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Sample records for infantile spinal muscular

  1. Learning about Spinal Muscular Atrophy

    Science.gov (United States)

    ... News Release Fischbeck Group Learning About Spinal Muscular Atrophy What is spinal muscular atrophy? What are the ... for Spinal Muscular Atrophy What is spinal muscular atrophy? Spinal muscular atrophy is a group of inherited ...

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

    Science.gov (United States)

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

    2016-08-01

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

  3. Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Spinal Muscular Atrophy (SMA) KidsHealth > For Parents > Spinal Muscular Atrophy (SMA) A A A What's in this article? ... Outlook en español Atrofia muscular espinal Spinal muscular atrophy, or SMA, is an inherited condition that causes ...

  4. Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    ... Habits for TV, Video Games, and the Internet Spinal Muscular Atrophy (SMA) KidsHealth > For Parents > Spinal Muscular Atrophy (SMA) Print ... treatment for the disease's most troubling symptoms. About SMA Normally, healthy nerve cells in the brain called ...

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

    Energy Technology Data Exchange (ETDEWEB)

    Baumbach, L.; Schiavi, A. [Univ. of Miami, FL (United States)] [and others

    1994-09-01

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

  6. Spinal muscular atrophy

    National Research Council Canada - National Science Library

    D'Amico, Adele; Mercuri, Eugenio; Tiziano, Francesco D; Bertini, Enrico

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis...

  7. Spinal Muscular Atrophy

    Science.gov (United States)

    Spinal muscular atrophy (SMA) is a genetic disease that attacks nerve cells, called motor neurons, in the spinal cord. These cells communicate with your voluntary muscles - the ones you can control, like in your ...

  8. Severe spinal muscular atrophy variant associated with congenital bone fractures.

    Science.gov (United States)

    Felderhoff-Mueser, Ursula; Grohmann, Katja; Harder, Anja; Stadelmann, Christine; Zerres, Klaus; Bührer, Christoph; Obladen, Michael

    2002-09-01

    Infantile autosomal recessive spinal muscular atrophy (type I) represents a lethal disorder leading to progressive symmetric muscular atrophy of limb and trunk muscles. Ninety-six percent cases of spinal muscular atrophy type I are caused by deletions or mutations in the survival motoneuron gene (SMNI) on chromosome 5q11.2-13.3. However, a number of chromosome 5q-negative patients with additional clinical features (respiratory distress, cerebellar hypoplasia) have been designated in the literature as infantile spinal muscular atrophy plus forms. In addition, the combination of severe spinal muscular atrophy and neurogenic arthrogryposis has been described. We present clinical, molecular, and autopsy findings of a newborn boy presenting with generalized muscular atrophy in combination with congenital bone fractures and extremely thin ribs but without contractures.

  9. Genetics Home Reference: spinal and bulbar muscular atrophy

    Science.gov (United States)

    ... Kennedy spinal and bulbar muscular atrophy Kennedy's disease SBMA X-linked spinal and bulbar muscular atrophy Related ... Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain. 2006 ...

  10. Tuina plus Ultrasonic Therapy for Infantile Muscular Torticollis

    Institute of Scientific and Technical Information of China (English)

    Shen Zhi-fang; Luo Kai-tao; Zhu Gao-feng; Jin Yue-qin

    2014-01-01

    Objective:To observe the clinical efficacy of tuina plus ultrasonic therapy in treating infantile muscular torticollis. Methods:Seventy kids with muscular torticollis were intervened by tuina plus ultrasonic therapy, and the efficacy was evaluated after 8-month treatment. Results: After 8-month treatment, 41 subjects were cured, accounting for 58.6%, 27 were improved, occupying 38.6%, 2 failed, occupying 2.8%, and the total effective rate was 97.2%. Conclusion: Tuina plus ultrasonic therapy can produce a significant efficacy in treating infantile muscular torticollis, without adverse effects.

  11. Types of SMA (Spinal Muscular Atrophy)

    Science.gov (United States)

    ... genes other than the SMN1 gene. Spinal Muscular Atrophy Respiratory Distress (SMARD) SMARD is a very rare ... and 50. It causes muscle weakness and wasting (atrophy) throughout the body, which is most noticeable in ...

  12. Atrofia muscular espinhal infantil progressiva relato de 12 casos

    OpenAIRE

    Maria Helena Fontana; Pörtner,Martin R.; Paulo A. K. Salim; Bobek,Paulo R.; Paulo R. da Roza

    1990-01-01

    Os autores relatam 12 casos de atrofia muscular espinhal infantil progressiva, diagnosticados no Hospital da Criança Santo Antonio, Porto Alegre. O diagnóstico foi realizado por exame clínico neurológico, dosagem de enzimas musculares séricas, eletroneuromiografia e biópsia muscular. Sâo analisados os aspectos clínicos de apresentação da doença, sua evolução e a investigação laboratorial, confrontando os resultados com os conceitos da literatura.

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

    Science.gov (United States)

    ... Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes muscle weakness ... muscle jerks (myoclonic epilepsy). In individuals with SMA-PME, spinal muscular atrophy results from a loss of ...

  14. Genetics Home Reference: spinal muscular atrophy

    Science.gov (United States)

    ... and abdomen, weakness in the leg muscles, involuntary muscle contractions, tremors, and a protrusion of the abdomen thought to be related to muscle weakness. Some affected individuals experience difficulty swallowing and problems with bladder and ... Frequency Spinal muscular atrophy affects 1 in 6,000 to 1 ...

  15. [Fractures in spinal muscular atrophy].

    Science.gov (United States)

    Febrer, Anna; Vigo, Meritxell; Rodríguez, Natalia; Medina, Julita; Colomer, Jaume; Nascimento, Andrés

    2013-09-01

    Objetivo. Determinar la frecuencia de fracturas en pacientes con atrofia muscular espinal, mecanismo de produccion, edad de aparicion y repercusion funcional. Pacientes y metodos. Se estudian 65 pacientes con atrofia muscular espinal. Se recogen las fracturas diagnosticadas mediante radiografia y se analizan los siguientes parametros: tipo de atrofia muscular espinal, marcha, edad en el momento de la fractura, mecanismo de produccion, localizacion, tratamiento aplicado y repercusion funcional. Resultados. Presentaron fracturas 13 pacientes (20%), con un total de 20 (cuatro presentaron dos o mas fracturas). La edad media fue de 6,35 años. La localizacion fue en su mayoria en el femur y el mecanismo de produccion, en 12 casos por caidas y en 8 por traumatismo menor. No detectamos ninguna fractura vertebral. Todas se trataron de manera conservadora. El unico paciente ambulante que presento una fractura dejo de caminar despues de la inmovilizacion. Conclusiones. La existencia de fracturas en estos pacientes interfiere en su calidad de vida y en el nivel funcional. Es importante la prevencion de las mismas en el manejo del paciente y vigilando la correcta postura en la silla de ruedas con sistemas de sujecion Deberian emprenderse mas estudios sobre la perdida de densidad mineral osea en estos pacientes y su posible relacion con las fracturas.

  16. Very severe spinal muscular atrophy (Type 0).

    Science.gov (United States)

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes.

  17. Proximal spinal muscular atrophy: current orthopedic perspective

    Directory of Open Access Journals (Sweden)

    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

  18. Muscular, Skeletal, and Neural Adaptations Following Spinal Cord Injury

    OpenAIRE

    Shields, Richard K.

    2002-01-01

    Spinal cord injury is associated with adaptations to the muscular, skeletal, and spinal systems. Experimental data are lacking regarding the extent to which rehabilitative methods may influence these adaptations. An understanding of the plasticity of the muscular, skeletal, and spinal systems after paralysis may be important as new rehabilitative technologies emerge in the 21st century. Moreover, individuals injured today may become poor candidates for future scientific advancements (cure) if...

  19. Spinal Muscular Atrophy: Current Therapeutic Strategies

    Science.gov (United States)

    Kiselyov, Alex S.; Gurney, Mark E.

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

  20. The Relationship between Osteogenesis Imperfecta and Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Babak Soltani

    2011-09-01

    Full Text Available ObjectiveA 4-month-old female with osteogenesis imperfecta (OI type II was admitted in PICU of our center due to severe respiratory distress and fever with a diagnosis of severe pneumonia, and mechanical ventilation was initiated. Due to severe hypotonia, NCV and EMG were performed, and spinal muscular atrophy (SMA type I was diagnosed.Keywords: Osteogenesis imperfecta; spinal muscular atrophy; hypotonia

  1. Congenital segmental spinal muscular atrophy: a case report.

    Science.gov (United States)

    Savaş, Tülin; Erol, Ilknur; Özkale, Yasemin; Saygi, Semra

    2015-03-01

    Spinal muscular atrophies are genetic disorders in which anterior horn cells in the spinal cord and motor nuclei of the brainstem are progressively lost. We present a patient with arthrogryposis due to congenital spinal muscular atrophy predominantly affecting the upper limbs. Spinal muscular atrophies with onset at birth may be a cause of arthrogryposis. Localized forms of neurogenic arthrogryposis have been divided into cervical and caudal forms. Our case is similar to the cases described by Hageman et al (J Neurol Neurosurg Psychiatry 1993;56:365-368): severe symmetric lower motor neuron deficit in the upper extremities at the time of birth, no history of injury to the cervical spinal cord or the brachial plexus during delivery, and severe muscle wasting suggesting chronic denervation in utero. Because there was improvement of our patient's situation, her disease was also possibly nonprogressive and sporadic. To our knowledge, this is the first reported case of a Turkish patient with congenital cervical spinal muscular atrophy. Congenital cervical spinal muscular atrophy affecting predominantly the upper limbs is a relatively rare form of motor neuron disease and should be considered in the differential diagnosis of infants with congenital contractures and severe muscle weakness by wasting mainly confined to the upper limbs.

  2. 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.

  3. Muscular, skeletal, and neural adaptations following spinal cord injury.

    Science.gov (United States)

    Shields, Richard K

    2002-02-01

    Spinal cord injury is associated with adaptations to the muscular, skeletal, and spinal systems. Experimental data are lacking regarding the extent to which rehabilitative methods may influence these adaptations. An understanding of the plasticity of the muscular, skeletal, and spinal systems after paralysis may be important as new rehabilitative technologies emerge in the 21st century. Moreover, individuals injured today may become poor candidates for future scientific advancements (cure) if their neuromusculoskeletal systems are irreversibly impaired. The primary purpose of this paper is to explore the physiological properties of skeletal muscle as a result of spinal cord injury; secondarily, to consider associated changes at the skeletal and spinal levels. Muscular adaptations include a transformation to faster myosin, increased contractile speeds, shift to the right on the torque-frequency curve, increased fatigue, and enhanced doublet potentiation. These muscular adaptations may be prevented in individuals with acute paralysis and partially reversed in individuals with chronic paralysis. Moreover, the muscular changes may be coordinated with motor unit and spinal circuitry adaptations. Concurrently, skeletal adaptations, as measured by bone mineral density, show extensive loss within the first six months after paralysis. The underlying science governing neuromusculoskeletal adaptations after paralysis will help guide professionals as new rehabilitation strategies evolve in the future.

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

    Science.gov (United States)

    ... Home Health Conditions SMARD1 spinal muscular atrophy with respiratory distress type 1 Enable Javascript to view the expand/ ... All Close All Description Spinal muscular atrophy with respiratory distress type 1 ( SMARD1 ) is an inherited condition that ...

  5. 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; Mercur

  6. 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

  7. 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;

  8. The Relationship between Osteogenesis Imperfecta and Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Babak Soltani

    2011-06-01

    Full Text Available ObjectiveA 4-month-old female with osteogenesis imperfecta (OI type II was admitted in PICU of our center due to severe respiratory distress and fever with a diagnosis of severe pneumonia, and mechanical ventilation was initiated. Due to severe hypotonia, NCV and EMG were performed, and spinal muscular atrophy (SMA type I was diagnosed.

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

    NARCIS (Netherlands)

    Veen, A; Molenbuur, B; Richardson, FJ

    2002-01-01

    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 reporte

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

    NARCIS (Netherlands)

    Wijngaarde, C A; Blank, A C; Stam, M; Wadman, R I; van den Berg, L H; van der Pol, W L

    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

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

    NARCIS (Netherlands)

    Veen, A; Molenbuur, B; Richardson, FJ

    2002-01-01

    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 reporte

  12. Skeletal muscle training for spinal muscular atrophy type 3

    NARCIS (Netherlands)

    Bartels, Bart; Montes, Jacqueline; van der Pol, W. Ludo; de Groot, Janke F.

    2016-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of skeletal muscle training on functional performance in people with spinal muscular atrophy (SMA) type 3 and to identify any adverse effects.

  13. Neuropathology and Therapeutic Intervention in Spinal and Bulbar Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Haruhiko Banno

    2009-03-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR. The histopathological finding in SBMA is loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic AR. Heat shock proteins, ubiquitin-proteasome system and transcriptional regulation are also potential targets of therapy development for SBMA.

  14. Spinal muscular atrophy: development and implementation of potential treatments.

    Science.gov (United States)

    Arnold, W David; Burghes, Arthur H M

    2013-09-01

    In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression.

  15. 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.

  16. [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.

  17. Large deletions within the spinal muscular atrophy gene region in a patient with spinal muscular atrophy type 3

    Institute of Scientific and Technical Information of China (English)

    Wei Wei; Chunyue Chen; Wenting Liu; Zhenfang Du; Xiaoling Chen; Xianning Zhang

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei, leading to progressive limb and trunk paralysis and muscular atrophy. Depending on the age of onset and maximum muscular function achieved, SMA is recognized as SMA1, SMA2, SMA3 or SMA4, and most patients have a deletion or truncation of the survival motor neuron 1 (SMN1) gene. In this report, we present a patient with a mild SMA phenotype, SMA3, and define his genetic abnormality. Tetra-primer amplification refractory mutation system PCR combined with restriction fragment length polymorphism analysis and array comparative genomic hybridization were used to determine the genetic variations in this patient. A 500 kb deletion in chromosome 5q13.2, including homozygous deletion of neuronal apoptosis inhibitory protein, and heterozygous deletion of occludin and B-double prime 1 was identified. This SMA region deletion did not involve SMN, indicating that SMN was likely to function normally. The phenotype was dependent of the large deletion and neuronal apoptosis inhibitory protein, occludin and B-double prime 1 may be candidate genes for SMA3.

  18. 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

    2017-02-02

    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.

  19. Strategies for treating scoliosis in children with spinal muscular atrophy.

    Science.gov (United States)

    Tobert, Daniel G; Vitale, Michael G

    2013-11-01

    Progressive pulmonary dysfunction is a major complication of spinal muscular atrophy (SMA). Growing constructs are a well-established alternative to spinal arthrodesis to maximize pulmonary growth. We describe patients who demonstrated sustained pulmonary function and improved quality of life following hybrid growing construct implantation. The purpose of this article is to demonstrate a range of approaches for managing scoliosis in children with SMA by utilizing vertical expandable prosthetic titanium rib implantation or growing rods with lateral rib fixation to improve clinical and patient-reported outcomes. Pulmonary compromise and quality of life decline are leading concerns in the SMA population. This case series highlights important surgical strategies that can be utilized to treat scoliosis in patients with SMA.

  20. Treatment of Infantile Muscular Torticollis with Tuina: A Report of 22 Cases

    Institute of Scientific and Technical Information of China (English)

    HAN Pei-feng; LI Yan-ping; HAN Chou-ping

    2004-01-01

    Twenty-two cases of infantile muscular torticollis were treated with such Tuina manipulations as pushing, kneading, grasping and wrenching with the following result: 18 cases got recovery, 3 cases got marked effect and 1 case got no effect. The whole effective rate was 95.4%.%以推、揉、拿、扳、拉等手法,治疗22例肌性斜颈患儿,治愈18例,显效3例,无效1例.总有效率95.4%.

  1. Atrofia muscular espinal en el niño Spinal muscular atrophy present in children

    Directory of Open Access Journals (Sweden)

    Nicolás Garófalo Gómez

    2009-09-01

    Full Text Available INTRODUCCIÓN. Las atrofias musculares espinales en la infancia (AME son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001. Se recopilaron los datos de 35 pacientes, 4 de ellos, fetos con confirmación prenatal de AME. Se precisaron las principales características clínicas, electromiográficas, de la biopsia muscular y de los estudios genéticos moleculares realizados en cada caso. RESULTADOS. La AME de tipo II resultó la forma clínica más frecuente (58 %, seguida por la AME de tipo I (42 %. Las principales manifestaciones clínicas resultaron la debilidad muscular generalizada con predominio proximal en extremidades, asociada a hipotonía y arreflexia osteotendinosa. La deleción de los exones 7 y 8 del gen SMN1 se detectó en 20 de 23 casos estudiados (87 %.INTRODUCTION: Spinal muscular atrophies (SMA in childhood are autosomal recessive genetic disorders, characterized by spinal and bulbar motoneurons degenerations. Aim of present paper was to describe the main clinical features in a series of children presenting SMA. METHODS: A retrospective study of patients with SMA seen in the Neurology and Neurosurgery Institute of Cuba from January, 2997 and December, 2001 was made. Data from 35 patients were available; four of them were fetus with prenatal confirmation of SMA. Main clinical, electromyography, muscular biopsy, and of molecular genetic studies performed in each case were determined. RESULTS: Type II SMA was the more frequent clinical presentation (58%, followed by type I SMA (42,%. Main clinical manifestations were a systemic muscular weakness with

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Katsuno, M; Adachi, H; Inukai, A; Sobue, G

    2003-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

  4. 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

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

    Directory of Open Access Journals (Sweden)

    Karen K Y Ling

    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.

  6. [Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Sobue, Gen

    2003-11-01

    Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.

  7. 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.

  8. 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.

  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. Cardiac defects contribute to the pathology of spinal muscular atrophy models.

    Science.gov (United States)

    Shababi, Monir; Habibi, Javad; Yang, Hsiao T; Vale, Spencer M; Sewell, Will A; Lorson, Christian L

    2010-10-15

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder, which is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6000 live births. The gene responsible for SMA is called Survival Motor Neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q, called SMN2. Motor neurons are the primary tissue affected in SMA. Although it is clear that SMA is a neurodegenerative disease, there are clinical reports that suggest that other tissues contribute to the overall phenotype, especially in the most severe forms of the disease. In severe SMA cases, a growing number of congenital heart defects have been identified upon autopsy. The most common defect is a developmental defect referred to as hypoplastic left heart. The purpose of this report is to determine whether cardiac tissue is altered in SMA models and whether this could contribute to SMA pathogenesis. Here we identified early-stage developmental defects in a severe model of SMA. Additionally, pathological responses including fibrosis and oxidative stress markers were observed shortly after birth in a less severe model of disease. Similarly, functional differences were detected between wild-type and early-stage SMA animals. Collectively, this work demonstrates the importance of cardiac development and function in these severe models of SMA.

  11. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

    Science.gov (United States)

    Kaifer, Kevin A.; Osman, Erkan Y.; Glascock, Jacqueline J.; Arnold, Laura L.; Cornelison, D.D.W.; Lorson, Christian L.

    2017-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy. Several SMN-independent pathways that could impinge upon the SMA phenotype have been examined with varied success. To identify disease-modifying pathways that could serve as stand-alone therapeutic targets or could be used in combination with an SMN-inducing compound, we investigated adeno-associated virus–mediated (AAV-mediated) gene therapy using plastin-3 (PLS3). Here, we report that AAV9-PLS3 extends survival in an intermediate model of SMA mice as well as in a pharmacologically induced model of SMA using a splice-switching ASO that increases SMN production. PLS3 coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways. PMID:28289706

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

    Science.gov (United States)

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

    2009-11-01

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

  13. The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy.

    Science.gov (United States)

    Lunke, Sebastian; El-Osta, Assam

    2009-06-01

    As the leading genetic cause for infantile death, Spinal Muscular Atrophy (SMA) has been extensively studied since its first description in the early 1890s. Though today much is known about the cause of the disease, a cure or effective treatment is not currently available. Recently the short chain fatty acid valproic acid, a drug used for decades in the management of epilepsy and migraine therapy, has been shown to elevate the levels of the essential survival motor neuron protein in cultured cells. In SMA mice, valproic acid diminished the severity of the disease phenotype. This effect was linked to the ability of the short chain fatty acid to suppress histone deacetylase activity and activate gene transcription. Since then, the study of different histone deacetylase inhibitors and their epigenetic modifying capabilities has been of high interest in an attempt to find potential candidates for effective treatment of SMA. In this review, we summarize the current knowledge about use of histone deacetylase inhibitors in SMA as well as their proposed effects on chromatin structure and discuss further implications for possible treatments of SMA arising from research examining epigenetic change.

  14. Whole-body vibration training in children with Duchenne muscular dystrophy and spinal muscular atrophy.

    Science.gov (United States)

    Vry, Julia; Schubert, Isabel J; Semler, Oliver; Haug, Verena; Schönau, Eckhard; Kirschner, Janbernd

    2014-03-01

    Whole-body-vibration training is used to improve muscle strength and function and might therefore constitute a potential supportive therapy for neuromuscular diseases. To evaluate safety of whole-body vibration training in ambulatory children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). 14 children with DMD and 8 with SMA underwent an 8-week vibration training programme on a Galileo MedM at home (3 × 3 min twice a day, 5 days a week). Primary outcome was safety of the training, assessed clinically and by measuring serum creatine kinase levels. Secondary outcome was efficacy as measured by changes in time function tests, muscle strength and angular degree of dorsiflexion of the ankles. All children showed good clinical tolerance. In boys with DMD, creatine kinase increased by 56% after the first day of training and returned to baseline after 8 weeks of continuous whole-body vibration training. No changes in laboratory parameters were observed in children with SMA. Secondary outcomes showed mild, but not significant, improvements with the exception of the distance walked in the 6-min walking test in children with SMA, which rose from 371.3 m to 402.8 m (p training is clinically well tolerated in children with DMD and SMA. The relevance of the temporary increase in creatine kinase in DMD during the first days of training is unclear, but it is not related to clinical symptoms or deterioration. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  15. Dominant inherited distal spinal muscular atrophy with atrophic and hypertrophic calves

    NARCIS (Netherlands)

    Groen, R J; Sie, O G; van Weerden, T W

    1993-01-01

    The clinical, electrophysiological, radiological and morphological data of 3 members of a family with autosomal dominant distal spinal muscular atrophy (DSMA) are reported. One patient has the clinical picture of peroneal muscular atrophy with atrophic calves. His father and sister suffer from cramp

  16. Dominant inherited distal spinal muscular atrophy with atrophic and hypertrophic calves

    NARCIS (Netherlands)

    Groen, R J; Sie, O G; van Weerden, T W

    1993-01-01

    The clinical, electrophysiological, radiological and morphological data of 3 members of a family with autosomal dominant distal spinal muscular atrophy (DSMA) are reported. One patient has the clinical picture of peroneal muscular atrophy with atrophic calves. His father and sister suffer from cramp

  17. The gross motor function measure is a valid and sensitive outcome measure for spinal muscular atrophy.

    Science.gov (United States)

    Nelson, Leslie; Owens, Hollis; Hynan, Linda S; Iannaccone, Susan T

    2006-06-01

    Spinal muscular atrophy is a genetic disease of the anterior horn cell with high morbidity rate in childhood. Certain drugs may be of benefit and are in or under consideration for Phase II trials. Outcome measures that are age appropriate and representative of disease activity remain under study. Several have not yet been validated for spinal muscular atrophy. The Gross Motor Function Measure is a measure of motor function. We showed previously that the Gross Motor Function Measure is a reliable outcome measure to assess motor function in children with spinal muscular atrophy. By collating our data from 40 spinal muscular atrophy patients, ages 5 through 17 years, we now show the validity of the Gross Motor Function Measure when compared to Quantitative Muscle Testing and ambulatory status in children with spinal muscular atrophy. The median for Gross Motor Function Measure total scores for walkers was 237 (range: 197-261) and for non-walkers, 64 (range: 4-177; PGross Motor Function Measure is valid and sensitive as an outcome measure for clinical trials in pediatric spinal muscular atrophy.

  18. Clinical features of adult spinal muscular atrophy:46 cases

    Institute of Scientific and Technical Information of China (English)

    Xiaojun He; Ping Zhang; Guanghui Chen

    2006-01-01

    BACKGROUND: Spinal muscular atrophy (SMA) is a kind of degenerative disease of nervous system. There are 4 types in clinic, especially types Ⅰ, Ⅱ and Ⅲ are common, and the researches on those 3 types are relative mature. Type Ⅳ is a kind of adult spinal muscular atrophy (ASMA), which has low incidence rate and is often misdiagnosed as amyotrophic lateral sclerosis, muscular dystrophy, cervical syndrome, or others.OBJECTIVE: To observe the clinical features of 46 ASMA patients and analyze the relationship between course and activity of daily living.DESIGN: Case analysis.SETTING: Departments of Neurology of the 81 Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA.PARTICIPANTS: A total of 46 ASMA patients were selected from the Departments of Neurology of the 81Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA between April 1998 and January 2002. All patients were consentient. Among 46 cases, there were 37 males and 9 females with the mean age of 42 years. The patients' courses in all ranged from 6 months to 23 years, concretely, courses of 37 cases were less than or equal to 5 years, and those of 9 cases were more than or equal to 6 years.METHODS : ① All the 46 ASMA patients were asked to check blood sedimentation, anti O, serum creatinine,creatine, blood creatine phosphokinase (CPK) and muscular biopsy as early as possible. ② X-ray was used to measure plain film of cervical vertebra borderline film of cranium and neck at proximal end of upper limb of 25 cases and plain film of abdominal vertebra at proximal end of lower limb of 17 cases.③ Cerebrospinal fluid of lumbar puncture was checked on 42 cases, for routine examination, biochemical examination, and immunoglobulin examination. Electromyogram (EMG) was also examined to 42 cases. ④ Barthel index

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

    Science.gov (United States)

    Wijngaarde, C A; Blank, A C; Stam, M; Wadman, R I; van den Berg, L H; van der Pol, W L

    2017-04-11

    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 levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models. We systematically reviewed reported cardiac pathology in relation to SMN deficiency. To investigate the relevance of the possible association in more detail, we used clinical classification systems to characterize structural cardiac defects and arrhythmias. Seventy-two studies with a total of 264 SMA patients with reported cardiac pathology were identified, along with 14 publications on SMA mouse models with abnormalities of the heart. Structural cardiac pathology, mainly septal defects and abnormalities of the cardiac outflow tract, was reported predominantly in the most severely affected patients (i.e. SMA type 1). Cardiac rhythm disorders were most frequently reported in patients with milder SMA types (e.g. SMA type 3). All included studies lacked control groups and a standardized approach for cardiac evaluation. The convergence to specific abnormalities of cardiac structure and function may indicate vulnerability of specific cell types or developmental processes relevant for cardiogenesis. Future studies would benefit from a controlled and standardized approach for cardiac evaluation in patients with SMA.

  20. 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.

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

    Science.gov (United States)

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

    2012-09-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Clinical Characteristics of Cases with Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Mehmet Canpolat

    2016-04-01

    Full Text Available Introduction: The aim of this study is was to evaluate the clinical features of cases with diagnosis of spinal muscular atrophy (SMA. Materials and Methods: Thirty-eight pediatric patients were evaluated retrospectively. All patients were followed in the Pediatric Neurology Department of Erciyes University Faculty of Medicine. The diagnosis of patients had been confirmed by genetic analysis of homozygous deletions of survival motor neuron 1 gene. Detailed history, newborn symptoms, nutritional characteristics, initial complaints, physical examination, concomitant pathologies, genetic characteristics, and treatment modalities were investigated in all patients. Results: The study population consisted of 19 boys (50% and 19 girls (50%. The mean age of patients was 26.9±25.7 months (range: 3-96 months. The mean follow-up period was 12.2±13.3 months (range: 2-48 months. According to SMA classification, 22 patients (57.8% were type 1, 8 patients (21.1% were type 2, and 8 patients were (21.1% type 3. Neonatal respiratory distress, age at early diagnosis, nutritional problems, and recurrent lung diseases were detected as poor prognostic factors. Conclusions: SMA is a neuromuscular disease that requires multidisciplinary approach to medical care. There is a wide range of clinical severity. Identification of poor prognostic factors will help in terms of guiding close monitoring and timely treatments of children with SMA.

  4. Founder effect in spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Tanaka, F; Doyu, M; Ito, Y; Matsumoto, M; Mitsuma, T; Abe, K; Aoki, M; Itoyama, Y; Fischbeck, K H; Sobue, G

    1996-09-01

    We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.

  5. Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Katsuno, Masahisa; Tanaka, Fumiaki; Adachi, Hiroaki; Banno, Haruhiko; Suzuki, Keisuke; Watanabe, Hirohisa; Sobue, Gen

    2012-12-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. During the last two decades, basic and clinical research has provided important insights into the disease phenotype and pathophysiology. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. SBMA exclusively affects adult males, whereas females homozygous for the AR mutation do not manifest neurological symptoms. The ligand-dependent nuclear accumulation of the polyglutamine-expanded AR protein is central to the gender-specific pathogenesis of SBMA, although additional steps, e.g., DNA binding, inter-domain interactions, and post-translational modification of AR, modify toxicity. The interactions with co-regulators are another requisite for the toxic properties of the polyglutamine-expanded AR. It is also shown that the polyglutamine-expanded AR induces diverse molecular events, such as transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction, which play causative roles in the neurodegeneration in SBMA. The pathogenic AR-induced myopathy also contributes to the non-cell autonomous degeneration of motor neurons. Pre-clinical studies using animal models show that the pathogenic AR-mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in clinical trials. Pharmacological activation of cellular defense machineries, such as molecular chaperones, ubiquitin-proteasome system, and autophagy, also exerts neuroprotective effects in experimental models of SBMA.

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

    Directory of Open Access Journals (Sweden)

    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

  7. [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.

  8. Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

    Science.gov (United States)

    Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

    2017-03-01

    Smn(+/-) transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn(+/-) transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn(+/-) transgenic mouse increases their susceptibility to cell death

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Electrophysiological biomarkers in spinal muscular atrophy: proof of concept

    Science.gov (United States)

    David Arnold, W; Porensky, Paul N; McGovern, Vicki L; Iyer, Chitra C; Duque, Sandra; Li, Xiaobai; Meyer, Kathrin; Schmelzer, Leah; Kaspar, Brian K; Kolb, Stephen J; Kissel, John T; Burghes, Arthur H M

    2014-01-01

    Objective Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model. Methods Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy. Results CMAP was significantly reduced in SMNΔ7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. Interpretation These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials. PMID:24511555

  12. Observational Study of Spinal Muscular Atrophy Type 2 and 3

    Science.gov (United States)

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard; Kang, Peter; Oskoui, Maryam; Constantinescu, Andrei; Sproule, Douglas Michael; Foley, A. Reghan; Yang, Michele; Tawil, Rabi; Chung, Wendy; Martens, Bill; Montes, Jacqueline; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean M.; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Irvine, Carrie; Annis, Christine L.; Butler, Hailly; Caracciolo, Jayson; Montgomery, Megan; Marra, Jonathan; Koo, Benjamin; De Vivo, Darryl C.

    2013-01-01

    Objective To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA. Design A comprehensive multicenter, longitudinal, observational study. Setting The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites. Participants Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated. Intervention We collected demographic and medical history information and determined the SMN2 copy number. Main Outcome Measures Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function. Results There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function. Conclusions Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression. PMID:21320981

  13. Compound heterozygous mutation in two unrelated cases of Chinese spinal muscular atrophy patients

    Institute of Scientific and Technical Information of China (English)

    QU Yu-jin; SONG Fang; YANG Yan-ling; JIN Yu-wei; BAI Jin-li

    2011-01-01

    Background Infantile proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1(SMN1) and 5% cases are caused by compound heterozygous mutation (a SMN1 deletion on one allele and a subtle mutation on the other allele).Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism (RFLP) and genomic sequencing. Multiplex ligation-dependent probe amplification (MLPA) analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein (NAIP) in the patients. Further sequencing of SMN1allele-specific PCR (AS-PCR) and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G>T (p. Arg288Met) mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN (SMN2 17/SMN1 E8) identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.

  14. VERY SEVERE SPINAL MUSCULAR ATROPHY (TYPE 0: A REPORT OF THREE CASES

    Directory of Open Access Journals (Sweden)

    Mohammad BARZEGAR

    2010-10-01

    Full Text Available ObjectiveWe describe three patients with very severe Spinal Muscular Atrophy (SMA presented with reduced fetal movement in utero, profound hypotonia, severe weakness and respiratory insufficiency at birth. In all infants, electrodiagnostic studies were compatible with a neurogenic pattern. In genetic studies, all cases had homozygous deletions of exons 7 and 8 of Survival Motor Neuron (SMN and exon 5 of Neuronal Apoptosis Inhibitory Protein (NAIP gene. SMA should be considered in the differential diagnosis of reduced fetal movement and respiratory insufficiency at birth.Keywords:Spinal muscular atrophy, survival motor neuron gene, neonate

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

    OpenAIRE

    Bowerman Melissa; Murray Lyndsay M; Boyer Justin G; Anderson Carrie L; Kothary Rashmi

    2012-01-01

    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 (...

  16. Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy.

    Science.gov (United States)

    Shababi, Monir; Habibi, Javad; Ma, Lixin; Glascock, Jacqueline J; Sowers, James R; Lorson, Christian L

    2012-05-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death. Loss of a gene called Survival Motor Neuron 1 (SMN1) and, as a result, reduced levels of the Survival Motor Neuron (SMN) protein leads to SMA development. SMA is characterized by the loss of functional motor neurons in the spinal cord. However, accumulating evidence suggests the contribution of other organs to the composite SMA phenotype and disease progression. A growing number of congenital heart defects have been identified in severe SMA patients. Consistent with the clinical cases, we have recently identified developmental and functional heart defects in two SMA mouse models, occurring at embryonic stage in a severe SMA model and shortly after birth in a less severe model (SMN∆7). Our goal was to examine the late stage cardiac abnormalities in untreated SMN∆7 mice and to determine whether gene replacement therapy restores cardiac structure/function in rescued SMN∆7 model. To reveal the extent of the cardiac structural/functional repair in the rescued mice, we analyzed the heart of untreated and treated SMN∆7 model using self-complementary Adeno-associated virus (serotype 9) expressing the full-length SMN cDNA. We examined the characteristics of the heart failure such as remodeling, fibrosis, oxidative stress, and vascular integrity in both groups. Our results clearly indicate that fibrosis, oxidative stress activation, vascular remodeling, and a significant decrease in the number of capillaries exist in the SMA heart. The cardiac structural defects were improved drastically in the rescued animals, however, the level of impairment was still significant compared to the age-matched wildtype littermates. Furthermore, functional analysis by in vivo cardiac magnetic resonance imaging (MRI) revealed that the heart of the treated SMA mice still exhibits functional defects. In conclusion, cardiac abnormalities are only partially rescued in post-birth treated SMA animals and these

  17. Dysphagia in spinal muscular atrophy type II: more than a bulbar problem?

    NARCIS (Netherlands)

    Engel-Hoek, L. van den; Erasmus, C.E.; Bruggen, H.W. van; Swart, B.J.M. de; Sie, L.T.L.; Steenks, M.H.; Groot, I.J.M. de

    2009-01-01

    OBJECTIVE: In patients with spinal muscular atrophy (SMA) type II, feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. This case control study was designed to determine the underlying mechanisms of dysphagia in SMA type II. METHODS: Six

  18. Intrafamilial variable hearing loss in TRPV4 induced spinal muscular atrophy

    NARCIS (Netherlands)

    Oonk, A.M.M.; Ekker, M.S.; Huygen, P.L.M.; Kunst, H.P.M.; Kremer, H.; Schelhaas, J.J.; Pennings, R.J.E.

