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Sample records for spinobulbar muscular atrophy

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

    DEFF Research Database (Denmark)

    Dahlqvist, Julia Rebecka; Vissing, John

    2016-01-01

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

  2. 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.

  3. Differences in F-wave characteristics between Spinobulbar Muscular Atrophy and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Jia eFang

    2016-03-01

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

  4. Spinal Muscular Atrophy FAQ

    Science.gov (United States)

    ... SMA: Frequently Asked Questions What is Spinal Muscular Atrophy? Spinal Muscular Atrophy (SMA) is a genetic neuromuscular ... future trials in SMA. What is Spinal Muscular Atrophy with Respiratory Distress (SMARD)? SMARD and SMA are ...

  5. 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.

  6. Muscular atrophy in diabetic neuropathy

    DEFF Research Database (Denmark)

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

    1997-01-01

    Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non...... confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains...

  7. 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 ...

  8. Spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Lieberman, Andrew P

    2018-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative disorder of the neuromuscular system resulting in slowly progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease is caused by the expansion of a CAG/glutamine tract in the amino-terminus of the androgen receptor. That SBMA exclusively affects males reflects the fact that critical pathogenic events are hormone-dependent. These include translocation of the polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding of the mutant protein. Studies of the pathology of SBMA subjects have revealed nuclear aggregates of the mutant androgen receptor, loss of lower motor neurons in the brainstem and spinal cord, and both neurogenic and myopathic changes in skeletal muscle. Mechanisms underlying disease pathogenesis include toxicity in both lower motor neurons and skeletal muscle, where effects on transcription, intracellular transport, and mitochondrial function have been documented. Therapies to treat SBMA patients remain largely supportive, although experimental approaches targeting androgen action or promoting degradation of the mutant androgen receptor protein or the encoding RNA are under active study. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Therapeutics development for spinal muscular atrophy

    OpenAIRE

    Sumner, Charlotte J.

    2006-01-01

    Spinal muscular atrophy is an autosomal recessive motor neuron disease that is the leading inherited cause of infant and early childhood mortality. Spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1), but all patients retain a centromeric copy of the gene,SMN2. SMN2 produces reduced amounts of full-length SMN mRNA, and spinal muscular atrophy likely results from insufficient levels of SMN protein in motor neurons. The SMN protein plays ...

  10. Genetics Home Reference: spinal muscular atrophy

    Science.gov (United States)

    ... Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle Nerve. 2006 Dec;34(6):731-9. Citation on PubMed Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor ...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

  13. Neuronal involvement in muscular atrophy

    Directory of Open Access Journals (Sweden)

    Bruno Alejandro Cisterna

    2014-12-01

    Full Text Available The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels formed by connexins and other none selective channels, including P2X7 receptors, TRPV2 channels were demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically prevented in denervated muscles deficient in connexins 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned none selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., BDNF, agrin/Lrp4/MuSK and acetylcholine are among the possible perpetrators of repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.

  14. 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

  15. 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Rusmini, Paola; Simonini, Francesca; Crippa, Valeria; Bolzoni, Elena; Onesto, Elisa; Cagnin, Monica; Sau, Daniela; Ferri, Nicola; Poletti, Angelo

    2011-01-01

    Several types of motorneuron diseases are linked to neurotoxic mutant proteins. These acquire aberrant conformations (misfolding) that trigger deleterious downstream events responsible for neuronal dysfunction and degeneration. The pharmacological removal of misfolded proteins might thus be useful in these diseases. We utilized a peculiar motorneuronal disease model, spinobulbar muscular atrophy (SBMA), in which the neurotoxicity of the protein involved, the mutant androgen receptor (ARpolyQ), can be modulated by its ligand testosterone (T). 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) has already been proven to exert beneficial action in SBMA. Here we demonstrated that 17-AAG exerts its pro-degradative activity on mutant ARpolyQ without impacting on proteasome functions. 17-AAG removes ARpolyQ misfolded species and aggregates by activating the autophagic system. We next analyzed the 17-AAG effects on two proteins (SOD1 and TDP-43) involved in related motorneuronal diseases, such as amyotrophic lateral sclerosis (ALS). In these models 17-AAG was unable to counteract protein aggregation. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Advances in spinal muscular atrophy therapeutics.

    Science.gov (United States)

    Parente, Valeria; Corti, Stefania

    2018-01-01

    Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.

  17. 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.

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

    African Journals Online (AJOL)

    Rabah M. Shawky

    Deletion;. Chromosome 5;. Mutations. Abstract Spinal muscular atrophy (SMA) is characterized by progressive hypotonia and muscular weakness because of progressive degeneration of alpha motor neuron from anterior horn cells in the spinal cord. It is inherited by an autosomal recessive pattern. The precise frequency of ...

  19. Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

    Science.gov (United States)

    Montes, Jacqueline; Glanzman, Allan M; Mazzone, Elena S; Martens, William B; Dunaway, Sally; Pasternak, Amy; Riley, Susan O; Quigley, Janet; Pandya, Shree; De Vivo, Darryl C; Kaufmann, Petra; Chiriboga, Claudia A; Finkel, Richard S; Tennekoon, Gihan I; Darras, Basil T; Pane, Marika; Mercuri, Eugenio; Mcdermott, Michael P

    2015-12-01

    With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. © 2015 Wiley Periodicals, Inc.

  20. Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report

    Directory of Open Access Journals (Sweden)

    Scola Rosana Herminia

    2001-01-01

    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.

  1. LINKAGE MAPPING OF THE SPINAL MUSCULAR-ATROPHY GENE

    NARCIS (Netherlands)

    BURGHES, AHM; INGRAHAM, SE; KOTEJARAI, Z; ROSENFELD, S; HERTA, N; NADKARNI, N; DIDONATO, CJ; CARPTEN, J; HURKO, O; FLORENCE, J; MOXLEY, RT; COBBEN, JM; MENDELL, [No Value

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder resulting in loss of motor neurons. We have performed linkage analysis on a panel of families using nine markers that are closely linked to the SMA gene. The highest lod score was obtained with the marker D5S351 (Z(max) = 10.04

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  3. Interpretation of electrodiagnostic findings in sporadic progressive muscular atrophy

    NARCIS (Netherlands)

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

    2008-01-01

    Objective We present the electrophysiologic data at baseline of 37 patients who were included in our prospective study on sporadic adult-onset progressive muscular atrophy (PMA). The aim was to correlate electrophysiological. signs of lower motor neuron (LMN) loss with clinical signs of LMN loss,

  4. The diagnostic dilemma of progressive muscular atrophy.

    Science.gov (United States)

    Ayaz, Saeed Bin; Matee, Sumeera; Gill, Zaheer Ahmed; Khan, Atif Ahmed

    2015-02-01

    Progressive muscle atrophy is a rare subtype of motor neuron disease that affects only the lower motor neurons and presents as asymmetrical rapidly progressive muscle weakness, atrophy and normal sensations. The diagnostic electrophysiological findings are denervation potentials in three out of four body segments (bulbar, cervical, thoracic and lumbosacral). The disease is fatal and the management is supportive. We present the report of a 45-year-old female patient who presented with unilateral foot drop and rapidly progressed to profound weakness in muscles of all limbs, neck and back along with dysarthria and dysphagia. She had been operated twice for suspected cervical and lumbosacral intervertebral disc herniations and ultimately guided in right direction after muscle biopsy, nerve conduction studies and electromyography.

  5. Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells.

    Science.gov (United States)

    Oates, Emily C; Reddel, Stephen; Rodriguez, Michael L; Gandolfo, Luke C; Bahlo, Melanie; Hawke, Simon H; Lamandé, Shireen R; Clarke, Nigel F; North, Kathryn N

    2012-06-01

    Autosomal dominant congenital spinal muscular atrophy is characterized by predominantly lower limb weakness and wasting, and congenital or early-onset contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown. It has been hypothesized that differences in the timing and site of anterior horn cell loss in the central nervous system account for the variations in clinical phenotype between different forms of spinal muscular atrophy, but there has been a lack of neuropathological data to support this concept in dominant congenital spinal muscular atrophy. We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a reduction in anterior horn cell number in the lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the ventral nerve roots at these levels, in the absence of additional peripheral nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young age of the child at the time of autopsy, there was no pathological evidence of ongoing loss or degeneration of anterior horn cells suggesting that anterior horn cell loss in dominant congenital spinal muscular atrophy occurs in early life, and is largely complete by the end of infancy. These findings confirm that dominant congenital spinal muscular atrophy is a true form of spinal

  6. Hereditary distal spinal muscular atrophy with vocal cord paralysis.

    OpenAIRE

    Young, I D; Harper, P S

    1980-01-01

    A large kindred is described in which an unusual form of spinal muscular atrophy is segregating in an autosomal dominant manner. The disease presents most commonly in the teens with small muscle wasting in the hands, particularly involving median nerve musculature. Subsequently distal muscle wasting and weakness occur in the lower limbs. Vocal cord paralysis is a characteristic and potentially hazardous feature. No previous report of this condition has been found.

  7. New Frontiers in the Treatment of Spinal Muscular Atrophy

    LENUS (Irish Health Repository)

    Power, CL

    2018-03-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, with a current estimated incidence of 1 in 11,000 live births. Although there is a variable phenotype, 60% of patients with SMA have type 1 disease. Typically diagnosed by the age of six months, this severe form of the condition is characterised by progressive weakness and the failure to meet motor milestones. There is an early need for permanent assisted ventilation, without which the median life expectancy is less than two years.\\r\

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

    Science.gov (United States)

    Liew, Wendy K. M.

    2013-01-01

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

  9. 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.

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

    NARCIS (Netherlands)

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

    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

  11. Splice-Switching Therapy for Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Katharina E. Meijboom

    2017-06-01

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

  12. Pilot trial of clenbuterol in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Querin, Giorgia; D'Ascenzo, Carla; Peterle, Enrico; Ermani, Mario; Bello, Luca; Melacini, Paola; Morandi, Lucia; Mazzini, Letizia; Silani, Vincenzo; Raimondi, Monika; Mandrioli, Jessica; Romito, Silvia; Angelini, Corrado; Pegoraro, Elena; Sorarù, Gianni

    2013-06-04

    To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p clenbuterol on SBMA disease progression. This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.

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

    NARCIS (Netherlands)

    de Visser, M.; Verbeeten, B.

    1985-01-01

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

  14. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Saif Ahmad

    2016-01-01

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

  15. Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

    Science.gov (United States)

    Nash, L A; Burns, J K; Chardon, J Warman; Kothary, R; Parks, R J

    2016-01-01

    Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    Science.gov (United States)

    Tisdale, Sarah

    2015-01-01

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

  17. 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.

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

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    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.

  19. Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy.

    Science.gov (United States)

    Farrar, Michelle A; Vucic, Steve; Lin, Cindy S-Y; Park, Susanna B; Johnston, Heather M; du Sart, Desirée; Bostock, Hugh; Kiernan, Matthew C

    2011-11-01

    Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K(+) and Na(+) conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

  20. Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: evidence of activity-dependent conduction block.

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    Noto, Yu-ichi; Misawa, Sonoko; Mori, Masahiro; Kawaguchi, Naoki; Kanai, Kazuaki; Shibuya, Kazumoto; Isose, Sagiri; Nasu, Saiko; Sekiguchi, Yukari; Beppu, Minako; Ohmori, Shigeki; Nakagawa, Masanori; Kuwabara, Satoshi

    2013-09-01

    To clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders. We assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s-SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects. The FSS score was the highest in SMA/SBMA patients [4.9 ± 1.1 (mean ± SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 ± 1.0), whereas patients with multiple sclerosis (4.3 ± 1.6), myasthenia gravis (4.0 ± 1.6) or CIDP (4.3 ± 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls. SMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity. ADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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

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    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.

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

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    Melissa Bowerman

    2017-08-01

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

  3. Increasing Agrin Function Antagonizes Muscle Atrophy and Motor Impairment in Spinal Muscular Atrophy

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    Marina Boido

    2018-01-01

    Full Text Available Spinal muscular atrophy (SMA is a pediatric genetic disease, characterized by motor neuron (MN death, leading to progressive muscle weakness, respiratory failure, and, in the most severe cases, to death. Abnormalities at the neuromuscular junction (NMJ have been reported in SMA, including neurofilament (NF accumulation at presynaptic terminals, immature and smaller than normal endplates, reduced transmitter release, and, finally, muscle denervation. Here we have studied the role of agrin in SMAΔ7 mice, the experimental model of SMAII. We observed a 50% reduction in agrin expression levels in quadriceps of P10 SMA mice compared to age-matched WT controls. To counteract such condition, we treated SMA mice from birth onwards with therapeutic agrin biological NT-1654, an active splice variant of agrin retaining synaptogenic properties, which is also resistant to proteolytic cleavage by neurotrypsin. Mice were analyzed for behavior, muscle and NMJ histology, and survival. Motor behavior was significantly improved and survival was extended by treatment of SMA mice with NT-1654. At P10, H/E-stained sections of the quadriceps, a proximal muscle early involved in SMA, showed that NT-1654 treatment strongly prevented the size decrease of muscle fibers. Studies of NMJ morphology on whole-mount diaphragm preparations revealed that NT-1654-treated SMA mice had more mature NMJs and reduced NF accumulation, compared to vehicle-treated SMA mice. We conclude that increasing agrin function in SMA has beneficial outcomes on muscle fibers and NMJs as the agrin biological NT-1654 restores the crosstalk between muscle and MNs, delaying muscular atrophy, improving motor performance and extending survival.

  4. SPINAL MUSCULAR ATROPHY FROM NORTHERN IRAN: A CLINICAL AND GENETIC SPECTRUM OF TEN PATIENTS

    OpenAIRE

    M.R. Salehi Omran; A. Ghabeli Juibary

    2008-01-01

    AbstractObjectiveAutosomal recessive spinal muscular atrophy (SMA) is, after cystic fibrosis, the second most common fatal monogenic disorder and the second most common hereditary neuromuscular disease after duchenne dystrophy. The disease is characterized by degeneration of anterior horn cells leading to progressiveparalysis with muscular atrophy. Depending on the clinical type (Werdnig- Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III), some workers also have de...

  5. Sensoric Protection after Median Nerve Injury: Babysitter-Procedure Prevents Muscular Atrophy and Improves Neuronal Recovery

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    Beck-Broichsitter, Benedicta E.; Becker, Stephan T.; Lamia, Androniki; Fregnan, Federica; Geuna, Stefano; Sinis, Nektarios

    2014-01-01

    The babysitter-procedure might offer an alternative when nerve reconstruction is delayed in order to overcome muscular atrophy due to denervation. In this study we aimed to show that a sensomotoric babysitter-procedure after median nerve injury is capable of preserving irreversible muscular atrophy. The median nerve of 20 female Wistar rats was denervated. 10 animals received a sensory protection with the N. cutaneous brachii. After six weeks the median nerve was reconstructed by autologous n...

  6. 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.

  7. Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy.

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    Yonekawa, Takahiro; Komaki, Hirofumi; Saito, Yuko; Sugai, Kenji; Sasaki, Masayuki

    2013-02-01

    We examined the specific nerve conduction deficits distinguishing spinal muscular atrophy (SMA) subtypes I and II. Five SMA I patients (age, 0.2-1.1 years) and 10 SMA II patients (age, 1.0-2.8 years) were examined. Patients were compared to age-matched controls for motor and sensory conduction velocity (MCV and SCV) changes, compound muscle and sensory nerve action potential amplitudes (CMAP and SNAP), and F-wave occurrence (FO). Slower MCVs were found in three of five SMA I patients; all five exhibited markedly decreased CMAP amplitudes. Tibial nerve CMAP amplitudes significantly reduced in SMA II patients (pnerve of SMA II patients (p=0.031). Loss of motor units may be widespread in the early stage of SMA I, while specific to the legs in young SMA II patients. SMA I showed sensory nerve degeneration, especially of large myelinated fibers. SMA II showed no sensory nerve abnormalities. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

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    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.

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

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

    2017-08-01

    Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 ± 9.1%, which corresponded to an average deceleration of 0.37 ± 0.28 mm/s 2 . Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. Muscle Nerve 56: 230-236, 2017. © 2016 Wiley Periodicals, Inc.

  10. Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy.

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    Niebroj-Dobosz, I; Hausmanowa-Petrusewicz, I

    1989-09-01

    Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in infantile and juvenile spinal muscular atrophy (SMA) was determined. The total AChE activity was either normal or decreased in the childhood SMA (Type 1), the other SMA groups and disease controls (ALS, X-linked SMA). In the majority of SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found. This was accompanied by changes in the other asymmetric and globular forms. The latter was, however, not specific for SMA Type 1 cases. The ChE activity was increased in the majority of SMA cases as well as disease controls. The asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes is obscure.

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

    Science.gov (United States)

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

    2017-12-12

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

  12. Emerging therapies and challenges in spinal muscular atrophy.

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    Farrar, Michelle A; Park, Susanna B; Vucic, Steve; Carey, Kate A; Turner, Bradley J; Gillingwater, Thomas H; Swoboda, Kathryn J; Kiernan, Matthew C

    2017-03-01

    Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368. © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

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

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    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

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

    OpenAIRE

    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 (...

  15. Clinical and biochemical polymorphism of spinal muscular atrophy

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    M. G. Sokolova

    2017-01-01

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

  16. Natural history of infantile-onset spinal muscular atrophy.

    Science.gov (United States)

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

    2017-12-01

    Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891. © 2017 American Neurological Association.

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

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    Alexandra Prufer de Q-C. Araújo

    2005-03-01

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

  18. [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.

  19. Synaptic defects in type I spinal muscular atrophy in human development.

    Science.gov (United States)

    Martínez-Hernández, Rebeca; Bernal, Sara; Also-Rallo, Eva; Alías, Laura; Barceló, María Jesús; Hereu, Marta; Esquerda, Josep E; Tizzano, Eduardo F

    2013-01-01

    Childhood spinal muscular atrophy is an autosomal recessive neuromuscular disorder caused by alterations in the Survival Motor Neuron 1 gene that triggers degeneration of motor neurons within the spinal cord. Spinal muscular atrophy is the second most common severe hereditary disease of infancy and early childhood. In the most severe cases (type I), the disease appears in the first months of life, suggesting defects in fetal development. However, it is not yet known how motor neurons, neuromuscular junctions, and muscle interact in the neuropathology of the disease. We report the structure of presynaptic and postsynaptic apparatus of the neuromuscular junctions in control and spinal muscular atrophy prenatal and postnatal human samples. Qualitative and quantitative data from confocal and electron microscopy studies revealed changes in acetylcholine receptor clustering, abnormal preterminal accumulation of vesicles, and aberrant ultrastructure of nerve terminals in the motor endplates of prenatal type I spinal muscular atrophy samples. Fetuses predicted to develop milder type II disease had a similar appearance to controls. Postnatal muscle of type I spinal muscular atrophy patients showed persistence of the fetal subunit of acetylcholine receptors, suggesting a delay in maturation of neuromuscular junctions. We observed that pathology in the severe form of the disease starts in fetal development and that a defect in maintaining the initial innervation is an early finding of neuromuscular dysfunction. These results will improve our understanding of the spinal muscular atrophy pathogenesis and help to define targets for possible presymptomatic therapy for this disease. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  20. Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

    OpenAIRE

    Pedro Enrique Jiménez Caballero

    2012-01-01

    Kennedy′s disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter′s syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klin...

  1. Genotype-Phenotype Correlation in Chinese Patients with Spinal and Bulbar Muscular Atrophy

    OpenAIRE

    Ni, Wang; Chen, Sheng; Qiao, Kai; Wang, Ning; Wu, Zhi-Ying

    2015-01-01

    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 o...

  2. 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…

  3. Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy

    NARCIS (Netherlands)

    Raaphorst, J.; de Visser, M.; van Tol, M.-J.; Linssen, W.H.J.P.; van der Kooi, A.J.; de Haan, R.J.; van den Berg, L.H.; Schmand, B.

    2011-01-01

    Aim In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to

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

    NARCIS (Netherlands)

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

    1995-01-01

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

  5. Correlates of health related quality of life in adult patients with Spinal Muscular Atrophy

    NARCIS (Netherlands)

    Kruitwagen-van Reenen, Esther Th; Wadman, Renske I; Visser-Meily, Johanna MA; van den Berg, Leonard H; Schröder, Carin; van der Pol, W Ludo

    2016-01-01

    Introduction To improve care for patients with spinal muscular atrophy (SMA), we assessed the physical and mental quality of life (QoL) in 62 adult patients with SMA. Methods Physical component scores (PCS) and mental component scores (MCS) of the Short Form -36 Health Survey (SF-36) were obtained.

  6. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

    NARCIS (Netherlands)

    Scoto, Mariacristina; Rossor, Alexander M.; Harms, Matthew B.; Cirak, Sebahattin; Calissano, Mattia; Robb, Stephanie; Manzur, Adnan Y.; Martínez Arroyo, Amaia; Rodriguez Sanz, Aida; Mansour, Sahar; Fallon, Penny; Hadjikoumi, Irene; Klein, Andrea; Yang, Michele; de Visser, Marianne; Overweg-Plandsoen, W. C. G. Truus; Baas, Frank; Taylor, J. Paul; Benatar, Michael; Connolly, Anne M.; Al-Lozi, Muhammad T.; Nixon, John; de Goede, Christian G. E. L.; Foley, A. Reghan; Mcwilliam, Catherine; Pitt, Matthew; Sewry, Caroline; Phadke, Rahul; Hafezparast, Majid; Chong, W. K. Kling; Mercuri, Eugenio; Baloh, Robert H.; Reilly, Mary M.; Muntoni, Francesco

    2015-01-01

    To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Science.gov (United States)

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

    2016-01-01

    Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. 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 (pmuscular atrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard

  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......) or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. CONCLUSIONS: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma...

