry...... and multifocal electroretinography. Results: All three patients demonstrated partial or complete photoreceptor atrophy corresponding to partial or complete scotomata of retinal origin. Conclusion: Photoreceptor atrophy can be demonstrated early in the course of AZOOR, before ophthalmoscopically visible changes...

  6. Steroid-induced Kager's fat pad atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Taneja, Atul K. [Hospital Israelita Albert Einstein, Musculoskeletal Radiology Division, Imaging Department, Sao Paulo (Brazil); Musculoskeletal Imaging, Diagnostic Center, Hospital do Coracao (HCor) and Teleimagem, Sao Paulo, SP (Brazil); Santos, Durval C.B. [Hospital Israelita Albert Einstein, Musculoskeletal Radiology Division, Imaging Department, Sao Paulo (Brazil)

    2014-08-15

    We report a rare case of Kager's fat pad atrophy and fibrosis in a 60-year-old woman 1 year after a steroid injection for Achilles tendinopathy. There are few published reports of steroid-induced atrophy affecting deeper layers of fat tissue. To our knowledge, this case report is the first to illustrate its features using magnetic resonance imaging. A review of the scientific literature is also presented. (orig.)

  7. Costameric proteins in human skeletal muscle during muscular inactivity.

    Science.gov (United States)

    Anastasi, Giuseppe; Cutroneo, Giuseppina; Santoro, Giuseppe; Arco, Alba; Rizzo, Giuseppina; Bramanti, Placido; Rinaldi, Carmen; Sidoti, Antonina; Amato, Aldo; Favaloro, Angelo

    2008-09-01

    Costameres are regions that are associated with the sarcolemma of skeletal muscle fibres and comprise proteins of the dystrophin-glycoprotein complex and vinculin-talin-integrin system. Costameres play both a mechanical and a signalling role, transmitting force from the contractile apparatus to the extracellular matrix in order to stabilize skeletal muscle fibres during contraction and relaxation. Recently, it was shown that bidirectional signalling occurs between sarcoglycans and integrins, with muscle agrin potentially interacting with both types of protein to enable signal transmission. Although numerous studies have been carried out on skeletal muscle diseases, such as Duchenne muscular dystrophy, recessive autosomal muscular dystrophies and other skeletal myopathies, insufficient data exist on the relationship between costameres and the pathology of the second motor nerve and between costameric proteins and muscle agrin in other conditions in which skeletal muscle atrophy occurs. Previously, we carried out a preliminary study on skeletal muscle from patients with sensitive-motor polyneuropathy, in which we analysed the distribution of sarcoglycans, integrins and agrin by immunostaining only. In the present study, we have examined the skeletal muscle fibres of ten patients with sensitive-motor polyneuropathy. We used immunofluorescence and reverse transcriptase PCR to examine the distribution of vinculin, talin and dystrophin, in addition to that of those proteins previously studied. Our aim was to characterize in greater detail the distribution and expression of costameric proteins and muscle agrin during this disease. In addition, we used transmission electron microscopy to evaluate the structural damage of the muscle fibres. The results showed that immunostaining of alpha 7B-integrin, beta 1D-integrin and muscle agrin appeared to be severely reduced, or almost absent, in the muscle fibres of the diseased patients, whereas staining of alpha 7A

  8. Limb-girdle muscular dystrophy type 2D: clinical and genetic analysis of a family

    Directory of Open Access Journals (Sweden)

    Li-yu OU

    2017-09-01

    Full Text Available Objective To study the characteristics and diagnosis of limb-girdle muscular dystrophy type 2D (LGMD2D. Methods The clinical characteristics, EMG, muscle MRI and muscle pathological studies of 2 female patients in a family with LGMD2D were analyzed. Genetic analysis was used in the diagnosis of this disease. The cases were reported along with related literatures review. Results The onset of the proband and her younger sister occurred at 3 years old with progressive proximal muscle weakness of four limbs as the main clinical manifestation. The serum creatine kinase (CK was significantly high (> 50 × 10 3 U/L. EMG showed myogenic damage. Muscle MRI indicated partial muscle atrophy, fatness or fiber edema. Muscle pathological examination of the proband's younger sister revealed skeletal muscle necrosis and focal regeneration, partial striated muscle disappearance, and the muscle fibers in different sizes. Sequencing of all 10 coding exons of the SGCA gene in 2 patients revealed the same mutation: a c.262delT (p.Phe88SerfsX123 frameshift mutation in exon 3 and a c.409G > A (p.Glu137Lys missense mutation in exon 5. Their mother was a carrier of SGCA gene c.409G > A (p.Glu137Lys mutation. c.409G > A (p.Glu137Lys is a mutation already found, and c.262delT (p.Phe88SerfsX123 is a novel mutation. The proband's father did not take the genetic test for some reason. Conclusions In case of a female with Duchenne muscular dystrophy (DMD.like symptom, if she has been excluded from the DMD gene carrier, pedigree analysis and genetic analysis involving limb . girdle muscular dystrophy (LGMD should be conducted to facilitate the diagnosis of the LGMD and its subtypes. DOI: 10.3969/j.issn.1672-6731.2017.08.010