    2014-01-01

    OBJECTIVE: Mutations in the transient receptor potential vanilloid 4 gene (TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular

  19. 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 tra

  20. 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

  1. Clinical and mutational characteristics of spinal muscular atrophy with respiratory distress type 1 in the Netherlands

    NARCIS (Netherlands)

    Stalpers, Xenia L.; Verrips, Aad; Poll-The, Bwee Tien; Cobben, Jan-Maarten; Snoeck, Irma N.; de Coo, Irenaeus F. M.; Brooks, Alice; Bulk, Saskia; Gooskens, Rob; Fock, Annemarie; Verschuuren - Bemelmans, Cornelia; Sinke, Richard J.; de Visser, Marianne; Lemmink, Henny H.

    Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain

  2. Clinical and mutational characteristics of spinal muscular atrophy with respiratory distress type 1 in the Netherlands

    NARCIS (Netherlands)

    Stalpers, X.L.; Verrips, A.; Poll-The, B.T.; Cobben, J.M.; Snoeck, I.N.; Coo, I.F.M. de; Brooks, A.; Bulk, S.; Gooskens, R.; Fock, A.; Verschuuren-Bemelmans, C.; Sinke, R.J.; Visser, M. de; Lemmink, H.H.

    2013-01-01

    Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain

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

    Science.gov (United States)

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

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

  4. Intrafamilial variable hearing loss in TRPV4 induced spinal muscular atrophy

    NARCIS (Netherlands)

    Oonk, A.M.M.; Ekker, M.S.; Huygen, P.L.M.; Kunst, H.P.M.; Kremer, H.; Schelhaas, J.J.; Pennings, R.J.E.

    2014-01-01

    OBJECTIVE: Mutations in the transient receptor potential vanilloid 4 gene (TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular atr

  5. Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

    NARCIS (Netherlands)

    Hiel, J.A.P.; Engelen, B.G.M. van; Weemaes, C.M.R.; Broeks, A.; Verrips, A.; Laak, H.J. ter; Vingerhoets, H.M.; Heuvel, L.P.W.J. van den; Lammens, M.M.Y.; Gabreëls, F.J.M.; Last, J.I.; Taylor, A.M.R.

    2006-01-01

    The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosph

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

    Science.gov (United States)

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

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

  7. Physician attitudes towards ventilatory support for spinal muscular atrophy type 1 in Australasia

    NARCIS (Netherlands)

    Geevasinga, Nimeshan; Ryan, Monique M.

    2007-01-01

    Without ventilatory support, premature death from respiratory insufficiency is virtually universal in infants with spinal muscular atrophy type 1 (SMA1). With mechanical ventilation, however, long-term survival has been reported from numerous international centres. We aimed to characterize physician

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

    Science.gov (United States)

    Fayzullina, Saniya; Martin, Lee J

    2016-09-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.

  12. Distal spinal muscular atrophy and ophthalmoparesis. A case with selective type 2 fiber hypotrophy.

    Science.gov (United States)

    Dubrovsky, A; Taratuto, A L; Martino, R

    1981-09-01

    A patient had distal muscular atrophy involving the upper and lower extremities, ptosis of the lid, and ophthalmoparesis and cataracts. Muscle histochemistry and electromyographic examination showed lower motor neuron involvement. This case is similar to others described in the literature and designated as distal spinal muscular atrophy. The unique association with ophthalmologic signs can be considered either as a variant form of the disease or as a separate entity. Muscle biopsy showed selective type 2 muscle fiber hypotrophy in the biceps. A second biopsy specimen of the quadriceps showed type grouping with persistence of small type 2 fibers, suggesting that reinnervation capability is independent of neuronal trophic influence.

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

    Directory of Open Access Journals (Sweden)

    Geeta Gathwala

    2014-01-01

    Full Text Available 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.

  14. Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system

    OpenAIRE

    Maruyama, Hirofumi; Morino, Hiroyuki; Izumi, Yuishin; Noda, Kouichi; Kawakami, Hideshi

    2013-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive motor neuron disease. Lower and primary sensory neuronopathy is one of the major neuropathological changes that occurs in SBMA. However, many sings are common to SBMA and amyotrophic lateral sclerosis (ALS), and SBMA patients are sometimes diagnosed with ALS. Leuprorelin may be used to treat SBMA, but an accurate diagnosis is necessary for treatment and care. Genetic diagnosis can be performed to detect the expansion of a CAG r...

  15. The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Arnold, W; McGovern, Vicki L; Sanchez, Benjamin; Li, Jia; Corlett, Kaitlyn M; Kolb, Stephen J; Rutkove, Seward B; Burghes, Arthur H

    2016-03-01

    Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMN∆7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. SMA∆7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12days for comparison. Electrophysiological measures and electrical impedance myography detected significant differences at 12days between control and late-treated (4 or 6days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2days (patrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard electrophysiological

  16. 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.

  17. 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.

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

    Science.gov (United States)

    Xu, Chong-Chong; Denton, Kyle R; Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2016-01-01

    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.

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

    Science.gov (United States)

    Fayzullina, Saniya; Martin, Lee J

    2014-01-01

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

    Directory of Open Access Journals (Sweden)

    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.

  1. A novel lamin A/C gene mutation causing spinal muscular atrophy phenotype with cardiac involvement: report of one case.

    Science.gov (United States)

    Iwahara, Naotoshi; Hisahara, Shin; Hayashi, Takashi; Kawamata, Jun; Shimohama, Shun

    2015-02-20

    Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A/C gene mutations cause spinal muscular atrophy has not been established. We report a man aged 65 years who presented with amyotrophy of lower limbs, arrhythmia and cardiac hypofunction. He showed gait disturbance since childhood, and his family showed similar symptoms. Neurological and electrophysiological findings suggested spinal muscular atrophy type 3. Gene analysis of lamin A/C gene showed a novel nonsense mutation p.Q353X (c.1057C > T). Further investigations revealed that he and his family members had cardiac diseases including atrioventricular block. We report the first Japanese case of spinal muscular atrophy phenotype associated with lamin A/C mutation. When a patient presents a spinal muscular atrophy phenotype and unexplained cardiac disease, especially when the family history is positive, gene analysis of lamin A/C gene should be considered.

  2. Research Progress of the Massage Therapy in Treating Infantile Muscular Torticollis%推拿治疗婴幼儿肌性斜颈的研究进展

    Institute of Scientific and Technical Information of China (English)

    康轶鑫

    2009-01-01

    婴幼儿肌性斜颈采用推拿治疗可有效缩短疗程,避免因病情迁延不愈而致的后遗症.本研究为临床推拿治疗婴幼儿肌性斜颈提供了多种操作方法,以供临床医者根据自身情况选择应用.%Massage therapy is commonly used in the treatment of infantile muscular torticollis clinically.The massage therapy can reduce the therapeutic course effectively and prevent the occurrence of sequel due to long-term un-heating of the disease.This research provided many manipulative methods of massage in treating infantile muscular torticollis for clinical uses.

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

    Science.gov (United States)

    Carré, Amanda; Empey, Candice

    2016-02-01

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

  4. Distrofia muscular progressiva: alguns aspectos do diagnõstico diferencial

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    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.

  5. 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

  6. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

    Institute of Scientific and Technical Information of China (English)

    Zhi-Bo Wang; Xiaoqing Zhang; Xue-Jun Li

    2013-01-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease.Here,we developed a closely representative cell model of SMA by knocking down the disease-determining gene,survival motor neuron (SMN),in human embryonic stem cells (hESCs).Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons.Notably,the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated.Furthermore,these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-A7 (lacking exon 7)knockdown,and were specific to spinal motor neurons.Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes,including specific axonal defects and motor neuron loss.Finally,knockdown of SMNFL led to excessive mitochondrial oxidative stress in human motor neuron progenitors.The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine,a potent antioxidant,which prevented disease-related apoptosis and subsequent motor neuron death.Thus,we report here the successful establishment of an hESC-based SMA model,which exhibits disease gene isoform specificity,cell type specificity,and phenotype reversibility.Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  7. VERY SEVERE SPINAL MUSCULAR ATROPHY (TYPE 0: A REPORT OF THREE CASES

    Directory of Open Access Journals (Sweden)

    BARZEGAR mohammad MD

    2010-09-01

    Full Text Available AbstractObjectiveWe describe three patients with very severe Spinal Muscular Atrophy (SMA presented with reduced fetal movement in utero, profound hypotonia, severe weakness and respiratory insufficiency at birth. In all infants, electrodiagnostic studies were compatible with a neurogenic pattern. In genetic studies, all cases had homozygous deletions of exons 7 and 8 of Survival Motor Neuron (SMN and exon 5 of Neuronal Apoptosis Inhibitory Protein (NAIP gene. SMA should be considered in the differential diagnosis of reduced fetal movement and respiratory insufficiency at birth.

  8. 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....

  9. Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy

    OpenAIRE

    Johansen, Jamie A.; Yu, Zhigang; Mo, Kaiguo; Monks, D. Ashley; Lieberman, Andrew P.; Breedlove, S. Marc; Jordan, Cynthia L.

    2008-01-01

    With this paper, we deliberately challenge the prevailing neurocentric theory of the etiology of spinal bulbar muscular atrophy (SBMA). We offer data supporting an alternative view that androgen receptor (AR) acts in skeletal muscles to cause the symptoms of SBMA. While SBMA has been linked to a CAG repeat expansion in the AR gene and mutant AR is presumed to act in motoneurons to cause SBMA, we find that over-expression of wild type AR solely in skeletal muscle fibers results in the same and...

  10. Splicing regulation of the Survival Motor Neuron genes and implications for treatment of spinal muscular atrophy

    OpenAIRE

    Bebee, Thomas W.; Gladman, Jordan T.; Chandler, Dawn S.

    2010-01-01

    Proximal spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of the survival motor neuron (SMN) protein. The reduced SMN levels are due to loss of the survival motor neuron-1 (SMN1) gene. Humans carry a nearly identical SMN2 gene that generates a truncated protein, due to a C to T nucleotide alteration in exon 7 that leads to inefficient RNA splicing of exon 7. This exclusion of SMN exon 7 is central to the onset of the SMA disease, however, this offers a unique ther...

  11. Prenatal diagnosis of spinal muscular atrophy in Chinese by genetic analysis of fetal cells

    Institute of Scientific and Technical Information of China (English)

    WU Ting; DING Xin-sheng; LI Wen-lei; YAO Juan; DENG Xiao-xuan

    2005-01-01

    Background Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord.The survival motor neuron gene is SMA-determining gene deleted in approximately 95% of SMA patients.This study was undertaken to predict prenatal SMA efficiently and rapidly in families with previously affected child.Methods Prenatal diagnosis was made in 8 fetuses with a family history of SMA.Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the detection of the survival motor neuron gene.Results The survival motor neuron gene was not found in 6 fetuses, ruling out the diagnosis of SMA.Two fetuses were detected positive and the pregnancies were terminated.Conclusion Our method is effective and convenient in prenatal diagnosis of SMA.

  12. 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.

  13. Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Katsuno, Masahisa; Banno, Haruhiko; Suzuki, Keisuke; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2010-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Lower motor neurons in the anterior horn of the spinal cord and those in the brainstem motor nuclei are predominantly affected in SBMA, and other neuronal and nonneuronal tissues are also widely involved to some extent. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption and mitochondrial dysfunction. Results of animal studies suggest that androgen deprivation and activation of protein quality control systems are potential therapies for SBMA.

  14. 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.

  15. Head and Arm Tremor in X-linked Spinal and Bulbar Muscular Atrophy

    Science.gov (United States)

    Aicua, Irene; Verhagen, Okker; Arenaza, Naroa; Cubo, Esther

    2014-01-01

    Background X-linked spinal and bulbar muscular atrophy (SBMA) is a rare adult-onset neuronopathy. Although tremor is known to occur in this disease, the number of reported cases of SBMA with tremor is rare, and the number with videotaped documentation is exceedingly rare. Our aim was to describe/document the characteristic signs of tremor in spinal and bulbar muscular atrophy. Case Report We report a case of a 58-year-old male with a positive family history of tremor. On examination, the patient had jaw and hand tremors but he also exhibited gynecomastia, progressive bulbar paresis, and wasting and weakness primarily in the proximal limb muscles. The laboratory tests revealed an elevated creatine phosphokinase. Genetic testing was positive for X-SBMA, with 42 CAG repeats. Discussion Essential tremor is one of the most common movement disorders, yet it is important for clinicians to be aware of the presence of other distinguishing features that point to alternative diagnoses. The presence of action tremor associated with muscle atrophy and gynecomastia should lead to a suspicion of SBMA. PMID:25374767

  16. Dysphagia in spinal muscular atrophy type II: more than a bulbar problem?

    Science.gov (United States)

    van den Engel-Hoek, L; Erasmus, C E; van Bruggen, H W; de Swart, B J M; Sie, L T L; Steenks, M H; de Groot, I J M

    2009-11-24

    In patients with spinal muscular atrophy (SMA) type II, feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. This case control study was designed to determine the underlying mechanisms of dysphagia in SMA type II. Six children with SMA type II and 6 healthy matched controls between 6.4 and 13.4 years of age were investigated during swallowing liquid and solid food in 2 different postures using surface EMG (sEMG) of the submental muscle group (SMG) and a video fluoroscopic swallow study (VFSS). The VFSS showed postswallow residue of solid food in the vallecula and above the upper esophageal sphincter (UES), which can be responsible for indirect aspiration. Better results in swallowing were achieved in a more forward head position. These findings were supported by the sEMG measurements of the SMG during swallowing. Dysphagia in spinal muscular atrophy type II is due to a neurologic dysfunction (lower motor neuron problems from the cranial nerves in the brainstem) influencing the muscle force and efficiency of movement of the tongue and the submental muscle group in combination with a biomechanical component (compensatory head posture). The results suggest an integrated treatment with an adapted posture during meals and the advice of drinking water after meals to prevent aspiration pneumonias.

  17. Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Sahashi, Kentaro; Katsuno, Masahisa; Hung, Gene; Adachi, Hiroaki; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Iida, Madoka; Bennett, C Frank; Sobue, Gen

    2015-11-01

    Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target.

  18. 婴儿型脊肌萎缩症合并肺炎患儿的护理%Nursing care of spinal muscular atrophy complicated with pneumonia

    Institute of Scientific and Technical Information of China (English)

    王海勤; 喻筱倩; 周琴; 李承; 项慧慧; 吴轶璇

    2014-01-01

    Objective We summarized the nursing care experience of spinal muscular atrophy complicated with pneumonia.Methods The measures of nursing care to the 9 children patients were comprised of preventing sputum blockage; preventing suffocating due to milk choking; paying special attention to the time being when the sputum blockage and milk choking occurred; early detection of paralysis of respiratory muscle; and training nursing skills to the families,and so on.Results All 9 children patients were cured and discharged from hospital.Conclusions The measure of targeting nursing intervention to the children with infantile spinal muscular atrophy and pneumonia could improve therapeutic effect and reduce mortality rate.%目的 总结婴儿型脊肌萎缩症合并肺炎的护理经验.方法 对9例婴儿型脊肌萎缩症合并肺炎的患儿给予预防突发痰堵窒息、呛奶窒息,关注痰堵、呛奶高危时间段,警惕呼吸肌麻痹的发生,培训家庭救护技能等护理措施.结果 9例患儿肺炎均治愈出院.结论 对婴儿型脊肌萎缩症合并肺炎的患儿实施针对性的护理干预措施,能提高治疗效果,降低死亡率.

  19. 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

  20. 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

  1. Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy

    NARCIS (Netherlands)

    Neveling, Kornelia; Martinez-Carrera, Lilian A.; Hoelker, Irmgard; Heister, Angelien; Verrips, Aad; Hosseini-Barkooie, Seyyed Mohsen; Gilissen, Christian; Vermeer, Sascha; Pennings, Maartje; Meijer, Rowdy; te Riele, Margot; Frijns, Catharina J. M.; Suchowersky, Oksana; MacLaren, Linda; Rudnik-Schoeneborn, Sabine; Sinke, Richard J.; Zerres, Klaus; Lowry, R. Brian; Lemmink, Henny H.; Garbes, Lutz; Veltman, Joris A.; Schelhaas, Helenius J.; Scheffer, Hans; Wirth, Brunhilde

    2013-01-01

    Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown.

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

    Science.gov (United States)

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

    2016-03-01

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

  3. 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......- and 72 CM patients. The psychometric properties of the FSS were evaluated by means of classical test theories for each of the disease groups. If abnormal fatigue was present in the disease group, the construct of fatigue was evaluated by means of focus group interviews. RESULTS: Fatigue was rare in SMA...... 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...

  4. Adiposity is increased among High-Functioning, Non-Ambulatory Patients with Spinal Muscular Atrophy

    Science.gov (United States)

    Sproule, Douglas M.; Montes, Jacqueline; Dunaway, Sally; Montgomery, Megan; Battista, Vanessa; Koenigsberger, Dorcas; Martens, Bill; Shen, Wei; Punyanitya, Mark; Benton, Maryjane; Butler, Hailly; Caracciolo, Jayson; Mercuri, Eugenio; Finkel, Richard; Darras, Basil; De Vivo, Darryl C.; Kaufmann, Petra

    2010-01-01

    The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith Functional Motor Scale, Expanded score into three cohorts: Low-Functioning Non-Ambulatory (type 2 with Hammersmith score 85th percentile for age and gender (connoting “at risk of overweight”) versus 9 of 19 subjects (47%) in the Low-Functioning Non-Ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA. PMID:20610154

  5. Diagnosis of Progressive Spinal Muscular Atrophy by Using Polymerase Chain Reaction

    Institute of Scientific and Technical Information of China (English)

    姚娟; 丁新生; 陈克连; 程虹; 邓晓萱; 沈鸣九; 王颖

    2001-01-01

    Objective To understand the deletion in the survival motor neuron gene (SMN) of childhood-onset spinal muscular atrophy (SMA) in Chinese, and the value of diagnosis of SMA using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)method. Methods Deletions of SMN gene of exon 7 and 8 in 10 cases of presumed SMA, and 20 normal controls from 6 families and 30 unrelated controls were performed by PCR-RFLP analysis. Results Deletions of SMN gene detected in 9 of 10 (90%) cases of presumed SMA . No deletions of SMN in the telomere were found in the other members of families and controls.Conclusion PCR-RFLP is a sensitive, specific and simple method in diagnosis of SMA.

  6. Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions.

    Science.gov (United States)

    Fratta, Pietro; Collins, Toby; Pemble, Sally; Nethisinghe, Suran; Devoy, Anny; Giunti, Paola; Sweeney, Mary G; Hanna, Michael G; Fisher, Elizabeth M C

    2014-02-01

    Trinucleotide repeat disorders are a heterogeneous group of diseases caused by the expansion, beyond a pathogenic threshold, of unstable DNA tracts in different genes. Sequence interruptions in the repeats have been described in the majority of these disorders and may influence disease phenotype and heritability. Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a CAG trinucleotide expansion in the androgen receptor (AR) gene. Diagnostic testing and previous research have relied on fragment analysis polymerase chain reaction to determine the AR CAG repeat size, and have therefore not been able to assess the presence of interruptions. We here report a sequencing study of the AR CAG repeat in a cohort of SBMA patients and control subjects in the United Kingdom. We found no repeat interruptions to be present, and we describe differences between sequencing and traditional sizing methods.

  7. Patient with spinal muscular atrophy with respiratory distress type 1 presenting initially with hypertonia.

    Science.gov (United States)

    Han, Chunxi; Mai, Jiahui; Tian, Tian; He, Yanxia; Liao, Jianxiang; Wen, Feiqiu; Yi, Xin; Yang, Yun

    2015-05-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene and characterized by life-threatening respiratory distress due to irreversible diaphragmatic paralysis between 6weeks and 6months of age. In this study, we describe a two-month-old boy who presented with hypertonia at first and developed to hypotonia progressively, which was in contrast to the manifestations reported previously. Bone tissue compromise was also observed as one of the unique symptoms. Muscle biopsy indicated mild myogenic changes. He was misdiagnosed until genetic screening to be confirmed as SMARD1. SMARD1 is a clinical heterogeneous disease and this case broadens our perception of its phenotypes.

  8. 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...... as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim...... at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents....

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

    Science.gov (United States)

    Boido, Marina; Vercelli, Alessandro

    2016-01-01

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

  10. 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...... measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. RESULTS: W(max) increased by 18%, and CS activity increased by 35%. There was no significant change in Vo(2max...

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

    Science.gov (United States)

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

    2015-08-26

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

  12. In Vitro and In Vivo Modeling of Spinal and Bulbar Muscular Atrophy.

    Science.gov (United States)

    Pennuto, Maria; Basso, Manuela

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease characterized by late-onset, progressive degeneration of lower motor neurons and skeletal muscle atrophy. SBMA is caused by expansions of a CAG trinucleotide repeat in the gene encoding the androgen receptor (AR). One striking feature of SBMA is sex specificity: SBMA fully manifests only in males, whereas females show subclinical or mild disease manifestations even when homozygous for the mutation. Since the identification of the mutation responsible for SBMA in 1991, several cell and animal models have been developed to recapitulate the main features of disease in vitro and in vivo. In this review, we describe the most widely used cellular and animal models of SBMA, highlighting advantages and disadvantages in the use of these models to gain mechanistic and therapeutic insights into SBMA.

  13. [Somatic mosaicism of expanded CAG trinucleotide repeat in spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Tanaka, F; Ito, Y; Sobue, G

    1999-04-01

    The CAG repeat in spinal and bulbar muscular atrophy (SBMA) is relatively stable in mitotic and meiotic processes as compared with other CAG repeat diseases. Previous reports indicate that SBMA does not manifest somatic mosaicism. However, detailed analysis in various tissues from 20 SBMA including 4 autopsied patients revealed the presence of the tissue-specific pattern of mosaicism. The prominent somatic mosaicism was observed in the cardiac and skeletal muscles, which are predominantly composed of postmitotic cells, and in the skin, prostate, and testis. The central nervous system (CNS) tissues, liver, and spleen showed smallest mosaicism. Such tissue-specific pattern of somatic mosaicism in SBMA is not explained by cell composition with different cell turnover rates. Other cell specific factors are likely more important for the somatic mosaicism in SBMA.

  14. Genotype-phenotype correlation in Chinese patients with spinal and bulbar muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Wang Ni

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is an X-linked recessive motor neuron disease characterized by slowly progressive weakness and atrophy of proximal limbs and bulbar muscles. To assess the genotype-phenotype correlation in Chinese patients, we identified 155 patients with SBMA and retrospectively examined available data from laboratory tests and neurophysiological analyses. Correlations between genotype and phenotype were analyzed. There was an inverse correlation between the length of CAG repeats and age at first muscle weakness (p<0.0001. The serum creatine kinase level showed a significant inverse correlation with disease duration and the age at examination (p=0.019 and p=0.004, respectively. Unlike previous classification of motor- and sensory-dominant phenotypes, all findings of nerve conduction, except the amplitudes of median nerve compound motor action potential, were positively correlated to the length of CAG repeats. A significant decline in sensory nerve action potential amplitudes may assist differential diagnosis of SBMA.

  15. Spinal and bulbar muscular atrophy (SBMA): somatic stability of an expanded CAG repeat in fetal tissues.

    Science.gov (United States)

    Jedele, K B; Wahl, D; Chahrokh-Zadeh, S; Wirtz, A; Murken, J; Holinski-Feder, E

    1998-08-01

    Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron degenerative disease caused by an expanded trinucleotide repeat. Unlike most other trinucleotide repeat diseases, SBMA shows limited meiotic instability, and evidence thus far indicates absence of somatic instability in adults. Data regarding the presence of fetal tissue somatic mosaicism is unavailable. We present a family in which a woman whose father had SBMA requested prenatal testing. After informed consent. molecular genetic evaluation showed the male fetus to carry the SBMA repeat elongation. Testing of fetal tissues after elective pregnancy termination showed no somatic mosaicism in the CAG repeat length. This is the first report of molecular genetic analysis of multiple tissues in an affected fetus, and only the second report of prenatal diagnosis in SBMA.

  16. [Anti-androgen therapy for spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Katsuno, Masahisa; Banno, Haruhiko; Suzuki, Keisuke; Hashizume, Atsushi; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2012-01-01

    Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. [Triplet repeat disease, with particular emphasis of spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Sobue, G

    2000-12-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG-repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA). Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA) and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. Processing of the polyglutamine containing proteins by proteases liberate truncated polyglutamine tract, which may cause neurodegeneration as demonstrated in transgenic mice and transfected cells. In addition to cellular toxicity, truncated and expanded polyglutamine tracts have been shown to form intranuclear inclusions (NI). The NIs formed by the disease protein are a common pathological feature of these diseases. In SBMA, NIs containing AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as cerb or creb-binding protein (CBP) sequestrated in the NI may alter the major intracellular transcriptional signal transduction, and ultimately may result in neuronal degeneration. The ubiquitin-proteasome pathway may also contribute to the pathogenesis of CAG-repeat diseases. As for the therapeutic strategies, many possibilities have been demonstrated. Overexpression of Hsp70 and Hsp40 chaperones act together to protect a cultured neuronal cell model of SBMA from a cellular toxicity of expanded polyglutamine tract.

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

    Science.gov (United States)

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

    2015-09-01

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

  20. Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

    Institute of Scientific and Technical Information of China (English)

    Yu-hua LIANG; Xiao-ling CHEN; Zhong-sheng YU; Chun-yue CHEN; Sheng BI; Lian-gen MAO; Bo-lin ZHOU; Xian-ning ZHANG

    2009-01-01

    Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. Three types of SMA are rec-ognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: SMA1, SMA2, and SMA3. The survival of motor neuron (SMN) gene has been identified as an SMA determining gene, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is considered to be a modifying factor of the severity of SMA. The main objective of this study was to analyze the deletion of SMN1 and NAIP genes in southern Chinese children with SMA. Here, polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was performed to detect the deletion of both exon 7 and exon 8 of SMNI and exon 5 of NAIP in 62 southern Chinese children with strongly suspected clinical symptoms of SMA. All the 32 SMAI patients and 76% (13/17) of SMA2 patients showed homozygous deletions for exon 7 and exon 8, and all the 13 SMA3 patients showed single deletion of SMN1 exon 7 along with 24% (4/17) of SMA2 patients. Eleven out of 32 (34%) SMA1 patients showed NAIP deletion, and none of SMA2 and SMA3 patients was found to have NAIP deletion. The findings of homozygous deletions of exon 7 and/or exon 8 of SMN1 gene confirmed the diagnosis of SMA, and suggested that the deletion of SMN1 exon 7 is a major cause of SMA in southern Chinese children, and that the NA1P gene may be a modifying factor for disease severity of SMA 1. The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis and preimplantation genetic diagnosis of SMA.

  1. Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Katsuno, Masahisa; Adachi, Hiroaki; Waza, Masahiro; Banno, Haruhiko; Suzuki, Keisuke; Tanaka, Fumiaki; Doyu, Manabu; Sobue, Gen

    2006-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

  2. Pathogenesis-targeting therapeutics for spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Suzuki, Keisuke; Kastuno, Masahisa; Banno, Haruhiko; Sobue, Gen

    2009-08-01

    Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult-onset, lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons. Androgen deprivation therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is testosterone-dependent nuclear accumulation of the mutant AR. Suppression of disease progression by leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis-targeting therapeutics.

  3. Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

    Science.gov (United States)

    Lund, A; Udd, B; Juvonen, V; Andersen, P M; Cederquist, K; Davis, M; Gellera, C; Kölmel, C; Ronnevi, L O; Sperfeld, A D; Sörensen, S A; Tranebjaerg, L; Van Maldergem, L; Watanabe, M; Weber, M; Yeung, L; Savontaus, M L

    2001-06-01

    SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

  4. Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA).

    Science.gov (United States)

    Banno, Haruhiko; Katsuno, Masahisa; Suzuki, Keisuke; Tanaka, Fumiaki; Sobue, Gen

    2012-07-01

    Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin-proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10 years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.

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

    Science.gov (United States)

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

    2016-05-01

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

  6. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  7. Using General Anesthesia plus Muscle Relaxant in a Patient with Spinal Muscular Atrophy Type IV: A Case Report.

    Science.gov (United States)

    Liu, Xiu-Fen; Wang, Dong-Xin; Ma, Daqing

    2011-01-01

    Spinal muscular atrophy (SMA) is a rare genetic disease characterized by degeneration of spinal cord motor neurons, which results in hypotonia and muscle weakness. Patients with type IV SMA often have onset of weakness from adulthood. Anesthetic management is often difficult in these patients as a result of muscle weakness and hypersensitivity to neuromuscular blocking agents as shown by (Lunn and Wang; 2008, Simic; 2008, and Cifuentes-Diaz et al.; 2002). Herein we report a case of anesthetic management of a patient with SMA type IV for mammectomy and review some other cases of SMA patients receiving different kinds of anesthesia.

  8. High-frequency chest-wall oscillation in a noninvasive-ventilation-dependent patient with type 1 spinal muscular atrophy.

    Science.gov (United States)

    Keating, Joanna M; Collins, Nicola; Bush, Andrew; Chatwin, Michelle

    2011-11-01

    With the recent increased use of noninvasive ventilation, the prognoses of children with neuromuscular disease has improved significantly. However, children with muscle weakness remain at risk for recurrent respiratory infection and atelectasis. We report the case of a young girl with type 1 spinal muscular atrophy who was dependent on noninvasive ventilation, and in whom conventional secretion-clearance physiotherapy became insufficient to clear secretions. We initiated high-frequency chest-wall oscillation (HFCWO) as a rescue therapy, and she had improved self-ventilation time. This is the first case report of HFCWO for secretion clearance in a severely weak child with type 1 spinal muscular atrophy. In a patient with neuromuscular disease and severe respiratory infection and compromise, HFCWO can be used safely in combination with conventional secretion-clearance physiotherapy.

  9. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients.

    Science.gov (United States)

    Atsuta, Naoki; Watanabe, Hirohisa; Ito, Mizuki; Banno, Haruhiko; Suzuki, Keisuke; Katsuno, Masahisa; Tanaka, Fumiaki; Tamakoshi, Akiko; Sobue, Gen

    2006-06-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.

  10. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

    OpenAIRE

    Krebs, Stefan; Medugorac, Ivica; Röther, Susanne; Strässer, Katja; Förster, Martin

    2007-01-01

    The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucia...

  11. Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells.

    OpenAIRE

    Renvoisé, Benoît; Khoobarry, Kevinee; Gendron, Marie-Claude; Cibert, Christian; Viollet, Louis; Lefebvre, Suzie

    2006-01-01

    Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an ...

  12. Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy.

    Science.gov (United States)

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

    2012-12-06

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

  13. An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy.

    Science.gov (United States)

    Luo, Minjie; Liu, Liu; Peter, Inga; Zhu, Jun; Scott, Stuart A; Zhao, Geping; Eversley, Chevonne; Kornreich, Ruth; Desnick, Robert J; Edelmann, Lisa

    2014-02-01

    Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups. SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing. An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups. Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.

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

    Science.gov (United States)

    McGovern, Vicki L; Massoni-Laporte, Aurélie; Wang, Xueyong; Le, Thanh T; Le, Hao T; Beattie, Christine E; Rich, Mark M; Burghes, Arthur H M

    2015-01-01

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

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.

    Science.gov (United States)

    Porensky, Paul N; Mitrpant, Chalermchai; McGovern, Vicki L; Bevan, Adam K; Foust, Kevin D; Kaspar, Brain K; Wilton, Stephen D; Burghes, Arthur H M

    2012-04-01

    Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino (MO) oligomer against ISS-N1 [HSMN2Ex7D(-10,-29)], and delivered this MO to postnatal day 0 (P0) SMA pups (Smn-/-, SMN2+/+, SMNΔ7+/+) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to >100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.

  19. Comparison of spinal alignment, muscular strength, and quality of life between women with postmenopausal osteoporosis and healthy volunteers.

    Science.gov (United States)

    Miyakoshi, N; Kudo, D; Hongo, M; Kasukawa, Y; Ishikawa, Y; Shimada, Y

    2017-08-07

    This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p < 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (p < 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (p < 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (p < 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (p < 0.05 each). These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice

    Science.gov (United States)

    Sumner, Charlotte J.; Wee, Claribel D.; Warsing, Leigh C.; Choe, Dong W.; Ng, Andrew S.; Lutz, Cathleen; Wagner, Kathryn R.

    2009-01-01

    There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-β family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn−/−) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA. PMID:19477958

  2. Dependence on care experienced by people living with Duchenne muscular dystrophy and spinal cord injury.

    Science.gov (United States)

    Martinsen, Bente; Dreyer, Pia

    2012-04-01

    Being dependent on care in a hospital or in a traditional homecare setting may generate an experience of inferiority in patients. In a private home, dependence is easier to bear if the dependent person has the possibility to influence the planning of care. Little is known about the experience of being dependent on care in a private home, where the dependent person employs his or her own helpers. The aim of this study was to describe the meaning of dependence on care in a private home setting among people living with help requirements for all aspects of daily life. The article draws on two interview studies of people with high cervical spinal cord injury and men with Duschenne muscular dystrophy. Transcriptions of the interviews were analyzed according to a phenomenological hermeneutic approach influenced by Paul Ricoeur's philosophy of interpretation. The meaning of all the interview texts is presented as four short stories. Four themes were identified: the helper as liberating, the paramount verbalization of own needs, the creative engagement in life, and accessibility as an issue in everyday life. Dependence on care was identified to be a movement between freedom and restriction, where the helpers played a crucial role, because it was key that they were sensitive to the signals they got and were able to transform words into meticulous actions.

  3. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

    Science.gov (United States)

    Ramsey, Danielle; Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

  4. Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

    Science.gov (United States)

    Navon, R; Khosravi, R; Melki, J; Drucker, L; Fontaine, B; Turpin, J C; N'Guyen, B; Fardeau, M; Rondot, P; Baumann, N

    1997-05-01

    Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

  5. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.

    Science.gov (United States)

    Ottesen, Eric W

    2017-01-01

    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.

  6. Cardiac function in types II and III spinal muscular atrophy: should we change standards of care?

    Science.gov (United States)

    Bianco, Flaviana; Pane, Marika; D'Amico, Adele; Messina, Sonia; Delogu, Angelica Bibiana; Soraru, Gianni; Pera, Maria Carmela; Mongini, Tiziana; Politano, Luisa; Baranello, Giovanni; Vita, Gianluca; Tiziano, Francesco Danilo; Morandi, Lucia; Bertini, Enrico; Mercuri, Eugenio

    2015-02-01

    In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care. Georg Thieme Verlag KG Stuttgart · New York.