  11. Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy

    OpenAIRE

    Farrar, Michelle A.; Vucic, Steve; Lin, Cindy S.-Y.; Park, Susanna B.; Johnston, Heather M.; du Sart, Desir?e; Bostock, Hugh; Kiernan, Matthew C.

    2011-01-01

    Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimul...

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

    OpenAIRE

    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 s...

  13. Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype of BICD2 mutations.

    Science.gov (United States)

    Rudnik-Schöneborn, Sabine; Deden, Florian; Eggermann, Katja; Eggermann, Thomas; Wieczorek, Dagmar; Sellhaus, Bernd; Yamoah, Alfred; Goswami, Anand; Claeys, Kristl G; Weis, Joachim; Zerres, Klaus

    2016-09-01

    Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496-500, 2016. © 2016 Wiley Periodicals, Inc.

  14. Muscle proteolytic system modulation through the effect of taurine on mice bearing muscular atrophy.

    Science.gov (United States)

    Khalil, Rania M; Abdo, Walied S; Saad, Ahmed; Khedr, Eman G

    2017-12-02

    Skeletal muscle atrophy occurs in different catabolic conditions and mostly accompanied with upregulation of Muscle ring finger 1 (MuRF1) gene which is one of the master regulatory genes in muscle atrophy. Taurine amino acid is widely distributed in different tissues and has anti-inflammatory and antioxidant effects. This study aimed to investigate the potential influence of taurine on muscle atrophy induced by reduced mechanical loading. Twenty-eight Albino mice were used, and divided equally into four groups: group I (control); group II (immobilization); group III (immobilization + taurine); and group IV (taurine). Quadriceps muscle sections were taken for histopathology, immunohistochemical analysis of caspase 3 expression, and qRT-PCR of MuRF1 gene. Our data revealed Zenker necrosis associated with axonal injury of the nerve trunk of the immobilized muscle together with increase of caspase 3 expression and upregulation of MuRF1 gene. While, taurine supplementation alleviated the muscular and neural tissues damage associated with disuse skeletal muscle atrophy through downregulation of MuRF1 gene and decrease of tissue caspase 3 expression. In conclusion, taurine may be helpful to counteract apoptosis and up-regulated MuRF1 gene expression related to muscle atrophy, which might be hopeful for a large number of patients.

  15. [Sporadic case of non-progressive neurogenic muscular atrophy localized in both calf muscles].

    Science.gov (United States)

    Hara, Kenju; Tateyama, Maki; Suzuki, Naoki; Shibano, Ken; Tanaka, Keiko; Ishiguro, Hideaki

    2013-01-01

    A 60-year-old woman was admitted to our hospital because of difficulty in standing on her toes. Neurological examination showed muscle weakness in both calf muscles. Her serum creatine kinase (CK) level was slightly elevated. MRI revealed hyper-intense signals localized in both the gastrocnemius and soleus muscles. Histological examinations of biopsied muscle specimens showed a marked variation in fiber size, small angular fibers, and hypertrophic and splitting fibers, but no muscle fiber necrosis or regeneration or inflammatory cell infiltration. ATPase stained sections showed small grouped atrophy of type 1 fibers. NADH-TR stained sections showed target/targetoid fibers predominantly in type 1 fibers. Dysferlin immunoreactivity was normal. Follow-up clinical evaluation for one year showed no progression. This patient was diagnosed as having an unknown type of spinal muscular atrophy or benign calf amyotrophy. Sporadic cases characterized by elderly-onset, neurogenic muscular atrophy localized in both calf muscles, and non-progressive course are extremely rare in Japan.

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

    Directory of Open Access Journals (Sweden)

    Irene Aicua

    2014-10-01

    Full Text Available 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.

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

    Science.gov (United States)

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

    2016-01-01

    Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern). Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  18. Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

    Directory of Open Access Journals (Sweden)

    Pedro Enrique Jiménez Caballero

    2012-01-01

    Full Text Available Kennedy′s disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter′s syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klinefelter′s syndrome. Genetic study of Kennedy′s disease was normal. Our patient differs from those with Kennedy′s disease in the absence of bulbar and sensory symptoms. It is suggested that the X chromosome plays an important role in the biology of motor neurons.

  19. 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.

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

    Science.gov (United States)

    Ni, Wang; Chen, Sheng; Qiao, Kai; Wang, Ning; Wu, Zhi-Ying

    2015-01-01

    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 (pnerve 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.

  1. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    Science.gov (United States)

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. © 2013 Anatomical Society.

  2. [Spinal muscular atrophy mimicking myotonic dystrophy: a case report and clinical, pathological and genetic analysis].

    Science.gov (United States)

    Luo, Li-xia; Pan, Qian; Xia, Kun; Tang, Bei-sha; Jiang, Hong

    2012-08-01

    To investigate a patient featuring a complex neuromuscular disease phenotype. A comprehensive analysis integrating clinical investigation, electrophysiological testing, pathological analysis and mutation screening was carried out. The patient has presented clinical and pathological manifestations mimicking Duchenne muscular dystrophy. However, genetic analysis has identified no deletion in 21 exons of Dystrophin gene, no pathologic expansion of CTG repeats in DMPK gene or CCTG repeats in ZFN9 gene. Instead, a homozygous deletion of exons 7 and 8 in SMN gene was discovered. A rare case of spinal muscular atrophy (SMA) was verified by genetic diagnosis. SMA is a group of neuromuscular disorders with great phenotypic heterogeneity and sometimes cannot be diagnosed by clinical manifestations, electrophysiological and pathological changes alone. Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.

  3. Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1.

    Science.gov (United States)

    Ikeda, Azusa; Yamashita, Sumimasa; Tsuyusaki, Yu; Tanaka, Mio; Tanaka, Yukichi; Hashiguchi, Akihiro; Takashima, Hiroshi; Goto, Tomohide

    2018-02-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2015-02-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures...... 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...

  6. 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.

  7. 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.

  8. Sensoric protection after median nerve injury: babysitter-procedure prevents muscular atrophy and improves neuronal recovery.

    Science.gov (United States)

    Beck-Broichsitter, Benedicta E; Becker, Stephan T; Lamia, Androniki; Fregnan, Federica; Geuna, Stefano; Sinis, Nektarios

    2014-01-01

    The babysitter-procedure might offer an alternative when nerve reconstruction is delayed in order to overcome muscular atrophy due to denervation. In this study we aimed to show that a sensomotoric babysitter-procedure after median nerve injury is capable of preserving irreversible muscular atrophy. The median nerve of 20 female Wistar rats was denervated. 10 animals received a sensory protection with the N. cutaneous brachii. After six weeks the median nerve was reconstructed by autologous nerve grafting from the contralateral median nerve in the babysitter and the control groups. Grasping tests measured functional recovery over 15 weeks. At the end of the observation period the weight of the flexor digitorum sublimis muscle was determined. The median nerve was excised for histological examinations. Muscle weight (P nerve fiber (P = 0.0409), and nerve surface (P = 0.0184) in the babysitter group. We conclude that sensory protection of a motor nerve is capable of preserving muscule weight and we may presume that metabolism of the sensory nerve was sufficient to keep the target muscle's weight and vitality.

  9. Sensoric Protection after Median Nerve Injury: Babysitter-Procedure Prevents Muscular Atrophy and Improves Neuronal Recovery

    Directory of Open Access Journals (Sweden)

    Benedicta E. Beck-Broichsitter

    2014-01-01

    Full Text Available The babysitter-procedure might offer an alternative when nerve reconstruction is delayed in order to overcome muscular atrophy due to denervation. In this study we aimed to show that a sensomotoric babysitter-procedure after median nerve injury is capable of preserving irreversible muscular atrophy. The median nerve of 20 female Wistar rats was denervated. 10 animals received a sensory protection with the N. cutaneous brachii. After six weeks the median nerve was reconstructed by autologous nerve grafting from the contralateral median nerve in the babysitter and the control groups. Grasping tests measured functional recovery over 15 weeks. At the end of the observation period the weight of the flexor digitorum sublimis muscle was determined. The median nerve was excised for histological examinations. Muscle weight (P<0.0001 was significantly superior in the babysitter group compared to the control group at the end of the study. The histological evaluation revealed a significantly higher diameter of axons (P=0.0194, nerve fiber (P=0.0409, and nerve surface (P=0.0184 in the babysitter group. We conclude that sensory protection of a motor nerve is capable of preserving muscule weight and we may presume that metabolism of the sensory nerve was sufficient to keep the target muscle’s weight and vitality.

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

    Science.gov (United States)

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

    2013-03-01

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

  11. Decremental responses to repetitive nerve stimulation in x-linked bulbospinal muscular atrophy.

    Science.gov (United States)

    Kim, Jee Young; Park, Kee Duk; Kim, Seung-Min; Sunwoo, Il Nam

    2013-01-01

    X-linked bulbospinal muscular atrophy (X-BSMA) is characterized by bulbar and spinal muscular weakness and fasciculations. Although X-BSMA is a motor neuronopathy, there are several reports of myasthenic symptoms or decremental responses to repetitive nerve stimulation (RNS). We report the results of applying the RNS test to 15 patients among 41 with genetically confirmed X-BSMA; these 15 patients complained of fatigue, ease of becoming tired, or early muscular exhaustion. The 3-Hz RNS test was performed on the trapezius, nasalis, orbicularis oculi, flexor carpi ulnaris, and abductor digiti quinti muscles. A decrement greater than 10% was considered abnormal. Additionally, a pharmacologic response to neostigmine was identified in three patients. A significant decrement was observed in 67% of patients, and was most common in the trapezius muscle (nine cases). The decrement of the trapezius muscle response ranged from 15.9% to 36.9%. The decrement was inversely correlated with the amplitude of compound muscle action potentials at rest. Neostigmine injection markedly improved the decrement in three patients, who showed noticeable decremental responses to 3-Hz RNS. This study shows that myasthenic symptoms and abnormal decremental responses to low-rate RNS are common in X-BSMA.

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Bowerman Melissa

    2012-03-01

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

  14. 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

  15. Is head balance a major determinant for swallowing problems in patients with spinal muscular atrophy type 2?

    NARCIS (Netherlands)

    Engel-Hoek, L. van den; Swart, B.J.M. de; Erasmus, C.E.; Groot, I.J.M. de

    2008-01-01

    A child with spinal muscular atrophy type 2 was referred for evaluation of eating and swallowing problems. The dysphagia evaluation demonstrated coughing during eating and drinking and occasionally stertorous when eating solid food. The videofluoroscopic swallow study showed a late upper esophageal

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

    Science.gov (United States)

    Custer, Sara K; Androphy, Elliot J

    2014-07-01

    Abnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remain unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

    Science.gov (United States)

    Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

    2011-01-01

    SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

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

    Science.gov (United States)

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

    2014-01-01

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

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Lokesh Lingappa

    2016-01-01

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

  1. Revised upper limb module for spinal muscular atrophy: Development of a new module.

    Science.gov (United States)

    Mazzone, Elena S; Mayhew, Anna; Montes, Jacqueline; Ramsey, Danielle; Fanelli, Lavinia; Young, Sally Dunaway; Salazar, Rachel; De Sanctis, Roberto; Pasternak, Amy; Glanzman, Allan; Coratti, Giorgia; Civitello, Matthew; Forcina, Nicola; Gee, Richard; Duong, Tina; Pane, Marika; Scoto, Mariacristina; Pera, Maria Carmela; Messina, Sonia; Tennekoon, Gihan; Day, John W; Darras, Basil T; De Vivo, Darryl C; Finkel, Richard; Muntoni, Francesco; Mercuri, Eugenio

    2017-06-01

    There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients. An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale. Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups. The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. Muscle Nerve 55: 869-874, 2017. © 2016 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  4. 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.

  5. Spinal muscular atrophy: Selective motor neuron loss and global defect in the assembly of ribonucleoproteins.

    Science.gov (United States)

    Beattie, Christine E; Kolb, Stephen J

    2018-02-17

    Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair. Thus, SMA is an exemplar, selective motor neuron disorder that is caused by defects in fundamental RNA processing events. A detailed molecular understanding of how motor neurons fail, and why other neurons do not, in SMA will yield important principals about motor neuron maintenance and neuronal specificity in neurodegenerative diseases. Copyright © 2018. Published by Elsevier B.V.

  6. 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.

  7. 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.

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

    Science.gov (United States)

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

    2015-08-01

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

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

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    Kleyn, P.W.; Wang, C.H.; Vitale, E.; Pan, J.; Ross, B.M.; Grunn, A.; Palmer, D.A.; Warburton, D.; Brzustowicz, L.M.; Gilliam, T.G. (New York State Psychiatric Institute, NY (United States)); Lien, L.L.; Kunkel, L.M. (Howard Hughes Medical Institute, Boston, MA (United States))

    1993-07-15

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

  10. [Atypical distribution of muscular atrophy in a 29-year-old man with polymyositis and anti-SRP antibodies].

    Science.gov (United States)

    Miwa, Michiaki; Nakamura, Yuki; Nagasaka, Takamura; Shindo, Kazumasa; Takiyama, Yoshihisa

    2012-01-01

    A 29-year-old man developed muscle weakness in the neck at age 27. An increasing serum creatine kinase (CK) activity was detected. The first examination at our hospital revealed severe muscular atrophy at the front of the neck. Subsequently, muscular atrophy and weakness developed in the shoulders and upper extremities with an increasing serum CK level, which reached 9,159 IU/l. Needle electromyography (EMG) was not able to reveal typical myopathic change represented low-amplitude motor unit potentials (MUPs) in the proximal parts of the upper and lower extremities at the first examination, but in the course of the disease, the MUPs amplitude decrease in the same muscles. Serum examination gave a positive result for anti-signal recognition particle (SRP) antibodies. A biopsy of the deltoid muscle revealed necrotizing myopathy including small angular fiber-like atrophy without inflammatory cell infiltration or fibrotic proliferation. He was treated with prednisolone and tacrolimus with the diagnosis of polymyositis. The characteristic feature in this patient is that muscular atrophy and weakness were mainly observed in the neck. Moreover, the neurogenic changes on EMG in the early stage are also observed on atypical. Polymyositis with anti-SRP antibodies has the distinctive feature of typical polymyositis with cellular infiltration clinically and pathologically. In this respect, this case has striking and suggestive features of polymyositis with anti-SRP antibodies.

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

    NARCIS (Netherlands)

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

    2017-01-01

    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

  12. Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients with Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    2012-06-01

    patients with spinal muscular atrophy (SMA). SMA causes significant disability, and there is no effective drug treatment. Maximizing function, endurance...REPORTABLE OUTCOMES: An abstract entitled "Falls and Spinal Muscular Atrophy (SMA): Exploring Cause and Prevention" was presented at the...Rubenstein LZ, Josephson KR. The epidemiology of falls and syncope . Clin Geriatr Med 2002;18:141-158. Wang HY, Yang YH, Jong YJ. Evaluation of muscle

  13. Unusual case of sciatic nerve and deep pelvic endometriosis with lumbosacral plexus spread presenting with muscular atrophy and foot drop

    Directory of Open Access Journals (Sweden)

    Narvir Singh Chauhan

    2017-01-01

    Full Text Available Endometriosis is an important disorder which affects women in the childbearing age group. In addition to the commonly observed intrapelvic sites, it can very rarely affect extrapelvic location such as the sciatic nerve. We describe an uncommon case of sciatic endometriosis leading to gross muscular atrophy and foot drop. The patient additionally had perineural extension of endometriosis along the ipsilateral lumbosacral trunk and coexisting intrapelvic endometrial implants in retrocervical area, uterosacral ligament, and urinary bladder wall.

  14. Neurogenic muscular atrophy and low density of large myelinated fibres of sural nerve in chorea-acanthocytosis

    OpenAIRE

    Ohnishi, A; Sato, Y; Nagara, H; Sakai, T; Iwashita, H; Kuroiwa, Y; Nakamura, T; Shida, K

    1981-01-01

    In three cases of chorea-acanthocytosis (acanthocytosis and neurological disease, or familial degeneration of the basal ganglia with acanthocytosis), biopsies of short peroneal muscles and sural nerves were studied histologically. The muscles showed groups of atrophic fibres with clumping of sarcolemmal nuclei in all cases. It was concluded that neurogenic muscular atrophy should be included as one of the main pathological findings in chorea-acanthocytosis. The sural nerves showed a small num...

  15. Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy.

    Science.gov (United States)

    Simon, Christian M; Dai, Ya; Van Alstyne, Meaghan; Koutsioumpa, Charalampia; Pagiazitis, John G; Chalif, Joshua I; Wang, Xiaojian; Rabinowitz, Joseph E; Henderson, Christopher E; Pellizzoni, Livio; Mentis, George Z

    2017-12-26

    The hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells.

    Science.gov (United States)

    Harahap, Nur Imma Fatimah; Nurputra, Dian Kesumapramudya; Ar Rochmah, Mawaddah; Shima, Ai; Morisada, Naoya; Takarada, Toru; Takeuchi, Atsuko; Tohyama, Yumi; Yanagisawa, Shinichiro; Nishio, Hisahide

    2015-12-01

    Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1 . Although the SMN1 homolog SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of SMN1 . Salbutamol, a β2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels in a dose-dependent manner in SMA fibroblast cells lacking SMN1 , though no significant changes in SMN2 mRNA levels were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and deubiquitinase inhibitor, respectively. Co-immunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating β2-adrenergic receptor-PKA pathways.

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

    Science.gov (United States)

    Boyd, Penelope J; Tu, Wen-Yo; Shorrock, Hannah K; Groen, Ewout J N; Carter, Roderick N; Powis, Rachael A; Thomson, Sophie R; Thomson, Derek; Graham, Laura C; Motyl, Anna A L; Wishart, Thomas M; Highley, J Robin; Morton, Nicholas M; Becker, Thomas; Becker, Catherina G; Heath, Paul R; Gillingwater, Thomas H

    2017-04-01

    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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

    2010-11-01

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

  2. Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice.

    Science.gov (United States)

    Ruiz, Rocío; Casañas, Juan José; Torres-Benito, Laura; Cano, Raquel; Tabares, Lucía

    2010-01-20

    Low levels of survival motor neuron (SMN) protein result in spinal muscular atrophy (SMA), a severe genetic disease characterized by motor impairment and premature lethality. Although SMN is a ubiquitous protein, motor neurons are much more vulnerable to low levels of SMN than other cells. To gain insight into the pathogenesis of SMA, we have compared synaptic function of motor terminals in wild-type and severe SMA mice at different ages and in two proximal muscles. Our results show that mutant muscle fibers fire normal action potentials and that multi-innervated terminals are functional. By studying the characteristics of the three main components of synaptic transmission in nerve terminals (spontaneous, evoked, and asynchronous release), we found that the kinetics of the postsynaptic potentials are slowed and evoked neurotransmitter release is decreased by approximately 55%. In addition, asynchronous release is increased approximately 300%, indicating an anomalous augmentation of intraterminal bulk Ca(2+) during repetitive stimulation. Together, these results show that the reduction of SMN affects synaptic maturation, evoked release, and regulation of intraterminal Ca(2+) levels.

  3. Neurotransmitter release in motor nerve terminals of a mouse model of mild spinal muscular atrophy.

    Science.gov (United States)

    Ruiz, Rocío; Tabares, Lucía

    2014-01-01

    Spinal muscular atrophy is a genetic disease which severity depends on the amount of SMN protein, the product of the genes SMN1 and SMN2. Symptomatology goes from severe neuromuscular impairment leading to early death in infants to slow progressing motor deficits during adulthood. Much of the knowledge about the pathophysiology of SMA comes from studies using genetically engineered animal models of the disease. Here we investigated one of the milder models, the homozygous A2G SMA mice, in which the level of the protein is restored to almost normal levels by the addition of a mutated transgene to the severe SMN-deficient background. We examined neuromuscular function and found that calcium-dependent neurotransmitter release was significantly decreased. In addition, the amplitude of spontaneous endplate potentials was decreased, the morphology of NMJ altered, and slight changes in short-term synaptic plasticity were found. In spite of these defects, excitation contraction coupling was well preserved, possibly due to the safety factor of this synapse. These data further support that the quasi-normal restoration of SMN levels in severe cases preserves neuromuscular function, even when neurotransmitter release is significantly decreased at motor nerve terminals. Nevertheless, this deficit could represent a greater risk of motor impairment during aging or after injuries. © 2013 Anatomical Society.

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

    Science.gov (United States)

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

    2015-11-01

    We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. The motor neuron response to SMN1 deficiency in spinal muscular atrophy.

    Science.gov (United States)

    Kang, Peter B; Gooch, Clifton L; McDermott, Michael P; Darras, Basil T; Finkel, Richard S; Yang, Michele L; Sproule, Douglas M; Chung, Wendy K; Kaufmann, Petra; de Vivo, Darryl C

    2014-05-01

    The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (-6.32 μV/year, P = 0.10), and stable CMAP amplitude. The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. Copyright © 2013 Wiley Periodicals, Inc.