  9. Histopathologic Evolution of Cardiomyopathy in a Canine Model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Lygia M.M. Malvestio

    2015-07-01

    Full Text Available Duchenne muscular dystrophy (DMD is a recessive X-linked disorder characterized for mutation in dystrophin gene and manifested by progressive degeneration and necrosis of skeletal and cardiac muscle with replacement leading to generalized muscular weakness and atrophy. The dog Golden Retriever Muscular Dystrophy (GRMD is the best experimental model for DMD, with genotypic and phenotypic manifestations closely of human disease. Similar to patients with DMD, heart failure is a major cause of death in GRMD animals. The objective of this study was to evaluate the pathological progression of myocardial lesions from GRMD dogs in different ages in order to clarify the pathogenesis of Duchenne´s cardiomyopathy. Fragments of left and right ventricle and interventricular septum, from 18 GRMD dogs between 6 to 51 months were collected, fixed, dehydrated, clarified, and finally embedded in paraffin. Five micrometer thick serial sections were obtained and stained with Hematoxylin-Eosin (HE, Picrosirius red, and Von Kossa. Histological analyses were performed at the light microscopy. Myocardial lesions were observed in all GRMD dogs and the sequence of cardiac lesion classified according to according to the age included: abnormal calcium accumulation, myofibrillar necrosis, proliferation of granulation tissue, endomysial and perimysial fibrosis, and finally myocardial fatty infiltration. Interestingly, several Anitschkow cells, the hallmark of rheumatic carditis, were detected in inflammatory infiltrate present at granulation tissue. Our results demonstrate the sequence of cardiac lesions that determine the cardiomyopathy in Golden Retriever dogs affected by DMD and exhibit, for the first time, the Anitschkow cells in the histological findings of this cardiomyopathy. These results are relevant for to clarify the pathogenesis of cardiomyopathy in dogs and humans affected by DMD.

  10. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Falzarano, Maria Sofia; Passarelli, Chiara; Ferlini, Alessandra

    2014-02-01

    Antisense therapy is a powerful tool for inducing post-transcriptional modifications and thereby regulating target genes associated with disease. There are several classes of antisense oligonucleotides (AONs) with therapeutic use, such as double-stranded RNAs (interfering RNAs, utilized for gene silencing, and single-stranded AONs with various chemistries, which are useful for antisense targeting of micro-RNAs and mRNAs. In particular, the use of AONs for exon skipping, by targeting pre-mRNA, is proving to be a highly promising therapy for some genetic disorders like Duchenne muscular dystrophy and spinal muscular atrophy. However, AONs are unable to cross the plasma membrane unaided, and several other obstacles still remain to be overcome, in particular their instability due to their nuclease sensitivity and their lack of tissue specificity. Various drug delivery systems have been explored to improve the bioavailability of nucleic acids, and nanoparticles (NPs) have been suggested as potential vectors for DNA/RNA. This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy.

  11. Diagnóstico diferencial das distrofias musculares com referência especial às alterações enzimáticas Differential diagnosis of muscular dystrophies with special reference to enzymatic activities

    Directory of Open Access Journals (Sweden)

    H. Heick

    1967-06-01

    ços musculares, tais fibras freqüentemente apresentam alterações idênticas às encontráveis nas distrofias musculares miopáticas hereditárias.The enzymes ALD, CPK, GOT, CPT, LDH and MDH were studied in the serum of 221 patients suffering from progressive muscular dystrophy and in 43 cases of infantile and pseudomyopathic muscular dystrophy. Besides, the activity of 25 enzymes was measured in the muscular tissue. All findings were statistically revised. Serum enzymes are increased in all of the 3 types of muscular dystrophy; in most cases of the Duchenne type, however, many times over the other types. The difference is not specific, but can be explained by the considerably more marked progression of muscle degeneration in the Duchenne type. The enzyme increases are already existent at birth and reach a maximum before clinical manifestation of the disease. The activities of all serum enzymes decrease with longer duration of the disease. This phenomenon also occurs in the majority of all serum enzymes. Up to now, modifications indicating a specific abnormality of metabolism could not be stated. Likewise in spinal muscular atrophies of the Kugelberg-Welander type, there appear the same enzyme losses in the muscle and significant increases of the enzyme activities in serum can be demonstrated. This does not apply to the infantile forms of Werdnig-Hoffmann type and this fact might be explained by the almost complete motorial inactivation. The hypothesis that the efflux of enzymes from the muscular cell might point to a disordered membrane permeability as initial process of muscular dystrophies, is likewise refuted by finding necrotic muscular fibers, already in the earliest preclinical stage of the disease. The serum enzyme findings are of limited value for establishing a clinical differential diagnosis. Only extremely marked increases of activity do reliably point to the Duchenne type.