  7. A Short Antisense Oligonucleotide Ameliorates Symptoms of Severe Mouse Models of Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Jeffrey M Keil

    2014-01-01

    Full Text Available Recent reports underscore the unparalleled potential of antisense-oligonucleotide (ASO-based approaches to ameliorate various pathological conditions. However, in vivo studies validating the effectiveness of a short ASO (<10-mer in the context of a human disease have not been performed. One disease with proven amenability to ASO-based therapy is spinal muscular atrophy (SMA. SMA is a neuromuscular disease caused by loss-of-function mutations in the survival motor neuron 1 (SMN1 gene. Correction of aberrant splicing of the remaining paralog, SMN2, can rescue mouse models of SMA. Here, we report the therapeutic efficacy of an 8-mer ASO (3UP8i in two severe models of SMA. While 3UP8i modestly improved survival and function in the more severe Taiwanese SMA model, it dramatically increased survival, improved neuromuscular junction pathology, and tempered cardiac deficits in a new, less severe model of SMA. Our results expand the repertoire of ASO-based compounds for SMA therapy, and for the first time, demonstrate the in vivo efficacy of a short ASO in the context of a human disease.

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

    Science.gov (United States)

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

    2010-10-15

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

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

    Science.gov (United States)

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

    2015-04-01

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

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

    Science.gov (United States)

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

    2016-03-01

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

  11. Improved single-cell protocol for preimplantation genetic diagnosis of spinal muscular atrophy.

    Science.gov (United States)

    Burlet, Philippe; Frydman, Nelly; Gigarel, Nadine; Bonnefont, Jean Paul; Kerbrat, Violaine; Tachdjian, Gérard; Frydman, René; Munnich, Arnold; Steffann, Julie; Ray, Pierre F

    2005-09-01

    To develop and validate a simple and reliable single-cell analysis protocol for the preimplantation genetic diagnosis (PGD) of spinal muscular atrophy (SMA). Molecular tests based on specific enzymatic digestion have already been described for SMA diagnosis. We modified the amplified DNA fragments so as to introduce a novel restriction site that provides an internal control for the completeness of the digestion. The genetics and reproduction departments of two teaching hospitals. Six informed couples at risk of transmitting SMA. All patients underwent standard procedures associated with intracytoplasmic sperm injection. Improvement of SMA diagnostic efficiency and accuracy on single cell. One hundred fifty lymphocytes were analyzed with our protocol. One hundred percent diagnostic accuracy was achieved from both homozygous normal and SMN1-deleted leukocytes. Successful molecular analysis was achieved for 36 of 42 biopsied embryos (86%). Twenty-five normal embryos were transferred, but no pregnancy was achieved. We developed an improved protocol for PGD of SMA that is simple, robust, and accurate; unfortunately, no pregnancies were achieved for any of the six patients who have undergone PGD in the program thus far.

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    Science.gov (United States)

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

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

    Science.gov (United States)

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

    2014-05-01

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

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

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    Brzustowicz, L.M.; Penchaszadeh, G.K.; Gilliam, T.C.; Allitto, B.A.; Theve, R.; Michaud, L.; Sugarman, E.; Handelin, B.L.; Chatkupt, S.; Koenigsberger, M.R. (Univ. of Medicine and Dentistry of New Jersey, Newark, NJ (United States))

    1994-03-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

  19. Performance of the timed "up & go" test in spinal muscular atrophy.

    Science.gov (United States)

    Dunaway, Sally; Montes, Jacqueline; Garber, Carol Ewing; Carr, Brendan; Kramer, Samantha S; Kamil-Rosenberg, Shirit; Strauss, Nancy; Sproule, Douglas; De Vivo, Darryl C

    2014-08-01

    The timed "up & go" (TUG) test is a quick measure of balance and mobility. TUG scores correlate with clinical, functional, and strength assessment and decline linearly over time. Reliability and validity have not been tested in spinal muscular atrophy (SMA). Fifteen ambulatory SMA participants performed TUG testing and strength, functional, and clinical assessments. Intraclass correlation coefficients quantified test-retest reliability. Convergent validity was determined using Pearson correlation coefficients. Test-retest reliability was excellent for all participants. TUG was associated significantly with total leg and knee flexor strength, as well as the Hammersmith Functional Motor Scale Expanded, the 10-meter walk/run, and 6-minute walk tests. TUG findings were not associated with knee extensor strength, pulmonary function, or fatigue. In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA. Copyright © 2013 Wiley Periodicals, Inc.

  20. Minor cognitive disturbances in X-linked spinal and bulbar muscular atrophy, Kennedy's disease.

    Science.gov (United States)

    Kasper, Elisabeth; Wegrzyn, Martin; Marx, Ivo; Korp, Christin; Kress, Wolfram; Benecke, Reiner; Teipel, Stefan J; Prudlo, Johannes

    2014-03-01

    Spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, is an adult-onset hereditary neurodegenerative disorder, associated predominantly with a lower motor neuron syndrome and eventually endocrine and sensory disturbances. In contrast to other motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the impairment of cognition in SBMA is not well documented. We conducted a systematic cross-sectional neuropsychological study in order to investigate cognition in SBMA patients more thoroughly. We investigated 20 genetically proven SBMA patients compared to 20 age- and education-matched control subjects using a comprehensive neuropsychological test battery, measuring executive functioning, attention, memory and visuospatial abilities. The SBMA patients performed significantly worse than healthy controls in three sub-tests in the executive and attention domains. This low performance was in the working memory (digit span backward task), verbal fluency category (single letter fluency task) and memory storage capacity (digit span forward task). No disturbances were detected in other cognitive domains. The impairments were subclinical and not relevant to the patients' everyday functioning. In addition, no correlations were found between cognitive scores and the CAG repeat length. In conclusion, we found minor cognitive disturbances in patients with SBMA, which could indicate subtle frontal lobe dysfunction. These findings extend our neurobiological understanding of SBMA.

  1. [Molecular-targeted therapy for spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Sobue, Gen

    2010-11-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in males, whereas both heterozygous and homozygous females are usually asymptomatic. In a transgenic mouse model of SBMA, neuromuscular symptoms are markedly pronounced in the male mice, but far less severe in the female counterparts. Androgen deprivation through both surgical and chemical castration substantially suppresses nuclear accumulation of the pathogenic AR, and thereby improves symptoms in the male mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR. In a phase 2 clinical trial, 12-month treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed nuclear accumulation of the pathogenic AR. The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular abnormalities should be corrected.

  2. Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system.

    Science.gov (United States)

    Maruyama, Hirofumi; Morino, Hiroyuki; Izumi, Yuishin; Noda, Kouichi; Kawakami, Hideshi

    2013-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive motor neuron disease. Lower and primary sensory neuronopathy is one of the major neuropathological changes that occurs in SBMA. However, many sings are common to SBMA and amyotrophic lateral sclerosis (ALS), and SBMA patients are sometimes diagnosed with ALS. Leuprorelin may be used to treat SBMA, but an accurate diagnosis is necessary for treatment and care. Genetic diagnosis can be performed to detect the expansion of a CAG repeat in the androgen receptor gene in SBMA patients. To screen for this expansion, we used a microchip electrophoresis system. The discrepancy between the actual repeat length and that found by the microchip electrophoresis system was roughly dependent on the repeat length. The mean difference was -6.8 base pairs (bp) in SBMA patients, -0.30 bp in controls. The microchip electrophoresis results were approximately 2 CAG repeats shorter than the actual repeat length in SBMA patients. Using this method, we screened our ALS samples (31 were familial, 271 were sporadic): 4 subjects were diagnosed with SBMA; 2 had familial ALS, and 2 had sporadic ALS (0.7%). The microchip electrophoresis system is semi-quantitative, convenient and useful for screening a large number of samples.

  3. [Disease-modifying therapy for spinal and bulbar muscular atrophy (SBMA)].

    Science.gov (United States)

    Suzuki, Keisuke; Banno, Haruhiko; Katsuno, Masahisa; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2012-03-01

    Neurodegenerative diseases have long been construed as incurable disorders. However, therapeutic developments for these diseases are now facing a turning point, that is, analyses of cellular and animal models have provided insights into the pathogenesis of neurodegenerative diseases and have indicated rational therapeutic approaches. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. This disease is caused by the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. The results of animal studies suggest that testosterone-dependent nuclear accumulation of the pathogenic AR protein is a fundamental step in the neurodegenerative process. Androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue suppresses the toxicity of the mutant AR in animal models of SBMA. In a phase 3 trial, 48 weeks of treatment with leuprorelin acetate, an LHRH analogue, tended to improve swallowing function in a subgroup of SBMA patients with disease duration less than 10 years but did not significantly affect the total population. Disease duration might influence the efficacy of leuprorelin acetate, and therefore, a further clinical trial that involves sensitive outcome measures is in progress. Advances in basic and clinical research on SBMA are now paving the way for the clinical application of pathogenesis-targeting therapies. To optimize translational research related to the process of testing candidate therapies in humans, it is important to identify biomarkers that can be used as surrogate endpoints in clinical trials for neurodegenerative diseases.

  4. Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy.

    Science.gov (United States)

    Poort, Jessica E; Rheuben, Mary B; Breedlove, S Marc; Jordan, Cynthia L

    2016-09-01

    Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected by neuromuscular disease, whether NMJs in SBMA are similarly affected by disease is not known. Such information will shed light on whether defective NMJs might contribute to the loss of motor function and represent a potential therapeutic target for treating symptoms of SBMA. To address this gap in information, the morphology of NMJs was examined in two mouse models of SBMA, a myogenic model that overexpresses wildtype androgen receptor (AR) exclusively in muscle fibres and a knockin (KI) model expressing a humanized mutant AR gene. The tripartite motor synapse consisting of motor nerve terminal, terminal Schwann cells (tSCs) and postsynaptic specialization were visualized and analysed using confocal microscopy. Counter to expectation, we found no evidence of denervation in either model, but junctions in both models show pathological fragmentation and an abnormal synaptophysin distribution consistent with functionally weak synapses. Neurofilament accumulations were observed only in the myogenic model, even though axonal transport dysfunction is characteristic of both models. The ultrastructure of NMJs revealed additional pathology, including deficits in docked vesicles presynaptically, wider synaptic clefts, and simpler secondary folds postsynaptically. The observed pathology of NMJs in diseased SBMA mice is likely the morphological correlates of defects in synaptic function which may underlie motor impairments associated with SBMA.

  5. Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Andrew P. Lieberman

    2014-05-01

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

  6. Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.

    Science.gov (United States)

    Lund, A; Udd, B; Juvonen, V; Andersen, P M; Cederquist, K; Ronnevi, L O; Sistonen, P; Sörensen, S A; Tranebjaerg, L; Wallgren-Pettersson, C; Savontaus, M L

    2000-08-01

    We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.

  7. [Clinical features of a genetically identified spinal and 
bulbar muscular atrophy pedigree].

    Science.gov (United States)

    Wang, Zhe; Chen, Qihua; Li, Qiuxiang; Bi, Fangfang

    2016-10-28

    Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage. Muscle biopsy of propositus indicated a typical neurogenic amyotrophy. Genetic testing for SMA of mutation in SMN1 was negative, while for SBMA of androgen receptor showed the increased CAG repeat in exon 1, suggesting that although bulbar symptoms and androgen insensitivity are characteristic symptoms of SBMA, they are not obligatory for the diagnosis. In adult males with a chronic motor neuron syndrome without upper motor neuron signs, even in absence of the classical features of androgen insensitivity or bulbar findings, genetic testing for SBMA should be strongly considered.

  8. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Ling, Karen K Y; Gibbs, Rebecca M; Feng, Zhihua; Ko, Chien-Ping

    2012-01-01

    Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.

  9. Effect of baclofen combined with neural facilitation technique on the reduction of muscular spasm in patients with spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: Recent researches have demonstrated that baclofen is a commonly central anti-spasm drug. In addition, neural facilitation technique based on nerve development and neurophysiology is widely used for rehabilitation training of motor disorder after central nerve injury. However, whether baclofen combining with neural facilitation technique can relieve muscular spasm after spinal cord injury needs further studies.OBJECTIVE: To observe the effect of baclofen combining with neural facilitation technique on decreasing muscular tension in two lower extremities after spinal cord injury.DESIGN: Randomized controlled study.SETTING: Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College.PARTICIPANTS: A total of 28 patients with spinal cord injury, including 17 males and 11 females, whose age ranged from 31 to 71 years, were selected from Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College from March 2005 to September 2006. The illness course ranged from 22 to 54 days and the mean course was (38 ± 8) days. All patients were diagnosed as the first onset and the increase of extensor muscular tension in two lower extremities after thoracic vertebra injury by using spine MR or CT examination. Informed consents were obtained from all the patients.METHODS: All 28 patients who had upper motor neuronal paralysis in two lower extremities after spinal cord injury in thoracic vertebra region were randomly divided into treatment group and control group with 14 cases in each group. Patients in both groups received routine therapy, while those in the treatment group were treated with oral baclofen (the beginning dosage: 5 mg/time; three times per day, 5 mg was increased every three days; the maximal dosage was 60 mg/day; 6 weeks in total) (made in Weicai Pharmaceutical Co., Ltd.;tablet; batch number: HC20040029) combining with neural facilitation technique, which accorded

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Phosphatidylinositol 3-kinase p85 regulatory subunit gene and spinal muscular atrophy disease

    Directory of Open Access Journals (Sweden)

    Monica STAVARACHI

    2009-11-01

    Full Text Available Spinal muscular atrophy (SMA is a frequent neuromuscular disorder caused by motoneuronal apoptosis, as a result of SMN (Survival Motor Neuron protein deficiency. Although the SMA determining gene was identified, the molecular mechanism of the disease is not clearly understood, due to the heterogeneity of clinical manifestations. Trying to complete the molecular describing SMA picture, by identifying potential modulators factors, we investigated the relationship between phosphatidylinositol 3-kinase p85 regulatory subunit gene (PIK3R1 and SMA pathology. As IGF signaling pathway has been reported to play an important role in motoneurons survival and PIK3 is a key element of this cascade signaling, we focused on the relationship between PIK3R1 gene Met326Ile polymorphism and SMA type I, the most severe form of the disease. A total of 80 subjects (40 SMA type I patients and 40 unrelated healthy controls were included in the study. The statistical analyzes performed consequently to the genotyping by mismatch PCR-RFLP method, revealed that Met326Ile polymorphism is not associated with SMA type I disease: ORMet/Met = 0.398 with a p = 0.072 meanwhile ORMet = 0.495, p = 0.063. However, the Cochrane – Armitage test indicated that there is a statistically association trend between the analyzed polymorphism and SMA type I pathology: ORMet = 0.438, p = 0.032. We concluded that additional researches with an increased subjects number and replicates studies in other populations will clarify the investigated relationship and it may contribute to the SMA molecular mechanism understanding.

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

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    Kobayashi, Dione T; Shi, Jing; Stephen, Laurie; Ballard, Karri L; Dewey, Ruth; Mapes, James; Chung, Brett; McCarthy, Kathleen; Swoboda, Kathryn J; Crawford, Thomas O; Li, Rebecca; Plasterer, Thomas; Joyce, Cynthia; Chung, Wendy K; Kaufmann, Petra; Darras, Basil T; Finkel, Richard S; Sproule, Douglas M; Martens, William B; McDermott, Michael P; De Vivo, Darryl C; Walker, Michael G; Chen, Karen S

    2013-01-01

    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). 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. 12 of the 35 putative SMA biomarkers were significantly associated (pSMA 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. 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 neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

  13. A large animal model of Spinal Muscular Atrophy and correction of phenotype

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    Duque, Sandra I.; Arnold, W. David; Odermatt, Philipp; Li, Xiaohui; Porensky, Paul N.; Schmelzer, Leah; Meyer, Kathrin; Kolb, Stephen J.; Schümperli, Daniel; Kaspar, Brian K.; Burghes, Arthur H. M.

    2015-01-01

    Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset. PMID:25516063

  14. Physical exercise reduces cardiac defects in type 2 spinal muscular atrophy-like mice.

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    Biondi, Olivier; Lopes, Philippe; Desseille, Céline; Branchu, Julien; Chali, Farah; Ben Salah, Amina; Pariset, Claude; Chanoine, Christophe; Charbonnier, Frédéric

    2012-11-15

    Spinal muscular atrophy (SMA), the leading genetic cause of death in infants worldwide, is due to the misexpression of the survival of motor neuron protein, causing death of motor neurons. Several clinical symptoms suggested that, in addition to motor neurons, the autonomic nervous systems could be implicated in the cardiac function alterations observed in patienst with SMA. These alterations were also found in a severe SMA mouse model, including bradycardia and a reduction of sympathetic innervation, both associated with autonomic imbalance. In the present study, we investigate the extent of autonomic dysfunction and the effects of a running-based exercise on the altered cardiorespiratory function in type 2 SMA-like mice. We observed that the SMA induced: (1) a dramatic alteration of intrinsic cardiac conduction associated with bradycardia; (2) a severe cardiomyopathy associated with extensive ventricular fibrosis; and (3) a delay in cardiac muscle maturation associated with contractile protein expression defects. Furthermore, our data indicate that the sympathetic system is not only functioning, but also likely contributes to alleviate the bradycardia and the arrhythmia in SMA-like mice. Moreover, physical exercise provides many benefits, including the reduction of cardiac protein expression defect, the reduction of fibrosis, the increase in cardiac electrical conduction velocity, and the drastic reduction in bradycardia and arrhythmias resulting in the partial restoration of the cardiac function in these mice. Thus, modulating the cardiorespiratory function in SMA could represent a new target for improving supportive care and for developing new pharmacological and non-pharmacological interventions that would most certainly include physical exercise.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Responsiveness of the motor function measure in patients with spinal muscular atrophy.

    Science.gov (United States)

    Vuillerot, Carole; Payan, Christine; Iwaz, Jean; Ecochard, René; Bérard, Carole

    2013-08-01

    To assess the ability of the Motor Function Measure (MFM) to detect changes in the progression of spinal muscular atrophy (SMA). Observational, retrospective, multicenter cohort study. Seventeen departments of pediatric physical medicine. Volunteer patients with SMA (N=112) aged 5.7 to 59 years with no treatment other than physical therapy and nutritional or respiratory assistance. Not applicable. The distributions of the MFM scores (total score and 3 subscores) were analyzed per SMA subtype. The relationships between scores and age were studied. The slopes of score changes (reflecting MFM responsiveness) were estimated in patients with at least 6 months' follow-up and 2 MFMs. Hypothetical sample sizes for specific effect sizes in clinical trial scenarios are given. In 12 patients with SMA type 2 and 19 with SMA type 3 (mean ± SD follow-up, 25.8 ± 19mo), there was a moderate inverse relationship between age and the MFM total score. Patients with less than 6 months' follow-up showed little score changes. Patients with longer follow-ups showed a slow deterioration (-0.9 points/y for type 2 and -0.6 points/y for type 3). Substantial responsiveness was obtained with the MFM Dimension 2 subscore (proximal and axial motricity) in patients with SMA type 2 (standardized response mean [SRM]=1.29), and with the MFM Dimension 1 subscore (standing and transfers) in patients with SMA type 3 aged 10 to 15 years (SRM=.94). If further confirmed by larger studies, these preliminary results on the relative responsiveness of the MFM in SMA will foster its use in monitoring disease progression in patients who participate in clinical trials. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  17. [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.

  18. [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.

  19. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool

    Science.gov (United States)

    Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S.; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M.; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T.; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are ‘fit for purpose’. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials. PMID:28222119

  20. Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Rusmini, Paola; Crippa, Valeria; Giorgetti, Elisa; Boncoraglio, Alessandra; Cristofani, Riccardo; Carra, Serena; Poletti, Angelo

    2013-11-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease caused by an abnormal expansion of a tandem CAG repeat in exon 1 of the androgen receptor (AR) gene that results in an abnormally long polyglutamine tract (polyQ) in the AR protein. As a result, the mutant AR (ARpolyQ) misfolds, forming cytoplasmic and nuclear aggregates in the affected neurons. Neurotoxicity only appears to be associated with the formation of nuclear aggregates. Thus, improved ARpolyQ cytoplasmic clearance, which indirectly decreases ARpolyQ nuclear accumulation, has beneficial effects on affected motoneurons. In addition, increased ARpolyQ clearance contributes to maintenance of motoneuron proteostasis and viability, preventing the blockage of the proteasome and autophagy pathways that might play a role in the neuropathy in SBMA. The expression of heat shock protein B8 (HspB8), a member of the small heat shock protein family, is highly induced in surviving motoneurons of patients affected by motoneuron diseases, where it seems to participate in the stress response aimed at cell protection. We report here that HspB8 facilitates the autophagic removal of misfolded aggregating species of ARpolyQ. In addition, though HspB8 does not influence p62 and LC3 (two key autophagic molecules) expression, it does prevent p62 bodies formation, and restores the normal autophagic flux in these cells. Interestingly, trehalose, a well-known autophagy stimulator, induces HspB8 expression, suggesting that HspB8 might act as one of the molecular mediators of the proautophagic activity of trehalose. Collectively, these data support the hypothesis that treatments aimed at restoring a normal autophagic flux that result in the more efficient clearance of mutant ARpolyQ might produce beneficial effects in SBMA patients.

  1. Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients.

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    Borgia, Doriana; Malena, Adriana; Spinazzi, Marco; Andrea Desbats, Maria; Salviati, Leonardo; Russell, Aaron P; Miotto, Giovanni; Tosatto, Laura; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria; Vergani, Lodovica

    2017-01-13

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared to glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in NADH-stained muscle cross sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches towards improving the mitochondrial network are worth considering to support SBMA patients.

  2. Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Nakatsuji, Hideaki; Araki, Amane; Hashizume, Atsushi; Hijikata, Yasuhiro; Yamada, Shinichiro; Inagaki, Tomonori; Suzuki, Keisuke; Banno, Haruhiko; Suga, Noriaki; Okada, Yohei; Ohyama, Manabu; Nakagawa, Tohru; Kishida, Ken; Funahashi, Tohru; Shimomura, Iichiro; Okano, Hideyuki; Katsuno, Masahisa; Sobue, Gen

    2017-02-22

    This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

  3. Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Malena, Adriana; Pennuto, Maria; Tezze, Caterina; Querin, Giorgia; D'Ascenzo, Carla; Silani, Vincenzo; Cenacchi, Giovanna; Scaramozza, Annarita; Romito, Silvia; Morandi, Lucia; Pegoraro, Elena; Russell, Aaron P; Sorarù, Gianni; Vergani, Lodovica

    2013-07-01

    Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis.

  4. 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.

  5. The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism.

    Science.gov (United States)

    Vinograd-Byk, Hadar; Sapir, Tamar; Cantarero, Lara; Lazo, Pedro A; Zeligson, Sharon; Lev, Dorit; Lerman-Sagie, Tally; Renbaum, Paul; Reiner, Orly; Levy-Lahad, Ephrat

    2015-01-21

    Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews, and additional mutations in patients of different origins have recently been identified. VRK1 is a nuclear serine/threonine protein kinase known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads to downregulation of amyloid-β precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism.

  6. The prognostic value of pre-operative predicted forced vital capacity in corrective spinal surgery for Duchenne's muscular dystrophy.

    Science.gov (United States)

    Harper, C M; Ambler, G; Edge, G

    2004-12-01

    The majority of patients with Duchenne's muscular dystrophy require corrective spinal surgery for scoliosis to maintain seated balance and to slow the progression of respiratory compromise, thereby facilitating nursing and enhancing their quality of life. Traditionally patients with a pre-operative forced vital capacity (PFVC) of 30% or below predicted have been denied this surgery as it was thought that the incidence of postoperative complications was unacceptably high. We present data collected prospectively from 45 consecutive operations undertaken in our unit. These cases indicate that there is no clinically significant difference in operative and postoperative outcomes between patients with PFVC > 30% and vital.

  7. 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 ...

  8. Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy.

    Science.gov (United States)

    Sleigh, James N; Barreiro-Iglesias, Antón; Oliver, Peter L; Biba, Angeliki; Becker, Thomas; Davies, Kay E; Becker, Catherina G; Talbot, Kevin

    2014-02-15

    Spinal muscular atrophy (SMA) is characterized by the selective loss of spinal motor neurons owing to reduced levels of survival motor neuron (Smn) protein. In addition to its well-established role in assembling constituents of the spliceosome, diverse cellular functions have been proposed for Smn, but the reason why low levels of this widely expressed protein result in selective motor neuron pathology is still debated. In longitudinal studies of exon-level changes in SMA mouse model tissues, designed to determine the contribution of splicing dysfunction to the disease, we have previously shown that a generalized defect in splicing is unlikely to play a causative role in SMA. Nevertheless, we identified a small subset of genes that were alternatively spliced in the spinal cord compared with control mice before symptom onset, indicating a possible mechanistic role in disease. Here, we have performed functional studies of one of these genes, chondrolectin (Chodl), known to be highly expressed in motor neurons and important for correct motor axon outgrowth in zebrafish. Using in vitro and in vivo models of SMA, we demonstrate altered expression of Chodl in SMA mouse spinal motor neurons, show that Chodl has distinct effects on cell survival and neurite outgrowth and that increasing the expression of chodl can rescue motor neuron outgrowth defects in Smn-depleted zebrafish. Our findings thus link the dysregulation of Chodl to the pathophysiology of motor neuron degeneration in SMA.

  9. Combination of valproic acid and morpholino splice-switching oligonucleotide produces improved outcomes in spinal muscular atrophy patient-derived fibroblasts.

    Science.gov (United States)

    Farrelly-Rosch, Anna; Lau, Chew Ling; Patil, Nitin; Turner, Bradley J; Shabanpoor, Fazel

    2017-09-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans possess a second nearly identical copy of SMN1, known as SMN2. However, SMN2 produces only 10-20% functional SMN protein due to aberrant splicing of its pre-mRNA that leads to the exclusion of exon 7. This level of SMN is insufficient to rescue the phenotype. Recently developed splice-switching antisense oligonuclotides (SSO) have shown great promise in correcting the aberrant splicing of SMN2 towards producing functional SMN protein. Several FDA approved drugs are being repurposed for SMA treatment including valproic acid (VPA), a histone deacetylase inhibitor, which has been shown to increase overall SMN2 expression. In this study, we have characterised the effects of single and combined treatment of VPA and a SSO based on phosphorodiamidate morpholino oligomer (PMO) chemistry. We conjugated both VPA and PMO to a single cell-penetrating peptide (Apolipoprotein E (ApoE)) for their simultaneous intracellular delivery. Treatment of SMA Type I patient-derived fibroblasts with the conjugates showed no additive increase in the level of full-length SMN2 mRNA expression over both 4 and 16 h treatments indicating that conjugation of VPA to ApoE-PMO has limited benefit. However, treatment with a combination of VPA and ApoE-PMO induced more favourable splice switching activity than either agent alone, promoting exon 7 inclusion in SMN2 transcripts. Our results suggest that combination therapy of VPA and ApoE-PMO is superior in upregulating SMN2 production in vitro, as compared to singular treatment of each compound at both transcriptional and protein levels. This study provides the first indication of a novel dual therapy approach

  10. Whole transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).

    Science.gov (United States)

    Kernohan, Kristin D; Frésard, Laure; Zappala, Zachary; Hartley, Taila; Smith, Kevin S; Wagner, Justin; Xu, Hongbin; McBride, Arran; Bourque, Pierre R; Consortium, Care Rare Canada; Bennett, Steffany A L; Dyment, David A; Boycott, Kym M; Montgomery, Stephen B; Warman-Chardon, Jodi

    2017-03-02

    At least 15% of disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in non-coding regions. Whole transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(pC;p.Lys168Asn) and provided a molecular diagnosis of autosomal recessive spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for non-hematological conditions, providing a diagnosis for these otherwise unsolved patients. This article is protected by copyright. All rights reserved.

  11. Brief report: phenotypic rescue of induced pluripotent stem cell-derived motoneurons of a spinal muscular atrophy patient.

    Science.gov (United States)

    Chang, Tammy; Zheng, Weiyan; Tsark, Walter; Bates, Steven; Huang, He; Lin, Ren-Jang; Yee, Jiing-Kuan

    2011-12-01

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders in humans and is a common genetic cause of infant mortality. The disease is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord and muscular atrophy in the limbs and trunk. One function of SMN involves RNA splicing. It is unclear why a deficiency in a housekeeping function such as RNA splicing causes profound effects only on motoneurons but not on other cell types. One difficulty in studying SMA is the scarcity of patient's samples. The discovery that somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) raises the intriguing possibility of modeling human diseases in vitro. We reported the establishment of five iPSC lines from the fibroblasts of a type 1 SMA patient. Neuronal cultures derived from these SMA iPSC lines exhibited a reduced capacity to form motoneurons and an abnormality in neurite outgrowth. Ectopic SMN expression in these iPSC lines restored normal motoneuron differentiation and rescued the phenotype of delayed neurite outgrowth. These results suggest that the observed abnormalities are indeed caused by SMN deficiency and not by iPSC clonal variability. Further characterization of the cellular and functional deficits in motoneurons derived from these iPSCs may accelerate the exploration of the underlying mechanisms of SMA pathogenesis.

  12. Efecto residual del ejercicio de fuerza muscular en la prevención secundaria de la obesidad infantil

    OpenAIRE

    Fabián Vásquez; Erik Díaz; Lydia Lera; Jorge Meza; Isabel Salas; Pamela Rojas; Eduardo Atalah; Raquel Burrows

    2013-01-01

    Introducción: La elevada prevalencia de la obesidad en escolares chilenos (23,1%), hace necesario la aplicación de intervenciones que incorporen el ejercicio físico de fuerza muscular, pues éste muestra gran eficacia en niños obesos. Objetivo: Evaluar el efecto residual del ejercicio físico de fuerza muscular sobre la grasa corporal, el síndrome metabólico y la condición física en escolares obesos. Métodos: La muestra incluyó 111 escolares obesos, entre 8 y 13 años, de 3 colegios de la ciudad...

  13. Awake behaving electrophysiological correlates of forelimb hyperreflexia, weakness and disrupted muscular synchronization following cervical spinal cord injury in the rat

    Science.gov (United States)

    Ganzer, Patrick Daniel; Meyers, Eric Christopher; Sloan, Andrew Michael; Maliakkal, Reshma; Ruiz, Andrea; Kilgard, Michael Paul; Rennaker, Robert LeMoine

    2016-01-01

    Spinal cord injury usually occurs at the level of the cervical spine and results in profound impairment of forelimb function. In this study, we recorded awake behaving intramuscular electromyography (EMG) from the biceps and triceps muscles of the impaired forelimb during volitional and reflexive forelimb movements before and after unilateral cervical spinal cord injury (cSCI) in rats. C5/C6 hemicontusion reduced volitional forelimb strength by more than 50% despite weekly rehabilitation for one month post-injury. Triceps EMG during volitional strength assessment was reduced by more than 60% following injury, indicating reduced descending drive. Biceps EMG during reflexive withdrawal from a thermal stimulus was increased by 500% following injury, indicating flexor withdrawal hyperreflexia. The reduction in volitional forelimb strength was significantly correlated with volitional and reflexive biceps EMG activity. Our results support the hypothesis that biceps hyperreflexia and descending volitional drive both significantly contribute to forelimb strength deficits after cSCI and provide new insight into dynamic muscular dysfunction after cSCI. The use of multiple automated quantitative measures of forelimb dys-function in the rodent cSCI model will likely aid the search for effective regenerative, pharmacological, and neuroprosthetic treatments for spinal cord injury. PMID:27033345

  14. 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.; Stam, Marloes; Jansen, Marc D.; van der Weegen, Yana; Wijngaarde, Camiel A.; Harschnitz, Oliver; Sodaar, Peter; Braun, Kees P. J.; Dooijes, Dennis; Lemmink, Henny H.; van den Berg, Leonard H.; van der Pol, W. Ludo

    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

  15. 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

  16. 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...

  17. 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

  18. 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 characteri

  19. 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.; Stam, Marloes; Jansen, Marc D.; van der Weegen, Yana; Wijngaarde, Camiel A.; Harschnitz, Oliver; Sodaar, Peter; Braun, Kees P. J.; Dooijes, Dennis; Lemmink, Henny H.; van den Berg, Leonard H.; van der Pol, W. Ludo

    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 s

  20. 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

  1. 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

  2. 脊髓性肌萎缩症伴开(牙合)1例%Spinal muscular atrophy with open bite: A case report

    Institute of Scientific and Technical Information of China (English)

    郑闱颖; 林军

    2013-01-01

    Spinal muscular atrophy is one rare type of autosomal recessive disorder.The disease is characterized by the progressive degeneration of spinal cord anterior horn motor neurons and brainstem motor nuclei,which leads to muscle atrophy and paralysis.One case of spinal muscular atrophy with open bite was reported here.%脊髓性肌萎缩症是由于脊髓前角运动神经元和脑干运动神经核变性而导致肌无力、肌萎缩的一种罕见的常染色体隐形遗传疾病.该病临床上极为罕见,本文报道1例脊髓性肌萎缩症伴开(牙合)的病例.

  3. Isolation of mineralizing Nestin+ Nkx6.1+ vascular muscular cells from the adult human spinal cord

    Directory of Open Access Journals (Sweden)

    Guillon Hélène

    2011-10-01

    Full Text Available Abstract Background The adult central nervous system (CNS contains different populations of immature cells that could possibly be used to repair brain and spinal cord lesions. The diversity and the properties of these cells in the human adult CNS remain to be fully explored. We previously isolated Nestin+ Sox2+ neural multipotential cells from the adult human spinal cord using the neurosphere method (i.e. non adherent conditions and defined medium. Results Here we report the isolation and long term propagation of another population of Nestin+ cells from this tissue using adherent culture conditions and serum. QPCR and immunofluorescence indicated that these cells had mesenchymal features as evidenced by the expression of Snai2 and Twist1 and lack of expression of neural markers such as Sox2, Olig2 or GFAP. Indeed, these cells expressed markers typical of smooth muscle vascular cells such as Calponin, Caldesmone and Acta2 (Smooth muscle actin. These cells could not differentiate into chondrocytes, adipocytes, neuronal and glial cells, however they readily mineralized when placed in osteogenic conditions. Further characterization allowed us to identify the Nkx6.1 transcription factor as a marker for these cells. Nkx6.1 was expressed in vivo by CNS vascular muscular cells located in the parenchyma and the meninges. Conclusion Smooth muscle cells expressing Nestin and Nkx6.1 is the main cell population derived from culturing human spinal cord cells in adherent conditions with serum. Mineralization of these cells in vitro could represent a valuable model for studying calcifications of CNS vessels which are observed in pathological situations or as part of the normal aging. In addition, long term propagation of these cells will allow the study of their interaction with other CNS cells and their implication in scar formation during spinal cord injury.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    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. PMID:28122039

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

    Science.gov (United States)

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

    2014-11-01

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

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

    Science.gov (United States)

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

    2016-07-14

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

  9. Frontotemporal cognitive function in X-linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients.

    Science.gov (United States)

    Soukup, Georg Rüdiger; Sperfeld, Anne-Dorte; Uttner, Ingo; Karitzky, Jochen; Ludolph, Albert Christian; Kassubek, Jan; Schreiber, Herbert

    2009-11-01

    A cross-sectional neuropsychological study of cognitive functions in 20 male patients with genetically proven spinal and bulbar muscular atrophy (SBMA) was performed, with a comparison of their cognitive performance with that of 20 age- and education-matched control subjects. Neuropsychological assessment covered executive functioning, memory, and attentional control. The SBMA patients revealed deficits in verbal and non-verbal fluency as well as concept formation. Additionally, they showed significant memory deficits in all of the investigated domains of working memory, short-term and long-term memory. With respect to attentional control, the SBMA patients underperformed in relevant subtests, although performance differences did not reach significance overall. We conclude that fronto-temporal cognitive functions are impaired in SMBA, although at a subclinical level. Thus, functional deficits in SBMA are not confined to motor neurons but also affect extramotor networks.