  6. Patient-identified impact of symptoms in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Guber, Robert D; Kokkinis, Angela D; Schindler, Alice B; Bendixen, Roxanna M; Heatwole, Chad R; Fischbeck, Kenneth H; Grunseich, Christopher

    2018-01-01

    The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. This study describes symptoms from the patient's perspective and the impact these symptoms have on QoL. We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes. From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials. Muscle Nerve 57: 40-44, 2018. © 2017 The Authors. Muscle & Nerve Published by Wiley Periodicals, Inc.

  7. A case of congenital spinal muscular atrophy with pain due to a mutation in TRPV4.

    Science.gov (United States)

    Fleming, Jason; Quan, Dianna

    2016-12-01

    We present a patient with congenital spinal muscular atrophy associated with pain, subjective sensory loss, right talipes equinovarus, delayed walking, and progressive gait impairment. A sister and niece reportedly had Charcot-Marie-Tooth 1A, but the patient's electromyogram showed an axonal motor neuropathy or neuronopathy. We identified a c.806G>A TRPV4 gene mutation causing an Arg269His amino acid substitution. TRPV4 mutations cause variable phenotypes including axonal sensorimotor neuropathy and motor neuropathy or neuronopathy. Associated features may include arthrogryposis, skeletal dysplasia, vocal cord paresis, sensorineural hearing loss and respiratory weakness. Skeletal X-rays can identify orthopedic causes of pain in patients with TRPV4 mutations, and imaging evidence of bone deformities in patients with suspected hereditary axonal neuropathy, pain and an unknown genetic diagnosis may help lead to a diagnosis of a TRPV4 mutation. Even when a patient's genetic diagnosis is presumed to be known, electrodiagnostic testing is warranted to verify the diagnosis. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2013-01-01

    Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease caused by mutations and deletions within the survival motor neuron 1 (SMN1) gene. Although other tissues may be involved, motor neurons remain primary pathological targets, with loss of neuromuscular junctions (NMJs) representing an early and significant event in pathogenesis. Although defects in axonal outgrowth and pathfinding have been observed in cell culture and in lower organisms upon Smn depletion, developmental defects in mouse models have been less obvious. Here, we have employed the Smn(2B/-) mouse model to investigate NMJ remodelling during SMA pathology, induced reinnervation, and paralysis. We show that whilst NMJs are capable of remodelling during pathogenesis, there is a marked reduction in paralysis-induced remodelling and in the nerve-directed re-organisation of acetylcholine receptors. This reduction in remodelling potential could not be attributed to a decreased rate of axonal growth. Finally, we have identified a loss of terminal Schwann cells which could contribute to the defects in remodelling/maintenance observed. Our work demonstrates that there are specific defects in NMJ remodelling in an intermediate SMA mouse model, which could contribute to or underlie pathogenesis in SMA. The development of strategies that can promote the remodelling potential of NMJs may therefore be of significant benefit to SMA patients. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Six-minute walk test is reliable and valid in spinal muscular atrophy.

    Science.gov (United States)

    Dunaway Young, Sally; Montes, Jacqueline; Kramer, Samantha S; Marra, Jonathan; Salazar, Rachel; Cruz, Rosangel; Chiriboga, Claudia A; Garber, Carol Ewing; De Vivo, Darryl C

    2016-11-01

    The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016. © 2016 Wiley Periodicals, Inc.

  10. 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.

  11. Defective neuromuscular junction organization and postnatal myogenesis in mice with severe spinal muscular atrophy.

    Science.gov (United States)

    Dachs, Elisabet; Hereu, Marta; Piedrafita, Lídia; Casanovas, Anna; Calderó, Jordi; Esquerda, Josep E

    2011-06-01

    A detailed pathologic analysis was performed on Smn(-/-);SMN2 mice as a mouse model for human type I spinal muscular atrophy (SMA). We provide new data concerning changes in the spinal cord, neuromuscular junctions and muscle cells, and in the organs of the immune system. The expression of 10 synaptic proteins was analyzed in 3-dimensionally reconstructed neuromuscular junctions by confocal microscopy. In addition to defects in postsynaptic occupancy, there was a marked reduction in calcitonin gene-related peptide and Rab3A in the presynaptic motor terminals of some, but not all, of the skeletal muscles analyzed. Defects in the organization of presynaptic nerve terminals were also detected by electron microscopy. Moreover, degenerative changes in muscle cells, defective postnatal muscle growth, and prominent muscle satellite cell apoptosis were also observed. All of these changes occurred in the absence of massive loss of spinal cord motoneurons. On the other hand, astroglia, but not microglia, increased in the ventral horn of newborn SMA mice. In skeletal muscles, the density of interstitial macrophages was significantly reduced, and monocyte chemotactic protein-1 was downregulated. These findings raise questions regarding the primary contribution of a muscle cell defect to the SMA phenotype.

  12. SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

    Science.gov (United States)

    Wishart, Thomas M.; Huang, Jack P.-W.; Murray, Lyndsay M.; Lamont, Douglas J.; Mutsaers, Chantal A.; Ross, Jenny; Geldsetzer, Pascal; Ansorge, Olaf; Talbot, Kevin; Parson, Simon H.; Gillingwater, Thomas H.

    2010-01-01

    Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA. PMID:20705736

  13. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Tosolini, Andrew P; Sleigh, James N

    2017-01-01

    Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where , which , what , and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

  14. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Andrew P. Tosolini

    2017-12-01

    Full Text Available Spinal muscular atrophy (SMA and amyotrophic lateral sclerosis (ALS are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

  15. Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Gabriel Olmos

    2013-05-01

    Full Text Available Spinal muscular atrophy (SMA is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD. In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons.

  16. Effect of prolonged ischaemic time on muscular atrophy and regenerating nerve fibres in transplantation of the rat hind limb.

    Science.gov (United States)

    Tsuji, Naoko; Yamashita, Shuji; Sugawara, Yasushi; Kobayashi, Eiji

    2012-09-01

    Our aim was to test the influence of cold ischaemia on replanted limbs, focusing on muscular atrophy and neurological recovery. Inbred wild-type and green fluorescent protein (GFP) transgenic (Tg) Lewis rats aged 8-10 weeks were used. The amputated limbs were transplanted at several cold ischaemic times (0, 1, 8, 12, 24, 48, and 72 hours). An arterial ischaemic model and a denervation model were used as controls. To study nerve regeneration, a GFP limb was transplanted on to the syngenic wild Lewis rat. These animals were evaluated histologically, electrophysiologically, and immunohistochemically. The longer the ischaemic time, the more evident was atrophy of the muscles. Electrophysiological investigation showed that the latency at 3 weeks was longer in the transplantation models than in the normal controls, particularly in the longer ischaemia group. Larger numbers of migrating Schwann cells were seen in the group with no delay than in the group that had been preserved for 12 hours. Ischaemia after amputation of a limb causes muscle cells to necrose and atrophy, and these changes worsen in proportion to the ischaemic preservation time. A delay in nerve regeneration and incomplete paralysis caused by malregeneration also affect muscular atrophy.

  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. PMID:25221469

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

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    Maia Lanfranco

    2017-06-01

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

  19. 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.

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

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    Dione T Kobayashi

    Full Text Available 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 (p<0.05 with motor function, with a 13(th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP for association with motor and other functional measures.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

  1. 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

    ABSTRACT 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. PMID:26586529

  2. Respiratory muscle function in infants with spinal muscular atrophy type I.

    Science.gov (United States)

    Finkel, Richard S; Weiner, Daniel J; Mayer, Oscar H; McDonough, Joseph M; Panitch, Howard B

    2014-12-01

    To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder. Respiratory insufficiency is the major cause of morbidity and mortality in infants with spinal muscular atrophy type I (SMA-I). Tests of respiratory muscle strength, endurance, and breathing patterns can be performed safely in SMA-I infants. Useful data can be collected which parallels the clinical course of pulmonary function in SMA-I. An exploratory study of respiratory muscle function testing and breathing patterns in seven infants with SMA-I seen in our neuromuscular clinic. Measurements were made at initial study visit and, where possible, longitudinally over time. We measured maximal inspiratory (MIP) and transdiaphragmatic pressures, mean transdiaphragmatic pressure, airway occlusion pressure at 100 msec of inspiration, inspiratory and total respiratory cycle time, and aspects of relative thoracoabdominal motion using respiratory inductive plethysmography (RIP). The tension time index of the diaphragm and of the respiratory muscles, phase angle (Φ), phase relation during the total breath, and labored breathing index were calculated. Age at baseline study was 54-237 (median 131) days. Reliable data were obtained safely for MIP, phase angle, labored breathing index, and the invasive and non-invasive tension time indices, even in very weak infants. Data obtained corresponded to the clinical estimate of severity and predicted the need for respiratory support. The testing employed was both safe and feasible. Measurements of MIP and RIP are easily performed tests that are well tolerated and provide clinically useful information for infants with SMA-I. © 2014 Wiley Periodicals, Inc.

  3. Synaptotagmin-2, and -1, linked to neurotransmission impairment and vulnerability in Spinal Muscular Atrophy.

    Science.gov (United States)

    Tejero, Rocío; Lopez-Manzaneda, Mario; Arumugam, Saravanan; Tabares, Lucía

    2016-11-01

    Spinal muscular atrophy (SMA) is the most frequent genetic cause of infant mortality. The disease is characterized by progressive muscle weakness and paralysis of axial and proximal limb muscles. It is caused by homozygous loss or mutation of the SMN1 gene, which codes for the Survival Motor Neuron (SMN) protein. In mouse models of the disease, neurotransmitter release is greatly impaired, but the molecular mechanisms of the synaptic dysfunction and the basis of the selective muscle vulnerability are unknown. In the present study, we investigated these open questions by comparing the molecular and functional properties of nerve terminals in severely and mildly affected muscles in the SMNΔ7 mouse model. We discovered that synaptotagmin-1 (Syt1) was developmentally downregulated in nerve terminals of highly affected muscles but not in low vulnerable muscles. Additionally, the expression levels of synaptotagmin-2 (Syt2), and its interacting protein, synaptic vesicle protein 2 (SV2) B, were reduced in proportion to the degree of muscle vulnerability while other synaptic proteins, such as syntaxin-1B (Stx1B) and synaptotagmin-7 (Syt7), were not affected. Consistently with the extremely low levels of both Syt-isoforms, and SV2B, in most affected neuromuscular synapses, the functional analysis of neurotransmission revealed highly reduced evoked release, altered short-term plasticity, low release probability, and inability to modulate normally the number of functional release sites. Together, we propose that the strong reduction of Syt2 and SV2B are key factors of the functional synaptic alteration and that the physiological downregulation of Syt1 plays a determinant role in muscle vulnerability in SMA.

  4. [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.

  5. [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.

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

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    Danielle Ramsey

    Full Text Available 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.

  7. 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.

  8. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.

    Science.gov (United States)

    Finkel, Richard S; Chiriboga, Claudia A; Vajsar, Jiri; Day, John W; Montes, Jacqueline; De Vivo, Darryl C; Yamashita, Mason; Rigo, Frank; Hung, Gene; Schneider, Eugene; Norris, Daniel A; Xia, Shuting; Bennett, C Frank; Bishop, Kathie M

    2016-12-17

    Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in

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

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    Dhruv Sareen

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

  10. Effect of prolonged ischaemic time on muscular atrophy and regenerating nerve fibres in transplantation of the rat hind limb

    OpenAIRE

    Tsuji, Naoko; Yamashita, Shuji; Sugawara, Yasushi; Kobayashi, Eiji

    2012-01-01

    Our aim was to test the influence of cold ischaemia on replanted limbs, focusing on muscular atrophy and neurological recovery. Inbred wild-type and green fluorescent protein (GFP) transgenic (Tg) Lewis rats aged 8?10 weeks were used. The amputated limbs were transplanted at several cold ischaemic times (0, 1, 8, 12, 24, 48, and 72 hours). An arterial ischaemic model and a denervation model were used as controls. To study nerve regeneration, a GFP limb was transplanted on to the syngenic wild...

  11. The effect of scoliosis surgery on pulmonary function in spinal muscular atrophy type II patients.

    Science.gov (United States)

    Chou, Shih-Hsiang; Lin, Gau-Tyan; Shen, Po-Chih; Lue, Yi-Jing; Lu, Cheng-Chang; Tien, Yin-Chun; Lu, Yen-Mou

    2017-06-01

    Various results of the previous literature related to surgical effect on pulmonary function of spinal muscular atrophy (SMA) patients might be due to different SMA type, different fusion level and technique. The aim of this study was to determine the value of scoliosis surgery for SMA type II patients with regard to pulmonary function, under the same fusion level, fusion technique and average long-term follow-up. Ten SMA II patients who underwent spinal correction procedures from 1993 to 2010 were identified. Data on clinical features and pulmonary function, including forced vital capacity (FVC) and forced expiratory volume in 1st second (FEV 1 ), were collected. The data on pulmonary function were divided into preoperative, postoperative short-term (0-5 years), mid-term (5-10 years), and long-term (>10 years). Statistical comparisons were made using the Wilcoxon test for pulmonary function and body weight analysis. Questions were answered by parents on how surgery influenced the frequency of respiratory infection and the ability to sit at school. The average length of postoperative pulmonary function follow-up was 12.3 years (range 4.9-15.9 years). There was no significant difference in FVC or FEV 1 between preoperative and each postoperative period. However, a significant decline from mid-term to long-term was observed (p = 0.028). Body weight increased significantly in all postoperative periods and was moderately correlated to pulmonary function (r = 0.526 for FVC). The answers to the questionnaire revealed that 80% of the patients had obvious improvement in the frequency of respiratory infection and 100% were tolerable sitting at school. Surgical correction for scoliosis in SMA II patients results in pulmonary function being maintained during long-term follow-up. In addition, the advantages of surgery also include body weight gain, better sitting tolerance, and reduced frequency of respiratory infection.

  12. Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy.

    Science.gov (United States)

    Sun, Y; Grimmler, M; Schwarzer, V; Schoenen, F; Fischer, U; Wirth, B

    2005-01-01

    The autosomal recessive spinal muscular atrophy (SMA), a neuromuscular disease and frequent cause of early death in childhood, is caused in 96% of patients by homozygous absence of the survival motor neuron gene (SMN1). The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. A comprehensive molecular genetic analysis of 34 SMA patients who carry one SMN1 gene is presented, including 18 that were previously published. Haplotype analysis with the microsatellite markers Ag1-CA and C212 in these SMA families turned out to be a reliable accessory method in predicting known SMN1 mutations in SMA patients carrying one SMN1 copy. Five novel missense mutations were identified that are localized in: exon 2a c.88G>A (p.D30N) and c.131A>T (p.D44V); exon 3 c.283G>C (p.G95R) and c.332C>G (p.A111G); and exon 6 c.784A>G (p.S262G), respectively. The survival motor neuron (SMN) protein has been shown to be a component of a large complex (termed the SMN complex) that promotes the formation of spliceosomal U small nuclear ribonucleoproteins (snRNPs). Within this complex, SMN forms oligomers and directly interacts via its N-terminus with SMN-interacting protein 1 (SIP1) and via its central Tudor domain with spliceosomal (Sm) proteins. We performed in vitro interaction studies to test whether SMA-causing missense mutations identified in this study interfere with the reported interactions of SMN. Our results show that mutations p.G95R and p.A111G reduce SMN binding to Sm proteins, further confirming the previous finding that the Tudor domain is the essential binding site of SMN to Sm-proteins. However, all mutations, including those in exon 2a, a region shown to be important for the binding of SMN to SIP1, do not disturb the

  13. The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1).

    Science.gov (United States)

    Diers, Alexander; Kaczinski, Marcel; Grohmann, Katja; Hübner, Christoph; Stoltenburg-Didinger, Gisela

    2005-09-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is genetically and clinically distinct from classic spinal muscular atrophy (SMA1). It results from mutations in the gene encoding immunoglobulin mu-binding protein 2 (IGHMBP2) on chromosome 11q13. Patients develop distally pronounced muscular weakness and early involvement of the diaphragm, resulting in respiratory failure. Sensory and autonomic nerves are also affected at later stages of the disease. We investigated peripheral nerves, skeletal muscles and neuromuscular junctions (NMJ) ultrastructurally in five unrelated patients and three siblings with genetically confirmed SMARD1. In mixed motor and sensory nerves we detected Wallerian degeneration and axonal atrophy similar to the ultrastructural findings described in SMA1. Isolated axonal atrophy was evident in purely sensory nerves. All investigated NMJ of patients with SMARD1 were dysmorphic and lacked a terminal axon. Moreover, we also observed characteristics of neuropathies, such as abnormalities in myelination, that have not been described in spinal muscular atrophies so far. Based on these findings we conclude that impairment of IGHMBP2 function leads to axonal degeneration, abnormal myelin formation, and motor end-plate degeneration.

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

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    C.A. Kim

    1999-12-01

    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.As amiotrofias espinhais progressivas (SMAs constituem as doenças degenerativas de origem genética letais mais comuns do sistema nervoso central e mais freqüentes dentre as doenças autossômicas recessivas após a mucoviscidose. A incidência estimada das SMAs é de aproximadamente 1:10.000 nativivos. Clinicamente, as SMAs são classificadas em mais grave (doença de Werdnig-Hoffmann, tipo I, intermediária (tipo II e tardia e benigna (doença de Kugelberg-Welander, tipo III. O gene para os três tipos de SMAs foi mapeado no cromossomo 5 q11.2-13.3. Foram identificados dois genes candidatos na mesma região: SMN (sobrevida do neurônio motor e NAIP (proteína inibidora de apoptose neuronal. Estudamos ambos genes em 87 pacientes

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

    NARCIS (Netherlands)

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

    1995-01-01

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

  16. 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

  17. 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...

  18. 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

  19. 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.

    2017-01-01

    Key points 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. Abstract 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

  20. 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 demonstrated

  1. Effect of the Butyrate Prodrug Pivaloyloxymethyl Butyrate (AN9) on a Mouse Model for Spinal Muscular Atrophy.

    Science.gov (United States)

    Edwards, Jonathan D; Butchbach, Matthew E R

    2016-11-29

    Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.

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

    Directory of Open Access Journals (Sweden)

    Xing Chen

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

  3. Correlation between the CAG repeat size and electrophysiological findings in patients with spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Kim, Hyunjin; Lim, Young-Min; Lee, Eun-Jae; Oh, Yeo Jin; Kim, Kwang-Kuk

    2018-04-01

    Spinal and bulbar muscular atrophy (SBMA) is caused by the expansion of a CAG repeat in the androgen receptor gene. The relationship between the CAG repeat size and electrophysiological findings is not completely understood. We retrospectively analyzed 62 SBMA patients to assess the correlation between their CAG repeat size and electrophysiological findings. In multiple regression analysis including age at examination and disease duration, we identified a negative correlation between the CAG repeat size and the compound muscle action potential (CMAP) amplitude. No significant correlation was found between the CAG repeat size and sensory nerve action potential (SNAP) amplitude. Contrary to previous reports of motor- and sensory-dominant phenotypes correlating with CAG repeat sizes, the CAG repeat size was negatively correlated only with CMAP amplitude, and not with SNAP amplitude. Muscle Nerve 57: 683-686, 2018. © 2017 Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    Ser-Chen Fu

    2013-06-01

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

  5. 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

    2015-10-22

    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.

  6. Muscular hypertrophy and atrophy in normal rats provoked by the administration of normal and denervated muscle extracts.

    Science.gov (United States)

    Agüera, Eduardo; Castilla, Salvador; Luque, Evelio; Jimena, Ignacio; Leiva-Cepas, Fernando; Ruz-Caracuel, Ignacio; Peña, José

    2016-12-01

    This study was conducted to determine the effects of extracts obtained from both normal and denervated muscles on different muscle types. Wistar rats were used and were divided into a control group and four experimental groups. Each experimental group was treated intraperitoneally during 10 consecutive days with a different extract. These extracts were obtained from normal soleus muscle, denervated soleus, normal extensor digitorum longus, and denervated extensor digitorum longus. Following treatment, the soleus and extensor digitorum longus muscles were obtained for study under optic and transmission electron microscope; morphometric parameters and myogenic responses were also analyzed. The results demonstrated that the treatment with normal soleus muscle and denervated soleus muscle extracts provoked hypertrophy and increased myogenic activity. In contrast, treatment with extracts from the normal and denervated EDL had a different effect depending on the muscle analyzed. In the soleus muscle it provoked hypertrophy of type I fibers and increased myogenic activity, while in the extensor digitorum longus atrophy of the type II fibers was observed without changes in myogenic activity. This suggests that the muscular responses of atrophy and hypertrophy may depend on different factors related to the muscle type which could be related to innervation.

  7. Nosology of Juvenile Muscular Atrophy of Distal Upper Extremity: From Monomelic Amyotrophy to Hirayama Disease—Indian Perspective

    Directory of Open Access Journals (Sweden)

    Kaukab Maqbool Hassan

    2013-01-01

    Full Text Available Since its original description by Keizo Hirayama in 1959, “juvenile muscular atrophy of the unilateral upper extremity” has been described under many nomenclatures from the east. Hirayama disease (HD, also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy.

  8. Molecular bases of spinal muscular atrophy: the survival motor neuron gene

    OpenAIRE

    Tizzano, Eduardo; Baiget Bastús, Montserrat

    2001-01-01

    L'atròfia muscular espinal (AME) és una malaltia neuromuscular autosòmica recessiva caracteritzada per Ia degeneració i Ia pèrdua de Ies motoneurones de Ia banya anterior de Ia medul·la espinal. Les manifestacions clíniques més característiques són una debilitat proximal simètrica i una atròfia muscular progressiva. La identificació del gen SMN1 com a gen determinant de I'AME obre noves alternatives per a I'estudi de Ia malaltia. En Ia majoria dels pacients es detecta I'absència del gen SMN1 ...