  12. FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

    Directory of Open Access Journals (Sweden)

    Gerrard Dave

    2007-04-01

    Full Text Available Abstract Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight.

  13. Artificial urinary sphincter in male patients with spina bifida: Comparison of perioperative and functional outcomes between bulbar urethra and bladder neck cuff placement.

    Science.gov (United States)

    Khene, Zine-Eddine; Paret, Fanny; Perrouin-Verbe, Marie-Aime E; Prudhomme, Thomas; Hascoet, Juliette; Nedelec, Mathilde; Kerdraon, Jacques; Menard, Helene; Jezequel, Magali; Le Normand, Loïc; Manunta, Andrea; Game, Xavier; Peyronnet, Benoit

    2017-10-13

    To evaluate the perioperative and long-term functional outcomes of bladder neck and peribulbar cuff placement of an artificial urinary sphincter (AUS) in a population of adult male patients with spinal dysraphism. A retrospective analysis of the French spina bifida (SB) network database was performed. Patients who underwent implantation of an AUS from January 1985 to November 2015 were selected and stratified into two groups according to cuff location: bladder neck vs. bulbar urethra. Explantation-free and revision-free device survivals were estimated using the Kaplan-Meier method and compared using the log rank test. Cox regression models were used to assess prognostic factors of AUS device failure. Sixty-five patients were included. Most patients were not wheelchair-bound. The cuff was implanted around the bulbar urethra in 46 procedures (59%) and around the bladder neck in 32 procedures (41%). Median revision-free device survivals were 11.7 and 14.3 years (p=0.73) and median explantation-free device survivals were 18.5 and 24.5 years (p=0.08) in peribulbar and bladder neck groups respectively. In multivariate analysis, clean-intermittent catheterization was the only predictor of AUS device failure (no influence of cuff location). At the last follow-up, satisfactory continence was similar in both groups (83% vs. 75%, p=0.75). In SB male patients, the morbidity and functional outcomes were similar between bladder neck and bulbar urethra cuff placement but with a trend towards a longer survival without explantation in the bladder neck group. Clean-intermittent catheterization was the only predictor of shorter device survival in multivariate analysis. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  14. Contribution of white matter hyperintensities, medial temporal lobe atrophy and cortical atrophy on outcome, seven to twelve years after ECT in severely depressed geriatric patients

    NARCIS (Netherlands)

    Oudega, M.L.; Dols, A.; Adelerhof, I.; Rozing, M.; Wattjes, M.P.; Comijs, H.C.; Barkhof, F.; Eikelenboom, P.; Stek, M.L.; van Exel, E.

    2015-01-01

    Background Depression and cognitive decline are highly prevalent and often coexisting, however, the association between depression and dementia remains unclear. White matter hyperintensities (WMH), medial temporal lobe atrophy (MTA) and global cortical atrophy (GCA) are associated with depression,

  15. Muscular and non-muscular contributions to maximum power cycling in children and adults: implications for developmental motor control

    OpenAIRE

    Korff, T.; Hunter, EL; Martin, JC

    2009-01-01

    This article is available open access through the publisher’s website at the link below. During submaximal cycling, children demonstrate a different distribution between muscular and non-muscular (gravitational and motion-dependent) forces when compared with adults. This is partly due to anthropometric differences. In this study, we tested the hypothesis that during maximum power cycling, children would construct the task (in terms of the distribution between muscular and non-muscular peda...

  16. Familial spastic paraplegia, axonal sensory-motor polyneuropathy and bulbar amyotrophy with facial dysmorphia: new cases of Troyer-like syndrome.