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

    Science.gov (United States)

    Chen, Xing; Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    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.

  11. Mechanisms mediating spinal and bulbar muscular atrophy: Investigations into polyglutamine-expanded androgen receptor function and dysfunction

    Directory of Open Access Journals (Sweden)

    Lenore K. Beitel

    2013-05-01

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

  12. Efecto residual del ejercicio de fuerza muscular en la prevención secundaria de la obesidad infantil

    Directory of Open Access Journals (Sweden)

    Fabián Vásquez

    2013-04-01

    Full Text Available Introducción: La elevada prevalencia de la obesidad en escolares chilenos (23,1%, hace necesario la aplicación de intervenciones que incorporen el ejercicio físico de fuerza muscular, pues éste muestra gran eficacia en niños obesos. Objetivo: Evaluar el efecto residual del ejercicio físico de fuerza muscular sobre la grasa corporal, el síndrome metabólico y la condición física en escolares obesos. Métodos: La muestra incluyó 111 escolares obesos, entre 8 y 13 años, de 3 colegios de la ciudad de Santiago. La intervención temprana (n = 60 ejecutó en paralelo ejercicio físico de fuerza muscular, educación alimentaria y apoyo psicológico durante 3 meses. La intervención tardía (n = 51, incorporó los primeros 3 meses, sólo la intervención educativa y el apoyo psicológico, y el ejercicio se agregó entre los 3 y 6 meses. A los 9 meses post-intervención, se evaluó el efecto residual del ejercicio físico. La grasa corporal se determinó por ecuaciones antropométricas. El síndrome metabólico se diagnóstico por el criterio de Cook. La condición física se evaluó por la distancia recorrida en el test de seis minutos. Resultados: El porcentaje grasa corporal disminuyó al final de la intervención y aumentó post-intervención, con la excepción de los hombres de la intervención temprana. La distancia recorrida se incrementó al final de la intervención, pero se redujo en la post-intervención. El síndrome metabólico, disminuyó al término de la intervención incrementando post-intervención (p < 0,05. Conclusiones: La sustentabilidad del ejercicio es fundamental para mantener los cambios, lo que se comprueba al evaluar el efecto residual del ejercicio físico sobre la grasa corporal, el síndrome metabólico y la condición física.

  13. IPLEX administration improves motor neuron survival and ameliorates motor functions in a severe mouse model of spinal muscular atrophy.

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

    2012-09-25

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

  14. 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.

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

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

    2013-01-01

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

  16. Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.

    Science.gov (United States)

    Shabanpoor, Fazel; Hammond, Suzan M; Abendroth, Frank; Hazell, Gareth; Wood, Matthew J A; Gait, Michael J

    2017-06-01

    Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141-150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.

  17. 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.

  18. 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.

  19. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy

    Science.gov (United States)

    Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M.; Karp, Gary; Chen, Karen S.; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A.; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID:26931466

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

    Science.gov (United States)

    Giorgetti, Elisa; 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 (or dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the antiandrogen Bicalutamide (Casodex(®)), which slows down AR activation and nuclear translocation, and the disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of trehalose and Bicalutamide was also efficient in the removal of insoluble species of AR with a very long polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of Bicalutamide and trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA.

  1. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.

    Science.gov (United States)

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M; Yang, Ben; Shi, Han; Sze, Christie C; Hong, Benjamin Taige; Su, Susan C; Cantu, Jorge A; Topczewski, Jacek; Crawford, Thomas O; Ko, Chien-Ping; Sumner, Charlotte J; Ma, Long; Ma, Yong-Chao

    2015-04-15

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration.

  2. 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.

  3. 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.

  4. Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery.

    Science.gov (United States)

    Glascock, Jacqueline J; Osman, Erkan Y; Wetz, Mary J; Krogman, Megan M; Shababi, Monir; Lorson, Christian L

    2012-03-01

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present, SMN2. SMN2 is retained in all SMA patients and encodes the same protein as SMN1. However, SMN1 and SMN2 differ by a silent C-to-T transition at the 5' end of exon 7, causing alternative splicing of SMN2 transcripts and low levels of full-length SMN. SMA is monogenic and therefore well suited for gene-replacement strategies. Recently, self-complementary adeno-associated virus (scAAV) vectors have been used to deliver the SMN cDNA to an animal model of disease, the SMNΔ7 mouse. In this study, we examine a severe model of SMA, Smn(-/-);SMN2(+/+), to determine whether gene replacement is viable in a model in which disease development begins in utero. Using two delivery paradigms, intracerebroventricular injections and intravenous injections, we delivered scAAV9-SMN and demonstrated a two to four fold increase in survival, in addition to improving many of the phenotypic parameters of the model. This represents the longest extension in survival for this severe model for any therapeutic intervention and suggests that postsymptomatic treatment of SMA may lead to significant improvement of disease severity.

  5. Decreased stathmin expression ameliorates neuromuscular defects but fails to prolong survival in a mouse model of spinal muscular atrophy.

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    Wen, Hsin-Lan; Ting, Chen-Hung; Liu, Huei-Chun; Li, Hung; Lin-Chao, Sue

    2013-04-01

    Spinal muscular atrophy (SMA), a genetic neurodegenerative disorder, is caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene that result in SMN deficiency. SMN deficiency impairs microtubule networks in Smn-deficient cells and in SMA-like motor neuron cultures. Microtubule defects can be restored by knockdown of the stathmin gene (Stmn), which is upregulated in SMA. However, whether in vivo reduction of stathmin levels could improve the pathology of SMA has not been investigated. Here we generated SMA-like mice in a Stmn knockout (KO) background through a series of genetic crosses. Analyses of motor performance and histology showed that heterozygous StmnKO (Stmn(+/-)) but not homozygous StmnKO (Stmn(-/-)) ameliorates some SMA defects, with increased microtubule densities in sciatic axons, improved motor performance, enhanced NMJ maturation, and mitigated neuroinflammation. However, Stmn deletion does not prolong the lifespan of SMA-like mice, suggesting that stathmin dysregulation and microtubule disruption are not a cause but rather a consequence of SMA pathology. This work demonstrates that limiting the amount of stathmin in SMA-like mice is effective in reducing their neuromuscular defects, whereas induced aberrant expression of stathmin in SMA-like animals is detrimental.

  6. 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.

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

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

    2014-05-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy--a preliminary study.

    Science.gov (United States)

    Gawel, Malgorzata; Kostera-Pruszczyk, Anna; Lusakowska, Anna; Jedrzejowska, Maria; Ryniewicz, Barbara; Lipowska, Marta; Gawel, Damian; Kaminska, Anna

    2015-03-01

    Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (P < 0.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (P < 0.05). Increased SMUP amplitude values correlated with decreased HFMS scores (P < 0.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed.

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

    Science.gov (United States)

    Boroughs, Deborah S

    2017-04-29

    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).

  10. Increased fat mass and high incidence of overweight despite low body mass index in patients with Spinal Muscular Atrophy

    Science.gov (United States)

    Sproule, Douglas M.; Montes, Jacqueline; Montgomery, Megan; Battista, Vanessa; Koenigsberger, Dorcas; Shen, Wei; Punyanitya, Mark; De Vivo, Darryl C.; Kaufmann, Petra

    2009-01-01

    Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m2), fat-free (FFMI, lean mass/height in m2) and fat (FMI, fat mass/height in m2) mass indexes were estimated in 25 children (ages 5–18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was ≥ 50th percentile in 11 (44%) and ≥ 85th in 5 (20%). FFMI was reduced (p<0.005) and FMI was increased (P<0.005) in the overall study cohort. FMI was ≥ 50th, ≥ 85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75th, 50th and 3rd percentiles maximized sensitivity and specificity for FMI ≥ 95th, ≥ 85th and ≥ 50th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA. PMID:19427208

  11. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy.

    Science.gov (United States)

    Krebs, Stefan; Medugorac, Ivica; Röther, Susanne; Strässer, Katja; Förster, Martin

    2007-04-17

    The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.

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

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    Michael O. Harris-Love

    2014-01-01

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

  13. Rapid genetic diagnosis and prenatal diagnosis of spinal muscular atrophy by denaturing high-performance liquid chromatography

    Institute of Scientific and Technical Information of China (English)

    ZHU Hai-yan; WU Ling-qian; PAN Qian; TANG Bei-sha; LIANG De-sheng; LONG Zhi-gao; DAI He-ping; XIA Kun; XIA Jia-hui

    2006-01-01

    @@ Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder1 (1in 6000 to 10 000 births) caused by mutations in the SMN1 gene at 5q13. More than 90%-98% of SMA patients show homozygous deletion of SMN1,2which has proved to be useful in the diagnosis of SMA. But it is hampered because of the existence of a highly homologous gene, SMN2.3 Based on nucleotide mismatches between SMN1 and SMN2,the following two DNA tests are usually performed:single-strand conformational polymorphism (SSCP)3and polymerase chain reaction (PCR) followed by a restriction enzyme digestion.4,5 In this study we developed a new method for rapid genetic diagnosis of SMA by denaturing high-performance liquid chromatography (DHPLC), which is based on different retention of homoduplexes and heteroduplexes in detecting the homozygous deletion of SMN1. Both genetic and prenatal diagnoses were performed successfully for a SMA family by DHPLC, which was confirmed as a rapid and effective technique for detecting the deletion of SMN1.

  14. Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.

    Science.gov (United States)

    Tapia, Olga; Bengoechea, Rocío; Palanca, Ana; Arteaga, Rosa; Val-Bernal, J Fernando; Tizzano, Eduardo F; Berciano, María T; Lafarga, Miguel

    2012-05-01

    Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

  15. Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells.

    Science.gov (United States)

    Renvoisé, Benoît; Khoobarry, Kevinee; Gendron, Marie-Claude; Cibert, Christian; Viollet, Louis; Lefebvre, Suzie

    2006-02-15

    Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an exon7-encoded C-terminus. To examine the domains required for the intranuclear localization of SMN, we have used fluorescently tagged protein mutants transiently overexpressed in mammalian cells. The basic amino acid residues direct nucleolar localization of SMN mutants. The Tudor domain promotes localization of proteins in the nucleus and it cooperates with the basic amino acid residues and the tyrosine-glycine-box for protein localization in Cajal bodies. Moreover, the most frequent disease-linked mutant SMNDeltaex7 reduces accumulation of snRNPs in Cajal bodies, suggesting that the C-terminus of SMN participates in targeting to Cajal bodies. A reduced number of Cajal bodies in patient fibroblasts associates with the absence of snRNPs in Cajal bodies, revealing that intranuclear snRNA organization is modified in disease. These results indicate that direct and indirect mechanisms regulate localization of SMN in Cajal bodies.

  16. 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.

  17. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

    Science.gov (United States)

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J.; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P.; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA. PMID:28117338

  18. Analysis of the conformation of the androgen receptor in spinal bulbar muscular atrophy by atomic force microscopy.

    Science.gov (United States)

    Jochum, Tobias; Cato, Andrew C B

    2014-01-01

    Spinal bulbar muscular atrophy (SBMA) (also known as Kennedy's disease) is a motor degenerative disease caused by an amplification of the polyglutamine stretch at the N-terminus of the human androgen receptor (AR). Amplifications larger than 40 glutamine residues are thought to lead to the disease. A characteristic feature of this disease is a ligand-dependent misfolding and aggregation of the mutant receptor that lead to the death of motor neurons. Initially, large cytoplasmic and nuclear aggregates reaching sizes of 6 μm were thought to be the pathogenic agents. Later studies have suggested that oligomeric species with sizes of less than 1 μm that occur prior to the formation of the larger aggregates are the toxic agents. However, there have been disagreements regarding the shape of these oligomers, as most studies have been carried out with peptide fragments of the androgen receptor containing different lengths of polyglutamine stretch. We have isolated the wild-type AR with a polyglutamine stretch of 22 (ARQ22) and a mutant receptor with a stretch of 65 (ARQ65) using a baculovirus system and have analyzed the oligomeric structures formed by these receptors with atomic force microscopy. This method has allowed us to determine the conformations of the full-length wild-type and mutant AR and revealed the conformation of the mutant AR that causes SBMA.

  19. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

  20. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes.

    Science.gov (United States)

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-24

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA.

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

    Science.gov (United States)

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

    2015-01-01

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

  2. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN.

    Science.gov (United States)

    Foust, Kevin D; Wang, Xueyong; McGovern, Vicki L; Braun, Lyndsey; Bevan, Adam K; Haidet, Amanda M; Le, Thanh T; Morales, Pablo R; Rich, Mark M; Burghes, Arthur H M; Kaspar, Brian K

    2010-03-01

    Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect approximately 60% of motor neurons when injected intravenously into neonatal mice. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA.

  3. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens.

    Science.gov (United States)

    Sugarman, Elaine A; Nagan, Narasimhan; Zhu, Hui; Akmaev, Viatcheslav R; Zhou, Zhaoqing; Rohlfs, Elizabeth M; Flynn, Kerry; Hendrickson, Brant C; Scholl, Thomas; Sirko-Osadsa, Deborah Alexa; Allitto, Bernice A

    2012-01-01

    Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

  4. [The role of RNA splicing in the pathogenesis of spinal muscular atrophy and development of its therapeutics].

    Science.gov (United States)

    Sahashi, Kentaro; Sobue, Gen

    2014-12-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Degeneration of alpha-motor neurons that results in progressive paralysis is a pathological hallmark of SMA. Recently, peripheral-tissue involvement has also been reported in SMA. Patients have low levels of functional SMN which is attributed to alternative splicing in SMN2, a gene closely-related to SMN1. This decrease in the expression of SMN, a ubiquitously expressed protein involved in promoting snRNP assembly required for splicing, is responsible for SMA. However, the mechanism through which decrease in SMN levels causes SMA remains unclear. Currently, no curative treatment is available for SMA, but SMN restoration is thought to be necessary and sufficient for cure. Antisense oligonucleotides (ASOs) can be designed to specifically alter splicing patterns of target pre-mRNAs. We identified an ASO that redirects SMN2 splicing and is currently in clinical trials for use as RNA-targeting therapeutics. Further, we have also reported a novel application of splicing-modulating ASOs--creation of animal phenocopy models of diseases by inducing mis-splicing. Exploring the relationship between the spatial and temporal effects of therapeutic and pathogenic ASOs yields relevant insights into the roles of SMN in SMA pathogenesis and into its normal physiological functions. This knowledge, in turn, contributes to the ongoing development of targeted therapeutics.

  5. Sleep disorders in spinal and bulbar muscular atrophy (Kennedy's disease): a controlled polysomnographic and self-reported questionnaires study.

    Science.gov (United States)

    Romigi, Andrea; Liguori, Claudio; Placidi, Fabio; Albanese, Maria; Izzi, Francesca; Uasone, Elisabetta; Terracciano, Chiara; Marciani, Maria Grazia; Mercuri, Nicola Biagio; Ludovisi, Raffaella; Massa, Roberto

    2014-05-01

    No data are available regarding the occurrence of sleep disorders in spinal and bulbar muscular atrophy (SBMA). We investigated the sleep-wake cycle in SBMA patients compared with healthy subjects. Nine SBMA outpatients and nine age-matched and sex-matched healthy controls were evaluated. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). The Epworth Sleepiness Scale was used in order to evaluate excessive daytime sleepiness. All participants underwent a 48-h polysomnography followed by the multiple sleep latency test. Time in bed, total sleep time and sleep efficiency were significantly lower in SBMA than controls. Furthermore, the apnea-hypopnea index (AHI) was significantly higher in SBMA than controls. Obstructive sleep apnea (OSA: AHI >5/h) was evident in 6/9 patients (66.6 %). REM sleep without atonia was evident in three patients also affected by OSA and higher AHI in REM; 2/9 (22.2 %) SBMA patients showed periodic limb movements in sleep. The global PSQI score was higher in SBMA versus controls. Sleep quality in SBMA is poorer than in controls. OSA is the most common sleep disorder in SBMA. The sleep impairment could be induced both by OSA or/and the neurodegenerative processes involving crucial areas regulating the sleep-wake cycle.

  6. Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy

    Directory of Open Access Journals (Sweden)

    Erica S. Chevalier-Larsen

    2012-01-01

    Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA, a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone treatment had no effect on motor function. Testosterone treatment also failed to affect cellular markers of disease, including inclusion formation (the accumulation of large nuclear aggregates of mutant AR protein and levels of unphosphorylated neurofilament heavy chain. These data suggest that the mechanism of disease in SBMA saturates at close to endogenous hormone levels and that individuals with SBMA who take, or have taken, testosterone for its putative therapeutic properties are unlikely to suffer adverse effects.

  7. Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy.

    Science.gov (United States)

    Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Chua, Jason P; Sun Kim, Hong; Lieberman, Andrew P; Breedlove, S Marc; Jordan, Cynthia L

    2014-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

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

    Science.gov (United States)

    Yamada, Shinichiro; Hashizume, Atsushi; Hijikata, Yasuhiro; Inagaki, Tomonori; Suzuki, Keisuke; Kondo, Naohide; Kawai, Kaori; Noda, Seiya; Nakanishi, Hirotaka; Banno, Haruhiko; Hirakawa, Akihiro; Koike, Haruki; Halievski, Katherine; Jordan, Cynthia L; Katsuno, Masahisa; Sobue, Gen

    2016-01-01

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Altered Levels of MicroRNA-9, -206, and -132 in Spinal Muscular Atrophy and Their Response to Antisense Oligonucleotide Therapy.

    Science.gov (United States)

    Catapano, Francesco; Zaharieva, Irina; Scoto, Mariacristina; Marrosu, Elena; Morgan, Jennifer; Muntoni, Francesco; Zhou, Haiyan

    2016-07-05

    The identification of noninvasive biomarkers to monitor the disease progression in spinal muscular atrophy (SMA) is becoming increasingly important. MicroRNAs (miRNAs) regulate gene expression and are implicated in the pathogenesis of neuromuscular diseases, including motor neuron degeneration. In this study, we selectively characterized the expression of miR-9, miR-206, and miR-132 in spinal cord, skeletal muscle, and serum from SMA transgenic mice, and in serum from SMA patients. A systematic analysis of miRNA expression was conducted in SMA mice with different disease severities (severe type I-like and mild type III-like) at different disease stages (pre-, mid-, and late-symptomatic stages), and in morpholino antisense oligonucleotide-treated mice. There was differential expression of all three miRNAs in spinal cord, skeletal muscle and serum samples in SMA mice. Serum miRNAs were altered prior to the changes in spinal cord and skeletal muscle at the presymptomatic stage. The altered miR-132 levels in spinal cord, muscle, and serum transiently reversed to normal level after a single-dose morpholino antisense oligomer PMO25 treatment in SMA mice. We also confirmed a significant alteration of miR-9 and miR-132 level in serum samples from SMA patients. Our study indicates the potential of developing miRNAs as noninvasive biomarkers in SMA.

  14. 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.

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

    Science.gov (United States)

    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.

  16. [Molecular Features of SMA-related Genes in Spinal Muscular Atrophy Patients of Han Nationality in Southwest China.

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    Wang, Min-Jin; Wang, Jun; Bai, Meng-Ge; Zhou, Wen-Jing; Wu, Li-Juan; Tang, Si-Shi; Lu, Xiao-Jun; Ying, Bin-Wu

    2016-11-01

    To investigate the molecular features of spinal muscular atrophy (SMA) related genes in SMA patients of Han nationality of southwest of China. We collected 62 unrelated patients of SMA and 50 unrelated healthy individuals in this study.The copy numbers of survival motor neuron gene (SMN) and uronal-apoptosis inhibitory protein gene (NAIP) were measured by using multiplex ligation-dependent probe amplification (MLPA). Of 62 patients,the copy number of SMA1-4 were 30.65% (19/62),41.94%(26/62),16.13% (10/62),11.29% (7/62),respectively.The deletion of SMN1 exon 7 accounts for 98.38% (61/62).The deletion of SMN1 exon 8 accounts for 82.26% (51/62).Among SMA 1 patients,the homozygous deletion of NAIP exon 5 accounts for 68.42% (13/19) and heterzygous deletion accounts for 26.32% (5/19).Among SMA2-4patients,the homozygous deletion of NAIP exon 5 accounts for 13.95% (6/43) and heterzygous deletion accounts for 62.79% (27/43).Furthermore,68.42% (13/19) patients of SMA1have 1 copy and 2 copies of SMN2 gene,84.62% (22/26) patients of SMA 2 have more than 2 copies of SMN2 gene,90.00% (9/10) SMA3 and 85.71% (6/7) SMA4 have over 2 copies of SMN2 gene and even have 5 and 6 copy of SMN2 gene. The deletion of SMN1 gene is the main cause of SMA,and the change of SMN2 and NAIP copy number can affect the severity of SMA.

  17. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.

    Science.gov (United States)

    Singh, N N; Howell, M D; Androphy, E J; Singh, R N

    2017-05-09

    Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here, we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.Gene Therapy advance online publication, 25 May 2017; doi:10.1038/gt.2017.34.

  18. 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.

  19. Genotype-Phenotype Correlation of SMN1 and NAIP Deletions in Korean Patients with Spinal Muscular Atrophy

    Science.gov (United States)

    Ahn, Eun-Ji; Yum, Mi-Sun; Kim, Eun-Hee; Yoo, Han-Wook; Lee, Beom Hee; Kim, Gu-Hwan

    2017-01-01

    Background and Purpose Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients. Methods Thirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed. Results Deletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008). Conclusions Homozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA. PMID:27730768

  20. Microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy disease/spinal bulbar muscular atrophy.

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    Kaiguo Mo

    Full Text Available BACKGROUND: Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA. We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ AR knock-in model (AR113Q, a polyQ AR transgenic model (AR97Q, and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR. HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR. METHODOLOGY/PRINCIPAL FINDINGS: We performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington's Disease, and to those common to muscle atrophy from diverse causes. CONCLUSIONS/SIGNIFICANCE: By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA.

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

    Science.gov (United States)

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

    2014-01-01

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

  2. Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Nihei, Yoshihiro; Ito, Daisuke; Okada, Yohei; Akamatsu, Wado; Yagi, Takuya; Yoshizaki, Takahito; Okano, Hideyuki; Suzuki, Norihiro

    2013-03-22

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. Ligand-dependent nuclear accumulation of mutant AR protein is a critical characteristic of the pathogenesis of SBMA. SBMA has been modeled in AR-overexpressing animals, but precisely how the polyglutamine (polyQ) expansion leads to neurodegeneration is unclear. Induced pluripotent stem cells (iPSCs) are a new technology that can be used to model human diseases, study pathogenic mechanisms, and develop novel drugs. We established SBMA patient-derived iPSCs, investigated their cellular biochemical characteristics, and found that SBMA-iPSCs can differentiate into motor neurons. The CAG repeat numbers in the AR gene of SBMA-iPSCs and also in the atrophin-1 gene of iPSCs derived from another polyQ disease, dentato-rubro-pallido-luysian atrophy (DRPLA), remain unchanged during reprogramming, long term passage, and differentiation, indicating that polyQ disease-associated CAG repeats are stable during maintenance of iPSCs. The level of AR expression is up-regulated by neuronal differentiation and treatment with the AR ligand dihydrotestosterone. Filter retardation assays indicated that aggregation of ARs following dihydrotestosterone treatment in neurons derived from SBMA-iPSCs increases significantly compared with neurological control iPSCs, easily recapitulating the pathological feature of mutant ARs in SBMA-iPSCs. This phenomenon was not observed in iPSCs and fibroblasts, thereby showing the neuron-dominant phenotype of this disease. Furthermore, the HSP90 inhibitor 17-allylaminogeldanamycin sharply decreased the level of aggregated AR in neurons derived from SBMA-iPSCs, indicating a potential for discovery and validation of candidate drugs. We found that SBMA-iPSCs possess disease-specific biochemical features and could thus open new avenues of research into not only SBMA, but also other polyglutamine diseases.

  3. 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 BACKGROUND: 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. OBJECTIVE: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches. MATERIALS AND METHODS: 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. RESULTS: 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. DISCUSSION: 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

  4. The experiences of families living with the anticipatory loss of a school-age child with spinal muscular atrophy - the parents' perspectives.

    Science.gov (United States)

    Yang, Bao-Huan; Mu, Pei-Fan; Wang, Wen-Sheng

    2016-09-01

    To probe into parents' anticipatory loss of school-age children with Type I or II spinal muscular atrophy. Spinal muscular atrophy is a rare disorder that causes death. Children die early due to either gradual atrophy or an infection of the lungs. Therefore, family members experience anticipatory loss, which causes grief before the actual loss. Family members feel physically and mentally exhausted, which results in a family crisis. Therefore, it is important to explore their experiences related to anticipatory loss to assist with the adjustment of the families to their circumstances. This study applied a phenomenology method and purposive sampling. The 19 parents who participated in this study were referred to us by two medical centers in Taiwan. Their average age was 32-49 years. Using in-depth interviews, this study explored parents' anticipatory loss. The interviews were recorded and transcribed. Meanings were extracted using Giorgi analysis, and precision was assessed according to Guba and Lincoln, which was treated as the evaluation standard. Four themes were identified from the parents' interviews. The themes included enduring the helplessness and pressure of care, suffering due to the child's rare and unknown condition, loss of hope and a reinforcement of the parent-child attachment, and avoiding the pressure of death and enriching the child's life. The research findings help nurses identify anticipatory loss among parents of school-age children with type I or II spinal muscular atrophy. They enhance health professionals' understanding of the panic that occurs in the society surrounding the families, family members' dynamic relationships, and the families' demands for care. In an attempt to providing intersubjective empathy and support with family having a child with type I and II SMA, nurses may recognize relevant family reactions and enhancing their hope and parent-child attachment. Encourage family members and child go beyond the pressure of death and

  5. [Translation and validation of the Egen Klassifikation scale for the Spanish population: functional assessment for non-ambulatory individuals with Duchenne's muscular dystrophy and spinal muscular atrophy].

    Science.gov (United States)

    Fagoaga, Joaquín; Girabent-Farrés, Montserrat; Bagur-Calafat, Caritat; Febrer, Anna; Steffensen, Birgit F

    2013-06-01

    Introduccion. La escala Egen Klassifikation (EK) es un cuestionario que valora la capacidad funcional de personas con distrofia muscular de Duchenne y atrofia muscular espinal no ambulantes y que estan en silla de ruedas. Objetivo. Traducir y validar la EK para la poblacion espanola, como instrumento de medicion de la capacidad funcional en dichos pacientes. Pacientes y metodos. Se realiza, en primer lugar, una traduccion-retrotraduccion de la EK en la poblacion espanola y, posteriormente, se practica el estudio de fiabilidad de la version traducida al espanol de dicha escala. Se llevan a cabo tres mediciones a 30 pacientes con edades comprendidas entre 4 y 67 anos. Dos de estas mediciones se realizan por el mismo observador, y la tercera, por un segundo observador, para evaluar la concordancia intra e interobservador. Resultados. Los valores obtenidos referidos a la puntuacion total de los items de la escala, suma EK, reflejan un indice de fiabilidad del 0,995. Tambien muestran una fiabilidad superior a 0,86 en cada uno de los items, tanto en las observaciones intra como interobservador. Conclusiones. La version espanola de la EK es un instrumento valido y fiable para la poblacion espanola, como herramienta de medicion de la capacidad funcional en pacientes con distrofia muscular de Duchenne y atrofia muscular espinal no ambulantes y que estan en silla de ruedas.

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

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    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.

  7. 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...

  8. Relationship between the pathology of skeletal muscle and muscular atrophy in adult spinal muscular atrophy%成人型脊髓性肌萎缩症的骨骼肌病理与肌萎缩的关系

    Institute of Scientific and Technical Information of China (English)

    何晓军; 张平; 陈光辉

    2004-01-01

    背景:脊髓性肌萎缩症是运动神经元疾病中病变仅影响下运动神经元的一组疾病.成人型少见,目前对其研究较少.目的:总结成人型脊髓性肌萎缩症骨骼肌病理学特征.设计:以诊断为依据的回顾性研究.地点和对象:收集1998-02/2002-02在解放军第八一医院南京医学院第二附属医院和南京军区总医院经肌肉活检确诊的、有完整临床资料的门诊和住院患者共46例.方法:结合临床特征及病理学改变进行分析.主要观察指标:病史、家族史、完整体格检查、相关血液及血生化、肌电图和肌肉活检.结果:临床表现为进行性对称性肢体近端肌萎缩,肌无力,实验室检查血肌酸磷酸肌酶12例中轻度升高,肌电图检查2例正常,3例呈轻度肌源性损害,余37例呈神经元性损害,肌活检主要为小群性肌萎缩,腺苷三磷酸酶染色见同型肌群化及肌纤维代偿性肥大.结论:肌活检对成人型脊髓性肌萎缩症具有诊断和鉴别诊断意义.适当、持久的康复锻炼可能对维持患者的运动功能有帮助.%BACKGROUND: Spinal muscular atrophy is a group of diseases in motor neuronal diseases that only affect lower motor neurons, of which adult type is very rare and thereby only few researches available at present.OBJECTIVE: To summarize the pathological features of skeletal muscle in adult spinal muscular atrophy.DESIGN: A retrospective study based on diagnosis.SETTING and PARTICIPANTS: Totally 46 cases from outpatient and inpatient departments during February 1998 to February 2002 of the 81 Hospital of Chinese PLA with confirmed muscular biopsy and complete clinical data were collected.INTERVENTIONS: Combined analysis with clinical features and pathological changes.MAIN OUTCOME MEASURES: Case history, family history, complete physical examination, relative blood and blood biochemistry, electromyogram (EMG) and muscle biopsy.RESULTS: The clinical manifestations were progressive

  9. [Evolution of functional capacity, assessed with the Egen Klassifikation scale, in the Spanish population with spinal muscular atrophy or Duchenne muscular dystrophy. A three year longitudinal study].

    Science.gov (United States)

    Fagoaga, J; Girabent-Farres, M; Bagur-Calafat, C; Steffensen, B F

    2015-10-16

    Introduccion. La atrofia muscular espinal (AME) y la distrofia muscular de Duchenne (DMD) son dos enfermedades neuromusculares que evolucionan con perdida progresiva de la fuerza muscular y, en consecuencia, perdida de la capacidad funcional. La valoracion con escalas de medicion permite conocer mejor y cuantificar esta involucion, asi como tomar decisiones terapeuticas para anticiparse a los problemas y mejorar la calidad de vida de las personas afectas de estas patologias. Objetivo. Estudiar los cambios de la capacidad funcional de un grupo de pacientes con AME y DMD en un periodo de tres años. Pacientes y metodos. Diecinueve personas de la poblacion española afectas de AME o DMD, a las que se valoro con la escala Egen Klassifikation en dos ocasiones, en un periodo de tres años. Resultados. Los resultados obtenidos reflejan una disminucion de la capacidad funcional de estas personas durante este periodo de tiempo, con una diferencia significativa en la suma total de la escala (p = 0,003). Todos los items de la escala tuvieron valoraciones inferiores despues de tres años, y se llego a la significacion estadistica en la valoracion de la capacidad de mover las manos y de toser. Conclusion. La capacidad funcional de los pacientes con AME y DMD disminuye de forma significativa en tres años.

  10. The PedsQL™ in Pediatric Patients with Spinal Muscular Atrophy: Feasibility, Reliability, and Validity of the Pediatric Quality of Life Inventory™ Generic Core Scales and Neuromuscular Module

    Science.gov (United States)

    Iannaccone, Susan T.; Hynan, Linda S.; Morton, Anne; Buchanan, Renee; Limbers, Christine A.; Varni, James W.

    2009-01-01

    For Phase II and III clinical trials in children with Spinal Muscular Atrophy (SMA), reliable and valid outcome measures are necessary. Since 2000, the American Spinal Muscular Atrophy Randomized Trials (AmSMART) group has established reliability and validity for measures of strength, lung function, and motor function in the population from age 2 years to 18 years. The PedsQL™ (Pediatric Quality of Life Inventory™) Measurement Model was designed to integrate the relative merits of generic and disease-specific approaches, with disease-specific modules. The PedsQL™ 3.0 Neuromuscular Module was designed to measure HRQOL dimensions specific to children ages 2 to 18 years with neuromuscular disorders, including SMA. One hundred seventy-six children with SMA and their parents completed the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Neuromuscular Module. The PedsQL™ demonstrated feasibility, reliability and validity in the SMA population. Consistent with the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL, the majority of intercorrelations among the Neuromuscular Module Scales and the Generic Core Scales were in the medium to large range, supporting construct validity. For the purposes of a clinical trial, the PedsQL™ Neuromuscular Module and Generic Core Scales provide an integrated measurement model with the advantages of both generic and condition-specific instruments. PMID:19846309

  11. Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.

    Science.gov (United States)

    Heine, Erin M; Berger, Tamar R; Pluciennik, Anna; Orr, Christopher R; Zboray, Lori; Merry, Diane E

    2015-05-15

    Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis.

  12. Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1.

    Science.gov (United States)

    Krieger, Frank; Elflein, Nicole; Saenger, Stefanie; Wirthgen, Elisa; Rak, Kristen; Frantz, Stefan; Hoeflich, Andreas; Toyka, Klaus V; Metzger, Friedrich; Jablonka, Sibylle

    2014-05-01

    Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd(2J)) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd(2J) mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd(2J) mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in

  13. Dipolar cortico-muscular electrical stimulation: a novel method that enhances motor function in both - normal and spinal cord injured mice

    Directory of Open Access Journals (Sweden)

    Ahmed Zaghloul

    2010-09-01

    Full Text Available Abstract Background Electrical stimulation of the central and peripheral nervous systems is a common tool that is used to improve functional recovery after neuronal injury. Methods Here we described a new configuration of electrical stimulation as it was tested in anesthetized control and spinal cord injury (SCI mice. Constant voltage output was delivered through two electrodes. While the negative voltage output (ranging from -1.8 to -2.6 V was delivered to the muscle via transverse wire electrodes (diameter, 500 μm located at opposite ends of the muscle, the positive output (ranging from + 2.4 to +3.2 V was delivered to the primary motor cortex (M1 (electrode tip, 100 μm. The configuration was named dipolar cortico-muscular stimulation (dCMS and consisted of 100 pulses (1 ms pulse duration, 1 Hz frequency. Results In SCI animals, after dCMS, cortically-elicited muscle contraction improved markedly at the contralateral (456% and ipsilateral (457% gastrocnemius muscles. The improvement persisted for the duration of the experiment (60 min. The enhancement of cortically-elicited muscle contraction was accompanied by the reduction of M1 maximal threshold and the potentiation of spinal motoneuronal evoked responses at the contralateral (313% and ipsilateral (292% sides of the spinal cord. Moreover, spontaneous activity recorded from single spinal motoneurons was substantially increased contralaterally (121% and ipsilaterally (54%. Interestingly, spinal motoneuronal responses and muscle twitches evoked by the test stimulation of non-treated M1 (received no dCMS were significantly enhanced as well. Similar results obtained from normal animals albeit the changes were relatively smaller. Conclusion These findings demonstrated that dCMS could improve functionality of corticomotoneuronal pathway and thus it may have therapeutic potential.

  14. Spinal Muscular Atrophy

    Science.gov (United States)

    ... Botulinum toxin may be used to treat jaw spasms or drooling. Excessive saliva can be treated with ... Botulinum toxin may be used to treat jaw spasms or drooling. Excessive saliva can be treated with ...