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

    Science.gov (United States)

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

    2016-08-01

    To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  10. X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron.

    Science.gov (United States)

    Hodgkinson, Victoria L; Dale, Jeffery M; Garcia, Michael L; Weisman, Gary A; Lee, Jaekwon; Gitlin, Jonathan D; Petris, Michael J

    2015-06-01

    ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy.

    Science.gov (United States)

    Sison, Samantha L; Patitucci, Teresa N; Seminary, Emily R; Villalon, Eric; Lorson, Christian L; Ebert, Allison D

    2017-09-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2.

    Science.gov (United States)

    Yoshioka, Mieko; Morisada, Naoya; Toyoshima, Daisaku; Yoshimura, Hajime; Nishio, Hisahide; Iijima, Kazumoto; Takeshima, Yasuhiro; Uehara, Tomoko; Kosaki, Kenjiro

    2018-04-01

    The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression. Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family. BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  13. A young man with spinal muscular atrophy and impending respiratory arrest.

    Science.gov (United States)

    Winters, Janine Penfield; Weisleder, Pedro

    2011-02-01

    From a statutory standpoint, the decision-making capacity of adolescents differs significantly from that of adults because adolescents are considered to lack the experience and judgment necessary to make legally binding decisions. Furthermore, in the case of minors, the principle of protection of life tends to outweigh the principle of autonomy. Here we present the hypothetical case of a 16-year-old boy with spinalmuscular atrophy type II who was admitted to the intensive care unit for severe respiratory distress. We focus on the tension that developed among the patient, his parents, and his physicians when the need for emergency mechanical ventilation became apparent. We review the legal and ethical premises under which adolescents are permitted to make legally binding decisions, ie, the emancipated minor and the mature minor doctrines. Finally, we discuss the concepts of protectionism and liberationism as they apply to adolescents' decision-making capacity.

  14. Peroneal muscular atrophy with pyramidal tract features (hereditary motor and sensory neuropathy type V): a clinical, neurophysiological, and pathological study of a large kindred.

    OpenAIRE

    Frith, J A; McLeod, J G; Nicholson, G A; Yang, F

    1994-01-01

    A large family with autosomal dominant inheritance of peroneal muscular atrophy, associated with extensor plantar responses in some cases, has been studied. Onset was usually in the first two decades and spasticity was not a feature. Nerve conduction studies in 21 cases and light and electron microscope findings on six sural nerve biopsies were similar to those in hereditary motor and sensory neuropathy type II.

  15. Combined application of neutrophin-3 gene and neural stem cells is ameliorative to delay of denervated skeletal muscular atrophy after tibial nerve transection in rats.

    Science.gov (United States)

    Lin, Sen; Xu, Jianguang; Hu, Shaonan; Xu, Lei; Zhang, Changqing; Wang, Yang; Gu, Yudong

    2011-01-01

    Examination of the therapeutic efficacy of neural stem cells (NSCs) has recently become the focus of much investigation. In this study we present an insight of the effects of combined application with neurotrophin-3 (NT-3) and NSCs that derived from rat embryo spinal cord on delaying denervated skeletal muscular atrophy after tibial nerve was severed. NT-3 gene was amplified by PCR and subcloned into lentiviral vector pWPXL-MOD to construct a lentiviral expression vector pWPXL-MOD-NT-3. A positive clone expressing NT-3 (named NSCs-NT-3) was obtained and used for differentiation in vitro and transplantation. Sixty adult rats, whose tibial nerves were sectioned, were divided into two groups: one grafted with NSCs-NT-3 (experimental group, n = 30) and the other with NSCs transfected by pWPXL-MOD (control group, n = 30). The cell survival and differentiation, NT-3 gene expression, and effect of delaying denervated skeletal muscular atrophy were examined through immunohistostaining, RT-PCR, Western blot, electrophysiological analysis, and mean cross-sectional area (CSA) of gastrocnemius, respectively. The results show that the NT-3 gene, which is comprised of 777 bp, was cloned and significantly different expression were detected between NSCs and NSCs-NT-3 in vitro. Quantitative analysis of the choline acetyltransferase (ChAT) immunopositive cells revealed a significant increase in experimental group compared to the control group 4 weeks after implantation (p muscular atrophy is indicated in the EMG examination and mean CSA of gastrocnemius. These findings suggest that the neural stem cells expressing NT-3 endogenously would be a better graft candidate for the delay of denervated skeletal muscular atrophy.

  16. Study of Survival Motor Neuron protein regulation and the role of autophagy in Spinal Muscular Atrophy

    OpenAIRE

    Periyakaruppiah, Ambika

    2015-01-01

    L'atròfia muscular espinal (SMA) és un trastorn genètic, causada per la pèrdua o la mutació del gen de la supervivencia de les neurones motores 1 (SMN1), cosa que condueix a una reducció dels nivells de la proteïna SMN i una disfunció selectiva de les MN. S’ha descrit que la reducció d’SMN causa la degeneració de les neurites i la mort cel•lular sense les característiques apoptòtiques clàssiques, però els esdeveniments directes que condueixen a la degeneració de les MN en l’SMA encara són des...

  17. Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn (2b/-) mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Murray, Lyndsay M; Beauvais, Ariane; Gibeault, Sabrina; Courtney, Natalie L; Kothary, Rashmi

    2015-09-15

    The term motor neuron disease encompasses a spectrum of disorders in which motor neurons are the lost. Importantly, while some motor neurons are lost early in disease and others remain intact at disease end-stage. This creates a valuable experimental paradigm to investigate the factors that regulate motor neuron vulnerability. Spinal muscular atrophy is a childhood motor neuron disease caused by mutations or deletions in the SMN1 gene. Here, we have performed transcriptional analysis on differentially vulnerable motor neurons from an intermediate mouse model of Spinal muscular atrophy at a presymptomatic time point. We have characterised two differentially vulnerable populations, differing in the level neuromuscular junction loss. Transcriptional analysis on motor neuron cell bodies revealed that reduced Smn levels correlate with a reduction of transcripts associated with the ribosome, rRNA binding, ubiquitination and oxidative phosphorylation. Furthermore, P53 pathway activation precedes neuromuscular junction loss, suggesting that denervation may be a consequence, rather than a cause of motor neuron death in Spinal muscular atrophy. Finally, increased vulnerability correlates with a decrease in the positive regulation of DNA repair. This study identifies pathways related to the function of Smn and associated with differential motor unit vulnerability, thus presenting a number of exciting targets for future therapeutic development.

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

    Directory of Open Access Journals (Sweden)

    Li-Ting Wang

    2014-05-01

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

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy

    Science.gov (United States)

    Ruggiu, Matteo; McGovern, Vicki L.; Lotti, Francesco; Saieva, Luciano; Li, Darrick K.; Kariya, Shingo; Monani, Umrao R.; Burghes, Arthur H. M.

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1. PMID:22037760

  2. Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

    Science.gov (United States)

    Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

    2017-07-01

    Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

  3. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. 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.

  5. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3.

    Science.gov (United States)

    Khirani, Sonia; Colella, Marina; Caldarelli, Valeria; Aubertin, Guillaume; Boulé, Michèle; Forin, Véronique; Ramirez, Adriana; Fauroux, Brigitte

    2013-11-01

    Spinal muscular atrophy (SMA) is a common genetic disorder that causes severe hypotonia and weakness, and often fatal restrictive lung disease. The aim of the study was to describe the natural history of the respiratory involvement in patients with SMA type 2 and 3 in order to assess the relevance of the clinical classification and identify the parameters associated with the earliest and most rapid decline over time. Thirty-one patients aged 3-21 years were followed over a 10-year period. Lung function, blood gases, respiratory mechanics and muscle strength with recording of oesogastric pressures were measured during routine follow-up. At least two measurements were available in 16 patients (seven type 2 and nine type 3). Among all the volitional and non-volitional, invasive and non-invasive tests, forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP) were shown to be the most informative parameters, showing lower values in SMA type 2, with however a similar rate of decline in patients with SMA type 2 and 3. Our results confirm an earlier decline in lung and respiratory muscle function in patients classified as SMA type 2 as compared with patients classified as type 3. This decline can be assessed by two simple non-invasive tests, FVC and SNIP, with the last maneuver being feasible and reliable in the youngest children, underlying its interest for the monitoring of children with SMA. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Raúl Sánchez-Lanzas

    2017-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Richard S Finkel

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

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

    Directory of Open Access Journals (Sweden)

    Thomas O Crawford

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

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

    Science.gov (United States)

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

    2016-11-03

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

  10. 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. Copyright © 2015 the authors 0270-6474/15/356038-13$15.00/0.

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

    Science.gov (United States)

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

    2013-03-01

    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-Δ7 (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 SMN-FL 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients.

    Science.gov (United States)

    Grotto, Sarah; Cuisset, Jean-Marie; Marret, Stéphane; Drunat, Séverine; Faure, Patricia; Audebert-Bellanger, Séverine; Desguerre, Isabelle; Flurin, Vincent; Grebille, Anne-Gaëlle; Guerrot, Anne-Marie; Journel, Hubert; Morin, Gilles; Plessis, Ghislaine; Renolleau, Sylvain; Roume, Joëlle; Simon-Bouy, Brigitte; Touraine, Renaud; Willems, Marjolaine; Frébourg, Thierry; Verspyck, Eric; Saugier-Veber, Pascale

    2016-11-29

    Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

  14. Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I.

    Science.gov (United States)

    Nobutoki, Tatsuro; Ihara, Toshiaki

    2015-12-01

    Spinal muscular atrophy type I (SMA-I) is characterized by progressive muscle weakness with onset in early infancy, usually resulting in mortality before two years of age. However, the processes underlying the pathophysiological progression of the disease remain unclear. Prior to the onset of muscle weakness, a regression of local capillaries is observed along with motor neuron loss. Local populations of neurons, astrocytes, and vascular endothelial cells constitute a neurovascular unit (NVU), in which neuronal and synaptic metabolism is tightly coupled to capillary blood flow by astrocyte-mediated vasodilatory control. We hypothesize that survival motor neuron protein deficiency and initial neuronal dysfunction leads to the regression of vascular beds and the disruption of NVU function. As a result, local capillary blood flow becomes insufficient, leading to metabolic stress in neurons, endothelial cells, pericytes, and astrocytes, ultimately disrupting the astrocytic regulation of capillaries. This pathogenic process may accelerate the loss of anterior horn motor neurons, leading to the further regression of capillaries and astroglial dysfunction. Hypocapnia, resulting from dehydration and hyperventilation during therapeutic manual ventilation, might further damage the NVU. Moreover, disruption of the microcirculation may affect sympathetic and sensory neurons in the spinal cord, contributing to sympathetic hyperactivity and sensory nerve degeneration, respectively. These mutually reinforcing processes may underlie the progression of muscle weakness during infancy in SMA-I. Therefore, disruption of the NVU and a stressful neurovascular environment in the anterior horn may play important roles in disease initiation and/or progression in SMA-I. The NVU is therefore a critical therapeutic target for treating SMA-I. Our hypothetical model may provide insight into why most neuroprotective strategies that do not address astroglial and vascular cell dysfunction have

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

    Science.gov (United States)

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

    2016-03-08

    To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. Results from this study support continued development of nusinersen for treatment of SMA. This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. © 2016 American Academy of Neurology.

  16. ULTRASTRUCTURAL STUDIES ON MUSCULAR ATROPHY IN MAREK'S DISEASE : I. DENERVATION ATROPHY IN CHICKEN SKELETAL MUSCLE A LIGHT AND ELECTRON MICROSCOPIC STUDY

    OpenAIRE

    MADARAME, Hiroo; FUJIMOTO, Yutaka; MORIGUCHI, Ryozo

    1986-01-01

    When denervation was performed by nerve-cutting and nerve-crushing in chickens, three phases could be observed morphologically. The first phase was characterized by foregoing degenerative changes of the neuro-muscular junctions (axon terminals), followed by atrophic changes of the muscle fibers. The second phase was characterized by irregular arrangement of the myofilaments in atrophic muscle fibers and appearance of regenerative muscular changes by 20 days after denervation. By this time, no...

  17. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

  19. 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...... the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can...

  20. Spinal muscular atrophy

    Science.gov (United States)

    ... Names Werdnig-Hoffmann disease; Kugelberg-Welander disease Images Superficial anterior muscles Scoliosis References Darras BT, Markowitz JA, ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  1. 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 ...

  2. Spinal Muscular Atrophy (SMA)

    Science.gov (United States)

    ... of SMA can survive long into adulthood, and academic and workplace achievements are common. Type 4 SMA (adult-onset SMA) ... 5s. These “extra” SMN2 genes can lessen the impact of a flaw in both SMN1 genes. ... helpful products and devices, social and family issues, and much more. Other MDA ...

  3. Spinal Muscular Atrophy

    Science.gov (United States)

    ... some people retain independence. Proper nutrition and a balanced diet are essential to maintaining weight and strength. People ... some people retain independence. Proper nutrition and a balanced diet are essential to maintaining weight and strength. People ...

  4. [Acidic fibroblast growth factor for preventing motor endplate degeneration and muscular atrophy after motor nerve injury: a morphological and electrophysiological study].

    Science.gov (United States)

    Yang, Shao-an; Jin, An-min; Zou, Xiao-ying; Xiao, Xiao-tao; Xiao, Sha

    2006-03-01

    To explore measures to prevent motor endplate degeneration and muscular atrophy after motor nerve injury. Thirty Sprague-Dawley rats were randomized into 3 equal groups. In two of the groups, the right common peroneal nerves of the rats were transected and immediately sutured with implantation of collagen gel carrier of acidic fibroblast growth factor (aFGF) or the empty carrier into the denervated tibialis anterior muscles. In the control group, the transected nerves were sutured without implantation. Six weeks after the operation, morphological and electrophysiological examinations were performed. In the control rats and those with empty collagen gel carrier implantation, obvious motor endplate degeneration and muscular atrophy occurred, which were not obvious in rats receiving aFGF carrier implantation. The decrement of repetitive nerve stimulation was significantly greater in the former two groups than in the latter. Implantation of collagen gel carrier of aFGF may prevent motor endplate degeneration and facilitate functional recovery of the neuromuscular junction after motor nerve injury.

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

  6. Spinal Muscular Atrophy, types I and II: What are the differences in body composition and resting energy expenditure?

    Science.gov (United States)

    Bertoli, Simona; De Amicis, Ramona; Mastella, Chiara; Pieri, Giulia; Giaquinto, Ester; Battezzati, Alberto; Leone, Alessandro; Baranello, Giovanni

    2017-12-01

    Different neuromuscular functional domains in types I and II Spinal Muscular Atrophy (SMAI and SMAII) could lead to differences in body composition (BC) and resting energy expenditure (REE). Their identification could provide the key to defining appropriate strategies in clinical dietary management, but data comparing SMAI and SMAII in terms of BC and REE are not yet available. We measured total and regional fat (FM), lean (LBM), mineral (BMC) masses, body water (total, intra- and extra-cellular, TBW, ICW, ECW) and REE in a sample of SMAI and II children, matched for age and sex, and also adjusting for body size to compare these features of the two SMA phenotypes. 15 SMAI and 15 SMAII children, (M/F = 9/6 vs 9/6, age 3.6 ± 1.9 vs 3.5 ± 1.8 years, p = 0.99), confirmed genetically, were measured as follows: Anthropometric measurements [Body Weight (BW), Supine Length (SL), Arm Length (AL), Femur Length (FL), Tibia Length (TL)], Dual x-ray Energy Absorptiometry (DEXA) [total and segmental FM, LBM, FFM, and BMC], Bioelectrical impedance (BIA) [TBW, ICW, ECW] and Indirect Calorimetry (REE, respiratory quotients) were collected by the same trained dietician. BW, SL and Body Mass Index (BMI) Z-scores were calculated according to CDC Growth Charts (2000). SMA children had high percentages of FM and a lower percentage of TBW and ECW compared to the respective reference values for sex and age, whereas the BMC percentages did not differ, even splitting the two phenotypes. SMA I children had a lower BW and BMI-Z score compared to children with SMA II, but similar total and segmental FM. On the contrary, total FFM and LBM were significantly lower in SMAI (7290.0 ± 1729.1 g vs 8410.1 ± 1508.4 g; 6971.8 ± 1637.1 g vs 8041.7 ± 1427.7 g, p = 0.039, p = 0.037, respectively), particularly at the trunk level. Arm BMC also resulted significantly lower in SMAI. The measured REE values were similar (684 ± 143 kcal/day vs 703 ± 122 Kcal/day p = 0

  7. [Questionnaire survey conducted on the parents of patients with spinal muscular atrophy type 1 in Japan regarding switch devices, language development, upper extremity function and QOL].

    Science.gov (United States)

    Sakai, Shinya; Maki, Makoto; Sakai, Naoko; Sudoh, Akira; Kato, Mitsuhiro; Saitoh, Shinji

    2012-11-01

    As information required to rehabilitate, we aimed to clarify the use of switch devices, language development, upper extremity function, and quality of life (QOL) in patients with spinal muscular atrophy (SMA) type 1 in Japan. A questionnaire survey was conducted on the parents of these patients. A total of 48 completed questionnaires were collected. The median age of patients with SMA type 1 was 8 years (range, 13 months to 27 years). The patients used a switch device were 46.5%. Their language development was delayed, and their voluntary movement in the distal upper extremities was relatively retained. In QOL, parents' labor and burden for the care of patients were high. It is necessary to provide specialist support that contributes to the spread of communication devices, which improve their motor function, language development and overall QOL.

  8. 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

    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...... elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes......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...

  9. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

    Science.gov (United States)

    Kim, Jeong-Ki; Caine, Charlotte; Awano, Tomoyuki; Herbst, Ruth; Monani, Umrao R

    2017-07-01

    Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. 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. © 2015 Anatomical Society.

  12. Spinal muscular atrophy with respiratory distress type 1 (SMARD1) Report of a Spanish case with extended clinicopathological follow-up.

    Science.gov (United States)

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

    2016-01-01

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

  13. Label-free quantitative proteomic profiling identifies disruption of ubiquitin homeostasis as a key driver of Schwann cell defects in spinal muscular atrophy.

    Science.gov (United States)

    Aghamaleky Sarvestany, Arwin; Hunter, Gillian; Tavendale, Amy; Lamont, Douglas J; Llavero Hurtado, Maica; Graham, Laura C; Wishart, Thomas M; Gillingwater, Thomas H

    2014-11-07

    Low levels of survival of motor neuron (SMN) protein cause the neuromuscular disease spinal muscular atrophy (SMA), characterized by degeneration of lower motor neurons and atrophy of skeletal muscle. Recent work demonstrated that low levels of SMN also trigger pathological changes in Schwann cells, leading to abnormal axon myelination and disrupted deposition of extracellular matrix proteins in peripheral nerve. However, the molecular pathways linking SMN depletion to intrinsic defects in Schwann cells remained unclear. Label-free proteomics analysis of Schwann cells isolated from SMA mouse peripheral nerve revealed widespread changes to the Schwann cell proteome, including disruption to growth/proliferation, cell death/survival, and molecular transport pathways. Functional clustering analyses revealed significant disruption to a number of proteins contributing to ubiquitination pathways, including reduced levels of ubiquitin-like modifier activating enzyme 1 (Uba1). Pharmacological suppression of Uba1 in Schwann cells was sufficient to reproduce the defective myelination phenotype seen in SMA. These findings demonstrate an important role for SMN protein and ubiquitin-dependent pathways in maintaining Schwann cell homeostasis and provide significant additional experimental evidence supporting a key role for ubiquitin pathways and, Uba1 in particular, in driving SMA pathogenesis across a broad range of cells and tissues.

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

    Directory of Open Access Journals (Sweden)

    C. Pelizzari

    2008-02-01

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

  15. 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.

  16. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.

    Science.gov (United States)

    Archibald, Alison Dalton; Smith, Melanie Jane; Burgess, Trent; Scarff, Katrina Louise; Elliott, Justine; Hunt, Clare Elizabeth; Barns-Jenkins, Caitlin; Holt, Chelsea; Sandoval, Karina; Siva Kumar, Vanessa; Ward, Lisa; Allen, Emily Caroline; Collis, Sarah Valerie; Cowie, Shannon; Francis, David; Delatycki, Martin B; Yiu, Eppie Mildred; Massie, R John; Pertile, Mark Domenic; du Sart, Desirée; Bruno, Damien; Amor, David J

    2017-10-26

    PurposeTo describe our experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).MethodsCarrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counseling with prenatal/preimplantation genetic diagnosis available to those at increased risk.ResultsScreening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers' partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA).ConclusionThe combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counseling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential.Genet Med advance online publication, 26 October 2017; doi:10.1038/gim.2017.134.

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

    Science.gov (United States)

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

    2017-09-07

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

  18. Morphological Characteristics of Motor Neurons Do Not Determine Their Relative Susceptibility to Degeneration in a Mouse Model of Severe Spinal Muscular Atrophy

    Science.gov (United States)

    Mutsaers, Chantal A.; Thomson, Derek; Hamilton, Gillian; Parson, Simon H.; Gillingwater, Thomas H.

    2012-01-01

    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. PMID:23285108

  19. 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.

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

    Science.gov (United States)

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

    2016-10-01

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

  1. Evaluation of therapeutic electrical stimulation to improve muscle strength and function in children with types II/III spinal muscular atrophy.