    Science.gov (United States)

    Bertini, E; Sabatelli, M; Di Capua, M; Cilio, M R; Mignogna, T; Federico, A; Tonali, P

    1998-01-01

    We studied two Libyan siblings, born to healthy consanguineous parents, who had suffered from a progressive neurological disorder, characterized by facial dysmorphia, ataxia, spastic paraplegia and an axonal sensory-motor polyneuropathy, since the age of 3 years. The clinical picture progressed slowly over a 6-year period to involve also bulbar and distal limb muscles. Interestingly, we found unusual tubulofilamentous inclusions in peripheral nerves and presynaptic buttons at the neuromuscular junctions. Describing the clinical picture of this presumably new disorder, we comment on the difference from similar conditions.

  17. Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study.

    Science.gov (United States)

    Qian, Ying; McGraw, Sarah; Henne, Jeff; Jarecki, Jill; Hobby, Kenneth; Yeh, Wei-Shi

    2015-10-24

    The clinical features of SMA, which range along a spectrum of severity, are relatively well described. In contrast, the literature on how individuals with SMA and their families experience this condition is limited. To address this gap, we undertook a qualitative study with individuals affected by SMA Types I, II and III, parents of those affected, and clinicians. We completed 16 focus group sessions and 37 interviews in the US with 96 participants including: 21 with individuals with SMA; 64 parents of individuals affected by SMA; and 11 clinicians who specialize in the care of SMA patients. The Diagnostic Journey: Families reported substantial diagnostic delays owing to: 1) lack of awareness and knowledge about SMA; 2) the difficulty of distinguishing normal from abnormal development; and 3) the challenge of differential diagnosis. Lack of sensitivity in how clinicians communicated this potentially devastating diagnosis compounded parents' negative impressions. Newborn Screening: Parents generally held positive views about adding SMA to newborn screening panels. For example, it would: 1) enable earlier access to care; 2) shorten the diagnostic journey; and 3) give families more time to prepare to care for a disabled child. Some noted negative outcomes such as prematurely affecting a parent's relationship with a child before symptoms are evident. The Psychosocial Impact of Living with SMA: Ten thematic areas characterized the impact: 1) confronting premature death; 2) making difficult treatment choices; 3) fearing the loss of functional ability; 4) coming to terms with lost expectations; 5) loss of sleep and stress; 6) stigma; 7) limitations on social activities; 8) independence; 9) uncertainty and helplessness; and 10) family finances. The results of this study suggest high levels of burden experienced by individuals with SMA and their families. The difficulties of living with SMA begin with the long and often arduous process of finding a diagnosis for their child. Newborn screening for SMA is seen as an important step toward shortening this journey. The psychosocial effects of coping with SMA are substantial and wide ranging both for the individual living with this condition and family members of affected individuals.

  18. Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy

    National Research Council Canada - National Science Library

    Bäumer, Dirk; Lee, Sheena; Nicholson, George; Davies, Joanna L; Parkinson, Nicholas J; Murray, Lyndsay M; Gillingwater, Thomas H; Ansorge, Olaf; Davies, Kay E; Talbot, Kevin

    2009-01-01

    .... Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death...

  19. A study of dynamic F-waves in juvenile spinal muscular atrophy of the distal upper extremity (Hirayama disease).

    Science.gov (United States)

    Zheng, Chaojun; Zhu, Yu; Yang, Shuo; Lu, Feizhou; Jin, Xiang; Weber, Robert; Jiang, Jianyuan

    2016-08-15

    The study aimed to analyse changes in the upper limb F-waves during neck flexion in patients with Hirayama disease (HD). This study included 41 healthy subjects, 38 HD patients and 24 patients with amyotrophic lateral sclerosis (ALS). Bilateral F-waves were consecutively recorded 20 times with the neck both in the standard position and after persistent neck flexion for 30min. The persistence, minimal latencies, chronodispersion, F/M ratios and amplitudes of the F-waves and repeater F-waves were compared between the standard neck and neck flexion positions. During neck flexion, repeater F-waves were found in more HD patients, the percentage of both the ulnar and median repeater F-waves increased significantly, and higher F/M ratios were observed on the symptomatic side (Pneck flexion (P>0.05). HD might be more likely to present as a position-related dysfunction rather than a spinal cord-intrinsic disease. Thus, HD patients could be counselled to avoid neck flexion for long periods of time to prevent further damage, especially in the progressive stage of the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. The heart in limb girdle muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, A. J.; de Voogt, W. G.; Barth, P. G.; Busch, H. F.; Jennekens, F. G.; Jongen, P. J.; de Visser, M.

    1998-01-01

    OBJECTIVE: To assess the frequency, nature, and severity of cardiac abnormalities in limb girdle muscular dystrophy, and its relation to age and weakness in various genotypes. DESIGN: In 26 autosomal dominant, 38 autosomal recessive, and 33 sporadic strictly defined patients with limb girdle