  15. Spinal Muscular Atrophy

    Science.gov (United States)

    ... most often affected. Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints, ... of SMA include: Congenital SMA with arthrogryposis (persistent contracture of joints with fixed abnormal posture of the ...

  16. Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    ... also enjoy such hobbies as computer technology and music com- position (including the publication of two songs ... men as old as 60. In those few women who have the disease, the symptoms are usually ...

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

    Science.gov (United States)

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

    2015-08-06

    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.

  18. Progression of spinal deformity in wheelchair-dependent patients with Duchenne muscular dystrophy who are not treated with steroids: coronal plane (scoliosis) and sagittal plane (kyphosis, lordosis) deformity.

    Science.gov (United States)

    Shapiro, F; Zurakowski, D; Bui, T; Darras, B T

    2014-01-01

    We determined the frequency, rate and extent of development of scoliosis (coronal plane deformity) in wheelchair-dependent patients with Duchenne muscular dystrophy (DMD) who were not receiving steroid treatment. We also assessed kyphosis and lordosis (sagittal plane deformity). The extent of scoliosis was assessed on sitting anteroposterior (AP) spinal radiographs in 88 consecutive non-ambulatory patients with DMD. Radiographs were studied from the time the patients became wheelchair-dependent until the time of spinal fusion, or the latest assessment if surgery was not undertaken. Progression was estimated using a longitudinal mixed-model regression analysis to handle repeated measurements. Scoliosis ≥ 10° occurred in 85 of 88 patients (97%), ≥ 20° in 78 of 88 (89%) and ≥ 30° in 66 of 88 patients (75%). The fitted longitudinal model revealed that time in a wheelchair was a highly significant predictor of the magnitude of the curve, independent of the age of the patient (p lordosis (16 (27%) abnormal and seven (11%) normal). This study provides a baseline to assess the effects of steroids and other forms of treatment on the natural history of scoliosis in patients with DMD, and an approach to assessing spinal deformity in the coronal and sagittal planes in wheelchair-dependent patients with other neuromuscular disorders.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Nicole Armbruster

    2016-01-01

    Full Text Available 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.

  1. 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.

  2. 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...

  3. GRS defective axonal distribution as a potential contributor to distal spinal muscular atrophy type V pathogenesis in a new model of GRS-associated neuropathy.

    Science.gov (United States)

    Seo, Ah Jung; Park, Byung Sun; Jung, Junyang

    2014-11-01

    Distal spinal muscular atrophy type V (dSMA-V), a hereditary axonal neuropathy, is a glycyl-tRNA synthetase (GRS)-associated neuropathy caused by a mutation in GRS. In this study, using an adenovirus vector system equipped with a neuron-specific promoter, we constructed a new GRS-associated neuropathy mouse model. We found that wild-type GRS (WT) is distributed in peripheral axons, dorsal root ganglion (DRG) cell bodies, central axon terminals and motor neuron cell bodies in the mouse model. In contrast, the L129P mutant GRS was localized in DRG and motor neuron cell bodies. Thus, we propose that the disease-causing L129P mutant is linked to a distribution defect in peripheral nerves in vivo.

  4. VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models

    Science.gov (United States)

    2014-01-01

    Background Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA. Methods and results Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models. Conclusion Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target. PMID:24405637

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

    Science.gov (United States)

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

    2015-10-01

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

  6. Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial.

    Directory of Open Access Journals (Sweden)

    Andreea Mihaela Seferian

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2016-04-07

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

  9. Mutant superoxide dismutase 1 (SOD1), a cause of amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies.

    Science.gov (United States)

    Kariya, Shingo; Re, Diane B; Jacquier, Arnaud; Nelson, Katelyn; Przedborski, Serge; Monani, Umrao R

    2012-08-01

    Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are among the most common motor neuron diseases to afflict the human population. A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process. In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear 'gems' by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.

  10. 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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2016-01-01

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

  12. Impacto del ejercicio de fuerza muscular en la prevención secundaria de la obesidad infantil: intervención al interior del sistema escolar

    OpenAIRE

    Fabián Vásquez; Erik Díaz; Lydia Lera; Jorge Meza; Isabel Salas; Pamela Rojas; Eduardo Atalah; Raquel Burrows

    2013-01-01

    Introducción: El ejercicio físico es una importante herramienta terapéutica para prevenir y tratar la obesidad y disminuir las alteraciones metabólicas asociadas al desarrollo de las enfermedades crónicas no transmisibles. Objetivo: Evaluar el impacto de una intervención al interior del sistema escolar, que incluye el ejercicio de fuerza muscular, educación alimentaria y apoyo psicológico en escolares obesos. Métodos: Se trabajó con 120 escolares obesos, entre 8 y 13 años, reclutados en 3 col...

  13. Neural electrophysiological features and gene diagnosis of 85 patients with spinal muscular atrophy%85例脊髓性肌萎缩症临床、神经电生理特征与基因诊断分析

    Institute of Scientific and Technical Information of China (English)

    张云茜; 章印红; 和璇; 张晓敏; 王婷娟; 王建林

    2016-01-01

    Objective To explore the relations of clinical phenotypes of type Ⅰ-ⅣV spinal muscular atrophy (SMA) with neural electrophysiological features and survival motor neuron (SMN)gene.Methods A total of 85 patients with SMA,including 46 with infantile form in which 19 of type Ⅰ and 27 of type Ⅱ,24 with juvenile form (type Ⅲ),and 15 with adult form (type ⅣV),were involved in this clinical study.Their clinical data were analyzed.The neural conduction,needle electromyography (EMG)and SMN1 gene deletion were analyzed.Results There existed different clinical features among patients who suffered from type Ⅰ to type ⅣV SMA.However,the major clinical features of SMA were displayed by progressively aggravating of flaccid paralysis in muscles of the four limbs,and the younger of the patients,the more serious of the clinical manifestations.EMG exhibited neurogenic lesion in all 43 SMA patients,33 patients presented generalized neurogenic lesions,and the abnormal degree of muscles in lower limbs was more severe than that of upper limbs,and the proximal muscles was more severe than that of the distal ones.The abnormal rate of spontaneous potential,weak contraction with raise potential and amplitude of compound motor active potential in adult and juvenile SMA were significantly lower than those in infantile SMA.SMN1 gene exon 7 and 8 were detected in all 85 patients with SMA.A total of 61 patients were found with deletion of exon 7 and/or 8 in SMN1 gene.Infantile SMA patients enjoyed 95.7% (44/46) detection rate,juvenile SMA patients enjoyed 70.8% (17/24) detection rate;no adult SMA patients were found with deletion ofexon 7 and/or 8 in SMN1 gene.Conclusions The more serious of clinical manifestations in SMA patients,the higher abnormality rote in electrophysiological tests.The exons deletion in SMN1 gene could result in alterations of SMA phenotypes,but it has nothing to do with the severity of SMA.Gene deletion analysis of SMN1 gene can be considered as the

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

    OpenAIRE

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

    2011-01-01

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precedes the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any ...

  15. Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy.

    Science.gov (United States)

    Tseng, Yu-Ting; Chen, Cheng-Sheng; Jong, Yuh-Jyh; Chang, Fang-Rong; Lo, Yi-Ching

    2016-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.

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

    Directory of Open Access Journals (Sweden)

    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. Impacto del ejercicio de fuerza muscular en la prevención secundaria de la obesidad infantil: intervención al interior del sistema escolar

    Directory of Open Access Journals (Sweden)

    Fabián Vásquez

    2013-04-01

    Full Text Available Introducción: El ejercicio físico es una importante herramienta terapéutica para prevenir y tratar la obesidad y disminuir las alteraciones metabólicas asociadas al desarrollo de las enfermedades crónicas no transmisibles. Objetivo: Evaluar el impacto de una intervención al interior del sistema escolar, que incluye el ejercicio de fuerza muscular, educación alimentaria y apoyo psicológico en escolares obesos. Métodos: Se trabajó con 120 escolares obesos, entre 8 y 13 años, reclutados en 3 colegios. El Grupo 1 (n = 60, fueron intervenidos simultáneamente con ejercicio físico, educación alimentaria y apoyo psicológico durante 3 meses. El Grupo 2 (n = 60, durante el mismo período, recibió sólo la intervención educativa y el apoyo psicológico, siendo intervenido con ejercicio entre los 3 y los 6 meses. Se evaluó IMC, perímetro de cintura, grasa corporal, síndrome metabólico y factores de riesgo cardiovasculares. Resultados: A los 3 meses, hubo diferencias significativas entre ambos grupos en la variación del zIMC, circunferencia cintura, grasa corporal, síndrome metabólico, obesidad abdominal, hipertrigliceridemia e hiperglicemia de ayuno. En el grupo 1, estos parámetros disminuyeron y aumentaron, en el grupo 2. Entre los 3-6 meses, en el grupo 2, hubo una disminución significativa en la obesidad abdominal, presión arterial elevada e hipertrigliceridemia, en tanto en el grupo 1, aumento significativo de la presión arterial elevada sin variaciones en los otros factores de riesgo cardiovasculares. Conclusiones: Se demostró el impacto positivo del ejercicio físico de fuerza muscular en la reducción de la grasa corporal, del síndrome metabólico y de los factores de riesgo cardiovasculares. Este trabajo refuerza el uso del ejercicio como tratamiento de la obesidad y de sus comorbilidades en escolares.

  18. Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara; Lievens, Patricia M J; Polanco, Maria J; Milioto, Carmelo; Chivet, Mathilde; Monaghan, John; Mishra, Ashutosh; Badders, Nisha; Aggarwal, Tanya; Grunseich, Christopher; Sambataro, Fabio; Basso, Manuela; Fackelmayer, Frank O; Taylor, J Paul; Pandey, Udai Bhan; Pennuto, Maria

    2015-01-01

    Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis.

  19. Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy

    Science.gov (United States)

    Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara; Lievens, Patricia M.J.; Polanco, Maria J.; Milioto, Carmelo; Chivet, Mathilde; Monaghan, John; Mishra, Ashutosh; Badders, Nisha; Aggarwal, Tanya; Grunseich, Christopher; Sambataro, Fabio; Basso, Manuela; Fackelmayer, Frank O.; Taylor, J. Paul; Pandey, Udai Bhan; Pennuto, Maria

    2015-01-01

    Summary Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis. PMID:25569348

  20. Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Belsham, D D; Yee, W C; Greenberg, C R; Wrogemann, K

    1992-10-01

    Herein we describe a family with X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), an adult onset neuromuscular disease characterized by slow progression, predominant proximal and bulbar muscle weakness. One frequent association is the appearance of gynecomastia. This disorder was previously shown to be linked to the locus DXYS1 on the proximal long arm of the X chromosome. Recently, a report implicated a mutation at the N-terminus of the androgen receptor gene involving amplification of CAG repeats as the cause of X-linked SBMA. We studied this region of the androgen receptor in a kindred clinically suspected but not confirmed of having X-linked SBMA by the polymerase chain reaction (PCR) followed by Southern analysis and DNA sequencing. The mutated allele was found to have an increased number of 51 CAG repeats confirming the clinical diagnosis of SBMA. Normal individuals revealed 23 repeat numbers within the normal range, while another unrelated X-linked SBMA patient had an enlarged CAG repeat region. The carrier or disease status could be established or confirmed in 12 individuals of this family on the basis of detecting normal and disease alleles reflected by the number of CAG repeats.

  1. Muscular weakness in individuals with HIV associated with a disorganization of the cortico-spinal tract: a multi-modal MRI investigation.

    Directory of Open Access Journals (Sweden)

    Charlotte Bernard

    Full Text Available Motor impairment is highly prevalent in HIV-infected patients. Here, we assess associations between peripheral muscular deficits as evaluated by the 5 sit-to-stand test (5STS and structural integrity of the motor system at a central level. Eighty-six HIV-infected patients receiving combination antiretroviral therapy and with no major cerebral events, underwent an MRI scan and the 5STS. Out of 86 participants, forty presented a score greater than two standard deviations above mean normative scores calculated for the 5STS and were therefore considered as motor-impaired. MRI-structural cerebral parameters were compared to the unimpaired participants. Fractional Anisotropy (FA, Axial Diffusivity (AD and Radial Diffusivity (RD, reflecting microstructural integrity, were extracted from Diffusion-Tensor MRI. Global and regional cerebral volumes or thicknesses were extracted from 3D-T1 morphological MRI. Whereas the two groups did not differ for any HIV variables, voxel-wise analysis revealed that motor-impaired participants present low FA values in various cortico-motor tracts and low AD in left cortico-spinal tract. However, they did not present reduced volumes or thicknesses of the precentral cortices compared to unimpaired participants. The absence of alterations in cortical regions holding motor-neurons might argue against neurodegenerative process as an explanation of White Matter (WM disorganization.

  2. The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex.

    Science.gov (United States)

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

    2016-06-17

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

  3. Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA).

    Science.gov (United States)

    Rademacher, Sebastian; Verheijen, Bert M; Hensel, Niko; Peters, Miriam; Bora, Gamze; Brandes, Gudrun; Vieira de Sá, Renata; Heidrich, Natascha; Fischer, Silke; Brinkmann, Hella; van der Pol, W Ludo; Wirth, Brunhilde; Pasterkamp, R Jeroen; Claus, Peter

    2017-10-15

    Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. 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....... This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of c......BCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm...

  5. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery.

    Science.gov (United States)

    Bevan, Adam K; Hutchinson, Kirk R; Foust, Kevin D; Braun, Lyndsey; McGovern, Vicki L; Schmelzer, Leah; Ward, Jennifer G; Petruska, Jeffrey C; Lucchesi, Pamela A; Burghes, Arthur H M; Kaspar, Brian K

    2010-10-15

    Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse.

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

    Science.gov (United States)

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

    2015-07-01

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

  7. Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Sophie R Thomson

    Full Text Available Spinal muscular atrophy (SMA is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS, suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA.

  8. The spinal muscular atrophy gene region at 5q13.1 has a paralogous chromosomal region at 6p21.3.

    Science.gov (United States)

    Banyer, J L; Goldwurm, S; Cullen, L; van der Griend, B; Zournazi, A; Smit, D J; Powell, L W; Jazwinska, E C

    1998-03-01

    Paralogous regions are duplicated segments of chromosomal DNA that have been acquired during the evolution of the genome. Subsequent divergent evolution of the genes within paralogous regions can lead to the formation of gene families. Here, we report the identification of a region on Chromosome (Chr) 6 at 6p21.3 that is paralogous with the Spinal Muscular Atrophy (SMA) gene region on Chr 5 at 5q13.1. Partial characterization of this region identified nine sequences all of which are highly homologous to DNA sequences of the SMA gene region at 5q13.1. These sequences include four beta-glucuronidase sequences, two retrotransposon sequences, a novel cDNA, a Sequence Tagged Site (STS), and one that is homologous to exon 9 of the Neuronal Apoptosis Inhibitor Protein (NAIP) gene. The 6p21.3 paralogous SMA region may contain genes that are related to those in the SMA region at 5q13.1; however, a direct association of this region with SMA is unlikely given that no linkage of SMA with Chr 6 has been reported.

  9. p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model.

    Science.gov (United States)

    Doi, Hideki; Adachi, Hiroaki; Katsuno, Masahisa; Minamiyama, Makoto; Matsumoto, Shinjiro; Kondo, Naohide; Miyazaki, Yu; Iida, Madoka; Tohnai, Genki; Qiang, Qiang; Tanaka, Fumiaki; Yanagawa, Toru; Warabi, Eiji; Ishii, Tetsuro; Sobue, Gen

    2013-05-01

    Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR.

  10. 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.

  11. 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.

  12. Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

    Science.gov (United States)

    Pasternak, Amy; Sideridis, Georgios; Fragala-Pinkham, Maria; Glanzman, Allan M; Montes, Jacqueline; Dunaway, Sally; Salazar, Rachel; Quigley, Janet; Pandya, Shree; O'Riley, Susan; Greenwood, Jonathan; Chiriboga, Claudia; Finkel, Richard; Tennekoon, Gihan; Martens, William B; McDermott, Michael P; Fournier, Heather Szelag; Madabusi, Lavanya; Harrington, Timothy; Cruz, Rosangel E; LaMarca, Nicole M; Videon, Nancy M; Vivo, Darryl C De; Darras, Basil T

    2016-12-01

    In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016. © 2016 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2015-03-01

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

  14. 儿童型脊髓性肌萎缩症遗传学研究进展%Advances in the genetics of spinal muscular atrophy in childhood

    Institute of Scientific and Technical Information of China (English)

    刘维亮; 李芳

    2010-01-01

    儿童型脊髓性肌萎缩症是常见的遗传性神经肌肉病,为常染色体隐性遗传.SMN1基因纯合缺失和微小突变是该病的主要病因,其高度同源拷贝SMN2基因可调节疾病的严重性,两个基因间功能的不同是编码区单个核苷酸不同致沉默突变使SMN2转录翻译大为降低.组蛋白脱乙酰基酶抑制剂在临床治疗实验中已显示出较好前景.%Spinal muscular atrophy in childhood is one of the most common neuromuscular disorders with an autosomal recessive mode of inheritance. The main pathogenesis is homozygous loss and small intragenic mutations of the SMN1. SMN2 ,as a very identical copy of SMN1, modulates the disease severity. The functional difference between both genes is a variance of single nucleotide within the coding region, causing silent mutation obviously to decrease SMN2 transcripts. Histone deacetylase inhibitors have been shown better perspective in clinical trials.

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

    Science.gov (United States)

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

    2016-01-01

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

  16. Improvement in reflux gastroesophagitis in a patient with spinal muscular atrophy after surgical correction of kyphoscoliosis: a case report.

    Science.gov (United States)

    Yang, Jae Hyuk; Kasat, Niraj Sharad; Suh, Seung Woo; Kim, Seung Young

    2011-12-01

    Scoliosis, a three-dimensional deformity, has secondary effects on the gastrointestinal system. Reflux gastroesophagitis with hiatus hernia in patients with scoliosis is difficult to manage. We present a patient in whom primary correction of a spinal deformity was associated with resolution of symptoms of reflux. A 15-year-old girl with severe thoracolumbar kyphoscoliosis visited our scoliosis research institute complaining of back pain, positional imbalance, intermittent respiratory tract infections, and gastrointestinal discomfort such as pain, dysphagia, and heartburn for several years. On preoperative CT, her abdominal organs were in a deviant position, and esophagogastroduodenoscopy revealed severe reflux gastroesophagitis, Los Angeles classification (LA) Grade D, and a sliding hiatus hernia. After kyphoscoliosis correction, the patient's truncal balance and pain improved. Postoperatively, the patient reported abdominal pain and dysphagia that gradually subsided after 3 weeks. At 1 year, the patient had no abdominal complaints secondary to reflux gastroesophagitis, and episodes of recurrent respiratory tract infections were substantially reduced. Postoperative evaluation showed the reflux gastroesophagitis had improved to LA Grade A. Postoperative CT showed the abdominal cavity had expanded and the abdominal organs were more centered. The association between scoliosis and reflux gastroesophagitis is well documented. However, the secondary effects of scoliosis correction on gastrointestinal symptoms caused by reflux gastroesophagitis have not been investigated in detail. This patient illustrates the relationship between spinal deformity and gastrointestinal symptoms. Postural balance correction resulted in the alleviation of reflux gastroesophagitis symptoms secondary to hiatus hernia.

  17. Infantile sexuality

    DEFF Research Database (Denmark)

    Zeuthen, Katrine Egede; Gammelgård, Judy

    2010-01-01

    When first presented, Freud´s theory of infantile sexuality was a scandal. Not only was the claim that the small child sucking at the mother´s breast experiences a kind of pleasure that Freud without hesitation named sexual, the theory also turned the common understanding of human sexuality up...... vision of the sexual. Following a historic outline, we examine the theories that inspired by Laplanche, once more discuss infantile sexuality, and argue that infantile sexuality is clarified by combining the concept of the drive with what in effect is an inter-subjective point of view....

  18. 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 ...

  19. Muscular Dystrophy

    Science.gov (United States)

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

  20. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

    Science.gov (United States)

    Boczonadi, Veronika; Müller, Juliane S; Pyle, Angela; Munkley, Jennifer; Dor, Talya; Quartararo, Jade; Ferrero, Ileana; Karcagi, Veronika; Giunta, Michele; Polvikoski, Tuomo; Birchall, Daniel; Princzinger, Agota; Cinnamon, Yuval; Lützkendorf, Susanne; Piko, Henriett; Reza, Mojgan; Florez, Laura; Santibanez-Koref, Mauro; Griffin, Helen; Schuelke, Markus; Elpeleg, Orly; Kalaydjieva, Luba; Lochmüller, Hanns; Elliott, David J; Chinnery, Patrick F; Edvardson, Shimon; Horvath, Rita

    2014-07-03

    The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

  1. 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.

  2. 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.

  3. 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 (P0.05). 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.

  4. Effects of robotic-locomotor training on stretch reflex function and muscular properties in individuals with spinal cord injury.

    Science.gov (United States)

    Mirbagheri, Mehdi M; Kindig, Matthew W; Niu, Xun

    2015-05-01

    We sought to determine the therapeutic effect of robotic-assisted step training (RAST) on neuromuscular abnormalities associated with spasticity by characterization of their recovery patterns in people with spinal cord injury (SCI). Twenty-three motor-incomplete SCI subjects received one-hour RAST sessions three times per week for 4 weeks, while an SCI control group received no training. Neuromuscular properties were assessed using ankle perturbations prior to and during the training, and a system-identification technique quantified stretch reflex and intrinsic stiffness magnitude and modulation with joint position. Growth-mixture modeling classified subjects based on similar intrinsic and reflex recovery patterns. All recovery classes in the RAST group presented significant (p<0.05) reductions in intrinsic and reflex stiffness magnitude and modulation with position; the control group presented no changes over time. Subjects with larger baseline abnormalities exhibited larger reductions, and over longer training periods. Our findings demonstrate that RAST can effectively reduce neuromuscular abnormalities, with greater improvements for subjects with higher baseline abnormalities. Our findings suggest, in addition to its primary goal of improving locomotor patterns, RAST can also reduce neuromuscular abnormalities associated with spasticity. These findings also demonstrate that these techniques can be used to characterize neuromuscular recovery patterns in response to various types of interventions. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  5. 脊髓延髓肌肉萎缩症的临床特点%Clinical features of spinal and bulbar muscular atrophy

    Institute of Scientific and Technical Information of China (English)

    丛琳; 潘钰

    2012-01-01

    Objective To explore the elinical features of spinal and bulbar muscular atrophy(SBMA). Method The clinical data of 8 SBMA patients diagnosed by gene were analyzed retrospectively. Result All of the patients in ihis group were young middle-aped men. The initial symploin was weakness of lower limbs in 3 cases, myasthenia of limbs m 1 cast, harymastia in 2 cases, upper limbs postural tremor in 2 cases,. The main manifestations were progressive lower limbs and muscular atrophy. There was relatively serious in lower limbs, and the disease progresses slowly. All the patients have fascie, and upper limbs postural tremor was in 3 cases, tongue muscles atrophy and tremor in 5 cases, barymastia in 4 cases, and sexual function decrement in 2 cases. The serum creatine kinase was increased in all the patients, lipid abnormality in 5 cases, and sex hormones abnormality in 7 cases. Electromyogram (EMG) showed a wide range of neurogenic damage. The number of (CAG)n repeat in androgen receptors ( AR) gene was above 40. Conclusions SBMA shows a slowly progressing lower motor neuron paralysis and atrophy in spinal and bulbar muscles. The definite diagnosis of SBMA disease should he made by delecting the number of (CAG)n repeat of androgen receptor gene.%目的 探讨脊髓延髓肌肉萎缩症(SBMA)的临床特点.方法 对8例基因确诊的SBMA患者的临床资料进行回顾性分析.结果 本组患者均为中青年男性.首发症状为双下胺无力3例,四肢无力1例,乳房增大2例,双上肢姿位性震颤2例.主要临床表现为进行性肢体无力、肌肉萎缩,下肢重,病情进展缓慢.患者均出现束颤,出现双上肢姿位性震颤3例,舌肌萎缩和震颤5例,乳房增大4例,性功能减退2例.血清肌酸激酶均增高,血脂异常5例,性激素水平异常7例.肌电图均呈广泛神经源性损害.雄激素受体(AR)基因CAG重复序列数均>40次.结论 SBMA主要表现为缓慢进展的脊髓和延髓下运动神经元性瘫痪,确诊

  6. The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.

    Science.gov (United States)

    Hosseinibarkooie, Seyyedmohsen; Peters, Miriam; Torres-Benito, Laura; Rastetter, Raphael H; Hupperich, Kristina; Hoffmann, Andrea; Mendoza-Ferreira, Natalia; Kaczmarek, Anna; Janzen, Eva; Milbradt, Janine; Lamkemeyer, Tobias; Rigo, Frank; Bennett, C Frank; Guschlbauer, Christoph; Büschges, Ansgar; Hammerschmidt, Matthias; Riessland, Markus; Kye, Min Jeong; Clemen, Christoph S; Wirth, Brunhilde

    2016-09-01

    Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients.

    Science.gov (United States)

    Yamamoto, Tomoto; Sato, Hideyuki; Lai, Poh San; Nurputra, Dian Kesumapramudya; Harahap, Nur Imma Fatimah; Morikawa, Satoru; Nishimura, Noriyuki; Kurashige, Takashi; Ohshita, Tomohiko; Nakajima, Hideki; Yamada, Hiroyuki; Nishida, Yoshinobu; Toda, Soichiro; Takanashi, Jun-Ichi; Takeuchi, Atsuko; Tohyama, Yumi; Kubo, Yuji; Saito, Kayoko; Takeshima, Yasuhiro; Matsuo, Masafumi; Nishio, Hisahide

    2014-11-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or intragenic mutation of SMN1. SMA is classified into several subtypes based on clinical severity. It has been reported that the copy number of SMN2, a highly homologous gene to SMN1, is associated with clinical severity among SMA patients with homozygous deletion of SMN1. The purpose of this study was to clarify the genotype-phenotype relationship among the patients without homozygous deletion of SMN1. We performed molecular genetic analyses of SMN1 and SMN2 in 112 Japanese patients diagnosed as having SMA based on the clinical findings. For the patients retaining SMN1, the PCR or RT-PCR products of SMN1 were sequenced to identify the mutation. Out of the 112 patients, 106 patients were homozygous for deletion of SMN1, and six patients were compound heterozygous for deletion of one SMN1 allele and intragenic mutation in the retained SMN1 allele. Four intragenic mutations were identified in the six patients: p.Ala2Val, p.Trp92Ser, p.Thr274TyrfsX32 and p.Tyr277Cys. To the best of our knowledge, all mutations except p.Trp92Ser were novel mutations which had never been previously reported. According to our observation, clinical severity of the six patients was determined by the type and location of the mutation rather than SMN2 copy number. SMN2 copy number is not always associated with clinical severity of SMA patients, especially SMA patients retaining one SMN1 allele. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2011-01-01

    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. 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. 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. 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.

  10. The role of experiential knowledge within attitudes towards genetic carrier screening: A comparison of people with and without experience of spinal muscular atrophy.

    Science.gov (United States)

    Boardman, Felicity K; Young, Philip J; Warren, Oliver; Griffiths, Frances E

    2017-07-13

    Autosomal recessive conditions, while individually rare, are a significant health burden with limited treatment options. Population carrier screening has been suggested as a means of tackling them. Little is known, however, about the attitudes of the general public towards such carrier screening and still less about the views of people living with candidate genetic diseases. Here, we focus on the role that such experience has on screening attitudes by comparing views towards screening of people with and without prior experience of the monogenetic disorder, Spinal Muscular Atrophy. An exploratory sequential mixed methods design was adopted. In-depth qualitative interviews were used to develop two surveys. The surveys addressed attitudes towards carrier screening (pre-conceptual and prenatal) for SMA. 337 participants with SMA experience completed the SMA Screening Survey (UK) and 336 participants with no prior experience of SMA completed the UK GenPop Survey, an amended version of the SMA Screening Survey (UK). The majority of both cohorts were in favour of pre-conception and prenatal carrier screening, however people with experience of type II SMA were least likely to support either. Key differences emerged around perceptions of SMA, with those without SMA experience taking a dimmer view of the condition than those with. This study underscores the significance of prior experience with the condition to screening attitudes. It highlights the need for accurate and high-quality educational resources to support any future carrier screening programmes, that particularly in relation to rare genetic disorders like SMA that will fall outside the remit of everyday experience for the majority of the population. © 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2009-04-01

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

  13. 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.

  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)

    Nijssen, Jik; Frost‐Nylen, Johanna

    2015-01-01

    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. PMID:26502195

  15. Infantile sexuality

    DEFF Research Database (Denmark)

    Zeuthen, Katrine Egede; Gammelgård, Judy

    2010-01-01

    When first presented, Freud´s theory of infantile sexuality was a scandal. Not only was the claim that the small child sucking at the mother´s breast experiences a kind of pleasure that Freud without hesitation named sexual, the theory also turned the common understanding of human sexuality up-si...

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

    Directory of Open Access Journals (Sweden)

    Kathryn J Swoboda

    Full Text Available BACKGROUND: Valproic acid (VPA has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA in vitro and in vivo. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

  17. Clinical features of childhood-onset spinal muscular atrophy%儿童型脊肌萎缩症的临床特点

    Institute of Scientific and Technical Information of China (English)

    喻绪恩; 杨任民; 王训; 孙丹丹; 石永光; 付晓明; 周志华; 程楠; 胡纪源; 韩咏竹

    2011-01-01

    Objective To approach the clinical features of childhood-onset spinal muscular atrophy ( CSMA). Method The clinical data of 11 CSMA patients were analyzed retrospectively. Result In this group, the average age of onset was (6. 1 ±5.5) years old. The onset in all of them were chronic. The mainly clinical manifestations were limbs weakness, thinner and walking instability. The level of serum enzyme in 5 cases was rising slightly. The result of electromyography examination in 8 cases was neurogenic damage and the other 3 cases was normal. Muscle pathologic examination showed that the size of muscle fibers was inequality in all the cases, the different degree of myofibers grouping in 10 cases, nuclear ingression myofibers in 8 cases, with little keratosic fibers in 7 cases and target fibers in 6 cases. Conclusions The clinical features of CSMA are limb weakness and atrophy appeared in the childhood. The features of muscle electrophysiology and pathology are neurogenic damage.%目的 探讨儿童型脊肌萎缩症(CSMA)的临床特点.方法 回顾性分析11例CSMA患者的临床资料.结果 本组患者平均发病年龄为(6.1±5.5)岁,均为慢性起病,主要临床表现为四肢无力、变细及行走不稳;血清肌酶水平5例轻度升高;肌电图检查结果显示8例为神经源性损害,3例未见异常;肌肉病理学检查显示11例患者均出现肌纤维大小不等,10例出现程度不等的肌纤维类型群组化,8例核内移纤维,7例小角化纤维和6例靶纤维.结论 CSMA临床特征为儿童期出现的四肢无力和肌萎缩,肌肉神经电生理学及病理学特征是神经源性损害.

  18. 53例脊肌萎缩症Ⅱ型患者的临床特征①%Clinical Features of Spinal Muscular Atrophy TypeⅡ:53 Cases Report

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    Objective To investigate the clinical features of spinal muscular atrophy typeⅡ. Methods The data of clinical manifesta-tion, laboratory data, onset, diagnosis, and rehabilitation of 53 outpatients suffering from spinal muscular atrophy typeⅡ(SMA-Ⅱ) were analyzed. Results Among 53 patients with SMA-Ⅱconfirmed by molecular genetic tests, 27 patients were male while 26 were female. The mean age was 3.35 years (ranged 0.75~7.8 years), and the age receiving gene diagnosis was 17.27 months. Only 15%had a family history, and abnormalities were found in 23%patients' mothers during pregnancy. 83.4%of them had water choke cough, while 87%expectoration weakness. None of them had cough assist machines and had regular spirometry monitoring. 53%of the patients took semi-liquid diet, how-ever, none of them used stomach tube. Symmetrical flaccid paralysis was so remarkable, even muscle strength of lower limbs in 87.7%of these patients were only grades 1-2. 92%had scoliosis, while 83%had tendon contracture. EMG showed extensive neurogenic changes. All children did not accept normal pre-school education, and 85%patients did not accept formal rehabilitation. Conclusion Most of phenotype of SMA-Ⅱfor the children was similar and more severe in China. Most of the patient didn't get formal education, rehabilitation and care.%  目的探讨脊肌萎缩症(SMA)-Ⅱ型患者的临床特征。方法对门诊基因确诊的53例SMA-Ⅱ患者的临床和实验室资料给予分析,并进行问卷调查。结果男∶女为1.04∶1(27∶26)。本次就诊年龄为9个月~7.8岁,平均3.35岁。首次基因确诊平均年龄为17.27月龄。15%有家族史,其余均为散发。23%母亲孕期异常。87%患者反复感冒,咳痰无力,但均未进行常规肺活量监测,也未给予咳痰器辅助咳痰。83.4%患者有饮水呛咳。53%半流质饮食,均未予胃管辅助。所有患者均表现为四肢呈对称性、弛缓性瘫痪,下肢重于上肢,87.7%

  19. INFANTILE HAEMANGIOMA

    Directory of Open Access Journals (Sweden)

    Maria Armanda Passas

    2016-06-01

    Full Text Available Infantile hemangiomas are the most common softtissue tumors of infancy, occurring in approximately 3 to 10 percent of one-year-old children, with predominance in females. Despite the frequency of these tumors, their pathogenesis is not completely understood, and the best approach to their management remains controversial. They have a well-described natural history of rapid growth during early infancy followed by gradual involution, often leading to complete regression. Because of their spontaneous involution, most infantile hemangiomas do not require therapeutic intervention. However, in 10 to 15 % of cases, treatment is necessary because of local complications, life or physiological functioning is threatened or the long-term esthetic risk is too high.

  20. Transcranial magnetic stimulation (TMS) responses elicited in hindlimb muscles as an assessment of synaptic plasticity in spino-muscular circuitry after chronic spinal cord injury.

    Science.gov (United States)

    Petrosyan, Hayk A; Alessi, Valentina; Sisto, Sue A; Kaufman, Mark; Arvanian, Victor L

    2017-03-06

    Electromagnetic stimulation applied at the cranial level, i.e. transcranial magnetic stimulation (TMS), is a technique for stimulation and neuromodulation used for diagnostic and therapeutic applications in clinical and research settings. Although recordings of TMS elicited motor-evoked potentials (MEP) are an essential diagnostic tool for spinal cord injured (SCI) patients, they are reliably recorded from arm, and not leg muscles. Mid-thoracic contusion is a common SCI that results in locomotor impairments predominantly in legs. In this study, we used a chronic T10 contusion SCI rat model and examined whether (i) TMS-responses in hindlimb muscles can be used for evaluation of conduction deficits in cortico-spinal circuitry and (ii) if plastic changes at spinal levels will affect these responses. In this study, plastic changes of transmission in damaged spinal cord were achieved by repetitive electro-magnetic stimulation applied over the spinal level (rSEMS). Spinal electro-magnetic stimulation was previously shown to activate spinal nerves and is gaining large acceptance as a non-invasive alternative to direct current and/or epidural electric stimulation. Results demonstrate that TMS fails to induce measurable MEPs in hindlimbs of chronically SCI animals. After facilitation of synaptic transmission in damaged spinal cord was achieved with rSEMS, however, MEPs were recorded from hindlimb muscles in response to single pulse TMS stimulation. These results provide additional evidence demonstrating beneficial effects of TMS as a diagnostic technique for descending motor pathways in uninjured CNS and after SCI. This study confirms the ability of TMS to assess plastic changes of transmission occurring at the spinal level. Published by Elsevier B.V.