    Science.gov (United States)

    Fehlings, Darcy L; Kirsch, Susan; McComas, Alan; Chipman, Mary; Campbell, Kent

    2002-11-01

    The study aimed to evaluate the effect of low-intensity night-time therapeutic electrical stimulation (TES) on arm strength and function in children with intermediate type spinal muscular atrophy (SMA). The design was a randomized controlled trial with a 6-month baseline control period. Children were evaluated at baseline, 6, and 12 months. TES was applied from 6 to 12 months to the deltoid and biceps muscle, of a randomly selected arm with the opposite arm receiving a placebo stimulator. Thirteen individuals with SMA between 5 to 19 years of age were recruited into the study and eight completed the 12-month assessment. No statistically significant differences between the treatment and control arm were found at baseline, 6, and 12 months for elbow flexors, or shoulder abductors on quantitative myometry or manual muscle testing. There was no significant change in excitable muscle mass assessed by M-wave amplitudes, nor function on the Pediatric Evaluation of Disability Inventory (self-care domain). Therefore, in this study there was no evidence that TES improved strength in children with SMA.

  2. Molecular inversion probes equipped with discontinuous rolling cycle amplification for targeting nucleotide variants: Determining SMN1 and SMN2 genes in diagnosis of spinal muscular atrophy.

    Science.gov (United States)

    Kou, Hwang-Shang; Wang, Chun-Chi

    2017-07-18

    The novel techniques of molecular inversion probes (MIPs) combined with discontinuous rolling cycle amplification (DRCA) was developed for determination of the multi-nucleotide variants at single base. The different-length MIPs, a padlock-probe based technology, are designed to simultaneously recognize the identical nucleotide variants. After ligation and DRCA, the different-length genetic products representing the certain genotypes could be simply determined by the short-end capillary electrophoresis (CE) method. By using MIPs-DRCA method, the various gene dosages of SMN1 and SMN2 genes in homologous or heterologous subjects were successfully quantified for diagnosis of spinal muscular atrophy (SMA). The length of the MIP for SMN1 gene was 106 bp, and for SMN2 gene was 86 bp. After method optimization, the MIP products of SMN1 and SMN2 were well separated with the resolution of 1.13 ± 0.17 (n = 3) within 10 min. There were total of 56 DNA blind samples analyzed by this strategy, including 38 wild types, 12 carriers and 6 SMA patients, and the data of gene dosages was corresponding to those analyzed by conformation sensitive CE and denatured high performance liquid chromatography (DHPLC) methods. This MIPs-DRCA method which could be applied to simultaneously genotype multi nucleotide variants at single base, such as K-ras gene, was very feasible for determination of genetic diseases in clinical. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice.

    Science.gov (United States)

    Biondi, Olivier; Branchu, Julien; Sanchez, Gabriel; Lancelin, Camille; Deforges, Séverine; Lopes, Philippe; Pariset, Claude; Lécolle, Sylvie; Côté, Jocelyn; Chanoine, Christophe; Charbonnier, Frédéric

    2010-08-25

    Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons. It is still unclear whether activating motor units in SMA corrects the delay in the postnatal maturation of the motor unit resulting in an enhanced neuroprotection. In the present work, we demonstrate that an adequate NMDA receptor activation in a type 2 SMA mouse model significantly accelerated motor unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase of SMN expression resulting from a modification of SMN2 gene transcription pattern. These beneficial effects were dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. In addition, these results suggest that the NMDA-induced acceleration of motor unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different mouse models of severe SMA. The analysis of the intracellular signaling cascade that lay downstream the activated NMDA receptor revealed an unexpected reactivation of the CaMKII/AKT/CREB (cAMP response element-binding protein) pathway that induced an enhanced SMN expression. Therefore, pharmacological activation of spinal NMDA receptors could constitute a useful strategy for both increasing SMN expression and limiting motor neuron death in SMA spinal cord.

  4. 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. Copyright © 2015 the authors 0270-6474/15/350936-08$15.00/0.

  5. 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.

  6. 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.

  7. 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.

  8. Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4.

    Science.gov (United States)

    Wadman, R I; Wijngaarde, C A; Stam, M; Bartels, B; Otto, L A M; Lemmink, H H; Schoenmakers, M A G C; Cuppen, I; van den Berg, L H; van der Pol, W L

    2018-03-01

    Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene-augmenting therapies. We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type. We included 180 patients with SMA types 1-4 in the age range 1-77.5 years with median disease duration of 18 (range 0-65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross-sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously. Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages. © 2017 EAN.

  9. 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

    2016-03-03

    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. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  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

    2018-02-01

    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. 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. 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

  13. Transforaminal intrathecal delivery of nusinersen using cone-beam computed tomography for children with spinal muscular atrophy and extensive surgical instrumentation: early results of technical success and safety.

    Science.gov (United States)

    Weaver, John J; Natarajan, Niranjana; Shaw, Dennis W W; Apkon, Susan D; Koo, Kevin S H; Shivaram, Giri M; Monroe, Eric J

    2018-03-01

    Nusinersen, the only treatment approved by the United States Food and Drug Administration for spinal muscular atrophy (SMA), is delivered intrathecally. Many children with SMA have extensive spinal instrumentation and deformities, often precluding the use of standard approaches for gaining intrathecal access. Furthermore the anatomical distortion that often occurs with rotoscoliosis can complicate the use of fluoroscopic guidance. Compared to fluoroscopy, CT affords superior guidance for complex needle placements. This opens up alternatives to the posterior (interlaminar) technique, including transforaminal and caudal approaches. This study describes the early results of technical success, complications and radiation dose of intrathecal delivery of nusinersen using cone-beam CT guidance with two-axis fluoroscopic navigational overlay. We conducted a retrospective review of 15 consecutive nusinersen injections performed in four children with SMA and extensive spinal hardware precluding standard posterior lumbar puncture techniques. These children were treated using transforaminal thecal access employing cone-beam CT with navigational overlay. We analyzed results including technical success, complications and total fluoroscopy time. All procedures were technically successful. No major complications and one minor complication were reported; the minor complication was a post-procedural neuropathic headache that was attributed to procedural positioning and was treated successfully with gabapentin. The average procedural fluoroscopy time and air kerma were 1.9 min and 55.8 mGy, respectively. Cone-beam CT guidance with two-axis navigational overlay is a safe, effective method for gaining transforaminal intrathecal access in children with spinal abnormalities and hardware precluding the use of standard techniques.

  14. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Home Health Conditions Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Printable PDF Open All ... by progressive muscle weakness and wasting (atrophy). The Duchenne and Becker types of muscular dystrophy are two ...

  15. Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy.

    Science.gov (United States)

    Guidetti, D; Sabadini, R; Ferlini, A; Torrente, I

    2001-01-01

    Commencing with the work carried out during the epidemiological survey of amyotrophic lateral sclerosis in the period 1980-1992 and the pathology follow-up, we carried out a perspective incidence, prevalence and mortality survey of X-linked bulbar and spinal muscular atrophy (X-BSMA) in the province of Reggio Emilia in Northern Italy. Based on 11 patients (eight familial and three sporadic cases), the mean incidence per year for the period 1980 through 1997, as evaluated at the onset of symptoms, was 0.09 cases/100,000 for the total population and 0.19 cases/100,000 for the male population. On December 31, 1997, the prevalence rate was 1.6/100,000 for the total population and 3.3/100,000 for the male population. In the 18-year period of 1980-1997, the average yearly mortality rate was: 0.03 cases/100,000 per year for the total population and 0.06 cases/ 100,000 for the male population. The average age at onset was 44.8 +/- 10.1, and the average survival period was 27.3 +/- 2.3 years. The average age of the prevalence day was 58.9 +/- 14.9, and the average age at death was 71.3 +/- 4.7 years. Whereas the incidence rate of X-BSMA in the province of Reggio Emilia is 16 times lower that of amyotrophic lateral sclerosis (ALS), the incidence rate of progressive bulbar palsy in the male population is only slightly higher than X-BSMA; and the prevalence rate of ALS for males is two times the prevalence rate for X-BSMA, with overlapping of confidence intervals. X-BSMA is a rare disease, which is probably under-diagnosed, but due to the long survival period of this disease its frequency is not negligible. Because of the presence of sporadic cases or non-evident familial cases, it is appropriate to consider this diagnostic possibility in making a diagnosis of ALS in patients in whom lower motor neuron dysfunction or bulbar onset predominates.

  16. Learning about Spinal Muscular Atrophy

    Science.gov (United States)

    ... Genome Project Fact Sheets Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues Coverage & Reimbursement of Genetic ...

  17. Positive radionuclide imaging of miRNA expression using RILES and the human sodium iodide symporter as reporter gene is feasible and supports a protective role of miRNA-23a in response to muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Viorel Simion

    Full Text Available MicroRNAs (miRNAs are key players in many biological processes and are considered as an emerging class of pharmacology drugs for diagnosis and therapy. However to fully exploit the therapeutic potential of miRNAs, it is becoming crucial to monitor their expression pattern using medical imaging modalities. Recently, we developed a method called RILES, for RNAi-Inducible Luciferase Expression System that relies on an engineered regulatable expression system to switch-ON the expression of the luciferase gene when a miRNA of interest is expressed in cells. Here we investigated whether replacing the luciferase reporter gene with the human sodium iodide symporter (hNIS reporter gene will be also suited to monitor the expression of miRNAs in a clinical setting context. We provide evidence that radionuclide imaging of miRNA expression using hNIS is feasible although it is not as robust as when the luciferase reporter gene is used. However, under appropriate conditions, we monitored the expression of several miRNAs in cells, in the liver and in the tibialis anterior muscle of mice undergoing muscular atrophy. We demonstrated that radiotracer accumulation in transfected cells correlated with the induction of hNIS and with the expression of miRNAs detected by real time PCR. We established the kinetic of miRNA-23a expression in mice and demonstrated that this miRNA follows a biphasic expression pattern characterized by a loss of expression at a late time point of muscular atrophy. At autopsy, we found an opposite expression pattern between miRNA-23a and one of the main transcriptional target of this miRNA, APAF-1, and as downstream target, Caspase 9. Our results report the first positive monitoring of endogenously expressed miRNAs in a nuclear medicine imaging context and support the development of additional work to establish the potential therapeutic value of miRNA-23 to prevent the damaging effects of muscular atrophy.

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

    Science.gov (United States)

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

    2015-08-01

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

  19. 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

  20. Fulltext PDF

    Indian Academy of Sciences (India)

    Madhu urs

    PolyQ disorders include Huntington disease (HD), six distinct forms of spinocerebellar ataxia (SCA-1, 2, 3, 6,. 7 and 17), dentatorubropallidoluysian atrophy (DRPLA) and spinobulbar muscular atrophy (SBMA) (reviewed in Bates. 2005; Gatchel and Zoghbi 2005). Barring SBMA, which is. X-linked, all other polyQ disorders ...

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

    Directory of Open Access Journals (Sweden)

    Charles Pelizzari

    2008-06-01

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

  2. Effect of electroacupuncture on the expression of agrin and acetylcholine receptor subtypes in rats with tibialis anterior muscular atrophy induced by sciatic nerve injection injury.

    Science.gov (United States)

    Yu, Jianqi; Wang, Meng; Liu, Junying; Zhang, Xiaoming; Yang, Shengbo

    2017-08-01

    To investigate the effects of electroacupuncture (EA) on mRNA and protein expression of agrin, acetylcholine receptor (AChR)-ε and AChR-γ in a rat model of tibialis anterior muscle atrophy induced by sciatic nerve injection injury, and to examine the underlying mechanism of action. Fifty-four adult Sprague-Dawley rats were divided into four groups: healthy control group (CON, n=6); sciatic nerve injury group (SNI, n=24), comprising rats euthanased at 1, 2, 4 and 6 weeks, respectively, after penicillin injection-induced SNI (n=6 each); CON+EA group (n=12), comprising healthy rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA at GB30 and ST36); and SNI+EA group, comprising rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA). The sciatic nerve functional index (SFI), tibialis anterior muscle weight, muscle fibre cross-sectional area (CSA), and changes in agrin, AChR-ε, and AChR-γ expression levels were analysed. Compared with the control group (CON), SNI rats showed decreased SFI. The weight of the tibialis anterior muscle and muscle fibre CSA decreased initially and recovered slightly over time. mRNA/protein expression of agrin and AChR-ε were downregulated and AChR-γ expression was detectable (vs zero expression in the CON/CON+EA groups). There were no significant differences in CON+EA versus CON groups. However, the SNI+EA group exhibited significant improvements compared with the untreated SNI group (patrophy induced by sciatic nerve injection injury by upregulating agrin and AChR-ε and downregulating AChR-γ. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. 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

  4. 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. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan.

    Science.gov (United States)

    Sato, Kanji; Nakajima, Kishiko; Imamura, Hidehito; Deguchi, Takahisa; Horinouchi, Shuuji; Yamazaki, Kazuko; Yamada, Emiko; Kanaji, Yoshio; Takano, Kazue

    2002-12-01

    Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

  6. Muscular Dystrophy

    Science.gov (United States)

    ... The Search for a Cure Print 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 ...

  7. Dismantling Limb-Girdle Muscular Dystrophy

    OpenAIRE

    Narayanaswami, Pushpa

    2015-01-01

    Muscular dystrophy encompasses a diverse group of genetically determined muscle disorders. The first clinical description of the disorder is attributed to Giovanni Semmola, who, in 1829, described 2 boys affected by a disorder with prominent muscular hypertrophy.1 Between 1850 and 1868, Aran, Meryon, and Duchenne described a progressive atrophy of voluntary muscles, ultimately termed pseudohypertrophic muscular paralysis of children by Duchenne.1,2 Other descriptions followed: familial atroph...

  8. Molecular analysis of the eTG trinucleotide repeat in South African ...

    African Journals Online (AJOL)

    -4 When amplified, this trinucleotide repeat is responsible for DNA instability and molecular pathology. A similar mechanism of trinucleotide repeat expansion has been described in fragile X mental retardation syndrome. (CGG):·· spinobulbar muscular atrophy (CAG)' and, more. MRC Human Ecogenetics Research Unit, ...

  9. Muscular Dystrophy

    Science.gov (United States)

    ... that cause progressive weakness and loss of muscle mass. In muscular dystrophy, abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle. There are many different kinds of muscular dystrophy. ...

  10. Urogenital atrophy.

    Science.gov (United States)

    Calleja-Agius, J; Brincat, M P

    2009-08-01

    The major cause of urogenital atrophy in menopausal women is estrogen loss. The symptoms are usually progressive in nature and deteriorate with time from the menopausal transition. The most prevalent urogenital symptoms are vaginal dryness, vaginal irritation and itching. The classical changes in an atrophic vulva include loss of labial and vulvar fullness, with narrowing of the introitus and inflamed mucosal surfaces. Dyspareunia and vaginal bleeding from fragile atrophic skin are common problems. Other urogenital complaints include frequency, nocturia, urgency, incontinence and urinary tract infections. Atrophic changes of the vulva, vagina and lower urinary tract can have a large impact on the quality of life of the menopausal woman. However, hormonal and non-hormonal treatments can provide patients with the solution to regain previous level of function. Therefore, clinicians should sensitively question and examine menopausal women, in order to correctly identify the pattern of changes in urogenital atrophy and manage them appropriately.

  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. The Link Between Stress Disorders and Autonomic Dysfunction in Muscular Dystrophy

    OpenAIRE

    Rasna eSabharwal

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this p...

  13. Muscular Dystrophy

    Science.gov (United States)

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

  14. Muscular dystrophy

    Science.gov (United States)

    ... during pregnancy. Alternative Names Inherited myopathy; MD Images Superficial anterior muscles References Sarnat HB. Muscular dystrophies. In: ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

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

    Energy Technology Data Exchange (ETDEWEB)

    Laasonen, E.M.

    1984-01-01

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

  16. 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

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

    Directory of Open Access Journals (Sweden)

    Soraia Figueiredo de Souza

    2011-07-01

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

  18. Multiple System Atrophy (MSA)

    Science.gov (United States)

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

  19. Muscular Dystrophy

    Science.gov (United States)

    ... protein helps muscle cells keep their shape and strength. Without it, muscles break down and a person ... EDMD). The heart muscle may also be affected. Limb-girdle muscular dystrophy ... causes weakness in the lower legs. People with this type of MD might ...

  20. Brain atrophy during aging

    International Nuclear Information System (INIS)

    Matsuzawa, Taiju; Yamada, Kenji; Yamada, Susumu; Ono, Shuichi; Takeda, Shunpei; Hatazawa, Jun; Ito, Masatoshi; Kubota, Kazuo

    1985-01-01

    Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT. Brain atrophy was minimal in 34-35 years old in both sexes, increased exponentially to the increasing age after 34-35 years, and probably resulted in dementia, such as vascular or multi-infarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34-35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extent of brain atrophy (20 - 30 %) existed among aged subjects. Progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was the decrease in the cerebral blood flow. We have classified brain atrophy into sulcal and cisternal enlargement type (type I), ventricular enlargement type (type II) and mixed type (type III) according to the clinical study using NMR-CT. Brain atrophy of type I progresses significantly in almost all of the geriatric disorders. This type of brain atrophy progresses significantly in heavy smokers and drinkers. Therefore this type of brain atrophy might be caused by the decline in the blood flow in anterior and middle cerebral arteries. Brain atrophy of type II was caused by the disturbance of cerebrospinal fluid circulation after cerebral bleeding and subarachnoid bleeding. Brain atrophy of type III was seen in vascular dementia or multi-infarct dementia which was caused by loss of brain matter after multiple infarction, and was seen also in dementia of Alzheimer type in which degeneration of nerve cells results in brain atrophy. NMR-CT can easily detect small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy. (J.P.N.)

  1. The paradox of muscle hypertrophy in muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Distrofia muscular progressiva: alguns aspectos do diagnõstico diferencial

    Directory of Open Access Journals (Sweden)

    Sylvio Saraiva

    1960-09-01

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

  3. The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

    Science.gov (United States)

    Goldspink, G.; Goldspink, D.; Loughna, P.

    1984-01-01

    The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

  4. Brain atrophy during aging

    International Nuclear Information System (INIS)

    Matsuzawa, Taiju; Takeda, Shumpei; Hatazawa, Jun

    1985-01-01

    Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT and following results were obtained. Brain atrophy was minimal in 34 -- 35 years old in both sexes, increased exponentially to the increasing age after 34 -- 35 years, and probably resulted in dementia, such as vascular or multiinfarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34 -- 35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extents of brain atrophy (20 -- 30 %) existed among aged subjects. Some aged subjects had little or no atrophy of their brains, as seen in young subjects, and others had markedly shrunken brains associated with senility. From these results there must be pathological factors promoting brain atrophy with a great individual difference. We have studied the relation of intelligence to brain volume, and have ascertained that progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was decrease in the cerebral blood flow. MNR-CT can easily detected small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy, while X-CT can not. Therefore NMR-CT is very useful for detection of subtle changes in the brain. (J.P.N.)

  5. [Human myopathy and animal muscular dystrophy].

    Science.gov (United States)

    Schapira, G; Dreyfus, J C; Schapira, F

    1977-08-01

    Two hereditary muscular dystrophies similar to human progressive muscular dystrophy (P.M.D. Duchenne type) have been isolated in animals, one in mouse, the other in chicken. The decrease in the activity of glycogenolytic enzymes is similar to that observed in denervated muscle. Isozymic fetal types for several muscular enzymes have been observed as well in chicken as in man, but this fetal type may also be found in neurogenic atrophy. The release in circulation of muscle enzymes seems more specific. But the origin of the genetic lesion is still unknown. We describe here the three different theories about this problem: i.e. neurogenic, vascular, or myogenic. This last theory implies a trouble of membrane permeability.

  6. CABLES MUSCULARES

    Directory of Open Access Journals (Sweden)

    Alejandro Gómez

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

  7. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

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

  8. Osteoprotegerin protects against muscular dystrophy.

    Science.gov (United States)

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

    2015-04-01

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

  9. Carrier screening for spinal muscular atrophy in Italian population

    Indian Academy of Sciences (India)

    (I.R.C.C.S.), 94018 Troina (EN), Italy; Unità Operativa di Malattie Neuromuscolari, Associazione Oasi Maria SS. (I.R.C.C.S.), 94018 Troina (EN), Italy; Genetica Medica ARNAS Garibaldi Nesima, 95122 Catania, Italy; Unità Operativa di Neurologia per il Ritardo Mentale, Associazione Oasi Maria SS. (I.R.C.C.S.), 94018 Troina ...

  10. Carrier screening for spinal muscular atrophy in Italian population

    Indian Academy of Sciences (India)

    recessive disorder after cystic fibrosis and the most frequent genetic cause of infant mortality, with an incidence of one per. 6000–10,000 live births (Pearn 1980). Mutations in the sur- vival motor neuron gene (SMN1; HGNC: 11117), localized in 5q11.2-13.3 within a large inverted duplicated element, cause SMA types I, II, ...

  11. Carrier screening for spinal muscular atrophy in Italian population

    Indian Academy of Sciences (India)

    3Genetica Medica ARNAS Garibaldi Nesima, 95122 Catania, Italy. 5Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, 90128 Palermo, Italy. [Calì F., Ruggeri G., Chiavetta V., Scuderi C., Bianca S., Barone C., Ragalmuto A., Schinocca P., Vitello G. A., Romano V. and Musumeci S. 2014 Carrier screening for ...

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

    African Journals Online (AJOL)

    Type I was the commonest type (60.6%), followed by type II (26.79%), and type III (8.8%). Consanguinity was reported in 45.5 and family history in 47.8% of patients. Molecular study was done and 54.5% of patients (types I and II) have homozygous deletion of exon 7, 36.3% of whom had also homozygous deletion of exon 8 ...

  13. Genetics Home Reference: spinal and bulbar muscular atrophy

    Science.gov (United States)

    ... This receptor attaches (binds) to a class of hormones called androgens, which are involved in male sexual development. Androgens and androgen receptors also have other important functions in both males and females, such as regulating ...

  14. Duchenne muscular dystrophy

    Science.gov (United States)

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

  15. Meaning of Muscular Dystrophy

    Science.gov (United States)

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

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

    Science.gov (United States)

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

    2013-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Simon Hauerslev

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

  18. Histological investigations of muscle atrophy and end plates in two critically ill patients with generalized weakness

    NARCIS (Netherlands)

    Wokke, J.H.J.; Jennekens, F.G.I.; Oord, C.J.M. van den; Veldman, H.; Gijn, Jan van

    1988-01-01

    We describe pathological alterations at the light microscopical and ultrastructural level of motor end plates and muscle fibres in 2 critically ill patients with generalized muscular atrophy and weakness. Axonal degeneration of intramuscular nerve fibres was not conspicuous. The sural nerve in one

  19. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    Science.gov (United States)

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  20. The link between stress disorders and autonomic dysfunction in muscular dystrophy.

    Science.gov (United States)

    Sabharwal, Rasna

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time-(i) outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii) propose therapies that would improve behavioral and autonomic functions in muscular dystrophy.

  1. The Link Between Stress Disorders and Autonomic Dysfunction in Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Rasna eSabharwal

    2014-01-01

    Full Text Available Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time - (i outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii propose therapies that would improve behavioral and autonomic functions in muscular dystrophy.

  2. The link between stress disorders and autonomic dysfunction in muscular dystrophy

    Science.gov (United States)

    Sabharwal, Rasna

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time—(i) outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii) propose therapies that would improve behavioral and autonomic functions in muscular dystrophy. PMID:24523698

  3. Dominant optic atrophy

    DEFF Research Database (Denmark)

    Lenaers, Guy; Hamel, Christian; Delettre, Cécile

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    T Ashwini Kini

    2015-01-01

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

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

    OpenAIRE

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

    2014-01-01

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

  6. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-03-15

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

  7. 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.

  8. Chroroideremie et Atrophie Gyrata

    Directory of Open Access Journals (Sweden)

    G. Chams

    1957-01-01

    Full Text Available The authors describe case history of three patients who one-side progressive atrophy of the iris. Two of these'; cases became later a glaucoma which could' not' be treated' even surgidily. third patient' had a betercebromi~'of the same side. The authors. discuss t4e different theories for the pathogenesi~ o~ the pl:imary. progl:lcssive att:«;>phy o( the iris bu~ believe that sy~pathetic theory which is nearer to Fuchs' syndrom is more accepJable..

  9. The inheritance of peripapillary atrophy

    NARCIS (Netherlands)

    Healey, Paul R.; Mitchell, Paul; Gilbert, Clare E.; Lee, Anne J.; Ge, Dongliang; Snieder, Harold; Spector, Timothy D.; Hammond, Christopher J.

    PURPOSE. To estimate the relative importance of genes and environment in peripapillary atrophy type beta (beta-PPA) in a classic twin study. METHODS. Female twin pairs (n = 506) aged 49 to 79 years were recruited from the St. Thomas' UK Adult Twin Registry. Peripapillary atrophy was identified from

  10. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury

    Directory of Open Access Journals (Sweden)

    Meng Wang

    2016-01-01

    Full Text Available Glycyl-tRNA synthetase (GlyRS is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI, decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb. The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis.

  11. Computed tomography in Duchenne type muscular dystrophy

    International Nuclear Information System (INIS)

    Kawai, Mitsuru; Kunimoto, Masanari; Motoyoshi, Yasufumi; Kuwata, Takashi; Nakano, Imaharu

    1985-01-01

    The computed tomography (CT) scan was performed on 91 Duchenne type muscular dystrophy (DMD) patients on the following four levels; (1) at the level of L3 vertebra, (2) 2-3cm above the symphysis pubica, (3) midposition of the thigh, (4) largest-diameter section of the lower leg. The CT of muscles common to most of the DMD patients were as follows: 1. Muscle atrophy: Muscle atrophy was shown as a reduction in the cross-sectional area of the muscles. Very mild muscle atrophy could be detected either by the clearly identified muscle border or by scattered low-density areas of so-called ''moth-eaten'' appearance within muscles. 2. Fat infiltration: The decrease in radio-density of muscles was interpreted as infiltration of fatty tissue. This type of density change was further classified into diffuse, streaked, cobblestone and salt-and-pepper patterns according to the spacial distribution of low-density areas. 3. Selectivity pattern: As the chronological sequence of DMD muscle degeneration is usually different among individual muscles, it may be seen, in some stages, that some of the synergistic muscles are still only slightly involved, while the others are quite severely atrophied with evident fat infiltration. In certain stages of the disease, most of the patients show relative preservation of particular muscles although they assumed a rounded shape. The most resistent muscle was musculus gracilis, followed by the musculus sartorius, musculus semitendinosus (and/or musculus semimembranosus) in that order. According to the severity of the CT changes, 86 of the 91 patients were classed into five stages from A1 to A5. Morphological stages (A1-A5) were well correlated to the functional disability stages by Ueda with a correlation factor of r=0.88. (J.P.N.)

  12. Facioscapulohumeral muscular dystrophy

    Science.gov (United States)

    ... children. Alternative Names Landouzy-Dejerine muscular dystrophy Images Superficial anterior muscles References Preston DC, Shapiro BE. Proximal, ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  13. Becker muscular dystrophy

    Science.gov (United States)

    ... Names Benign pseudohypertrophic muscular dystrophy; Becker's dystrophy Images Superficial anterior muscles References Amato AA. Disorders of the ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-05-01

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

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

    International Nuclear Information System (INIS)

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

    1989-01-01

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

  16. Rhabdomyolysis featuring muscular dystrophies.

    Science.gov (United States)

    Lahoria, Rajat; Milone, Margherita

    2016-02-15

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

  17. 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.

  18. How Is Muscular Dystrophy Diagnosed?

    Science.gov (United States)

    ... Research Information Find a Study Resources and Publications Osteogenesis Imperfecta (OI) Condition Information NICHD Research Information Find ... Print How is muscular dystrophy diagnosed? The first step in diagnosing muscular dystrophy (MD) is a visit ...

  19. Therapeutic advances in muscular dystrophy

    OpenAIRE

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

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

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

    Science.gov (United States)

    Kovanda, Anja; Režen, Tadeja; Rogelj, Boris

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Daniel Cantarelli dos Santos

    2010-06-01

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

  2. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy

    Directory of Open Access Journals (Sweden)

    Agnieszka Madej-Pilarczyk

    2016-03-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMD, a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1 kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2, with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.

  3. Hemifacial atrophy treated with autologous fat transplantation

    Directory of Open Access Journals (Sweden)

    Gandhi Vijay

    2005-01-01

    Full Text Available A 23-year-old male developed right hemifacial atrophy following marphea profunda. Facial asymmetry due to residual atrophy was treated with autologous fat harvested from buttocks with marked cosmetic improvement.

  4. Duchenne muscular dystrophy carriers

    International Nuclear Information System (INIS)

    Matsumura, K.; Nakano, I.

    1989-01-01

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

  5. Duchenne muscular dystrophy.

    Science.gov (United States)

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  6. [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.

  7. Lobar atrophy without Pick bodies.

    Science.gov (United States)

    Hulette, C M; Crain, B J

    1992-01-01

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

  8. Cardio-Muscular Conditioner

    Science.gov (United States)

    1993-01-01

    In the mid-sixties, Gary Graham, a Boeing designer, developed a cardiovascular conditioner for a planned Air Force orbiting laboratory. After the project was cancelled, Graham participated in space station conditioning studies for the Skylab program. Twenty years later, he used this expertise to develop the Shuttle 2000-1, a physical therapy and athletic development conditioner, available through Contemporary Designs. The machine is used by football teams, sports clinics and medical rehabilitation centers. Cardiovascular fitness and muscular strength development are promoted through both kinetic and plyometric exercises.

  9. Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity.

    Science.gov (United States)

    Pellegrinelli, Vanessa; Rouault, Christine; Rodriguez-Cuenca, Sergio; Albert, Victorine; Edom-Vovard, Frédérique; Vidal-Puig, Antonio; Clément, Karine; Butler-Browne, Gillian S; Lacasa, Danièle

    2015-09-01

    Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three-dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1β as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  10. Regulation of a Notch3-Hes1 pathway and protective effect by a tocopherol-omega alkanol chain derivative in muscle atrophy.

    Science.gov (United States)

    von Grabowiecki, Yannick; Licona, Cynthia; Palamiuc, Lavinia; Abreu, Paula; Vidimar, Vania; Coowar, Djalil; Mellitzer, Georg; Gaiddon, Christian

    2015-01-01

    Muscular atrophy, a physiopathologic process associated with severe human diseases such as amyotrophic lateral sclerosis (ALS) or cancer, has been linked to reactive oxygen species (ROS) production. The Notch pathway plays a role in muscle development and in muscle regeneration upon physical injury. In this study, we explored the possibility that the Notch pathway participates in the ROS-related muscular atrophy occurring in cancer-associated cachexia and ALS. We also tested whether hybrid compounds of tocopherol, harboring antioxidant activity, and the omega-alkanol chain, presenting cytoprotective activity, might reduce muscle atrophy and impact the Notch pathway. We identified one tocopherol-omega alkanol chain derivative, AGT251, protecting myoblastic cells against known cytotoxic agents. We showed that this compound presenting antioxidant activity counteracts the induction of the Notch pathway by cytotoxic stress, leading to a decrease of Notch1 and Notch3 expression. At the functional level, these regulations correlated with a repression of the Notch target gene Hes1 and the atrophy/remodeling gene MuRF1. Importantly, we also observed an induction of Notch3 and Hes1 expression in two murine models of muscle atrophy: a doxorubicin-induced cachexia model and an ALS murine model expressing mutated superoxide dismutase 1. In both models, the induction of Notch3 and Hes1 were partially opposed by AGT251, which correlated with ameliorations in body and muscle weight, reduction of muscular atrophy markers, and improved survival. Altogether, we identified a compound of the tocopherol family that protects against muscle atrophy in various models, possibly through the regulation of the Notch pathway. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Thymic Atrophy: Experimental Studies and Therapeutic Interventions.

    Science.gov (United States)

    Majumdar, S; Nandi, D

    2018-01-01

    The thymus is essential for T cell development and maturation. It is extremely sensitive to atrophy, wherein loss in cellularity of the thymus and/or disruption of the thymic architecture occur. This may lead to lower naïve T cell output and limited TCR diversity. Thymic atrophy is often associated with ageing. What is less appreciated is that proper functioning of the thymus is critical for reduction in morbidity and mortality associated with various clinical conditions including infections and transplantation. Therefore, therapeutic interventions which possess thymopoietic potential and lower thymic atrophy are required. These treatments enhance thymic output, which is a vital factor in generating favourable outcomes in clinical conditions. In this review, experimental studies on thymic atrophy in rodents and clinical cases where the thymus atrophies are discussed. In addition, mechanisms leading to thymic atrophy during ageing as well as during various stress conditions are reviewed. Therapies such as zinc supplementation, IL7 administration, leptin treatment, keratinocyte growth factor administration and sex steroid ablation during thymic atrophy involving experiments in animals and various clinical scenarios are reviewed. Interventions that have been used across different scenarios to reduce the extent of thymic atrophy and enhance its output are discussed. This review aims to speculate on the roles of combination therapies, which by acting additively or synergistically may further alleviate thymic atrophy and boost its function, thereby strengthening cellular T cell responses. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  12. Microvillous inclusion disease (microvillous atrophy

    Directory of Open Access Journals (Sweden)

    Goulet Olivier

    2006-06-01

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

  13. Multidimensional Analysis on the Effect of Vocal Function Exercises on Aged Vocal Fold Atrophy.

    Science.gov (United States)

    Kaneko, Mami; Hirano, Shigeru; Tateya, Ichiro; Kishimoto, Yo; Hiwatashi, Nao; Fujiu-Kurachi, Masako; Ito, Juichi

    2015-09-01

    Age-related voice change is characterized as weak, harsh, and breathy. These changes are caused by histologic alteration of the lamina propria of the vocal fold mucosa as well as atrophy of the thyroarytenoid muscle. Several therapeutic strategies involving laryngeal framework surgery and injection laryngoplasty have been tried, but effects have been limited. Vocal function exercises (VFE) have been used to treat age-related vocal fold atrophy although the effectiveness has been shown with limited analysis. The present study aims to determine the effectiveness of VFE for the treatment of aged atrophy using multidimensional analysis. This is a retrospective study. Sixteen patients with vocal fold atrophy aged 65-81 years underwent voice therapy using VFE. Six patients with vocal fold atrophy aged 65-85 years were involved as a historical control group. The grade, roughness, breathiness, asthenia, strain (GRBAS) scale, stroboscopic examinations, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 (VHI-10) were performed before and after VFE. Normalized mucosal wave amplitude (NMWA), normalized glottal gap (NGG), and bowing index (BI) were measured by image analysis during stroboscopic examinations. After VFE, significant improvements were shown in GRBAS, maximum phonation time, jitter, NMWA, NGG, and VHI-10 although BI has not changed significantly. There were no significant improvements in the historical control. The data suggest that VFE produces significant improvement in subjective, objective, and patient self-evaluation and deserves further attention as a treatment for aged atrophy of the vocal fold. It was also suggested that VFE does not improve the vocal fold bowing but may improve muscular function during voicing. Copyright © 2015 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  14. Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge

    Directory of Open Access Journals (Sweden)

    Cláudio Martins

    2016-01-01

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

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

    Science.gov (United States)

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

    2014-10-11

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

  16. A quantitative study of the physiological cerebral atrophy with aging

    International Nuclear Information System (INIS)

    Nagata, K.

    1987-01-01

    A new method of discriminating pathological cerebral atrophy from physiological atrophy during aging is reported. The authors advocate a pixel counting method using a minicomputer for the quantitative measurement of cerebral atrophy. Five hundred cases were studied with this quantitative method and the normal range of the physiological atrophy was determined statistically. In order to estimate the degree of cerebral atrophy easily, the conventional linear measurement methods were compared with the pixel counting method using multivariant analysis, and a simple formula for the calculation of the degree of cerebral atrophy is proposed. Using this formula and the normal range, pathological cerebral atrophy is easily detectable. (orig.)

  17. Immunoproteasome in animal models of Duchenne muscular dystrophy.

    Science.gov (United States)

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

    2014-04-01

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

  18. Progress in research on molecular mechanism of facioscapulohumeral muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Xiao-dan LIN

    2017-09-01

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD, characterized by symmetric or asymmetric muscular weakness of the initial onset of facial, shoulder-girdle and upper arm muscles, and descending to limb muscles, is a classical autosomal dominant myopathy with high clinical diversity and relatively good prognosis. FSHD is catigorized into two types, FSHD1 and FSDH2. Previous studies have demonstrated that 95% patients with FSHD1 were associated with a contraction of D4Z4 microsatellite repeats on chromosome 4q35, which was pathogenic in the genetic backgrounds, including a special sequence of simple sequence length polymorphism (SSLP proximal to the D4Z4 repeats and the 4qA/4qB polymorphism distal to the repeats. In recent years, several reports have confirmed that 4q35 locus leads to DNA hypomethylation and inner DUX4 gene transcription by epigenetic effect. The abnormal expression of DUX4 further activates several genes, which inhibit myogenesis, sensitize cells to oxidative stress and induce muscle atrophy. And not only that, FSHD2 is formed by another methylation regulation gene—— SMCHD1 mutations. More and more evidences supported that toxic gain of function mechanism plays an important role in the occurrence of FSHD. The DUX4 gene becomes an important target for treatment study in the future. DOI: 10.3969/j.issn.1672-6731.2017.08.004

  19. Infraspinatus muscle atrophy in professional baseball players.

    Science.gov (United States)

    Cummins, Craig Anthony; Messer, Terry M; Schafer, Michael F

    2004-01-01

    Infraspinatus muscle atrophy has been observed in athletes who stress their upper extremities in an overhead fashion. The majority of such case reports have been in volleyball players, with far fewer cases reported in baseball players. Infraspinatus muscle atrophy occurs to a notable degree in professional baseball players. Retrospective cohort study. At the end of the 1999 baseball season, data were collected from all Major League Baseball teams in regards to players affected with infraspinatus muscle atrophy. Twelve of the 1491 major league professional baseball players were identified as having appreciable infraspinatus muscle atrophy. There was an increased prevalence of the muscle atrophy in professional pitchers (10 of 494, 4%) compared to position players (2 of 997, 0.2%) (P relief pitchers (2 of 10) (P = 0.036), pitchers who had played for more years at the major league level (8.7 +/- 4.9 versus 5.2 +/- 4.0) (P = 0.017), and pitchers who had thrown for more innings at the major league level (971.4 +/- 784.4 versus 485.0 +/- 594.6) (P <0.001). Infraspinatus atrophy was identified in 4.4% of major league starting pitchers and occurred in those pitchers who pitched for more years and innings during their major league career.

  20. Metabolismo muscular en el ejercicio

    OpenAIRE

    Martín Martín, Laura

    2017-01-01

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

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

    OpenAIRE

    MEZZANO ROBINSON, VALERIA; MEZZANO ROBINSON, VALERIA

    2007-01-01

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

  2. Duchenne muscular dystrophy: Case report and review

    OpenAIRE

    Rupam Sinha; Soumyabrata Sarkar; Tanya Khaitan; Soumyajit Dutta

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or resp...

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

    Directory of Open Access Journals (Sweden)

    Ronghua Wu

    2015-11-01

    Full Text Available Calpain 3 (CAPN3, also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA of gastrocnemius muscle were decreased gradually from 1–14 days and then recovery from 14–28 days. The active form of CAPN3 (~62 kDa protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury.

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

    Science.gov (United States)

    Wu, Ronghua; Yan, Yingying; Yao, Jian; Liu, Yan; Zhao, Jianmei; Liu, Mei

    2015-11-11

    Calpain 3 (CAPN3), also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA) of gastrocnemius muscle were decreased gradually from 1-14 days and then recovery from 14-28 days. The active form of CAPN3 (~62 kDa) protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA) injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury.

  5. Physiology of respiratory disturbances in muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Antonella Lo Mauro

    2016-12-01

    To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy. To understand the impact of respiratory disturbances in patients with muscular dystrophy. To provide a brief description of the main forms of muscular dystrophy with their respiratory implications.

  6. Physical therapy services received by individuals with spinal muscular atrophy (SMA).

    Science.gov (United States)

    Dunaway, Sally; Montes, Jacqueline; McDermott, Michael P; Martens, William; Neisen, Annie; Glanzman, Allan M; Pasternak, Amy; Riley, Susan; Sproule, Douglas; Chiriboga, Claudia; Finkel, Richard; Tennekoon, Gihan; Darras, Basil; De Vivo, Darryl; Pandya, Shree

    2016-01-01

    The consensus statement for standard of care in SMA recommends multidisciplinary medical care including physical therapy (PT) services. To date there are no reports regarding the implementation of these recommendations and the type of care or services received by individuals with SMA. The purpose of this study is to describe the PT services received by individuals with SMA. Interviews were conducted with patients or their caregivers at the Pediatric Neuromuscular Clinical Research (PNCR) Network sites from October 2011 to September 2012. Questions included information about clinical status of the patient, sociodemographic profile of the patient or caregiver, and PT services received in the past year, including the setting, frequency, duration and type of PT, and therapies administered by caregivers. Eighty-six percent of 105 participants reported receiving PT services, some in multiple settings: 62% in the neuromuscular clinic, 38% at school, 34% at home, and 13% in an outpatient clinic. Greater frequency of PT services received was associated with younger age and inability to walk, but not SMA type. This is the first multicenter study documenting PT services received by patients with SMA. Further research is needed to better understand the impact of PT services on the natural history of SMA.

  7. 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

    with nine items measures more than one construct of fatigue, eliminating the first two items improved scale properties. CONCLUSION: This study demonstrates that fatigue is characteristic in patients with CM, but not in patients with SMA II, in whom fatigue does not seem to impact daily life. While fatigue...

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

    Science.gov (United States)

    ... is produced from the mutated IGHMBP2 gene may play a role in the severity of SMARD1 . Individuals who have some functional protein are more likely to develop signs and symptoms later in childhood and retain a greater level of muscle function. ...

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

    Directory of Open Access Journals (Sweden)

    Hussien E Sultan

    2016-01-01

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    a 12-week training program, performing 42 30-minute sessions exercising at 65-70% of maximal oxygen uptake (VO2max ). VO2max , muscle strength, functional tests, and self-reported activities of daily living were assessed before and after the training. RESULTS: Training induced a 27 ± 3% increase in VO2......max (17 ± 2 to 21 ± 2 ml/kg/min, P VO2max in SMA III without causing muscle...