  1. Muscular Dystrophy

    Science.gov (United States)

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

  2. 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

  3. Infantile colic

    Directory of Open Access Journals (Sweden)

    Aleksandra Rurarz

    2016-12-01

    Full Text Available Infantile colic is one of the most common functional gastrointestinal disorders in infants, usually occurring between 2 weeks to 4 months of age. According to the definition, infantile colic is characterised by episodes of inconsolable crying, generally observed in the evening. Although these symptoms usually resolve spontaneously in the first six months of life, they often cause parental anxiety, leading to repeated medical appointments in search for help. Despite 40 years of research, the causes of this disorder are still unclear; hypersensitivity to cow’s milk protein, lactose intolerance, impaired gut microbiota, immaturity of the nervous system, the negative impact of tobacco smoke, inappropriate childcare techniques and psychosocial factors are believed to be involved in the pathogenesis. The treatment involves behavioural methods, i.e. reducing infant exposure to external stimuli. Breastfeeding mothers are advised to eliminate caffeine and hot spices from their diet and, in some cases, switch to a dairy-free diet. For formula-fed infants, it is recommended to use hydrolysates with a high degree of hydrolysis. Simethicone is commonly used in the pharmacological treatment as it reduces the surface tension of intestinal gases, enabling their easier elimination. The Rome III Diagnostic Criteria recommend to appropriately continue any method if considered effective by the parents, provided that there are no harmful consequences.

  4. [Functional assessment for people unable to walk due to spinal muscular atrophy and Duchenne muscular dystrophy. Translation and validation of the Egen Klassifikation 2 scale for the Spanish population].

    Science.gov (United States)

    Fagoaga, Joaquín; Girabent-Farrés, Montserrat; Bagur-Calafat, Caritat; Febrer, Anna; Steffensen, Birgit F

    2015-05-16

    Introduccion. La escala Egen Klassifikation 2 (EK2), ampliacion de la escala EK, evalua la capacidad funcional de personas con atrofia muscular espinal (AME) y distrofia muscular de Duchenne (DMD) que estan en fase de silla de ruedas. Esta version es mas especifica para la AME que su antecesora. Objetivo. Analizar la validez y fiabilidad de la version española de dicha escala como instrumento de medicion de la capacidad funcional en pacientes afectos de AME y DMD que estan en silla de ruedas. Pacientes y metodos. Primeramente se realizo una traduccion-retrotraduccion al español de la version en ingles de la EK2 y, posteriormente, se estudio la fiabilidad de la version traducida. Para ello, se seleccionaron 39 pacientes, de edades comprendidas entre 4 y 60 años, que fueron valorados por dos observadores. Para evaluar la concordancia intraobservador se realizaron dos evaluaciones por un mismo observador, y para la interobservador, se realizo una tercera evaluacion por un segundo observador. Resultados. Los valores obtenidos referidos a la puntuacion total de los items de la escala (suma EK2) reflejan una fiabilidad intra e interobservador excelente, de 0,993 y 0,988, respectivamente. Asimismo, para cada uno de los items, la fiabilidad fue excelente, a excepcion de un item, en el que fue buena. Conclusiones. La version española de la escala EK2 es un instrumento valido y fiable para la poblacion española como herramienta de medicion de la capacidad funcional en pacientes con AME y DMD que estan en silla de ruedas.

  5. 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

    Directory of Open Access Journals (Sweden)

    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

  6. Desarrollo neuromuscular en la atrofia muscular espinal

    OpenAIRE

    Martínez Hernàndez, Rebeca

    2012-01-01

    INTRODUCCIÓN: La atrofia muscular espinal (AME) es una enfermedad neuromuscular infantil caracterizada por la muerte de las neuronas motoras del asta anterior de la médula espinal. Como consecuencia de ello hay una degeneración y atrofia muscular, por lo que los pacientes mueren a menudo de insuficiencias respiratorias graves. La AME se clasifica en tres tipos principales según el grado de gravedad, la edad de aparición y las pautas motoras. Se trata de una enfermedad con patrón de herencia a...

  7. Estudio clínico, genético y molecular en un paciente con atrofia muscular espinal

    Directory of Open Access Journals (Sweden)

    Ibis Menéndez Alejo

    1998-03-01

    Full Text Available Las atrofias musculares espinales (AME infantiles son enfermedades neuromusculares hereditarias caracterizadas por la degeneración de las motoneuronas alfa del asta anterior de la médula espinal. La enfermedad de Werdnig-Hoffmann, AME tipo I, es la forma más grave, se transmite como un carácter autosómico recesivo y los afectados suelen fallecer durante el primer año de vida por fallo respiratorio. En este trabajo se presenta una familia cubana con 2 hijos con AME tipo I, en la cual el estudio molecular en uno de ellos permitió identificar los 2 cromosomas parentales asociados con ésta. Se encontró además en el paciente una deleción de ambas copias del gen SMN (exón 8 y del gen NAIP (exón 5. Los hallazgos ilustran la utilidad de estos estudios, con vistas a posibilitar el diagnóstico prenatal de la enfermedad.The infantile spinal muscular atrophies (SMA are hereditary neuromuscular diseases characterized by degenerated Alfa-motoneurons of the anterior spinal marrow horn. Werdning-Hoffman disease, Type 1 SMA, is the most serious affection being transmitted as an autosomal recessive character, so those affected may die from respiratory failures in the first year of life. This paper presents a Cuban family with two kids who suffer from Type-1 SMA; the molecular analysis carried out in one of them identified two parental chromosomes responsible for the disease. Also, a deletion of both copies of SMN gene (exon 8 and NAIP gene (exon 5 were discovered in this patient. These findings showed the usefulness of this kind of studies with a view to making a prenatal diagnosis of Werdning-Hoffman disease.

  8. 一种罕见的运动神经元病亚型:散发性面肩肱型脊肌萎缩症一例并文献复习%A rare subtype of Motor neuron disease: a case report of sporadic facioscapulohumeral spinal muscular atrophy and literature review

    Institute of Scientific and Technical Information of China (English)

    黄立伟; 雷革胜

    2013-01-01

    Objective To discuss the clinical feature and diagnosis of facioscapulohumeral spinal muscular atrophy.Methods The clinical data of a patient with facioscapulohumeral spinal muscular atrophy in 2006 was analyzed retrospectively.Results The patient developed muscular weakness invidiously in her twenty-six years old,and got worse progressively.The disease selectively affected muscles in face,should ergirdle and proximal arms in its early stage.Her serum muscle enzyme spectrum was normal.Electrophysiologic study and muscle biopsy showed lesions of neurogenic origin.Conclusion The clinical feature of facioscapulohumeral spinal muscular atrophy is much similar to FSH muscular dystrophy,a kind of myodystrophia.The disease can be diagnosed early by electrophysiologic study and muscle biopsy.%目的 探讨面肩肱型脊肌萎缩症的临床表现和早期诊断.方法 对我院2006年收治的1例患者临床资料结合文献进行回顾性分析.结果 该患者为青年女性,隐袭起病,进行性进展.初期表现为选择性累及颜面、肩胛带肌群和上肢近端肌群,早期血浆肌肉酶谱正常,电生理检查和肌肉活检均提示神经源性损害.结论 面肩肱型脊肌萎缩症与肌营养不良性面肩肱型肌萎缩临床上极为类似,应早期进行电生理和肌肉活检检查协助确诊.

  9. Dismorfia muscular

    OpenAIRE

    Assunção,Sheila Seleri Marques

    2002-01-01

    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 dismo...

  10. Muscular Dystrophy

    Science.gov (United States)

    ... It Like for Teens With MD? en español Distrofia muscular Aside from seeing the telethon on Labor Day ... and rule out other diseases that affect the muscles or nerves. Some tests measure how nerves and muscles are working. Others ...

  11. Muscular Dystrophy

    Science.gov (United States)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2000-11-01

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

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

    Science.gov (United States)

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

    2011-08-15

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

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

    Science.gov (United States)

    Chen, Po C; Gaisina, Irina N; El-Khodor, Bassem F; Ramboz, Sylvie; Makhortova, Nina R; Rubin, Lee L; Kozikowski, Alan P

    2012-01-18

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

  15. 脊髓性肌萎缩伴呼吸窘迫1型1例回顾性研究%Retrospective Study of One Case of Spinal Muscular Atrophy with Respiratory Distress Type 1

    Institute of Scientific and Technical Information of China (English)

    麦嘉卉; 马伟科; 韩春锡; 何颜霞; 廖建湘

    2015-01-01

    Aim To report the first case of spinal muscular atrophy with respiratory distress type 1 (SMARD1) in China and discuss the diagnosis strategy of SMARD1.Methods The history, physical examination, clinical exams and genetic analysis results of the patient with SMARD1 were retrospectively analyzed, and the related literatures were reviewed.Results At 1 month old, the patient had scaffold orthodontic treatment because of the hip dysplasia, then developed into muscle weakness, more evident in the distal parts and predominantly in the legs. At the age of 2 years old, she developed contractures of the knees and elbows. Respiratory failure happened at the age of 4 years and 10 months. Her blood tests and genetic analysis of SMN gene were not remarkable except for the slightly increased of creatine kinase and the aminotransferases. The EMG revealed neurogenic damages. Her chest X-ray reported eventration of the right diaphragm. IGHMBP2 gene sequencing identiifed homozygous mutation of c.1813 C>T. The diagnosis of SMARD1 was conformed. Conclusion SMARD1 is one of the variation types of spinal muscular atrophy, which manifested as irreversible diaphragmatic paralysis, respiratory failure between 6 weeks and 6 months of age, as well as progressive symmetrical muscular weakness and muscle atrophy. Nowadays, genetic analysis is the principal method for diagnosis.%目的:报道国内首例脊髓性肌萎缩伴呼吸窘迫1型(SMARD1)病例,探讨SMARD1的诊断和鉴别诊断。方法回顾性分析1例女性4岁10个月患儿的病史、体格检查、辅助检查以及基因检测结果,并结合文献进行讨论。结果患儿出生1个月,因“双侧髋关节发育不良”行支架矫正治疗1个月后发现四肢肌无力,下肢重于上肢、远端重于近端。2岁时出现膝关节和肘关节变形,4岁10个月时出现呼吸窘迫、呼吸衰竭。患儿血常规、生化、SMN基因检测均正常。肌酸激酶轻度升高。肌电图检查提示

  16. Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama's disease: a clinical variant of the benign monomelic amyotrophy

    Directory of Open Access Journals (Sweden)

    NASCIMENTO OSVALDO J. M.

    2000-01-01

    Full Text Available Hirayama's disease (HD is frequently found in Asia, and is rarely referred among westerners. It affects young people with higher incidence in males. It is a focal distal amyotrophy with unilateral or asymmetric bilateral involvement of C7, C8 and T1 innervated muscles. HD appears sporadically and has a benign evolution with clinical stabilization in around one year. We report four young male patients with clinical and electrophysiological alterations described in HD, which were followed-up during 5 years. Electromyographic findings were indicative of lower motor neuron involvement. We analyzed cervical MRI aiming at understanding if a questionable spinal cord compression could be implicated in the pathogenesis, but no abnormality was verified. In view of its clinical, and EMG characteristics, HD is no more than a benign monomelic amyotrophy (BMA clinical variant, and not a specific disease. This eponym could be considered only for the distal upper limb variant (Hirayama's variant of the BMA.

  17. Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama's disease): a clinical variant of the benign monomelic amyotrophy.

    Science.gov (United States)

    Nascimento, O J; Freitas, M R

    2000-09-01

    Hirayama's disease (HD) is frequently found in Asia, and is rarely referred among westerners. It affects young people with higher incidence in males. It is a focal distal amyotrophy with unilateral or asymmetric bilateral involvement of C7, C8 and T1 innervated muscles. HD appears sporadically and has a benign evolution with clinical stabilization in around one year. We report four young male patients with clinical and electrophysiological alterations described in HD, which were followed-up during 5 years. Electromyographic findings were indicative of lower motor neuron involvement. We analyzed cervical MRI aiming at understanding if a questionable spinal cord compression could be implicated in the pathogenesis, but no abnormality was verified. In view of its clinical, and EMG characteristics, HD is no more than a benign monomelic amyotrophy (BMA) clinical variant, and not a specific disease. This eponym could be considered only for the distal upper limb variant (Hirayama's variant) of the BMA.

  18. Distrofia neuroaxonal infantil: relato de dois casos

    OpenAIRE

    1999-01-01

    Descrevemos dois casos de distrofia neuroaxonal infantil ou doença de Seitelberger, que é doença rara, neurodegenerativa, com herança autossômica recessiva. O primeiro caso, sexo masculino, com 8 anos de idade, apresentava atraso do desenvolvimento psicomotor, ataxia e fraqueza muscular. Ao exame físico foi encontrado nistagmo horizontal e vertical com palidez do disco óptico, hipotonia e arreflexia profunda. O segundo caso, sexo masculino, com 1 ano e 6 meses de idade, apresentava atraso do ...

  19. Muscular disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930186 The diagnostic value of MRI on neuro-muscular disease.CHEN Qingtang(陈清棠),etal.Dept Neurol,1st Hosp,Beijing Med Univ,100034.Chin J Neurol & Psychiat 1992;25(5):267-269.The article concentrated on the study ofskeletal muscles of four extremities in 12 casesof different kinds of neuromuscular diseases and4 volunteers with MRI.The results revealed:MRI could clearly display individual muscle,muscle groups or abnormal muscles morphologi-

  20. TREATMENT OF 30 CASES OF INFANTILE HIGH FEVER WITH ERJIAN-POINT BLOOD-LETTING METHOD

    Institute of Scientific and Technical Information of China (English)

    李赛玲; 朱军

    2001-01-01

    High fever is referred to that the body temperature exceeds 39℃. Due to aplasia of the cerebral nerve system during infantile stage, continuous high fever may induce temporary functional disturbance of the brain, manifesting as sudden and transient loss of consciousness and local or general muscular spasm that is termed as infantile convulsion. The authors find in clinical practice that sometimes, administration of antipyretics as compound aspirin (APC), compound aminopyrine, etc. has no effect on infantile high fever, if treated with Erjian (MA-H 6) bleeding method, the body temperature may be decreased by 0.5~1.0℃. Here is the report.

  1. 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.

  2. The clinical and electrophysiological features of patients with spinal and bulbar muscular atrophy%脊髓延髓肌萎缩症临床及电生理特点分析

    Institute of Scientific and Technical Information of China (English)

    陈海; 笪宇威; 李韵; 张新卿; 贾建平

    2011-01-01

    Objective To analyze the clinical features of 5 Chinese patients with spinal and bulbar muscular atrophy ( SBMA ), a sex-linked inheritance disorder. Methods We collected the clinical data of 5 SBMA patients whose diagnosis were confirmed by gene examination to analyze their clinical features, as well as their serum levels of sex hormones, CSF, biochemical indicators and electromyogram. Results Patients with spinal and bulbar and muscular atrophy tend to have an adult onset, exhibiting a slow progression of lower motor neuronal weakness and atrophy involving limbs and bulbar zones. There was mild motor functional lesion. Part of the invalids presented signs of androgen insensitivity such as gynecomastia, the level of testosterone were increased. CAG were 43-51 ( mean 47. 2 ±3. 6). The degrees of creatine kinase( 481. 8 ±264. 8 IU/L ) were increased mildly. CSF were normal. Electromyogram had generally changes derived from lower motor neuron. Conclusions Basically, the clinical features of Chinese SBMA patients presents adult onset, slow progression of lower motor neuronal weakness and atrophy involving limbs and bulbar zones.%目的 分析5例脊髓延髓肌萎缩症患者的临床特征,以便临床医生对该病的认识.方法 收集基因确诊的5例脊髓延髓肌萎缩症患者的临床资料,分析其临床特点及血清性激素、各生化指标水平、脑脊液及肌电图特点.结果 脊髓延髓肌萎缩症患者青年发病,病情进展缓慢.神经系统表现为以肢体近端和延髓部受累为主的瘫痪.舌肌受累较早,运动功能损害较轻.血清睾酮(969.3±234.9ng/dl)、雌二醇(57.1±5.3pg/ml)水平增高,男性乳腺发育出现在病史较长的患者.三核苷酸(CAG)重复序列数目43~51(平均47.2±3.6pg/ml).患者的肌酸激酶(CK,481.8±264.8 IU/L)均增高,脑脊液检查均正常.肌电图为广泛神经源性损害.结论 脊髓延髓肌萎缩症患者的早期症状不典型,易误诊,临床特征为青年起

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

    Science.gov (United States)

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

    2011-09-01

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

  4. Literatura infantil sobre problemas infantiles: la diabetes

    OpenAIRE

    Lázaro Fernández, Patricia

    2015-01-01

    Debido al creciente número de casos de diabetes infantil que se está dando en la sociedad actual, no es raro encontrarse en las aulas cada vez más casos de esta enfermedad. Por esta razón, he decidido analizar dos libros sobre esta temática, para hacer un acercamiento del material seleccionado a las aulas y poder desarrollar junto con los niños un aprendizaje colectivo y cooperativo. En este trabajo se expone la importancia de la literatura y la literatura infantil como una ...

  5. Introduction to Infantile Tuina

    Institute of Scientific and Technical Information of China (English)

    ZHA Wei

    2004-01-01

    @@ Infantile Tuina is an important component of traditional Tuina therapy, whose unique treatment system was formed during the Ming and Qing Dynasties. Infantile Tuina is a treatment method performed on the children's body or acupoints by some Tuina techniques under the guidance of Chinese medical theory to treat their diseases. Infantile Tuina functions to unblock meridian and collateral, move qi and activate blood, regulate yingnutrient and wei-defensive, balance yin and yang, harmonize zang and fu organs, and enhance the body resistance against diseases. Hence, infantile Tuina cannot only treat many children's diseases, but also take the effect of prevention and healthcare. It does not need medical equipments, medicines and injection, not giving rise to side effects, thus the children are willing to accept it. Infantile Tuina can treat the emergency diseases,infantile diseases and some infectious diseases. Clinical practice has proven that infantile Tuina is quite effective for many children's diseases as well as children's healthcare. In recent years, academic communication gets more and more active.

  6. Propranolol for infantile hemangiomas.

    Science.gov (United States)

    Bagazgoitia, Lorea; Torrelo, Antonio; Gutiérrez, Juan Carlos López; Hernández-Martín, Angela; Luna, Paula; Gutiérrez, Marta; Baño, Antonio; Tamariz, Amalia; Larralde, Margarita; Alvarez, Roser; Pardo, Nuria; Baselga, Eulalia

    2011-01-01

    Propranolol has been used successfully in a limited number of children with infantile hemangiomas. This multicenter retrospective study describes the efficacy and adverse effects of propranolol in infantile hemangioma. Seventy-one infants with infantile hemangiomas were treated with oral propranolol, 1 mg/kg/12 hours, for at least 12 weeks. A photograph based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a scoring system of 10 as the original infantile hemangioma before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for infantile hemangiomas at 4 weeks (p < 0.001), at 8 weeks (p < 0.001 compared to the 4 wks value), at 12 weeks (p < 0.05 compared to the 8 wks value), and thereafter up to 32 weeks (p < 0.01 compared to the 16 wks value). The response of infantile hemangiomas to propranolol was similar regardless of sex, age at onset of treatment, type of involvement (segmental and nonsegmental), facial segments affected, special locations (eyelid, nasal tip, and parotid region), ulceration, and depth of infantile hemangiomas. Very few side effects were reported; mainly agitated sleep in 10 of 71 patients. In the series of patients in this study, oral propranolol 2 mg/kg/day was a well-tolerated and effective treatment for infantile hemangiomas. Prospective studies are needed to establish the exact role of propranolol in the treatment of infantile hemangiomas. © 2011 Wiley Periodicals, Inc.

  7. Spinal Headaches

    Science.gov (United States)

    ... who undergo a spinal tap (lumbar puncture) or spinal anesthesia. Both procedures require a puncture of the tough ... fluid is withdrawn from your spinal canal. During spinal anesthesia, medication is injected into your spinal canal to ...

  8. Propranolol (Infantile Hemangioma)

    Science.gov (United States)

    Propranolol oral solution is used to treat proliferating infantile hemangioma (benign [noncancerous] growths or tumors appearing on ... infants 5 weeks to 5 months of age. Propranolol is in a class of medications called beta ...

  9. Benign Familial Infantile Seizures

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-03-01

    Full Text Available The history, classification, clinical and EEG features, genetics, differential diagnosis, and outcome of “benign familial infantile seizures” (BFIS are reviewed from the Neurology Department, Bambino Gesu Children Hospital, Rome, Italy.

  10. Genetic initial study of spinal and bulbar muscular atrophy in a family of Chongqing%重庆一脊髓延髓肌肉萎缩症家系的基因检测研究

    Institute of Scientific and Technical Information of China (English)

    金鑫; 陈康宁; 史树贵; 张波; 胡俊

    2011-01-01

    Objective To detect the androgen receptor( AR ) gene of 3 patients suspected spinal and bulbar muscular atrophy ( SBMA ) in a Chongqing family and confirm the gene mutation. Methods Routine examinations on nervous system, including nerve electrophysiology, electromyography were performed and serum CK was determined. After informed consent, venous blood was taken and genomic DNA was extracted by standard method. The CAG repeat region in the first exon of AR gene was amplified by PCR and sequenced directly. Results These 3 patients'nerve electrophysiological study showed obvious nervous original damage and their serum CK values were elevated significantly. In the pedigree, these 3 individuals were clinically found to be ill with SBMA and their CAG repeats numbers were 56 in 2 patients and the other one with 51 CAG repeats. Conclusion We confirmed the diagnosis of SBMA in these 3 patients according to gene detect and report the first genetically proven SBMA pedigree in southwest of China. AR gene testing is the most reliable diagnostic method. It would be helpful for the genetic counseling of SBMA if we continue to study pathopoiesis gene in the pedigree. It has important significance for therapy and precaution of SBMA.%目的 对重庆一家系中3例临床诊断脊髓延髓肌肉萎缩症(SBMA)的患者行基因检测,证实其为SBMA家系.方法 对3例患者进行神经系统查体,常规检测神经电生理、肌电图、血清肌酸激酶(CK)等.抽取患者静脉血5ml,抽提基因组DNA,聚合酶链反应(PCR)扩增雄激素受体(AR)基因第一外显子CAG重复片段,PCR产物经1.2%琼脂糖凝胶电泳,异常样本进行直接测序.结果 3例患者肌电图均显示神经源性损害,血清CK均增高,经AR基因检测,2例患者CAG重复次数为56次,1例CAG重复次数为51次.结论 AR基因检测是诊断SMBA最可靠的方法,继续对该家系的致病相关基因进行研究将对该病的治疗和预防有重要意义.

  11. X-linked spinal and bulbar muscular atrophy (Kennedy's disease with long-term electrophysiological evaluation: case report Atrofia muscular bulbo-espinal ligada ao cromossomo X (doença de Kennedy com seguimento eletrofisiológico de longo prazo: relato de caso

    Directory of Open Access Journals (Sweden)

    João Aris Kouyoumdjian

    2005-03-01

    Full Text Available X-linked spinal and bulbar muscular atrophy or Kennedy's disease is an adult-onset motor neuronopathy caused by a CAG repeat expansion within the first exon of an androgen receptor gene. We report the case of a 66-year-old man, previously diagnosed with motor neuron disease (MND, who presented acute and reversible left vocal fold (dysphonia and pharyngeal paresis, followed by a slowly progressive weakness and also bouts of weakness, wasting and fasciculation on tongue, masseter, face, pharyngeal, and some proximal more than distal upper limb muscles, associated to bilateral hand tremor and mild gynecomastia. There were 5 electroneuromyography exams between 1989 and 2003 that revealed chronic reinnervation, some fasciculations (less than clinically observed and rare fibrillation potentials, and slowly progressive sensory nerve action potentials (SNAP abnormality, leading to absent/low amplitude potentials. PCR techniques of DNA analysis showed an abnormal number of CAG repeats, found to be 44 (normal 11-34. Our case revealed an acute and asymmetric clinical presentation related to bulbar motoneurons; low amplitude/absent SNAP with mild asymmetry; a sub-clinical or subtle involvement of proximal/distal muscles of both upper and lower limbs; and a probable evolution with bouts of acute dennervation, followed by an efficient reinnervation.Atrofia muscular bulbo-espinal ligada ao cromossomo X (doença de Kennedy é uma neuronopatia motora em adultos causada por expansões na repetição CAG no gene do receptor andrógeno. Neste relato, descreve-se o caso de homem de 66 anos, com diagnóstico prévio de doença do neurônio motor (DNM que apresentou quadro agudo e reversível de paresia de prega vocal (disfonia e de músculos faríngeos à esquerda; posteriormente seguiram-se surtos de fraqueza lentamente progressiva, atrofia e fasciculações em língua, masseter, face, faringe e membros superiores predominantemente proximal, associada a tremor

  12. 脊髓性肌萎缩症三例及其家系的基因突变分析%Mutation analysis of SMN1 gene in patients with spinal muscular atrophy

    Institute of Scientific and Technical Information of China (English)

    都娟; 瞿宇晋; 熊晖; 李尔珍; 金煜炜; 白晋丽; 王红; 宋昉

    2011-01-01

    objective Spinal muscular atrophy(SMA)is an autosomal recessive neuromuscular disorder.About 80%-90% of SMA patients are missing both copies of SMN1,and 5%-10% of patients are conlpound heterozygotes.In the present study.we aimed to analyze survival motor neuron 1(SMN1)gene mutation in three patients with spinal muscular athrophy and their families to explore the effect of mutation on SMN protein function and the relationship between mutation and clinical phenotype.Method According to the international criterion.all patients were diagnosed by a neurologist.Patient 1 is a 5 years old boy with SMA type Ⅱ.Patient 2,female,2.5 years old,was SMA type Ⅱ.Patient 3,female,9 years old,was SMA type Ⅲ.The brother of patient 3 was SMA type Ⅱ,too.The age at last examination was 14 years.Genomic DNA was extracted from peripheral blood leukocytes by using standard phenol/chloroform method and total RNA was extracted from whale blood with QIAamp RNA Blood Mini Kit.PCR/RFLP was used to detect the homozygosis deletion of the SMN1,exon 7, and multiplex ligation-dependent probe amplification(MLPA)were performed to analyze the gene dosage of sMN1 and SMN2 for each patient and his/her family members;reverse transcriptase(RT)-PCR and clone sequencing were conducted for identifying the point mutation of SMN1 in three patients.The sequencing of genomic DNA and MLPA were carried out in the 3 familiesmembers to confirm the transition of mutation.Result No homozygous deletion of the SMN1 exon 7 was observed in anv member of the 3 families.Case 1 and case 2 had one SMN1 copy compound with c.400G>A(p.Glu134Lys)mutation on it and SMN2 was two copies,respectively.Case 3 and her brother also had one copy of SMN1 and two copies of SMN2, and a mutation c.689C>T (P.Ser230Leu)occurred on the retained SMN1.All point mutations were from their fathers and deletion come from their mothers for SMN1gene.Conclusion In this work.P.Glu134Lys and P.Ser230Leu mutations were identified in three

  13. Para-muscular and trans-muscular approaches to the lumbar inter-vertebral foramen: an anatomical comparison

    OpenAIRE

    2005-01-01

    Foraminal and extra-foraminal disc herniations comprise up to 11.7% of all lumbar disc herniations. Facetectomy, which had been the classic approach, is now recognized as cause of pain and instability after surgery. Otherwise, posterior lateral approaches through a trans-muscular or a para-muscular technique offer no significant damage to key structures for spinal stability. The surgical anatomy of these approaches has already been described, but they were not compared. In order to quantify t...

  14. Giant infantile pulmonary hemangioma

    Energy Technology Data Exchange (ETDEWEB)

    Pandya, Rajul; Tummala, Venkat [Hurley Medical Center One Hurley Plaza, Department of Radiology, Flint, MI (United States)

    2010-12-15

    We present a very unusual case of giant infantile pulmonary hemangioma presenting as a large solitary pulmonary mass. This was successfully managed with surgical resection. Histological examination revealed that the mass was positive for GLUT-1 receptor, a marker for infantile hemangioma. To our knowledge only a few cases of pulmonary hemangioma have been described previously in the literature. Pulmonary hemangiomas are very rare lesions, most of them presenting as a pulmonary mass. This case emphasizes the fact that this rare lesion should be considered in the differential of an enhancing pulmonary mass in an infant. (orig.)

  15. Acute infantile motor unit disorder. Infantile botulism?

    Science.gov (United States)

    Clay, S A; Ramseyer, J C; Fishman, L S; Sedgwick, R P

    1977-04-01

    Eight infants with an acute reversible motor unit disorder are described, including two infants from whom Clostridum botulinum type A was isolated from stool specimens. The clinical spectrum includes constipation, cranial nerve deficits, pupillary involvement, and generalized hypotonic weakness. There were no deaths, and all infants have had complete clinical recovery. A characteristic electromyographic (EMG) pattern was present in part until clinical recovery. This distinctive pattern consisted of brief, small, abundant for power exerted motor unit potentials. This EMG pattern in the context of the clinical syndrome may well be diagnostic for acute infantile motor unit disorder.

  16. Gene diagnosis for spinal muscular atrophy and its application study%脊髓性肌萎缩症的基因诊断及其应用研究

    Institute of Scientific and Technical Information of China (English)

    曹东华; 任梅宏; 林长坤; 崔婉婷; 麻宏伟; 武盈玉; 金春莲

    2009-01-01

    目的 对脊髓性肌萎缩症患者及携带者进行基因诊断和产前基因诊断.方法 对26例脊髓性肌萎缩症患者应用PCR-限制性片段长度多态性(PCR-restiction fragment length polymorphism,PCR-RFLP)技术检测SMN1基因第7外显子是否缺失;对于患者的父母应用多重PCR结合变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)的方法进行携带者诊断;而既往生产过患儿的孕妇于孕中期抽取羊水,进行产前基因诊断.结果 26例脊髓性肌萎缩症患者中查出25例存在SMN1基因第7外显子纯合缺失;患者的父母全部为SMN1基因第7外显子杂合缺失携带者;对20名既往生产过患儿的孕妇进行了产前诊断,8名存在SMN1基因第7外显子纯合缺失.结论 PCR-RFLP、多重PCR结合DHPLC技术可应用于患者及携带者基因诊断;PCR-RFLP可用于脊髓性肌萎缩症的产前基因诊断.%Objective To establish an effective testing system for gene diagnosis, carrier detection and prenatal diagnosis for spinal muscular atrophy (SMA). Methods Twenty-six patients with SMA were directly tested with PCR-RFLP for exon 7 deletion in the SMN1 gene. Carrier detection was carried out with multi-PCR-DHPLC. Amniotic fluid was taken at the middle stage of gestation from pregnant women who had given birth to affected children. Results Twenty-five out of 26 patients were diagnosed as having SMN1 gene deletion. Fifty-two of their parents were found to be carriers of exon 7 deletion. Eight of 20 fetuses were diagnosed as having SMN1 gene deletion by PCR-RFLP. Conclusion PCR-RFLP and multi-PCR-DHPI.C techniques can provide rapid diagnosis for exon 7 deletion detection and carrier detection. PCR-RFLP may also be adapted for prenatal gene diagnosis of exon 7 deletion in SMN1 gene.

  17. 脐血间充质干细胞移植治疗儿童型脊肌萎缩症1例%Umbilical cord blood mesenchymal stem cell transplantation for treatment of a child with spinal muscular atrophy

    Institute of Scientific and Technical Information of China (English)

    杜玲; 杨华强; 王娜; 罗国君

    2011-01-01

    BACKGROUND: Many animal and clinical studies have reported that the safe and effective usage of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) transplantation for treatment of neurological genetic diseases.OBJECTIVE: To investigate the feasibility and effect of UCB-MSCs transplantation in the treatment of spinal muscular atrophy (SMA).METHODS: A child admitted at January 2010 had been confirmed as having SMA, and drug and rehabilitation therapies were invalid. Then, the child received UCB-MSCs transplantation via the first intravenous infusion and three times of subarachnoid injection, once a week, (4-6)×107 cells once and four times as a course. Neurological physical examination, biochemical test, muscle enzymes detection, FIM scoring and electromyography (EMG) examination were conducted. RESULTS AND CONCLUSION: Compared with prior to transplantation, the level of muscle enzymes decreased, FIM scores were increased from 68 to 93 points, EMG results showed that the motor units with re-contraction in each 10.0 ms were increased that the motor function was improved, the lower extremity muscle strength elevated, and the self-care ability was improved in the SMA child at 6 months after transplantation. During the 10-month follow-up, the child had no adverse effects. It is indicated that UCB-MSCs transplantation is effective to treat SMA, and the neurological function has a remarkable restoration.%背景:国内外已有实验动物和临床应用脐血间充质干细胞移植治疗神经系统遗传性疾病安全、有效的诸多报道.目的:探讨脐血间充质干细胞移植治疗儿童进行性脊髓性肌肉萎缩症的可行性及效果.方法:2010-01收治1例确诊为儿童进行性脊髓性肌肉萎缩症患儿,经药物及康复治疗无效,行脐血间充质干细胞移植治疗.移植途径采取首次静脉输注,后3次蛛网膜下腔注入,1次/周,每次细胞数量达(4~6)×107个,4次为1个疗程.治疗前和治疗后半年均需

  18. Behandling af infantile spasmer

    DEFF Research Database (Denmark)

    Hansen, Lars Kjaersgård; Rasmussen, Niels Henrik

    2006-01-01

    Infantile spasms (IS) are characterised by neurodevelopmental regression, a unique type of seizures and a hypsarrhythmic EEG pattern. Studies recommend the medical treatment of IS as a positive short-term outcome with respect to the spasms and in the resolution of the hypsarrhythmia. However, the...

  19. Infantile hypertrophic pyloric stenosis

    DEFF Research Database (Denmark)

    Pedersen, Rikke Neess; Garne, Ester; Loane, Maria;

    2008-01-01

    OBJECTIVE: The objective of this study was to present epidemiologic data on infantile hypertrophic pyloric stenosis (IHPS) from seven well-defined European regions, and to compare incidence and changes in incidence over time between these regions. METHODS: This was a population-based study using...

  20. Behandling af infantile spasmer

    DEFF Research Database (Denmark)

    Kjærsgård, Lars; Rasmussen, Niels

    2006-01-01

    Infantile spasms (IS) are characterised by neurodevelopmental regression, a unique type of seizures and a hypsarrhythmic EEG pattern. Studies recommend the medical treatment of IS as a positive short-term outcome with respect to the spasms and in the resolution of the hypsarrhythmia. However, the...

  1. Botulismo Infantil em Portugal – um lactente com hipotonia

    OpenAIRE

    Malveiro, D; C. Henriques; Flores, P.; Barata, D; Vieira, JP; Cabral, P.