  11. Progress study on the mechanism of CAG repeats dynamic mutation in polyQ disease

    Directory of Open Access Journals (Sweden)

    WANG Chun-rong

    2012-06-01

    Full Text Available Polyglutamine (polyQ disease is a group of neurodegenerative disorders caused by abnormal expansion of CAG repeats within coding regions of certain causative genes, which are translated into a series of abnormally expanded polyQ tracts causing cytotoxicity. So far, nine diseases caused by expanded polyQ tracts have been demonstrated including Huntington's disease (HD, spinobulbar muscular atrophy (SBMA, dentatorubral-pallidoluysian atrophy (DRPLA and several spinocerebellar ataxias subtypes (SCA. In human, long CAG repeats tend to expand during transmissions from parent to offspring, named as dynamic mutation, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. The review presents some novel mechanisms based on dynamic mutation.

  12. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2015-07-01

    digitorum longus GSM: grip strength measurement LV: left ventricle mRNA: messenger RNA TA: tibialis anterior TGF-β: transforming growth factor...kinase CNF: central nucleated fibers CTSB: cathepsin B DMD: Duchenne muscular dystrophy Dmd: dystrophin gene EBD: evan blue dye EDL: extensor

  13. Glucocorticoids for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-07-01

    Full Text Available Investigators at the Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, and other centers in the UK, conducted a prospective longitudinal study across 17 neuromuscular centers in the UK of 360 boys aged 3-15 years with Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off prednisolone for a mean duration of 4 years.

  14. Can endoscopic atrophy predict histological atrophy? Historical study in United Kingdom and Japan.

    Science.gov (United States)

    Kono, Shin; Gotoda, Takuji; Yoshida, Shigeaki; Oda, Ichiro; Kondo, Hitoshi; Gatta, Luigi; Naylor, Greg; Dixon, Michael; Moriyasu, Fuminori; Axon, Anthony

    2015-12-14

    To assess the diagnostic concordance between endoscopic and histological atrophy in the United Kingdom and Japan. Using published data, a total of 252 patients, 126 in the United Kingdom and 126 in Japan, aged 20 to 80 years, were evaluated. The extent of endoscopic atrophy was classified into five subgroups according to a modified Kimura-Takemoto classification system and was compared with histological findings of atrophy at five biopsy sites according to the updated Sydney system. The strength of agreement of the extent of atrophy between histology and visual endoscopic inspection showed good reproducibility, with a weighted kappa value of 0.76 (P atrophy (OR = 0.10, 95%CI: 0.03-0.36). The strength of agreement between endoscopic and histological atrophy, assessed by cancer risk-oriented grading, was reproducible, with a kappa value of 0.81 (95%CI: 0.75-0.87). Only nine patients (3.6%) were endoscopically underdiagnosed with antral predominant rather than extensive atrophy and were considered false negatives. Endoscopic grading can predict histological atrophy with few false negatives, indicating that precancerous conditions can be identified during screening endoscopy, particularly in patients in western countries.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we...

  16. Extensive Delayed Brain Atrophy after Resuscitation in a Patient with Multiple System Atrophy

    Directory of Open Access Journals (Sweden)

    Sazuku Nisitani

    2018-01-01

    Full Text Available Brain magnetic resonance imaging (MRI of multiple system atrophy (MSA shows atrophy in the cerebrum, cerebellum, and brainstem. It is also characterized by specific patterns such as hyperintense lateral putaminal rim. MRI of hypoxic encephalopathy shows atrophy mainly in the gray matter, and laminar necrosis in the cerebral cortex is often observed. Here, we report an MSA patient damaged by hypoxic insult and resuscitated after 18-min cardiac arrest. The brain of the patient developed severe atrophy within a period of 10 months. Furthermore, brain atrophy was observed in the white and gray matter, which preserved the brain atrophy pattern in MSA. We assume that alpha-synuclein oligomerization is involved in the neural cell death and brain atrophy. It might have caused further neural cell death in the brain damaged by hypoxia. Alpha-synuclein, which is involved in the pathogenesis of MSA, is suggested to be a prion. Misfolded alpha-synuclein may propagate through cell-to-cell transmission and cause wide pathological change, visible as atrophied MR imaging.

  17. Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Acary S. Bulle Oliveira

    1992-12-01

    Full Text Available To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

  18. Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Uluç Yis

    2016-01-01

    Full Text Available Megaconial congenital muscular dystrophy (OMIM 602541 is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB gene c.1031G>A (p.R344Q in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.

  19. Research progress of motor function assessments and their clinical applications in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Wei SHI

    2015-07-01

    Full Text Available Duchenne muscular dystrophy (DMD, clinically featured as progressive skeletal muscle atrophy with gradual loss of muscle strength and activity abilities, is the most common genetic muscular disease in children throughout the world. The core and continuous characteristic of DMD is motor dysfunction. Motor function assessments of DMD are now focusing on muscle strength, walking ability, range of motion and ability of activities, still without unified standards. Confirming the comprehensive, scientific, reasonable and accurate evaluation tools for DMD assessment is the premise of research in motor developmental rules of DMD, which will help to better understand the motor progress of DMD and to supply evidences for choosing treatment methods, confirming timing of intervention, assessing effect of treatments and designing rehabilitation plans. DOI: 10.3969/j.issn.1672-6731.2015.06.002

  20. Toxic myopathies: muscle biopsy features Miopatia tóxica: biópsia muscular

    Directory of Open Access Journals (Sweden)

    Rosana Herminia Scola

    2007-03-01

    Full Text Available Several drugs and toxic substances can cause muscular abnormalities and are frequent causes of acquired myopathies. We present a series of 32 patients, predominance of young adult patients, diagnosed with toxic myopathy. The most common substances inducing myopathy were corticosteroids (56.2% followed by the propoxyphene, neuroleptics, zidovudine and drug-induced hypokalemia. The investigation showed normal serum creatine kinase levels in 65.4%, myopathic pattern of the needle electromyography in 40% and the more frequent histological diagnosis of the muscle biopsy was type 2 fiber atrophy (59.3%. Clinical features, etiology, course of the disease, serum levels of muscular enzymes, electromyographic features and, especially, muscle biopsy features are discussed.Diversos medicamentos e substâncias tóxicas podem causar alterações musculares e são causas freqüentes de miopatia adquirida. Apresentamos uma série de 32 pacientes, predomínio de pacientes adulto jovens, com miopatia tóxica. As substâncias mais relacionadas com a miopatia foram os corticosteróides (56,2% seguidos pelo propoxifeno, neurolépticos, zidovudina e drogas indutoras de hipocalemia. A investigação mostrou níveis normais de creatino quinase sérica em 65,4%, eletromiografia de agulha com padrão miopático em 40% e o mais freqüente diagnóstico histológico da biópsia muscular foi atrofia de fibras do tipo 2 (59,3%. As manifestações clínicas, etiologia, tempo de evolução, nível sérico das enzimas musculares, alterações da eletroneuromiografia e, especialmente, da biópsia muscular são discutidos.

  1. Evaluation of skeletal muscular involvement in neuromuscular disorders with thallium-201 whole body scintigraphy

    International Nuclear Information System (INIS)

    Yamamoto, Shuhei; Sotobata, Iwao; Indo, Toshikatsu; Matsuoka, Yukihiko; Matsushima, Hideo; Suzuki, Akio; Abe, Tetsutaro; Sakuma, Sadayuki

    1986-01-01

    The extent as well as severity of pathologic changes of skeletal muscles were analyzed with thallium-201 whole body scintigraphy (WBS) in 29 cases of various types of neuromuscular diseases (18 cases of myogenic and 11 cases of neurogenic muscular diseases) and 14 cases of normal controls. After intravenous injection of 2 mCi of thallium-201 chloride, WBS was performed for 15 minutes using a gamma camera with twin-opposed large rectangular detectors. Counts at brachia, forearms, thighs, and calves were assessed after reconstruction of the scintigram of the whole body by taking the geometric mean of the anterior and posterior data. WBS showed uniform tracer activities in the 4 extremities in 12 cases among 14 controls. Laterality in distribution of counts of both legs and arms was noted in the remaining 2 controls. WBS revealed decrease of perfusion in the extremities with muscular atrophy and/or weakness in neuromuscular diseases. The overall diagnostic accuracy of WBS for evaluation of skeletal muscle involvement was 75 to 80 % except for the bilateral brachia for which it decreased to 65 %. All of the three cases of muscular dystrophy with pseudohypertrophy of the calves or thighs showed unequivocal decrease of perfusion of those regions in WBS. In conclusion, thallium-201 WBS was considered to be a useful clinical means in evaluating the extent and severity of muscular involvement of various types of neuromuscular disorders. (author)

  2. Cyclosporine increases muscular force generation in Duchenne muscular dystrophy.

    Science.gov (United States)

    Sharma, K R; Mynhier, M A; Miller, R G

    1993-03-01

    We investigated the effect of cyclosporine (CsA) on force generation in 15 boys with Duchenne muscular dystrophy (DMD) by obtaining monthly measures of tetanic force and maximum voluntary contraction (MVC) of both anterior tibial muscles. During 4 months of a natural history phase, both tetanic force and MVC declined significantly. During 8 weeks of CsA treatment (5 mg/kg/day), significantly increased tetanic force (25.8 +/- 6.6%) and MVC (13.6 +/- 4.0%) occurred within 2 weeks. The maximum mean increase during treatment was 35.2 +/- 5.9% (tetanic force) and 19.0 +/- 4.6% (MVC). Side effects from CsA, gastrointestinal and flu-like symptoms, were transient and self-limiting. Thus, as previously reported with prednisone, CsA increases muscular force generation in the anterior tibial muscles of DMD patients.

  3. Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

    Science.gov (United States)

    Lang, Franziska; Aravamudhan, Sriram; Nolte, Hendrik; Türk, Clara; Hölper, Soraya; Müller, Stefan; Günther, Stefan; Blaauw, Bert; Braun, Thomas

    2017-01-01

    ABSTRACT Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC) diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG) were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal. PMID:28546288

  4. Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

    Directory of Open Access Journals (Sweden)

    Franziska Lang

    2017-07-01

    Full Text Available Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.

  5. CT features of olivopontocerebellar atrophy in children

    International Nuclear Information System (INIS)

    Kumar, S.D.; Gururaj, A.K.; Jeans, W.D.

    1995-01-01

    Between 1990 and 1992, 14 children were seen in whom a clinical diagnosis of olivopontocerebellar atrophy (OPCA) had been made. The majority of patients presented with cerebellar ataxia and hypotonia. Five children had a family history of a similar illness in first-degree relatives. All cases had undergone clinical and neurologic examinations, routine laboratory tests and cranial CT. CT features were graded to quantitative the degree of atrophy in each cerebellar hemisphere, vermis and brain stem. All patients had varying degrees of atrophic changes of cerebellum, brain stem and cerebrum. These CT features appear to be distinctive enough to enable the diagnosis of OPCA to be made. (orig.)

  6. [Psoas muscular abscess in children].

    Science.gov (United States)

    Pires, A M; Reis, A G; Grisi, S J

    1996-01-01

    Symptoms of psoas muscular abscess in children are nonspecific and differential diagnosis is made among diseases included in childreńs acute hip pain syndrome, imaging tests being necessary for diagnostic confirmation. During the first semester of 1995, 48,550 children were examined in Pronto Socorro do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, four of them diagnosed as having psoas muscular abscess (2 females and 2 males, ages varying from 1 to 12 years). All of them had nonspecific clinical features and diagnosis was confirmed by abdominal ultrasound and/or computerized tomography. Staphylococcus aureus was isolated as the etiologic agent in 3 children, findings similar to the ones in literature.

  7. CT findings of muscular dystrophy

    International Nuclear Information System (INIS)

    Saitoh, Hiroshi

    1991-01-01

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

  8. Photoreceptor atrophy in acute zonal occult outer retinopathy

    DEFF Research Database (Denmark)

    Zibrandtsen, N.; Munch, I.C.; Klemp, K.

    2006-01-01

    and multifocal electroretinography. Results: All three patients demonstrated partial or complete photoreceptor atrophy corresponding to partial or complete scotomata of retinal origin. Conclusion: Photoreceptor atrophy can be demonstrated early in the course of AZOOR, before ophthalmoscopically visible changes...

  9. Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

    Directory of Open Access Journals (Sweden)

    Erika Hissong, M.D.

    2016-06-01

    Full Text Available Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

  10. Fluid biomarkers in multiple system atrophy

    DEFF Research Database (Denmark)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy

    2015-01-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagem...

  11. Sensorimotor gating deficits in multiple system atrophy

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Biernat, Heidi Bryde; Nikolic, Miki

    2014-01-01

    Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism's ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently...

  12. Assessment of vaginal atrophy: a review

    NARCIS (Netherlands)

    Weber, M. A.; Limpens, J.; Roovers, J. P. W. R.

    2015-01-01

    The aim of this study is to provide an evidence-based definition of vaginal atrophy (VA) and present an overview of subjective and objective measurements of VA applicable in clinical practice and research. A systematic literature search was performed in MEDLINE and EMBASE to identify studies

  13. Cube propagation for focal brain atrophy estimation

    DEFF Research Database (Denmark)

    Pai, Akshay Sadananda Uppinakudru; Sørensen, Lauge; Darkner, Sune

    2013-01-01

    Precise and robust whole brain, ventricle, and hippocampal atrophy measurements are important as they serve as biomarkers for Alzheimer’s disease. They are used as secondary outcomes in drug trials, and they correlate with the cognitive scores. When two successive scans are non-linearly aligned...

  14. Progressive Hemifacial Atrophy with Morphea of Cheek

    Directory of Open Access Journals (Sweden)

    Ajit Auluck

    2006-01-01

    Full Text Available Scleroderma is a rare collagen disorder in which fibrosis of skin, subcutaneous tissues and muscles can occur with occasional involvement of bones. Localized scleroderma is a benign condition but can cause significant deformity when it affects the face. We report a case of localized scleroderma of the face causing progressive hemifacial atrophy.

  15. White Matter Hyperintensities, Medial Temporal Lobe Atrophy, Cortical Atrophy, and Response to Electroconvulsive Therapy in Severely Depressed Elderly Patients

    NARCIS (Netherlands)

    Oudega, Mardien L.; van Exel, Eric; Wattjes, Mike P.; Comijs, Hannie C.; Scheltens, Philip; Barkhof, Frederik; Eikelenboom, Piet; de Craen, Anton J. M.; Beekman, Aartjan T. F.; Stek, Max L.

    2011-01-01

    Objective: Electroconvulsive therapy (ECT) is a valuable treatment option in severely depressed elderly patients. Structural abnormalities in the brain, such as white matter hyperintensities, medial temporal lobe atrophy (MTA), or global cortical atrophy, may influence therapeutic response. The

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

    Directory of Open Access Journals (Sweden)

    Jiménez Díaz, José Fernando

    2006-04-01

    Full Text Available ResumenDurante la práctica de la actividad física hay una gran incidencia de lesiones musculares, si bien se han llevado a cabo pocos estudios clínicos sobre el tratamiento y la resolución de las mismas. Desde el punto de vista etiopatogénico, hay que señalar que la incidencia de lesión es mayor en aquellos músculos poliarticulares en condiciones de acumulación de fatiga y con condiciones ambientales desfavorables. La clasificación de las lesiones musculares permite distinguir entre aquellas que no afectan a la fascia produciéndose un sangrado dentro del mismo (intramuscular o bien si la fascia también se rompe, el sangrado se sitúa entre los diferentes músculos (intermuscular. El tratamiento de estas lesiones se realizará combinando reposo, compresión, aplicación de frío y elevación del área lesionada así como el desarrollo de un adecuado programa de readaptación funcional que permita al jugador incorporarse lo antes posible a la dinámica del equipo. En la actualidad se está llevando a cabo opciones terapéuticas con factores de crecimiento, terapia génica y células madre, si bien todavía no están lo suficientemente desarrolladas.AbstractDuring the practice of the physical activity there is a great effect of muscular injuries, though few clinical studies have been carried out on the treatment and the resolution of the same ones. Inside the reasons it is necessary to indicate that the effect of injury is major in those muscles you will polyarticulate in situation of fatigue and with environmental unfavorable conditions.The classification of the muscular injuries allows to distinguish between those that do not affect the fascia producing the bled intramuscular or if the fascia also breaks, the bled one places between the different muscles (intermuscular.The treatment will be realized combining rest, compression, application of cold and elevation of these injuries as well as the development of a program of functional

  17. Regenerative Effects of Basic Fibroblast Growth Factor on Restoration of Thyroarytenoid Muscle Atrophy Caused by Recurrent Laryngeal Nerve Transection.

    Science.gov (United States)

    Kaneko, Mami; Tsuji, Takuya; Kishimoto, Yo; Sugiyama, Yoichiro; Nakamura, Tatsuo; Hirano, Shigeru

    2017-10-27

    Vocal fold atrophy following unilateral vocal fold paralysis is caused by atrophy of the thyroarytenoid (TA) muscle and remains a challenge. Medialization procedures are popular treatment options; however, hoarseness often remains due to the reduction in mass or tension of the TA muscle. Therefore, in addition to medialization procedures, TA muscle reinnervation is desirable. In vivo studies have shown the potential for basic fibroblast growth factor (bFGF) to affect muscular and nerve regeneration. The present study aimed to examine the regenerative effects of bFGF on restoration of TA muscle atrophy caused by recurrent laryngeal nerve transection. Prospective animal experiments with controls. TA muscle atrophy was induced by unilateral transection of the recurrent laryngeal nerve. One month after transection, different doses (200 ng, 100 ng, 10 ng) of bFGF in 50 µL were repeatedly injected into the TA muscle four times with an interval of 1 week between injections. Saline only was injected in the sham group. Larynges were harvested for histologic and immunohistochemical examination 4 weeks after the final injection. The cross-sectional TA muscle area was significantly larger in the bFGF-treated groups compared with the sham-treated groups. Immunohistochemistry indicated that bFGF significantly increases the number of neuromuscular junctions and satellite cells in the TA muscle. These results suggest that local application of bFGF to the TA muscle may improve TA muscle atrophy caused by recurrent laryngeal nerve paralysis. Furthermore, bFGF may have regenerative effects on both nerves and muscles. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  18. Cerebral atrophy in Parkinson's disease - represented in CT

    International Nuclear Information System (INIS)

    Becker, H.; Schneider, E.; Hacker, H.; Fischer, P.A.; Frankfurt Univ.

    1979-01-01

    To clarify the importance of brain atrophy in relation to the symptoms of Parkinson's disease, 173 patients were examined by computed tomography (CT). In 51.4% of the CT findings, brain atrophy was considered to be pathological. Statistically significant relations of age and sex were found with regard to the extent and localization of brain atrophy. Cortical atrophy also showed a significant dependence on duration of disease. Linear measurements at the lateral ventricles and the third ventricle lead us to assume that brain atrophy in Parkinson's patients is more prevalent than in normal patients within the scope of age involution. (orig.)

  19. Fukuyama type congenital muscular dystrophy with unusual features

    International Nuclear Information System (INIS)

    Mori, Hideo; Oguni, Hirokazu; Osawa, Makiko; Suzuki, Haruko; Fukuyama, Yukio

    1980-01-01

    The Fukuyama type congenital muscular dystrophy (F-CMD) has been generally recognized as a well delineated subgroup of progressive muscular dystrophy (PMD) with uniform clinical, pathological, and genetic features. However, there are still debate to be solved as to the etiology of the condition, because several neuropathological findings found in F-CMD brain allowed some investigators to hypothesize the intrauterine infection to be a primary causation. The authors reported here two families with two affected siblings in each. In the pedigree A, consanguineous parents produced two sisters, Case 1 (3-year-old) and Case 2 (14-month-old). Two patients in the pedigree B, the products of non-consanguineous parents, Case 3 (4-month-old male) and his elder sister already decreased, were affected with F-CMD and infantile spasms. In all cases, generalized weakness and hypotonia had been remarkable since their early infancy, and muscle atrophy, myopathic facies multiple joint contractures and mental dullness became evident gradually. The above-mentioned clinical features as well as laboratory findings including elevated serum CPK and myogenic EMG were compatible with those of typical F-CMD. However, they were characterized by the following three unusual features. 1. Muscle biopsy: In addition to an overwhelming myogenic change, there was a distinct inflammatory cell infiltration in all cases, and scattered small groups of atrophic fibers were present in Case 2. 2. Brain CT scanning: A symmetrical and extensive low density area was observed in the cerebral white matter in all cases. 3. A favorable response to prednisolone therapy was noted in all cases. (author)

  20. The roles of muscle stem cells in muscle injury, atrophy, and hypertrophy.

    Science.gov (United States)

    Fukada, So-Ichiro

    2018-01-31

    Skeletal muscle is composed of multinuclear cells called myofibers. Muscular dystrophy (a genetic muscle disorder) induces instability in the cell membrane of myofibers and eventually causes myofiber damage. Non-genetic muscle disorders, including sarcopenia, diabetes, bedridden immobility, and cancer cachexia, lead to atrophy of myofibers. In contrast, resistance training induces myofiber hypertrophy. Thus, myofibers exhibit a plasticity that is strongly affected by both intrinsic and extrinsic factors. There is no doubt that muscle stem cells (MuSCs, also known as muscle satellite cells) are indispensable for muscle repair/regeneration, but their contributions to atrophy and hypertrophy are still controversial. The present review focuses on the relevance of MuSCs to (1) muscle diseases, and (2) hypertrophy. Further, this review addresses fundamental questions about MuSCs to clarify the onset or progression of these diseases, and which might lead to development of a MuSC-based therapy. © The Authors 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  1. Cerebellar and cerebral atrophy in trichothiodystrophy

    International Nuclear Information System (INIS)

    Yoon, Hye-Kyung; Sargent, Michael A.; Poskitt, Kenneth J.; Prendiville, Julie S.