    2013-01-01

    O Botulismo Infantil (BI) constitui uma síndrome neuroparalítica rara, potencialmente fatal, causada pela neurotoxina do Clostridium botulinum. Descreve-se o primeiro caso reportado desde o início da notificação obrigatória em Portugal (1999). Lactente de dois meses, internado por prostração, dificuldade alimentar e obstipação. Constatou-se envolvimento inicial dos pares cranianos associado a fraqueza muscular progressiva, descendente e simétrica. Constituíam factores de risco o consumo...

  2. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature

    NARCIS (Netherlands)

    J.M.P. van den Hout (Johanna); A.T. van der Ploeg (Ans); O.P. van Diggelen (Otto); J.A. Smeitink; G.P. Smit; B.T. Poll-The; H.D. Bakker (Henk); M.C.B. Loonen; J.B.C. de Klerk (Johannes); A.J.J. Reuser (Arnold); W.C.J. Hop (Wim)

    2003-01-01

    textabstractOBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20 inf

  3. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature

    NARCIS (Netherlands)

    J.M.P. van den Hout (Johanna); A.T. van der Ploeg (Ans); O.P. van Diggelen (Otto); J.A.M. Smeitink (Jan); G.P. Smit; B.T. Poll-The; H.D. Bakker (Henk); M.C.B. Loonen (Christa); J.B.C. de Klerk (Johannes); A.J.J. Reuser (Arnold); W.C.J. Hop (Wim)

    2003-01-01

    textabstractOBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20

  4. 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.

  5. Infantile spasms and pigmentary mosaicism

    DEFF Research Database (Denmark)

    Hansen, Lars K; Bygum, Anette; Krogh, Lotte N

    2010-01-01

    Summary We present a 3-year-old boy with pigmentary mosaicism and persistent intractable infantile spasms due to mosaicism of chromosome 7. Getting the diagnosis of pigmentary mosaicism in a child with infantile spasms may not be easy, as most diagnostic work-up is done in infancy, at a time when...

  6. Genetisk udredning ved infantile spasmer

    DEFF Research Database (Denmark)

    Kjærsgaard Hansen, Lars; Ousager, Lilian Bomme; Møller, Rikke Steensbjerre;

    2012-01-01

    Infantile spasms are a symptom of a severe epileptic encephalopathy. It is important to determine the aetiology for a child's disease. When a standard programme for evaluating the aetiology of the infantile spasms is unsuccessful genetic causes should be considered. We suggest array CGH...

  7. Neonatal muscular manifestations in mitochondrial disorders.

    Science.gov (United States)

    Tulinius, Már; Oldfors, Anders

    2011-08-01

    During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation.

  8. ALGLUCOSIDASE ALFA — A NEW STAGE IN THE THERAPY OF INFANTILE POMPE DISEASE

    Directory of Open Access Journals (Sweden)

    E. N. Basargina

    2014-01-01

    Full Text Available Pompe disease is a rare severe hereditary disease caused by excessive glycogen storage in organs and target tissues due to the acid α-glucosidase gene mutation. Infantile and adult Pompe disease is characterized by involvement of cardiovascular, respiratory and muscular systems in the pathological process. The only specific method of treating Pompe disease is enzyme replacement therapy (intravenous administration of recombinant human acid glucosidase, the effectiveness whereof depends on the time the therapy started. Since such a therapy was introduced into practice, Pompe disease mortality decreased by 79%. 6 children with infantile Pompe disease were observed and treated at the cardiovascular care unit of the Scientific Center of Children’s Health in 2011‑2014. The article presents a clinical case demonstrating capabilities of diagnosing infantile Pompe disease in Russia and effective application of alglucosidase alfa in 4-month-old child. 

  9. Infantile pyoderma gangrenosum.

    LENUS (Irish Health Repository)

    McAleer, Maeve A

    2008-02-01

    Pyoderma gangrenosum (PG) is rare in infants. There have been 12 cases of PG in infants (<12 months old) reported in the past 25 years, to our knowledge. Six of these cases have been successfully controlled with systemic steroids, and one case with topical steroids alone. We report a case of an 8-month-old infant whose PG was aggressive and unresponsive to systemic steroids. Adjuvant treatment with cyclosporine was required to achieve healing. We review the previous cases of infantile PG and the therapeutic options in this age group.

  10. Infantile periocular hemangioma

    Directory of Open Access Journals (Sweden)

    Mehdi Tavakoli

    2017-01-01

    Full Text Available Infantile periocular hemangiomas (IPH are common benign vascular tumors that present early in childhood. They typically show a rapid nonlinear growth pattern a few weeks after birth during a proliferative phase, then continue with an involution phase and may result in serious ocular or systemic complications. Theses tumors may present in a range of small isolated lesions to multiple, diffuse involvements. Understanding the nature of the disease, the natural course, complications, indications for intervention, and treatment modalities would be helpful for ophthalmologists, who will likely be consulted for periocular cases. In this review, we present recent opinions about the pathogenesis, diagnosis, and treatment options for patients with IPH.

  11. Sillas de ruedas infantiles

    OpenAIRE

    Valle Gallego, Isabel

    2015-01-01

    Para la correcta elección de una silla de ruedas infantil debe tenerse en cuenta que los niños se encuentran en periodo de crecimiento y de desarrollo de sus capacidades psicomotoras. La utilización de una silla de ruedas y de sistemas de sedestación apropiados en cada momento, puede maximizar la independencia, favorecer el proceso de rehabilitación y retrasar la aparición de deformidades posturales. Debemos tener en cuenta, igualmente, que además de facilitar el desplazamiento, la silla debe...

  12. Infantile perianal protrusion.

    Science.gov (United States)

    Ferrari, Bruno; Taliercio, Vanina; Luna, Paula; Eugenia, Maria; Larralde, Margarita

    2014-12-14

    Infantile perianal protrusion is characterized by a skin fold located in the perianal area. It is a relatively recent reported condition and affects both infants and prepubertal children with a clear female predominance. Three types are recognized: constitutional/congenital, acquired, and associated with lichen sclerosus et atrophicus. We report eleven new cases, three of whom have the defect in locations that have been reported only once before. We would like to increase the awareness of this condition to avoid erroneous diagnostic and therapeutic procedures.

  13. L-alanine supplementation in late infantile glycogen storage disease type II.

    Science.gov (United States)

    Bodamer, Olaf A; Haas, Dorothea; Hermans, Monique M; Reuser, Arnold J; Hoffmann, Georg F

    2002-08-01

    We report a male with late infantile glycogen storage disease type II (Pompe's disease) who presented at 12 months of age with muscular hypotonia and developmental delay. Oral supplementation with L-alanine has been administered for 5 years. Progression of skeletal myopathy was slow, and cardiomyopathy resolved almost completely. L-alanine may be a valuable supplement for infants with glycogen storage disease type II.

  14. Pathogenesis of infantile hemangiomas.

    Science.gov (United States)

    Uihlein, Lily Changchien; Liang, Marilyn G; Mulliken, John B

    2012-08-01

    1.Review the key features of the life cycle of infantile hemangiomas.2.Highlight cellular and molecular pathways involved in hemangioma-genesis.3.Discuss theories that may account for hemangioma-genesis.In the past, it was believed that a mother's visual impressions or behavior during pregnancy caused the growth of infantile hemangioma in her unborn child. She might have had an excessive craving for strawberries, witnessed the slaughter of an animal, directly contacted human or animal blood, or mocked a child with a similar birthmark.1 This folklore began to slowly fade once hemangiomas were examined through the light microscope. In 1863, Virchow2 suggested that hemangiomas are composed of proliferating new blood vessels resulting from progressive irritation of tissue. In 1933, Laidlow and Murray3 proposed a phylogenetic origin for hemangiomas and hypothesized that hemangiomas are remnants of vascular tufts functioning as accessory lungs for primitive amphibia. Pack and Miller4 (1950) hypothesized that hemangiomas develop from embryonic islands of angioblastic cells that were isolated from the systemic vasculature during fetal development. Copyright 2012, SLACK Incorporated.

  15. El libro infantil en Colombia

    Directory of Open Access Journals (Sweden)

    Patricia Londoño

    1988-01-01

    Full Text Available Sabemos que desde el decenio de 1970 se aceleraron una serie de cambios en la vida de los niños en las ciudades colombianas y en el mundo editorial, que ampliaron el mercado de libros infantiles. Las librerías empezaron a ofrecer mayor variedad y cantidad de dichos libros, los cuales a veces han llegado a ocupar cuartos o secciones enteras. Hoy, Mundo Libro Infantil en Medellín y la librería del Centto Experimental del Libro Infantil y Juvenil en Bogotá trajinan exclusiva mente con este material.

  16. Imaging feature of infratentorial desmoplastic infantile and non-infantile tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun Gi; Lee, Seung Koo [Dept. of Radiology and Research Institute of Radiological Science, Severance Children' s Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Se Hoon [Dept. of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul (Korea, Republic of)

    2016-07-15

    To describe imaging features of infratentorial desmoplastic infantile or non-infantile tumors (DIT/DNIT). Four cases with infratentorial DIT/DNIT from our hospital and 5 cases from literature review were analyzed. Clinical data and MR imaging features were evaluated including location, size, shape, margin, composition, dural attachment, perilesional edema, and metastasis or multiplicity. The mean age was 9.2 years (range, 1-18 years). Most of the patients presented with headache or vomiting (4/9, 44.4%) and had no underlying disease (8/9, 88.9%). The major pathologic subtype was astrocytoma (6/9, 66.7%). On MR, majority of the tumors involved cerebellum and/or spinal cord (8/9, 88.9%) and the mean size of the tumors was 4.2 cm (range, 3.2-5 cm). The tumors were mainly solid (4/9, 44.4%) or mixed (4/9, 44.4%) in composition with lobulated shape (7/9, 77.8%) and well-defined margin (7/9, 77.8%). Two cases (2/7, 28.6%) showed dural attachment and all the cases had no or minimal perilesional edema (100%). Metastasis or multiplicity was frequently seen in 44.4% (4/9). Infratentorial DIT/DNIT occurred in relatively older children and the major tumor type was astrocytoma. They also had atypical imaging features showing mainly solid or mixed in composition with frequent metastasis or multiplicity.

  17. 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

  18. Muscular Dystrophy Association

    Science.gov (United States)

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

  19. Aspectos incomuns da paracoccidioidomicose infantil

    Directory of Open Access Journals (Sweden)

    Achiléa Lisboa Bittencourt

    1987-12-01

    Full Text Available São relatados dois casos de paracoccidioidomicose (PCM infantil. Em um deles, a principal manifestação da doença foi tumoração abdominal, simulando linfoma maligno não Hodgkin. O outro apresentou acentuado envolvimento articular, com ruptura da cápsula. Representam o segundo e terceiro casos de PCM infantil observados na Bahia, ambos procedentes de áreas urbanas.The authors present two cases of infantil para-coccidioidomycosis. In one case the main presentation was an abdominal mass that mimicked non- Hodgkin lymphoma. In the other case the child had a joint swelling with rupture of the capsule and the clinical diagnosis was piogenic arthritis. They represent the second and third cases of infantile paracoccidioidomycosis observed in the state of Bahia, all coming from urban areas.

  20. Detection of homozygous and heterozygous SMN deletions of spinal muscular atrophy in a single assay with multiplex ligation-dependent probe amplification%SMN基因缺失多重连接探针扩增法检测和识别脊柱肌肉萎缩症的纯合型或杂合型SMN基因缺失

    Institute of Scientific and Technical Information of China (English)

    Keith TOMASZEWICZ; Peter KANG; Bai-Lin WU

    2005-01-01

    Objective: Spinal muscular atrophy(SMA), an autosomal recessive neuromuscular degeneration of the anterior horn cells of the spinal cord and brain stem, results in one of the most common diseases with muscle fatigue and atrophy. Most SMA cases including all the types are due to the homozygous deletion of at least exon 7 within the survival motor neuron 1 (SMN-1) gene. Although a "golden standard" assay (PCR with mismatch primer followed by enzyme digestion) is very reliable for the identification of homozygous SMN-1 deletion, the carrier detection of heterozygous SMN-1 deletion remains a challenge. Methods: Some PCR-based gene dosage assays or multiplex PCR allow for the determination of the copy number of SMN-1 gene to identify heterozygous deletion, but these procedures are often time consuming and available on a limited clinical basis. Recently developed MLPA (multiplex ligation-dependent probe amplification) is an efficient procedure that can accurately analyze relative quantification to establish the copy number of the SMN gene. We performed a validation for simultaneous detection of homozygous SMN-1 deletions of SMA patients and heterozygous SMN-1 deletions of SMA carriers in a simple assay using a MLPA-SMA assay specific reagent. Results: Six out of 20 patients with SMA were found to have homozygous SMN-1 deletion, confirmed by the PCR/digestion assay. All 4 parents of the children with SMA had heterozygous SMN-1 deletion, confirmed by an independent relative quantitative analysis. Conclusion: MLPA provides a simple, rapid and accurate method of simultaneously detecting homozygous deletions and heterozygous deletions in a single assay for both SMN-1 and SMN-2 genes.

  1. Infantile urolithiasis: Diagnosis

    Directory of Open Access Journals (Sweden)

    M. Mehdizadah

    2005-08-01

    Full Text Available Introduction & Background: Urolithiasis in children is not a common disease in western countries. Urolithiasis in children is more located in the upper urinary tract and only 5-10% is seen in the bladder. The most com-mon stone composition differs in variable age groups but calcium oxalate seems to be the most common type in all children age groups. Clinical manifestations also differ in different age groups. In infants, growth retarda-tion (FTT and crying during crystaluria are the most common symptoms and signs. High resolution (HR sonography (7.5 MHz is an effective, noninvasive, and easy to access procedure for the diagnosis of infantile urolithiasis. Even with high resolution sonography (7.5 MHz we can determine the grading of nephrocalcino-sis in infants. Non radio-opaque stones are also diagnosed by HR sonography. Patients & Methods: This study tries to emphasize the importance and efficacy of high resolution sonography in the diagnosis of infantile urolithiasis by surveillance of 200 infants under 2 years old with urinary tract stones in Markaz-Tebi-Hospital during 1375 to 1383. Results: In this study the mean age was 12 months old (2 to 24 months and 55% were boys; 61% had positive family history; 54.5% (109 ones had no underlying metabolic disorder and among others 41 (20.5% had hy-percalciuria ( the most common ; 78 (39% had hematuria, 61 (30.5% had pyuria and 61 (30.5% had no ab-normality in U/A. In 63 (31.5%, urine culture was positive; 39 (31.5% had macroscopic hematuria. Their chief complaint was changing of urine color in 44 (22%, crystaluria in 37 (18.5%, UTI in 37 (31%, and no complaints in 20 (10%. FTT and crying during urination were observed in 25 (12.5% and 12 (6% of our pa-tients. In 79.5% of all infants, there was a positive sonographic finding that confirmed the stone. About the stone location according to the sonographic finding, 124 (62% had kidney stone, 10 (4.5% had ureter stone, and 25 (12.5% had bladder stone. In

  2. La obesidad infantil /

    OpenAIRE

    Pellitero Martinez, Cristina

    2013-01-01

    La obesidad infantil es la enfermedad de tipo nutricional que se da con más frecuencia en los niños de los países desarrollados, conlleva riesgos físicos y psicológicos y determinados estudios señalan que puede acortar la esperanza de vida en 13 años. En Castilla y León, la tasa de obesidad entre los niños en edad escolar es del 0,8%. La autora va a recoger datos y a realizar un estudio del desayuno que realizan estos niños por considerarlo la primera comida del día y la más importa...

  3. La obesidad infantil /

    OpenAIRE

    Pellitero Martinez, Cristina

    2013-01-01

    La obesidad infantil es la enfermedad de tipo nutricional que se da con más frecuencia en los niños de los países desarrollados, conlleva riesgos físicos y psicológicos y determinados estudios señalan que puede acortar la esperanza de vida en 13 años. En Castilla y León, la tasa de obesidad entre los niños en edad escolar es del 0,8%. La autora va a recoger datos y a realizar un estudio del desayuno que realizan estos niños por considerarlo la primera comida del día y la más importa...

  4. Hiperostosis cortical infantil

    OpenAIRE

    Salvador Javier Santos Medina; Orelvis Pérez Duerto

    2015-01-01

    La enfermedad de Caffey, o hiperostosis cortical infantil, es una rara enfermedad ósea autolimitada, que aparece de preferencia en lactantes con signos inespecíficos sistémicos; el más relevante es la reacción subperióstica e hiperostosis en varios huesos del cuerpo, con predilección en el 75-80 % de los casos por la mandíbula. Su pronóstico es bueno, la mayoría no deja secuelas. El propósito del presente trabajo es describir las características clínicas, presentes en un lactante de cinco mes...

  5. Infantile nephropathic cystinosis

    Directory of Open Access Journals (Sweden)

    Peco-Antić Amira

    2011-01-01

    Full Text Available Introduction. Infantile nephropathic cystinosis (INC is a metabolic disorder due to impaired carrier-mediated transport of cystine out of cellular lysosomes. Objective. To examine the prevalence and clinical characteristics of INC in paediatric patients with end- stage renal disease (ESRD in Serbia and give a recent statement of the disease. Methods. ESRD database of the Centre for Paediatric Renal Replacement Therapy (RRT in Serbia was used to identify all patients with INC who started RRT before age of 19 years during the period January 1980 - December 2008; their records concerning clinical characteristics, therapy and outcome were evaluated. Results. Only three of 298 paediatric patients with ESRD had INC. The first signs of the illness were recognised during infancy. Fancony syndrome was diagnosed in the second year, but the diagnosis of cystinosis was delayed at mean 6 years. ESRD occurred in the first decade of life. All patients under- went cadaver kidney transplantation. At the end of the study period all patients were alive. A 31-year-old female patient was on maintenance chemodialysis due to graft failure after functioning for 11 years. She was growth retarded, single, unemployed, with severe signs of renal dystrophy. Two male patients (14.3 and 14.7 years old had normal graft function, normal education, and good quality of life, although they were also severe growth retarded. Conclusion. The prevalence of infantile nephropathic cystinosis is low in Serbia. The diagnosis of cystinosis was delayed in all patients, although they exhibited the typical course of the disease.

  6. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    Science.gov (United States)

    2016-08-26

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

  7. Spinal injury

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000029.htm Spinal injury To use the sharing features on this page, ... move anyone who you think may have a spinal injury, unless it is absolutely necessary. For example, if ...

  8. Effect of unilateral exercise on spinal and pelvic deformities, and isokinetic trunk muscle strength

    OpenAIRE

    Jeon, Kyoungkyu; Kim, Soonyoung

    2016-01-01

    [Purpose] The purpose of this study was to collect basic data regarding the prevention of spinal and pelvic deformities by investigating the spinal shape and muscular function characteristics of imbalance reduction and functional improvement following asymmetric activities. [Subjects and Methods] The subjects were 14 archery athletes who mostly perform unilateral motion with spinal and pelvic pain, and 19 healthy subjects. All the participants were evaluated using spinal structure analysis an...

  9. INFANTILISM: THEORETICAL CONSTRUCT AND OPERATIONALIZATION

    Directory of Open Access Journals (Sweden)

    Yelena V. Sabelnikova

    2016-01-01

    Full Text Available The aim of the presented research is to define and operationalize theoretically the concept of infantilism and its construct. The content of theoretical construct «infantilism» is analyzed. Methods. The methods of theoretical research involve analysis and synthesis. The age and content criteria are analysed in the context of childhood and adulthood. The traits which can be interpreted as adult infantile traits are described. Results. The characteristics of adult infantilism in modern world taking into account the increasing of information flows and socio-economic changes are defined. The definition of the concept «infantilism» including its main features is given. Infantilism is defined as the personal organization including features and models of the previous age period not adequate for the real age stage with emphasis on immaturity of the emotional and volitional sphere. Scientific novelty. The main psychological characteristics of adulthood are described as the reflection, requirement to work and professional activity, existence of professional self-determination, possession of labor skills, need for selfrealization, maturity of the emotional and volitional sphere. As objective adulthood characteristics are considered the following: transition to economic and territorial independence of a parental family, and also development of new social roles, such as a worker, spouse, and parent. Two options of a possible operationalization of concept are allocated: objective (existence / absence in real human life of objective criteria of adulthood and subjective (the self-report on subjective feeling of existence / lack of psychological characteristics of adulthood. Practical significance consists in a construct operationalization of «infantilism» which at the moment has so many interpretations. That operationalization is necessary for the further analysis and carrying out various researches. 

  10. 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.

  11. Evaluation of Limb-Girdle Muscular Dystrophy

    Science.gov (United States)

    2014-03-06

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

  12. Infantile Haemangioma: Pathogenesis, Evaluation, and Therapy

    NARCIS (Netherlands)

    S.R. Janmohamed (Sherief)

    2014-01-01

    markdownabstract__Abstract__ This thesis contains of: 1) Studies describing the pathogenesis of infantile haemangioma 2) The development of a novel scoring system for infantile haemangioma activity 3) Studies evaluating different therapy options for infantile haemangioma Hypoxia is important in th

  13. Infantile Haemangioma: Pathogenesis, Evaluation, and Therapy

    NARCIS (Netherlands)

    S.R. Janmohamed (Sherief)

    2014-01-01

    markdownabstract__Abstract__ This thesis contains of: 1) Studies describing the pathogenesis of infantile haemangioma 2) The development of a novel scoring system for infantile haemangioma activity 3) Studies evaluating different therapy options for infantile haemangioma Hypoxia is important in th

  14. Distrofia neuroaxonal infantil: relato de dois casos Infantile neuroaxonal dystrophy: report of two cases

    Directory of Open Access Journals (Sweden)

    ROSANA HERMINIA SCOLA

    1999-12-01

    Full Text Available Descrevemos dois casos de distrofia neuroaxonal infantil ou doença de Seitelberger, que é doença rara, neurodegenerativa, com herança autossômica recessiva. O primeiro caso, sexo masculino, com 8 anos de idade, apresentava atraso do desenvolvimento psicomotor, ataxia e fraqueza muscular. Ao exame físico foi encontrado nistagmo horizontal e vertical com palidez do disco óptico, hipotonia e arreflexia profunda. O segundo caso, sexo masculino, com 1 ano e 6 meses de idade, apresentava atraso do desenvolvimento psicomotor e convulsões. No exame físico, apresentava atrofia de nervo óptico, hipertonia e hiperreflexia. A biópsia de nervo sural de ambos os pacientes mostrou aumento dos axônios, compatível com distrofia neuroaxonal. As características clínicas pleomórficas, bem como os achados neurofisiológicos variáveis tornam difícil firmar o diagnóstico, o qual é ajudado pela confirmação anatomopatológica dos esferóides neuroaxonais.We describe two cases of infantile neuroaxonal dystrophy, which is a rare, neurodegenerative disease, with autosomal recessive inheritance. The first case was an 8 year old boy, with arrested motor and mental development, ataxia and muscle weakness. On physical examination there was horizontal and vertical nystagmus, optic disc atrophy, hypotonia; deep tendon reflexes were absent. The second case was a 1.6 year old boy with arrested motor and mental development, and seizures. On physical examination there was optic atrophy, hypertonia and hyperreflexia. Both patients had on sural nerve biopsy neuronal enlargement, consistent with neuroaxonal dystrophy. Diagnosis without pathological confirmation with neuroaxonal spheroids is very difficult, because the clinical picture is variable and the neurophysiological findings are non specific.

  15. Ullrich Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Goknur Haliloglu

    2011-09-01

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

  16. Ullrich Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Goknur Haliloglu

    2011-06-01

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

  17. Dismorfia muscular Muscle dysmorphia

    OpenAIRE

    Sheila Seleri Marques Assunção

    2002-01-01

    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 dismo...

  18. Incorrecciones del habla infantil

    Directory of Open Access Journals (Sweden)

    María del Pino LECUONA NARANJO

    2009-11-01

    Full Text Available En el presente trabajo se pretende dar una visión de algunos rasgos característicos del lenguaje infantil, centrándonos especialmente en el estudio de los niños de 4 a 6 años de edad. Es pues, su finalidad fundamental la descripción y análisis de los rasgos que se pueden observar en la expresión verbal de los preescolares. Las diversas peculiaridades que van a ser objeto de examen se refieren a la emisión de incorrecciones de carácter fonético, morfológico y semántico. El análisis unificado de estos tres factores responde a la consideración de que todos surgen como consecuencia de un proceso de simplificación lingüística originado por un estado inconcluso de desarrollo del lenguaje.

  19. Infantile refsum disease: case report.

    Science.gov (United States)

    Choksi, Vaishali; Hoeffner, Ellen; Karaarslan, Ercan; Yalcinkaya, Cengiz; Cakirer, Sinan

    2003-01-01

    Infantile Refsum disease is a rare inborn error of phytanic acid metabolism. It is inherited in an autosomal recessive manner and frequently causes signs and symptoms in the neonate period. The only source of phytanic acid in humans is exogenous, from diet. We report the MR imaging findings in two cases of infantile Refsum disease and note the MR imaging changes that occurred over time because of further progression of the disease. The initial diagnosis in both patients was made on basis of history, clinical findings, and biochemical studies.

  20. 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...

  1. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... MD Living With MD en español Qué significa distrofia muscular Over Labor Day, just as you're going ... 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 ...

  2. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... MD Living With MD en español Qué significa distrofia muscular Over Labor Day, just as you're ... grown-up. This article talks about two types: Duchenne and Becker MD. Generally, only boys get Duchenne ...

  3. Organizando el aula infantil

    Directory of Open Access Journals (Sweden)

    María Luisa GARCÍA RODRÍGUEZ

    2009-11-01

    Full Text Available RESUMEN: La organización del aula es una importante "herramienta" en manos de la educadora o el educador, especialmente en las primeras edades. En consecuencia, es necesario poner todo el cuidado y atención posibles para conseguir un ambiente, a la vez agradable y práctico, que favorezca la vida y el aprendizaje de los niños y niñas de cero a seis años. Al principio de cada curso escolar se planificarán los aspectos físicos del aula, se organizarán los materiales y se distribuirá el tiempo. Para ello, deberán ser tenidas en cuenta las necesidades infantiles y los ámbitos madurativos en los que cada niña y cada niño deben progresar.ABSTRACT: The organization of the classroom is an important "tool" in the hands of the educator, especially during the early years. Consequently, it is necessary to take great care and give as much attention as possible to achieving an environment which is both pleasant and practical, as well as favourable to the lives and learning of children under six years of age. At the beginning of the school year the physical aspects of the classroom will be planned, the material organized and time distributed. For this purpose, the needs of the children, and the areas in which each child should advance and mature, must be taken into account.

  4. Hiperostosis cortical infantil

    Directory of Open Access Journals (Sweden)

    Salvador Javier Santos Medina

    2015-04-01

    Full Text Available La enfermedad de Caffey, o hiperostosis cortical infantil, es una rara enfermedad ósea autolimitada, que aparece de preferencia en lactantes con signos inespecíficos sistémicos; el más relevante es la reacción subperióstica e hiperostosis en varios huesos del cuerpo, con predilección en el 75-80 % de los casos por la mandíbula. Su pronóstico es bueno, la mayoría no deja secuelas. El propósito del presente trabajo es describir las características clínicas, presentes en un lactante de cinco meses de edad, atendido en el Hospital Pediátrico Provincial “Mártires de Las Tunas” con este diagnóstico, quien ingresó en el servicio de miscelánea B por una celulitis facial. Presentaba aumento de volumen en la región geniana izquierda, febrícola e inapetencia. Se impuso tratamiento con cefazolina y se egresó a los siete días. Acudió nuevamente con tumefacción blanda y difusa de ambas hemicaras, irritabilidad y fiebre. Se interconsultó con cirugía maxilofacial, se indicaron estudios sanguíneos y radiológicos. Se diagnosticó como enfermedad de Caffey, basado en la edad del niño, tumefacción facial sin signos inflamatorios agudos e hiperostosis en ambas corticales mandibulares a la radiografía AP mandíbula; unido a anemia ligera, leucocitosis y eritrosedimentación acelerada. El paciente se trató sintomáticamente y con antinflamatorios no esteroideos. Esta rara entidad se debe tener presente en casos de niños y lactantes con irritabilidad y fiebre inespecífica

  5. Infantile Spasm: A Review Article

    Directory of Open Access Journals (Sweden)

    Mohammad Mahdi TAGHDIRI

    2014-07-01

    Full Text Available How to Cite This Article: Taghdiri MM, Nemati H. Infantile Spasm: A Review Article. Iran J Child Neurol. 2014 Summer;8(3: 1-5.AbstractObjectiveInfantile spasm (IS is a convulsive disease characterized by brief, symmetric axial muscle contraction (neck, trunk, and/or extremities. IS is a type of seizure that was first described by West in 1841, who witnessed the seizure in his own son. West’s syndrome refers to the classic triad of spasms, characteristic EEG, and neurodevelopmental regression. Most cases involve flexors and extensors,but either of the types may be involved independently.IS, as its name implies, most often occurs during the first year of life with an incidence of approximately 1 per 2000-4000 live births. Most, but not all, patients with this disorder have severe EEG abnormalities; this pattern was originallyreferred to as hypsarrhythmia by Gibbs and Gibbs. Cases with known etiology or signs of brain damage are considered as symptomatic. The Overall prognosis of the disease is poor. Peak onset age of the epileptic syndrome is 3 to 7 months, which mainly occurs before 2 years of age in 93% of patients. Hypsarrhythmia is the EEG hallmark of IS, which comprised a chaotic, bilaterally asynchronous high-voltage polyspike, and slow wave discharges interspersed with multifocal spikes and slow waves.Etiological classification is as follows: 1 Symptomatic: with identifiable prenatal, perinatal, and postnatal causes with developmental delay at the presentation time; 2 Cryptogenic: unknown underlying cause, normal development at the onset of spasms, normal neurological exam and neuroimaging, and no abnormality in the metabolic evaluation; 3 Idiopathic: pure functional cerebral dysfunction with complete recovery, no residual dysfunction, normal neuroimaging and normal etiologic evaluation, and normal neurodevelopment.ReferencesInfantile Spasms. In: Jean Aicardi: Disease of Nervous system in childhood. 3th ed. Mac Keith

  6. Spinal infections.

    Science.gov (United States)

    Tay, Bobby K-B; Deckey, Jeffrey; Hu, Serena S

    2002-01-01

    Spinal infections can occur in a variety of clinical situations. Their presentation ranges from the infant with diskitis who is unwilling to crawl or walk to the adult who develops an infection after a spinal procedure. The most common types of spinal infections are hematogenous bacterial or fungal infections, pediatric diskitis, epidural abscess, and postoperative infections. Prompt and accurate diagnosis of spinal infections, the cornerstone of treatment, requires a high index of suspicion in at-risk patients and the appropriate evaluation to identify the organism and determine the extent of infection. Neurologic function and spinal stability also should be carefully evaluated. The goals of therapy should include eradicating the infection, relieving pain, preserving or restoring neurologic function, improving nutrition, and maintaining spinal stability.

  7. Spinal brucellosis.

    Science.gov (United States)

    Tali, E Turgut; Koc, A Murat; Oner, A Yusuf

    2015-05-01

    Spinal involvement in human brucellosis is a common condition and a significant cause of morbidity and mortality, particularly in endemic areas, because it is often associated with therapeutic failure. Most chronic brucellosis cases are the result of inadequate treatment of the initial episode. Recognition of spinal brucellosis is challenging. Early diagnosis is important to ensure proper treatment and decrease morbidity and mortality. Radiologic evaluation has gained importance in diagnosis and treatment planning, including interventional procedures and monitoring of all spinal infections.

  8. Spinal Stenosis

    Science.gov (United States)

    ... Pharyngitis, Adenitis Syndrome (Juvenile) Polymyalgia Rheumatica Psoriatic Arthritis Raynaud's Phenomenon Reactive Arthritis Rheumatoid Arthritis Scleroderma Sjogren's Syndrome Spinal Stenosis Spondyloarthritis Systemic Lupus Erythematosus (Juvenile) Takayasu's ...

  9. Infantile nystagmus and visual deprivation

    DEFF Research Database (Denmark)

    Fledelius, Hans C; Jensen, Hanne

    2014-01-01

    PURPOSE: To evaluate whether effects of early foveal motor instability due to infantile nystagmus might compare to those of experimental visual deprivation on refraction in a childhood series. METHODS: This was a retrospective analysis of data from the Danish Register for Blind and Weaksighted Ch...

  10. Literatura infantil e seus encantamentos

    Directory of Open Access Journals (Sweden)

    Joice Ribeiro da Silva

    2016-12-01

    Full Text Available Por meio das histórias contadas, lidas e dramatizadas as crianças são transportadas para mundos diferentes de suas vidas reais, onde podem fluir na imaginação, com os personagens de contos de fadas, lendas e demais narrativas presentes na Literatura Infantil. O objetivo principal deste artigo é compreender a importância da literatura na educação infantil, como ela está presente nas práticas pedagógicas desenvolvidas com uma turma de crianças na faixa etária de 4-5 anos. O estudo está baseado em uma pesquisa bibliográfica, com aporte de uma análise qualitativa, na interlocução teórica com os autores: Bruno Bettelheim; Luiz Percival Leme Brito; Sueli de Souza Cagneti; Maria Antonieta Antunes Cunha; Maria Alexandre de Oliveira e Luciana E. Ostetto. Palavras-chave: educação infantil; literatura infantil; contação de histórias; aprendizagem. 

  11. Infantile Colic: The Mysterious Crying

    Directory of Open Access Journals (Sweden)

    Shaheen Akter

    2012-07-01

    Full Text Available Infantile colic is a distressing condition in infants, pathogenesis of which is still not clear. Several treatment strategies have been attempted before, but only some of them proven successful. The aim of this paper is to review studies on treatment options for infantile colic. For this, a systematic literature review was done on studies regarding pathophysiology, medical and conventional interventions for infantile colic from 1954 to March 2011. Forty nine articles included in Cochrane database were reviewed. Fourteen studies on pathophysiology and risk factors, 7 studies on effect of infantlie colic on parents and family,19 studies on management, 5 studies on other related factors and 4 literature reviews were included for review. Pathophysiology has been described in various ways in different studies and yet not conclusive. Regarding studies on management, simethicone could not significantly control colic, dicyclomine hydrochloride had serious side effects and cimetropium bromide results were favourable, but milder side effects were noted. Some nutritional studies reported low-allergen maternal diets in breastfed infants but suitability of these methods are questionable in Bangladesh. Behavioural studies on the use of decreased stimulation and contingent music were favourable in some studies. Mixed herbal tea and probiotic like Lactobacillus reuteri studies showed encouraging results. There are some scientific evidences to support a low-allergen maternal diet in breastfed infants with infantile colic. Some encouraging results exist for mixed herbal tea, cimetropium bromide and probiotics.

  12. [Spanish consensus on infantile haemangioma].

    Science.gov (United States)

    Baselga Torres, Eulalia; Bernabéu Wittel, José; van Esso Arbolave, Diego L; Febrer Bosch, María Isabel; Carrasco Sanz, Ángel; de Lucas Laguna, Raúl; Del Pozo Losada, Jesús; Hernández Martín, Ángela; Jiménez Montañés, Lorenzo; López Gutiérrez, Juan Carlos; Martín-Santiago, Ana; Redondo Bellón, Pedro; Ruíz-Canela Cáceres, Juan; Torrelo Fernández, Antonio; Vera Casaño, Ángel; Vicente Villa, María Asunción

    2016-11-01

    Infantile haemangiomas are benign tumours produced by the proliferation of endothelial cells of blood vessels, with a high incidence in children under the age of one year (4-10%). It is estimated that 12% of them require treatment. This treatment must be administered according to clinical practice guidelines, expert experience, patient characteristics and parent preferences. The consensus process was performed by using scientific evidence on the diagnosis and treatment of infantile haemangiomas, culled from a systematic review of the literature, together with specialist expert opinions. The recommendations issued were validated by the specialists, who also provided their level of agreement. This document contains recommendations on the classification, associations, complications, diagnosis, treatment, and follow-up of patients with infantile haemangioma. It also includes action algorithms, and addresses multidisciplinary management and referral criteria between the different specialities involved in the clinical management of this type of patient. The recommendations and the diagnostic and therapeutic algorithms of infantile haemangiomas contained in this document are a useful tool for the proper management of these patients. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

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

    Science.gov (United States)

    2017-07-11

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

  14. Ullrich Congenital Muscular Dystrophy

    OpenAIRE

    2011-01-01

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

  15. Neonatal and infantile acne vulgaris: an update.

    Science.gov (United States)

    Serna-Tamayo, Cristian; Janniger, Camila K; Micali, Giuseppe; Schwartz, Robert A

    2014-07-01

    Acne may present in neonates, infants, and small children. Neonatal and infantile acne vulgaris are not considered to be rare. The presentation of acne in this patient population sometimes represents virilization and may portend later development of severe adolescent acne. Neonatal and infantile acne vulgaris must be distinguished from other cutaneous disorders seen in newborns and infants. Infantile acne tends to be more pleomorphic and inflammatory, thus requiring more vigorous therapy than neonatal acne.

  16. On resolving the enigma of infantile amnesia.

    Science.gov (United States)

    Howe, M L; Courage, M L

    1993-03-01

    Historical and current theories of infantile amnesia are examined. To evaluate the viability of these theories, as well as the phenomenon of infantile amnesia itself, a review of memory development from birth through the preschool years is provided, including an overview of relevant perceptual and neurological maturation. In the context of this review, extant theories of infantile amnesia are shown to falter, and it is concluded that infantile amnesia is a chimera of a previously unexplored relationship between the development of a cognitive sense of self and the personalization of event memory. This hypothesis is examined in detail and discussed in the context of related developments in language and social cognition.

  17. Infantile masturbation and paroxysmal disorders.

    Science.gov (United States)

    Omran, Mohammadreza Salehi; Ghofrani, Mohammad; Juibary, Ali Ghabeli

    2008-02-01

    A recurrent paroxysmal presentation in children leads to different diagnoses and among them are neurologic and cardiac etiologies. Infantile masturbation is not a well known entity and cannot be differentiated easily from other disorders. Aim of this study is to elucidate and differentiate this condition from epileptic seizures. We report 3 cases of 10 to 30 mth old girls of infantile masturbation that their symptoms initiated at 2, 3 and 8 mth of age. These present with contraction and extension of lower extremities, scissoring of legs, perspiration, changing face color. In 2 cases body rocking and legs rubbing initiated then there after. Masturbation is one of the paroxysmal non-epileptic conditions of early infancy and is in differential diagnosis of epileptic seizures.

  18. Propranolol-resistant infantile haemangiomas.

    Science.gov (United States)

    Caussé, S; Aubert, H; Saint-Jean, M; Puzenat, E; Bursztejn, A-C; Eschard, C; Mahé, E; Maruani, A; Mazereeuw-Hautier, J; Dreyfus, I; Miquel, J; Chiaverini, C; Boccara, O; Hadj-Rabia, S; Stalder, J-F; Barbarot, S

    2013-07-01

    Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol-resistant IH (PRIH) are mentioned in the literature. To describe the characteristics of PRIHs. A national, multicentre, retrospective, observational study was conducted from February 2011 to December 2011. All patients with PRIH evaluated by the members of the Groupe de Recherche Clinique en Dermatologie Pédiatrique from 1 January 2007 to 1 December 2011 were eligible. Among 1130 patients treated with propranolol for infantile haemangioma, 10 (0.9%) had PRIHs. Haemangioma propranolol resistance was observed at all ages during early childhood and at any proliferation stage. PRIH is a rare phenomenon that raises questions and merits further investigation. © 2013 British Association of Dermatologists.

  19. Condiciones familiares y maltrato infantil

    OpenAIRE

    María Luisa Platone

    2007-01-01

    El estudio discute las condiciones familiares (estructura y patrones interactivos del sistema familiar), consideradas como factores de riesgo en el maltrato infantil. Método. Investigación descriptiva multivariada (cuantitativa y cualitativa). Se analizaron los datos obtenidos en un estudio retrospetivo (1970-2000) en muestras representativas de escolares de escuelas públicas y privadas del área metropolitana de Caracas, Venezuela, en edades comprendidas de 5 a 13 años, y desde...

  20. Optimizing Bone Health in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Jason L. Buckner

    2015-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA, as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA.

  1. Infantile colic, facts and fiction

    Directory of Open Access Journals (Sweden)

    Kheir Abdelmoneim E M

    2012-07-01

    Full Text Available Abstract Infantile colic is one of the major challenges of parenthood. It is one of the common reasons parents seek medical advice during their child’s first 3 months of life. It is defined as paroxysms of crying lasting more than 3 hours a day, occurring more than 3 days in any week for 3 weeks in a healthy baby aged 2 weeks to 4 months. Colic is a poorly understood phenomenon affecting up to 30% of babies, underlying organic causes of excessive crying account for less than 5%. Laboratory tests and radiological examinations are unnecessary if the infant is gaining weight normally and has a normal physical examination. Treatment is limited and drug treatment has no role in management. Probiotics are now emerging as promising agents in the treatment of infantile colic. Alternative medicine (Herbal tea, fennel, glucose and massage therapy have not proved to be consistently helpful and some might even be dangerous. In conclusion infantile colic is a common cause of maternal distress and family disturbance, the cornerstone of management remains reassurance of parents regarding the benign and self-limiting nature of the illness. There is a critical need for more evidence based treatment protocols.

  2. Spinal Stenosis

    Science.gov (United States)

    ... lower part of the body. It resembles a “horse’s tail” ( cauda equina in Latin). What Causes Spinal ... of the spine fails, it usually places increased stress on other parts of the spine. For example, ...

  3. Spinal Hemangiomas

    Directory of Open Access Journals (Sweden)

    I.A. Norkin

    2010-06-01

    Full Text Available The given article considers the modern view on etiology, pathogenesis, classifications, clinical picture, diagnosis and treatment of spinal hemangiomas. Advantages of vertebroplasty over the other techniques of treatment of studied pathology are presented

  4. Spinal Stenosis

    Science.gov (United States)

    ... risk. Diseases such as arthritis and scoliosis can cause spinal stenosis, too. Symptoms might appear gradually or not at all. They include Pain in your neck or back Numbness, weakness, cramping, or pain in ...

  5. Spinal Infections

    Science.gov (United States)

    ... infections may occur following surgery or spontaneously in patients with certain risk factors. Risk factors for spinal infections include poor nutrition, immune suppression, human immunodeficiency virus (HIV) infection, cancer, diabetes and obesity. Surgical risk factors ...

  6. Spinal Hemangiomas

    OpenAIRE

    I.A. Norkin; S.V. Likhachev; A.Yu. Chomartov; A.I. Norkin; D.M. Puchinian

    2010-01-01

    The given article considers the modern view on etiology, pathogenesis, classifications, clinical picture, diagnosis and treatment of spinal hemangiomas. Advantages of vertebroplasty over the other techniques of treatment of studied pathology are presented

  7. Spinal Fusion

    Science.gov (United States)

    ... vertebrae. These include: treatment of a fractured (broken) vertebra; correction of deformity (spinal curves or slippages); elimination of pain from painful motion; treatment of instability; and treatment of some cervical disc herniations. One of the less controversial reasons ...

  8. Muscle diseases: the muscular dystrophies.

    Science.gov (United States)

    McNally, Elizabeth M; Pytel, Peter

    2007-01-01

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

  9. The clinical features of spinal and bulbar muscular atrophy (two case reports and literature review)%脊髓延髓肌萎缩症一家系患者的临床、电生理及分子遗传学特点

    Institute of Scientific and Technical Information of China (English)

    许辉; 蒋云; 朱小泉; 庄立; 龚涛; 陈海波

    2011-01-01

    Objective By analyzing the clinical manifestations of two patients with spinal and bulbar muscular atrophy (SBMA) and reviewing references, fully recognize SBMA in aspects of clinical features,pathogenesis, pathological features, diagnosis and differentiation, improving diagnostic rate. Methods In the two brothers with suspected SBMA, the clinical and eletrophysiological manifestations were analyzed and the repetition of CAG in the first exon of androgenic receptor (AR) was tested. Combined with reference review, the clinical features, pathology and pathogenesis were summarized. Results The two patients had typical SBMA manifestations. The number of CAG repetition in the first exon of AR was 49 in both of them. SBMA was then diagnosed. Conclusions To improve the diagnostic rate of SBMA, we must be familiar with its clinical features and take gene test on the early stage of the disease.%目的 通过分析2例脊髓延髓肌萎缩症 (SBMA)患者的临床表现并进行相关文献复习, 比较全面地认识SBMA的临床特点、发病机制、病理特点及诊断与鉴别诊断要点,提高SBMA诊断率.方法 对临床疑似SBMA的兄弟两人的临床和肌电图特点进行分析,并检测其雄激素受体(AR)基因第一外显子三核苷酸(CAG)串联重复情况.结合文献,总结SBMA的临床特点、病理基础和发生机制. 结果 2例患者均具有典型SBMA临床表现,AR基因CAG重复数均为49,可诊断为SBMA. 结论熟悉SBMA的临床特征,早期进行基因检测,可提高该病的诊断率.

  10. Birth Weight, Gestational Age, and Infantile Colic

    DEFF Research Database (Denmark)

    Milidou, Ioanna; Søndregaard, Charlotte; Jensen, Morten Søndergaard;

    Background Infantile colic is a condition of unknown origin characterized by paroxysms of crying during the first months of life. A few studies have identified low birth weight (BW) as a risk factor among infants born at term, while the association between gestational age (GA) and infantile colic......, low BW was associated with infantile colic only in infants born at term (gestational weeks 37-41), but not in pre- or post-term infants. Conclusion The results indicate that low birth weight and preterm birth are independently associated with infantile colic. After adjusting for gestational age, low...... birth weight increased the risk of infantile colic in children born at term (gestational weeks 37-41)....

  11. Isolated spinal accessory neuropathy and intracisternal schwannomas of the spinal accessory nerve

    Directory of Open Access Journals (Sweden)

    Abdullah M. Al-Ajmi

    2015-03-01

    Full Text Available We report a 40-year-old female patient presenting with isolated left spinal accessory neuropathy that developed insidiously over 6 years. She complained of ill-defined deep neck and shoulder pain. On examination, prominent sternocleidomastoid and trapezoid muscle weakness and atrophy, shoulder instability, and lateral scapular winging were observed. MRI identified a small mass of the cisternal portion of the spinal accessory nerve. Its appearance was typical of schwannoma. Surgical treatment was not offered because of the small tumor size, lack of mass effect and the questionable functional recovery in the presence of muscular atrophy.

  12. Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report Aracnodactilia contratural congênita com atrofia muscular espinhal: relato de caso

    Directory of Open Access Journals (Sweden)

    Rosana Herminia Scola

    2001-06-01

    Full Text Available We report the case of a 3-1/2-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA. The serum muscle enzimes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.Relatamos o caso de uma paciente do sexo feminino de 3 anos e 6 meses com hipotonia, contraturas de múltiplas articulações, aracnodactilia, polegares aduzidos, dolicostenomelia e orelhas externas anormais sugerindo o diagnóstico de aracnodactilia contratural congênita (ACC. As enzimas musculares eram normais e a eletromiografia de agulha mostrou desinervação ativa e crônica. A biópsia muscular mostrou desinervação ativa e crônica compatível com atrofia muscular espinhal. A análise dos exons 7 e 8 do gene do survival motor neuron por reação em cadeia de polimerase não mostrou deleções. Atrofia muscular neurogênica é uma nova anormalidade associada a ACC, sugerindo a heterogeneidade clínica da ACC.

  13. [Duchenne muscular dystrophy pathophysiology].

    Science.gov (United States)

    Péréon, Y; Mercier, S; Magot, A

    2015-12-01

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

  14. Infantile spasms: A prognostic evaluation

    Directory of Open Access Journals (Sweden)

    Mary Iype

    2016-01-01

    Full Text Available Background: Few papers address the comprehensive prognosis in infantile spasms and look into the seizure profile and psychomotor outcome. Objective: We aimed to follow up children with infantile spasms to study: a the etiology, demographics, semiology, electroencephalogram (EEG, and radiological pattern; b seizure control, psychomotor development, and EEG resolution with treatment; c the effects of various factors on the control of spasms, resolution of EEG changes, and psychomotor development at 3-year follow-up. Materials and Methods: Fifty newly diagnosed cases with a 1-12 month age of onset and who had hypsarrhythmia in their EEG were recruited and 43 were followed up for 3 years. Results: Of the children followed up, 51% were seizure-free and 37% had a normal EEG at the 3-year follow-up. Autistic features were seen in 74% of the children. Only 22.7% among the seizure-free (11.6% of the total children had normal vision and hearing, speech with narration, writing skills, gross and fine motor development, and no autism or hyperactivity. On multivariate analysis, two factors could predict bad seizure outcome — the occurrence of other seizures in addition to infantile spasms and no response to 28 days of adrenocorticotropic hormone (ACTH. No predictor could be identified for abnormal psychomotor development. Discussion and Conclusion: In our study, we could demonstrate two factors that predict seizure freedom. The cognitive outcome and seizure control in this group of children are comparable to the existing literature. However, the cognitive outcome revealed by our study and the survey of the literature are discouraging.

  15. Infantile spasms: A prognostic evaluation

    Science.gov (United States)

    Iype, Mary; Saradakutty, Geetha; Kunju, Puthuvathra Abdul Mohammed; Mohan, Devi; Nair, Muttathu Krishnapanicker Chandrasekharan; George, Babu; Ahamed, Shahanaz M.

    2016-01-01

    Background: Few papers address the comprehensive prognosis in infantile spasms and look into the seizure profile and psychomotor outcome. Objective: We aimed to follow up children with infantile spasms to study: a) the etiology, demographics, semiology, electroencephalogram (EEG), and radiological pattern; b) seizure control, psychomotor development, and EEG resolution with treatment; c) the effects of various factors on the control of spasms, resolution of EEG changes, and psychomotor development at 3-year follow-up. Materials and Methods: Fifty newly diagnosed cases with a 1-12 month age of onset and who had hypsarrhythmia in their EEG were recruited and 43 were followed up for 3 years. Results: Of the children followed up, 51% were seizure-free and 37% had a normal EEG at the 3-year follow-up. Autistic features were seen in 74% of the children. Only 22.7% among the seizure-free (11.6% of the total) children had normal vision and hearing, speech with narration, writing skills, gross and fine motor development, and no autism or hyperactivity. On multivariate analysis, two factors could predict bad seizure outcome — the occurrence of other seizures in addition to infantile spasms and no response to 28 days of adrenocorticotropic hormone (ACTH). No predictor could be identified for abnormal psychomotor development. Discussion and Conclusion: In our study, we could demonstrate two factors that predict seizure freedom. The cognitive outcome and seizure control in this group of children are comparable to the existing literature. However, the cognitive outcome revealed by our study and the survey of the literature are discouraging. PMID:27293335

  16. Cuento infantil ilustrado. Fisicamente editado

    OpenAIRE

    SÁNCHEZ FLORES, CRISTINA

    2015-01-01

    Se trata de un proyecto enfocado a la creación de un cuento infantil, escrito e ilustrado por la alumna. La memoria detalla cada parte del trabajo en su totalidad, describiendo de forma concisa el trabajo realizado en estos últimos meses, con el fin de crear un proyecto donde se aplique, integre y desarrolle los conocimientos, capacidades competencias y habilidades adquiridas durante los cuatro años del grado en Bellas Artes. El proyecto se ha basado en la ilustración, una de las muchas ramas...

  17. Tuina Treatment of Infantile Eczema

    Institute of Scientific and Technical Information of China (English)

    ZHAO Xiao-mei; LI Dong

    2004-01-01

    以推拿疗法联合西药治疗20例小儿湿疹患者,并以西药治疗18例作对照.两组有效率分别为100%和90.0%,疗效有差异(P<0.01).%Twenty cases of infantile eczema were treated by combination of Tuina therapy and Western medications, and 18 cases were treated by Western medications. The therapeutic effective rate was respectively 100% and 90.0% in the two groups, with a difference between them (P< 0.01).

  18. Massage for Infantile Colic: Review and Literature

    Directory of Open Access Journals (Sweden)

    Hamidreza Bahrami

    2016-06-01

    Full Text Available Background Infantile colic is a painful phase in the first months of infancy but no safe and effective conventional treatment exists. Massage is used in traditional medicine as a control and treatment method for infantile colic. The aim of this study is to evaluate the efficacy and safety of massage in the control and treatment of infantile colic. Materials and Methods We searched international database such as PubMed, EMBASE, Cochrane library, and Iranian databases such as SID, Magiran, Iranmedex using a searching strategy with key words "Infantile colic", "Massage", "Complementary of Alternative Medicine" during 2000 to 2015. Analysis of data extraction and quality evaluation of the literature were performed independently by two investigators. Results Most articles provides the strongest evidence for benefits of massage in stress, anxiety reduction, pain control, cancer, skin disease, weight gain, sleep, promote growth, development in premature infants, neuromuscular and gastrointestinal disease such as infantile colic. The infantile colic massage helps relax the gastrointestinal tract and good digestion.   Conclusion Our findings demonstrated that pediatric massage therapy is effective in the treatment of infantile colic.  Compared to other possible treatments for colic, massage is a safe and enjoyable procedure; the risk of serious adverse effects is low. The pediatrician should feel comfortable discussing massage therapy with patients and be able to refer patients to a qualified massage therapist as appropriate.

  19. The ligamento-muscular stabilizing system of the spine.

    Science.gov (United States)

    Solomonow, M; Zhou, B H; Harris, M; Lu, Y; Baratta, R V

    1998-12-01

    Electrical and mechanical stimulation of the lumbar supraspinous ligament of three patients with L4-L5 spinal deficits and of the feline model, respectively, was applied while recording electromyography on the multifidus muscles. To determine if mechanoreceptors in the human spine can reflexively recruit muscle force to stabilize the lumbar spine, and to demonstrate, in the feline model, that such ligamento-muscular synergy is elicited by mechanical deformation of the lumbar supraspinous ligament (and possibly of other spinal ligaments), the facet joint capsule, and the disc. The literature repeatedly confirms that ligaments have only a minor mechanical role in maintaining spine stability, and that muscular co-contraction of anterior and posterior muscles is the major stabilizing mechanism of the spine. The literature also points out that various sensory receptors are present in spinal ligaments, and that the ligaments are innervated by spinal and autonomic nerves. Data that describe how ligaments and muscles interact to provide stability to the spine were not found. The supraspinous ligament at L2-L3 and L3-L4 was electrically stimulated in three patients undergoing surgery to correct deficits at L4-L5. Electromyography was performed from the multifidus muscles at L2-L3 and L3-L4, bilaterally. In 12 cats, the supraspinous ligaments from L1-L2 to L6-L7 were mechanically deformed, sequentially, while electromyography was performed from the multifidus muscles of the six levels. Loading of the ligament was applied before and after each of the two vertebrae were externally fixed to prevent motion. Electromyograms were recorded from the multifidus muscles, bilaterally, in the two of the three patients, demonstrating a direct relationship to receptors in the supraspinous ligament. Electromyograms were recorded from the feline multifidus muscle with mechanical loading of the supraspinal ligament at each of the L1-L2 to L6-L7 motion segments. In the free-spine condition

  20. Muscle biopsy in Pompe disease Biópsia muscular na doença de Pompe

    Directory of Open Access Journals (Sweden)

    Lineu Cesar Werneck

    2013-05-01

    Full Text Available Pompe disease (PD can be diagnosed by measuring alpha-glucosidase levels or by identifying mutations in the gene enzyme. Muscle biopsies can aid diagnosis in doubtful cases. Methods: A review of muscle biopsy from 19 cases of PD (infantile, 6 cases; childhood, 4 cases; and juvenile/adult, 9 cases. Results: Vacuoles with or without glycogen storage were found in 18 cases. All cases had increased acid phosphatase activity. The vacuole frequency varied (almost all fibers in the infantile form to only a few in the juvenile/adult form. Atrophy of type 1 and 2 fibers was frequent in all forms. Atrophic angular fibers in the NADH-tetrazolium reductase and nonspecific esterase activity were observed in 4/9 of the juvenile/adult cases. Conclusion: Increased acid phosphatase activity and vacuoles were the primary findings. Most vacuoles were filled with glycogen, and the adult form of the disease had fewer fibers with vacuoles than the infantile or childhood forms.O diagnóstico da doença de Pompe (PD pode ser feito pela dosagem da enzima alfa-glicosidase ou pela mutação do seu gene codificador. A biópsia muscular pode ajudar em casos duvidosos. Métodos: Revisão das biópsias musculares de 19 casos de PD (forma infantil, 6 casos; infantil tardia, 4; e juvenil/adulto, 9. Resultados: Encontrados vacúolos em 18 casos, com ou sem depósito de glicogênio. Todos mostraram aumento da fosfatase ácida. Os vacúolos estavam presentes na maioria das fibras nas formas infantis, menos frequentes nas formas juvenil e mais raros nas formas do adulto. A atrofia de fibras dos tipos 1 e 2 ocorreram em todas as formas. Fibras atróficas na NADH-tetrazolium redutase e esterase não específica foram observadas em 4/9 das formas infantil tardia/adulta. Conclusões: Os dados mais frequentes foram vacúolos, preenchidos por glicogênio com atividade aumentada da fosfatase ácida. A forma adulta apresenta menor número de vacúolos que as formas infantil e infantil

  1. Un caso de psicosis infantil

    Directory of Open Access Journals (Sweden)

    Andrea Obando Cuellar

    2012-01-01

    Full Text Available Se expondrá el caso de Samuel un niño de 8 años de edad hospitalizado aparentemente por un cuadrode ansiedad, que en su evolución, y acorde a la evaluación clínica, expone claramente la sintomatología de una psicosis infantil. El proceso de evaluación indica cuadro psicótico infantil, presencia de fobias arcaicas, terrores sin nombre y desestructuración de la organización lingüística. Su sintomatología refiere manifestaciones somáticas, una sensación constante de amenazas externas a su juicio de realidad; y sensaciones de despersonalización y desbordamientos de su pensamiento. El mundo de las ideas sobrepasa al mundo de los afectos. Se presenta un infante matizado por fantasías de aniquilamiento y desafíos constantes de la aceptación de la realidad. Sobre el caso de Samuel, cabe mencionar que durante el proceso de hospitalización y recursos, los padres no concretarola asistencia terapéutica, ni la posibilidad de brindar un espacio analítico para la comprensión de la lógica y significado del evento traumático y la fantasía desorganizadora de la pérdida paterna. Nos preguntamos cuál era el significante de Samuel.

  2. Surdez infantil Childhood hearing impairment

    Directory of Open Access Journals (Sweden)

    Pedro Oliveira

    2002-05-01

    Full Text Available A Surdez Infantil é considerada actualmente um verdadeiro problema de Saúde Pública devido não só à sua elevada prevalência, mas sobretudo às múltiplas conseqüências que acarreta sob os mais variados prismas. Trata-se de um tema em constante evolução, sendo necessárias freqüentes actualizações por forma a acompanhar os avanços da técnica e do conhecimento. Este trabalho visa abordar de uma forma global mas sucinta o problema Surdez Infantil, dando particular ênfase aos Modelos de Rastreio e aos Métodos utilizados com esse fim.Childhood Hearing Impairment is nowadays considered as a Health Care matter due to its high prevalence and to its multiple consequences. As a developing subject, frequent updates are justified to keep up with the evolution of techniques and knowledge. This paper aims to discuss the matter from a global point of view, paying particular attention to the Screening Models and Instruments available.

  3. VIOLENCIA FAMILIAR Y MALTRATO INFANTIL

    Directory of Open Access Journals (Sweden)

    María Inés Bringiotti

    2005-01-01

    Full Text Available Este trabajo analiza las implicaciones del concepto "familia" señalando la multiplicidad de fenómenos y situaciones incluidos en el mismo. Su elucidación permitirá determinar los diversos tipos de familia y de riesgo que podemos encontrar en nuestro trabajo cotidiano. La evolución de ese concepto está directamente influida por las determinantes socioestructurales y culturales que en cada momento histórico contextualizan a los sujetos, así como las posibles situaciones de riesgo que deben enfrentar y los recursos con los que cuentan. Se analiza la influencia de las representaciones acerca de cómo debe ser una familia, en la actualidad las familias presentan diferentes formas o estructuras y ello no implica el cumplimiento o no de sus funciones. Esto permitirá establecer adecuadamente las diferentes estrategias de prevención y abordaje aplicables a cada situación. Se ejemplificará concretamente con situaciones problemáticas relacionados a los casos de violencia familiar y maltrato infantil, concretamente con la negligencia y el abuso sexual infantil.

  4. Clinical management of infantile cholelithiasis.

    Science.gov (United States)

    Jeanty, Cerine; Derderian, S Christopher; Courtier, Jesse; Hirose, Shinjiro

    2015-08-01

    Infantile cholelithiasis is a rare disease process, and management strategies are poorly defined. We therefore examined the risk factors, complications, and management of this disease at our institution. We retrospectively reviewed infants with cholelithiasis diagnosed on ultrasound between 1997 and 2013. Details of the patient's medical history, presentation, imaging findings, laboratory values, and treatment were reviewed and analyzed. Over the 16-year period, 50 infants were evaluated for cholelithiasis. Thirty-seven (74%) had at least one risk factor for gallstone development which included total parenteral nutrition, diuretic therapy, cephalosporin antibiotic treatment, sepsis, congenital heart disease (CHD), prematurity, or a malabsorptive gastrointestinal condition. Thirteen (26%) infants were symptomatic, most commonly presenting with emesis and jaundice. Complications from gallstones included choledocholithiasis (9), cholecystitis (3), and pancreatitis (1). Nearly half (6/13) of patients with complicated cholelithiasis had CHD. Of infants presenting with complications, 9 had a cholecystectomy, most commonly via a laparoscopic approach, 2 had an ERCP for choledocholithiasis, and 2 were medically managed. In patients managed conservatively, resolution of gallstones occurred in 25%. Infantile cholelithiasis has variable outcomes ranging from spontaneous resolution to choledocholithiasis or cholecystitis. While patients with complicated cholelithiasis often undergo an operation, infants <1year of age have higher anesthetic and surgical risks. Conservative management with ERCP or medical treatment can also be successful, which offers an alternative to operative intervention in properly selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Study on Genetic Diagnosis of Spinal Muscular Atrophy

    Institute of Scientific and Technical Information of China (English)

    丁新生; 姚娟; 程虹; 王颖; 侯熙德

    1998-01-01

    IntroductionChildhood-onsetspinalmuscularatrophy(SMA)isanautosomalrecessivedisease,afect-ing1/6000birthsinnorthAmericanandEur...

  6. Desmoplastic infantile ganglioglioma : a case report

    Energy Technology Data Exchange (ETDEWEB)

    Park, Won Kyu; Byun, Woo Mok; Kim, Dong Suk [Yeungnam Univ. School of Medicine, Kyongsan (Korea, Republic of)

    1999-05-01

    Desmoplastic infantile ganglioglioma is an uncommon variety of ganglioglioma that shows evidence of glial and ganglionic differentiation accompanied by an extreme desmoplastic reaction. A 16-month-old girl was admitted with a six-day history of left hemiparesis. MR imaging demonstrated a large multiseptated cystic mass, with a solid portion, in the white matter of the right frontotemporoparietal lobe. After contrast injections, the solid portion was clearly enhanced. The presence of desmoplastic infantile ganglioglioma was confirmed by surgical resection. We describe the characteristic radiologic and pathologic features of desmoplastic infantile ganglioglioma, and include a review of the literature.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Modifying muscular dystrophy through TGFβ

    OpenAIRE

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

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

  9. Genetics of Infantile Bilateral Striatal Necrosis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-09-01

    Full Text Available The gene mutation causing autosomal recessive infantile bilateral striatal necrosis (IBSN was identified in eight consanguineous Israeli Bedouin families, in a study at Schneider Children’s Medical Center, Petah Tikva, Israel, and other centers.

  10. Linear Nevus Sebaceum Syndrome and Infantile Spasms

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2008-03-01

    Full Text Available Two infants with linear nevus sebaceum syndrome and infantile spasms are reported from Safra Childrens Hospital, Sheba Medical Center, Tel Hashomer, Israel; and Hospital for Sick Children, Toronto, Canada.

  11. Infantile myofibromatosis: report of nine patients.

    Science.gov (United States)

    Larralde, Margarita; Hoffner, Mariana V; Boggio, Paula; Abad, María Eugenia; Luna, Paula C; Correa, Noemí

    2010-01-01

    Infantile myofibromatosis is a rare fibrous tumor of infancy that can be solitary or multiple. Although most of the cases are limited to the skin, in some instances systemic involvement can be present. Solitary tumors limited to the skin usually present a good prognosis with spontaneous regression. We performed a retrospective observational review of the clinical and pathologic characteristics of nine patients diagnosed as having infantile myofibromatosis, followed during a 10-year period in a Pediatric Dermatology Department.

  12. [Muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy].

    Science.gov (United States)

    Kulikov, A G; Tabiev, V I; Rassulova, M A

    2015-01-01

    The objective of the present study was to evaluate the possibilities for the correction of muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy. The study included 55 patients randomly allocated to two groups. Group 1 was comprised of the patients treated with the use of the common mineral baths, physiotherapy, therapeutic physical exercises, spinal massage, and whole body air-cryotherapy. Group 2 contained the patients who were treated in a similar way with the exception of whole body cryotherapy; they served as controls. Muscular disorders were diagnosed by means of functional muscular testing. The study has demonstrated the high prevalence of muscular disorders in the patients suffering from ankylosing spondylitis. Moreover, it revealed the profile of such disorders associated with ankylosing spondylitis and showed significant correlation between the results of functional muscular testing, BASMI and BASFI indices as well as characteristics of chest excursions (pankylosing spondylitis. It is concluded that the proposed approach can be recommended for the introduction in the combined therapeutic and rehabilitative treatment of muscular disorders associated with ankylosing spondylitis.

  13. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy.

    Science.gov (United States)

    Sun, Guilian; Haginoya, Kazuhiro; Wu, Yanling; Chiba, Yoko; Nakanishi, Tohru; Onuma, Akira; Sato, Yuko; Takigawa, Masaharu; Iinuma, Kazuie; Tsuchiya, Shigeru

    2008-04-15

    The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.

  14. Bed Rest Muscular Atrophy

    Science.gov (United States)

    Greenleaf, John E.

    2000-01-01

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

  15. Bed Rest Muscular Atrophy

    Science.gov (United States)

    Greenleaf, John E.

    2000-01-01

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

  16. Linfonodo pulmonar na paracoccidioidomicose aguda infantil (relato de um caso

    Directory of Open Access Journals (Sweden)

    Evanil Pires de Campos

    1992-09-01

    Full Text Available Observou-se a evolução de um linfonodo pulmonar na paracoccidioidomicose (PCM aguda infantil. Doente, masculino, 6 anos, branco, natural de Curitiba (PR, procedente de Guaratinguetá (SP, que há 3 meses desenvolveu quadro gripal, febre diária, bimodal, prolongada, precedida de calafrio, acompanhada de sudorese inodora, cefaléia frontal e anorexia. Diagnosticado e tratado como pneumonia por cinco dias, sem melhora do quadro. Há 2 meses, apresentou dor óssea nos braços e articulações do pé, com edema inflamatório e emagrecimento de 6 kg em 3 meses. Exame físico revelou: peso 20 kg; estatura 120 cm; P. A. 90/60 mmHg; facies atípica, hipoativo, palidez cutâneo-mucosa (+ +, hipotrofia muscular, adenopatiageneralizada, sopro sistólico suave em foco aórtico acessório e hepatesplenomegalia. Imunodifusão com exoantígeno glicoprotéico 43 kdpositiva (1/32. A biópsia de gânglio revelou Paracoccidioides brasiliensis. A radiologia demonstrou na primeira consulta, discreto infiltrado intersticial bilateral com linfoadenomegaliapara-hilar que desaparecu em 30 dias. Observou- se, ainda, massa tumoral mediastínica superior, hiperplasia do sistema fagocítico mononuclear e lesões osteolíticas nos 60 dias iniciais da evolução.

  17. Adolescent scar contracture scoliosis caused by back scalding during the infantile period

    Science.gov (United States)

    Wang, S. F.; Wang, B.; Wu, L.; Zhu, F.

    2007-01-01

    The study design was a retrospective study in adolescent scar contracture scoliosis caused by back scalding during the infantile period. The objective of the study was to investigate the pathogenesis, clinical manifestation and treatment of adolescent scar contracture scoliosis caused by back scalding during the infantile period. This condition seldom occurs and is not reported in current English literature. One patient was first treated with skin expansion, back scar excision and skin flap transfer, followed by anterior correction with TSRH instrumentation. Two patients were first treated with back scar excision and anterior spinal release. One patient was treated with posterior correction with TSRH instrumentation, and thoracoplasty was performed after 50 days in halo-wheelchair traction. The other patient was treated with posterior correction with TSRH instrumentation. No management of scalding was performed on the fourth patient. Anterior release and posterior correction were performed at an interval of 3 weeks. The deformities of four patients were well corrected. Trunk balance was restored and the pelvis leveled. The skin incision wounds healed well. Minor loss of correction was recorded during the last follow-up. Severe scar contracture caused by back scalding during the infantile period could lead to adolescent scoliosis. Its pathogenesis and clinical manifestation are different from the typical adolescent idiopathic scoliosis. The treatment of this kind of scoliosis should be individualized. PMID:17497186

  18. Spinal Cord Contusion

    Institute of Scientific and Technical Information of China (English)

    Gong Ju; Jian Wang; Yazhou Wang; Xianghui Zhao

    2014-01-01

    Spinal cord injury is a major cause of disability with devastating neurological outcomes and lim-ited therapeutic opportunities, even though there are thousands of publications on spinal cord injury annually. There are two major types of spinal cord injury, transaction of the spinal cord and spinal cord contusion. Both can theoretically be treated, but there is no well documented treatment in human being. As for spinal cord contusion, we have developed an operation with fabulous result.

  19. Acquired lumbar spinal stenosis.

    Science.gov (United States)

    Deasy, JoAnn

    2015-04-01

    Lumbar spinal stenosis is the most frequent reason for spinal surgery in patients over age 65 years. In this condition, narrowing of the lumbar spinal canal and nerve root canals leads to painful, debilitating compression of spinal nerves and blood vessels. As the population ages, an increasing number of patients will be diagnosed and treated for lumbar spinal stenosis by primary care providers. This article reviews the pathophysiology, diagnosis, and management of lumbar spinal stenosis in adults over age 50 years.

  20. Genetics Home Reference: infantile-onset spinocerebellar ataxia

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions IOSCA infantile-onset spinocerebellar ataxia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Infantile-onset spinocerebellar ataxia ( IOSCA ) is a progressive disorder that affects the ...