    2005-01-01

    Trichothiodystrophy is a rare neuroectodermal disorder of autosomal recessive inheritance that is characterized by brittle hair, nail dysplasia, ichthyosis, mental retardation, and gonadal failure. We describe a female patient whose cranial MRI revealed almost total lack of myelination in the supratentorial white matter, which is similar to the previously described cases. In addition, there was progressive cerebellar and cerebral atrophy, which has not been well documented in association with trichothiodystrophy. (orig.)

  2. Cerebellar and cerebral atrophy in trichothiodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hye-Kyung; Sargent, Michael A.; Poskitt, Kenneth J. [British Columbia Children' s Hospital, Department of Radiology, Vancouver, BC (Canada); Prendiville, Julie S. [British Columbia Children' s Hospital, Division of Paediatric Dermatology, Department of Paediatrics, Vancouver, BC (Canada)

    2005-10-01

    Trichothiodystrophy is a rare neuroectodermal disorder of autosomal recessive inheritance that is characterized by brittle hair, nail dysplasia, ichthyosis, mental retardation, and gonadal failure. We describe a female patient whose cranial MRI revealed almost total lack of myelination in the supratentorial white matter, which is similar to the previously described cases. In addition, there was progressive cerebellar and cerebral atrophy, which has not been well documented in association with trichothiodystrophy. (orig.)

  3. Space travel directly induces skeletal muscle atrophy

    Science.gov (United States)

    Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

    1999-01-01

    Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

  4. Physiology of respiratory disturbances in muscular dystrophies.

    Science.gov (United States)

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-12-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered

  5. Corpus callosum atrophy correlates with gray matter atrophy in patients with multiple sclerosis.

    Science.gov (United States)

    Klawiter, Eric C; Ceccarelli, Antonia; Arora, Ashish; Jackson, Jonathan; Bakshi, Sonya; Kim, Gloria; Miller, Jennifer; Tauhid, Shahamat; von Gizycki, Christian; Bakshi, Rohit; Neema, Mohit

    2015-01-01

    Atrophy of the corpus callosum is a recognized characteristic of multiple sclerosis (MS). We describe a new reliable method for measuring corpus callosum atrophy and correlate this with global cerebral atrophy measures. Whole brain 3T MRI was performed in 38 relapsing-remitting MS subjects and 21 healthy controls (HC). Brain global gray and white matter volumes were segmented with SPM8. The contour of the corpus callosum was outlined on the midline of 3-D T1-weighted images by a semiautomated edge-detection technique to determine the corpus callosum area (CCA). Normalized CCA was correlated with other brain atrophy measures in MS subjects. CCA was disproportionately lower in MS subjects vs. HC (20.1% mean decrease; P corpus callosum can have sensitivity as a useful imaging biomarker in patients with MS, even in patients with low disability levels. Both gray and white matter involvement in MS contribute to corpus callosum atrophy. Copyright © 2014 by the American Society of Neuroimaging.

  6. Muscular metastasis heralding medullary carcinoma of the thyroid

    Directory of Open Access Journals (Sweden)

    Rawdha Tekaya

    2013-09-01

    Full Text Available Medullary thyroid carcinoma (MTC commonly metastasizes locally to the cervical lymph nodes and distantly to the liver, lungs and bones. Metastatic involvement of the muscles is extremely rare. We reported an unusual case of undiagnosed MTC presenting with symptoms related to metastatic lesions of the brachoradialis and the gluteus medius muscles. A 53-year-old man consulted for a painful mass of the right forearm and atrophy of the quadriceps. Ultrasonography revealed a heterogeneous collection in the forearm. Computed tomographic scan showed a mass in the right lung, an enlargement of mediastinal lymph nodes and solid masses in the right gluteus medius and the left iliopoas muscle extending to the left iliac bone. Pulmonary biopsies displayed findings consistent with metastatic MTC. Fine needle aspiration cytology from the right arm swelling revealed a lesion with the same calcitonin immunostaining patterns as the lung metastasis. The diagnosis of multiple metastases (lung, muscle and bone of MTC is established. The patient has received local radiation therapy and was planned for chemotherapy. Muscular metastases from MTC are rare and although their prognosis is poor, local treatment may be worthwhile.

  7. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    Directory of Open Access Journals (Sweden)

    Alessandra Costa

    2014-01-01

    Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

  8. Network structure of brain atrophy in de novo Parkinson's disease.

    Science.gov (United States)

    Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

    2015-09-07

    We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation.

  9. Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach Distrofia muscular de Duchenne e Becker: abordagem molecular e imuno-histoquímica

    Directory of Open Access Journals (Sweden)

    Aline Andrade Freund

    2007-03-01

    Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains. The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.As distrofias musculares de Duchenne (DMD e de Becker (DMB são doenças causadas por mutação no gene da distrofina. Foram estudados 106 casos com a suspeita diagnóstica de DMD/BMD com a analise de 20 exons do gene da distrofina no sangue e biópsia muscular com imuno-histoquímica para distrofina em alguns casos. Em 71,7% dos casos foi encontrada deleção em pelo menos um dos exons, sendo que 68% das deleções localizam-se na região 3' hot spot. Foram encontradas deleções em 81,5% dos DMD e em todos os BMD, sendo que os sem deleção tinham deficiência de distrofina, incluindo a mulher com DMD. As portadoras sintomáticas não tinham deleções mas anormalidades na distribuição da distrofina no sarcolema. Os outros casos sem deleção, com auxilio da

  10. Duchenne muscular dystrophy: current cell therapies.

    Science.gov (United States)

    Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-07-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed.

  11. Novel in vitro platform to investigate myotube atrophy

    OpenAIRE

    Oelkrug, Christopher; Horn, Katharina; Makert, Gustavo R.; Schubert, Andreas

    2015-01-01

    The electrical current exclusion (ECE) principle provides an alternative to common methods of cell diameter measurement and especially in atrophy and cancer associated cachexia research. C2C12 myoblasts were differentiated into myotubes and treated with 100 μM dexamethasone to induce atrophy in vitro. Subsequently, they were incubated for 24 h with media containing different concentrations of curcumin and/or branched-chain amino acids (BCAAs) in order to counteract atrophy. After treatment wi...

  12. Acceleration of hippocampal atrophy rates in asymptomatic amyloidosis.

    Science.gov (United States)

    Andrews, K Abigail; Frost, Chris; Modat, Marc; Cardoso, M Jorge; Rowe, Chris C; Villemagne, Victor; Fox, Nick C; Ourselin, Sebastien; Schott, Jonathan M

    2016-03-01

    Increased rates of brain atrophy measured from serial magnetic resonance imaging precede symptom onset in Alzheimer's disease and may be useful outcome measures for prodromal clinical trials. Appropriate trial design requires a detailed understanding of the relationships between β-amyloid load and accumulation, and rate of brain change at this stage of the disease. Fifty-two healthy individuals (72.3 ± 6.9 years) from Australian Imaging, Biomarkers and Lifestyle Study of Aging had serial (0, 18 m, 36 m) magnetic resonance imaging, (0, 18 m) Pittsburgh compound B positron emission tomography, and clinical assessments. We calculated rates of whole brain and hippocampal atrophy, ventricular enlargement, amyloid accumulation, and cognitive decline. Over 3 years, rates of whole brain atrophy (p atrophy (p = 0.001, p = 0.023), and ventricular expansion (p atrophy rates were also independently associated with β-amyloid accumulation over the first 18 months (p = 0.003). Acceleration of left hippocampal atrophy rate was associated with baseline β-amyloid load across the cohort (p atrophy are associated with both baseline β-amyloid load and accumulation, and that there is presymptomatic, amyloid-mediated acceleration of hippocampal atrophy. Clinical trials using rate of hippocampal atrophy as an outcome measure should not assume linear decline in the presymptomatic phase. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Mechanisms regulating skeletal muscle growth and atrophy.

    Science.gov (United States)

    Schiaffino, Stefano; Dyar, Kenneth A; Ciciliot, Stefano; Blaauw, Bert; Sandri, Marco

    2013-09-01

    Skeletal muscle mass increases during postnatal development through a process of hypertrophy, i.e. enlargement of individual muscle fibers, and a similar process may be induced in adult skeletal muscle in response to contractile activity, such as strength exercise, and specific hormones, such as androgens and β-adrenergic agonists. Muscle hypertrophy occurs when the overall rates of protein synthesis exceed the rates of protein degradation. Two major signaling pathways control protein synthesis, the IGF1-Akt-mTOR pathway, acting as a positive regulator, and the myostatin-Smad2/3 pathway, acting as a negative regulator, and additional pathways have recently been identified. Proliferation and fusion of satellite cells, leading to an increase in the number of myonuclei, may also contribute to muscle growth during early but not late stages of postnatal development and in some forms of muscle hypertrophy in the adult. Muscle atrophy occurs when protein degradation rates exceed protein synthesis, and may be induced in adult skeletal muscle in a variety of conditions, including starvation, denervation, cancer cachexia, heart failure and aging. Two major protein degradation pathways, the proteasomal and the autophagic-lysosomal pathways, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These pathways involve a variety of atrophy-related genes or atrogenes, which are controlled by specific transcription factors, such as FoxO3, which is negatively regulated by Akt, and NF-κB, which is activated by inflammatory cytokines. © 2013 The Authors Journal compilation © 2013 FEBS.

  14. Cardiac atrophy after bed rest and spaceflight

    Science.gov (United States)

    Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

    2001-01-01

    Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

  15. Muscular dystrophy: from pathogenesis to strategy.

    Science.gov (United States)

    Hsu, Yaw-Don

    2004-06-01

    Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. It characterized by progressive muscle wasting and weakness of variable distribution and severity. There are several subgroups including Duchenne/Becker, fascioscapulohumeral, limb-girdle, oculopharngeal, and congenital muscular dystrophy. Diagnosis is dependent to the characteristic clinical features in distribution of predominant muscle weakness, disease course and age onset as well as variable serum concentration creatine kinase, muscle histology, and genetic inheritance. Nearly 30 genes and encoded proteins are known to give rise to various forms of muscular dystrophy. Development of new prospects therapy for the muscular dystrophies is a big challenge. The target of strategies is aimed at inducing of a functional protein and improving the function of muscle weakness. These strategies include gene, cell and pharmacological therapies. However, efficiency of systemic delivery vectors to targets, immune reaction to vector and gene products, and toxicity to vector that must be solved before an effective treatment is available.

  16. Duchenne muscular dystrophy: Case report and review.

    Science.gov (United States)

    Sinha, Rupam; Sarkar, Soumyabrata; Khaitan, Tanya; Dutta, Soumyajit

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  17. Limb-Girdle Muscular Dystrophy (LGMD)

    Science.gov (United States)

    ... Program Funding Opportunities Contact our Research Team For Families Clinical Trials Finder Tool Get Involved How to ... with LGMD normally encode proteins that play vital roles in muscle function, ... genders are affected equally. When limb-girdle muscular dystrophy ...

  18. Reality television and the muscular male ideal.

    Science.gov (United States)

    Dallesasse, Starla L; Kluck, Annette S

    2013-06-01

    Although researchers have examined the negative effects of viewing reality television (RTV) on women's body image, this research has not been extended to men. Exploring the extent to which RTV depicts men who embody the muscular ideal may enhance our understanding of the potential influence of this media genre. We explored the extent to which RTV depicted men who embodied the muscular ideal using a quantitative content analysis. Based on binomial tests, the primary male cast members of programs airing on networks popular among young adult men during the Fall 2009 broadcast season were more muscular, with lower levels of body fat, than average U.S. men. The chest-to-waist and shoulder-to-waist ratios of these cast members did not differ as a function of program type (i.e., reality drama, endurance, and romance). Young men who view RTV programs included in the present study would be exposed to an unrepresentative muscular ideal. Published by Elsevier Ltd.

  19. Duchenne muscular dystrophy: Case report and review

    Directory of Open Access Journals (Sweden)

    Rupam Sinha

    2017-01-01

    Full Text Available Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  20. [A 54-year-old man with progressive proximal muscle atrophy and gynecomastia].

    Science.gov (United States)

    Anno, M; Gotoh, K; Hirasawa, E; Mori, H; Nakajima, Y; Mizuno, Y

    1995-01-01

    We report a 54-year-old man with progressive proximal muscle atrophy and gynecomastia. The patient had an insidious onset of weakness in his lower extremities at age 14, in that he noted a difficulty in standing up from a chair. Soon after he noted some difficulty in climbing up stairs. At age 35, he noted weakness in his arms; his weakness slowly progressed in that he became unable to walk or stand alone before 40 years of age. He also noted gynecomastia at that age. He was admitted to our hospital for the work up on September 16, 1993, when he was 54-year-old. On admission, he was alert and oriented; his BP was 150/70 mmHg; he had bilateral gynecomastia, however, no other skeletal deformities were found. On neurologic examination, he was mentally sound without dementia, and his higher cerebral functions were normal. Cranial nerves also appeared intact without facial atrophy, dysarthria, or dysphagia; no atrophy was noted in the tongue. He had marked muscle atrophy in both upper and lower extremities more marked in the proximal portions; muscle strength was approximately in the range of 2/5 to 3/5 in the proximal parts, and 4/5 in the distal parts in both upper and lower extremities. No fasciculation was noted; muscle tone was flaccid; no ataxia was present. Deep reflexes were either lost or markedly diminished. No Babinski sign was noted. Sensation was intact. Laboratory examination revealed normal blood counts; serum CK was slightly increased to 131 IU/l; ECG showed complete right bundle branch block; EMG revealed no active units in the right biceps brachii, deltoid, quadriceps femoris, and triceps surae muscles; in other muscles tested, motor unit potentials of low amplitude and short duration were seen; in the right tibialis anterior muscle, however, motor unit potentials with an amplitude up to 6 m V were also seen. Nerve conduction velocities were normal. A diagnostic procedure was performed. He was discussed in the neurological CPC, and the chief discussant

  1. MRI of rotator cuff muscle atrophy in relation to glenohumeral joint incongruence in brachial plexus birth injury

    International Nuclear Information System (INIS)

    Poeyhiae, Tiina H.; Nietosvaara, Yrjaenae A.; Peltonen, Jari I.; Remes, Ville M.; Kirjavainen, Mikko O.; Lamminen, Antti E.

    2005-01-01

    Purpose: To evaluate rotator cuff muscles and the glenohumeral (GH) joint in brachial plexus birth injury (BPBI) using MRI and to determine whether any correlation exists between muscular abnormality and the development of glenoid dysplasia and GH joint incongruity. Thirty-nine consecutive BPBI patients with internal rotation contracture or absent active external rotation of the shoulder joint were examined clinically and imaged with MRI. In the physical examination, passive external rotation was measured to evaluate internal rotation contracture. Both shoulders were imaged and the glenoscapular angle, percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the greatest thickness of the subscapular, infraspinous and supraspinous muscles were measured. The muscle ratio between the affected side and the normal side was calculated to exclude age variation in the assessment of muscle atrophy. All muscles of the rotator cuff were atrophic, with the subscapular and infraspinous muscles being most severely affected. A correlation was found between the percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the extent of subscapular muscle atrophy (r s =0.45, P=0.01), as well as between its ratio (r s =0.5, P P=0.01). Severity of rotator cuff muscle atrophy correlated with increased glenoid retroversion and the degree of internal rotation contracture. Glenoid retroversion and subluxation of the humeral head are common in patients with BPBI. All rotator cuff muscles are atrophic, especially the subscapular muscle. Muscle atrophy due to neurogenic damage apparently results in an imbalance of the shoulder muscles and progressive retroversion and subluxation of the GH joint, which in turn lead to internal rotation contracture and deformation of the joint. (orig.)

  2. MRI of rotator cuff muscle atrophy in relation to glenohumeral joint incongruence in brachial plexus birth injury

    Energy Technology Data Exchange (ETDEWEB)

    Poeyhiae, Tiina H. [Helsinki University Central Hospital, Department of Radiology, PO Box 281, Helsinki (Finland); Helsinki University Central Hospital, Hospital for Children and Adolescents, Helsinki (Finland); Nietosvaara, Yrjaenae A.; Peltonen, Jari I. [Helsinki University Central Hospital, Hospital for Children and Adolescents, Helsinki (Finland); Remes, Ville M. [Helsinki University Central Hospital, Department of Orthopaedics, Surgical Hospital, Helsinki (Finland); Kirjavainen, Mikko O. [Helsinki University Central Hospital, Department of Orthopaedics and Traumatology, Helsinki (Finland); Lamminen, Antti E. [Helsinki University Central Hospital, Department of Radiology, PO Box 281, Helsinki (Finland)

    2005-04-01

    Purpose: To evaluate rotator cuff muscles and the glenohumeral (GH) joint in brachial plexus birth injury (BPBI) using MRI and to determine whether any correlation exists between muscular abnormality and the development of glenoid dysplasia and GH joint incongruity. Thirty-nine consecutive BPBI patients with internal rotation contracture or absent active external rotation of the shoulder joint were examined clinically and imaged with MRI. In the physical examination, passive external rotation was measured to evaluate internal rotation contracture. Both shoulders were imaged and the glenoscapular angle, percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the greatest thickness of the subscapular, infraspinous and supraspinous muscles were measured. The muscle ratio between the affected side and the normal side was calculated to exclude age variation in the assessment of muscle atrophy. All muscles of the rotator cuff were atrophic, with the subscapular and infraspinous muscles being most severely affected. A correlation was found between the percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the extent of subscapular muscle atrophy (r{sub s}=0.45, P=0.01), as well as between its ratio (r{sub s}=0.5, P P=0.01). Severity of rotator cuff muscle atrophy correlated with increased glenoid retroversion and the degree of internal rotation contracture. Glenoid retroversion and subluxation of the humeral head are common in patients with BPBI. All rotator cuff muscles are atrophic, especially the subscapular muscle. Muscle atrophy due to neurogenic damage apparently results in an imbalance of the shoulder muscles and progressive retroversion and subluxation of the GH joint, which in turn lead to internal rotation contracture and deformation of the joint. (orig.)

  3. Physiology of respiratory disturbances in muscular dystrophies

    OpenAIRE

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-01-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles an...

  4. Duchenne muscular dystrophy: the management of scoliosis

    Science.gov (United States)

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID:27757431

  5. Duchenne muscular dystrophy: current cell therapies

    OpenAIRE

    Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cel...

  6. Duchenne muscular dystrophy: the management of scoliosis.

    Science.gov (United States)

    Archer, James E; Gardner, Adrian C; Roper, Helen P; Chikermane, Ashish A; Tatman, Andrew J

    2016-09-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

  7. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. © 2015 American Society for Parenteral and Enteral Nutrition.

  8. Abnormal pain perception in patients with Multiple System Atrophy.

    Science.gov (United States)

    Ory-Magne, F; Pellaprat, J; Harroch, E; Galitzsky, M; Rousseau, V; Pavy-Le Traon, A; Rascol, O; Gerdelat, A; Brefel-Courbon, C

    2018-03-01

    Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Urogenital atrophy: diagnosis, sequelae, and management.

    Science.gov (United States)

    Keil, Kristinell

    2002-08-01

    It is estimated that 17% of our population will be over the age of 65 by the year 2030. As the body ages, many physiologic processes begin to decline. Health-care providers will need to be well-educated in the many sequelae of aging. Practitioners will especially need to focus on the health-care needs of women, since women have a longer life expectancy than men. Estrogen deprivation occurs in all women. Some will not have any symptoms, while others may experience all of its debilitating side effects: hot flashes, osteoporosis, insomnia, irritability, depression, and urogenital atrophy. Even though the latter is not life-threatening, it can alter a woman's quality of life considerably. Because it is easily treatable with minimal risk, all practitioners should become familiar with its presentation and management. This article discusses the many sequelae of urogenital atrophy: vulvovaginal irritation, urinary tract irritative symptoms and infection, urinary incontinence, and sexual dysfunction. Diagnosis and current management strategies are also discussed in detail.

  10. Oats induced villous atrophy in coeliac disease

    Science.gov (United States)

    Lundin, K E A; Nilsen, E M; Scott, H G; Løberg, E M; Gjøen, A; Bratlie, J; Skar, V; Mendez, E; Løvik, A; Kett, K

    2003-01-01

    The current trend is to allow coeliac disease (CD) patients to introduce oats to their gluten free diet. We sought further data from the clinical setting with regards to oats consumption by coeliac patients. Several oat products were tested for wheat contamination using a commercial enzyme linked immunoassay (ELISA) kit, and six samples were examined by an ELISA using a cocktail of monoclonal antibodies, mass spectrometry, and western blot analysis. Nineteen adult CD patients on a gluten free diet were challenged with 50 g of oats per day for 12 weeks. Serological testing and gastroduodenoscopy was performed before and after the challenge. Biopsies were scored histologically and levels of mRNA specific for interferon γ were determined by reverse transcription-polymerase chain reaction analysis. Oats were well tolerated by most patients but several reported initial abdominal discomfort and bloating. One of the patients developed partial villous atrophy and a rash during the first oats challenge. She subsequently improved on an oats free diet but developed subtotal villous atrophy and dramatic dermatitis during a second challenge. Five of the patients showed positive levels of interferon γ mRNA after challenge. Some concerns therefore remain with respect to the safety of oats for coeliacs. PMID:14570737

  11. Geographic atrophy: Etiopathogenesis and current therapies.

    Science.gov (United States)

    Sastre-Ibáñez, M; Barreiro-González, A; Gallego-Pinazo, R; Dolz-Marco, R; García-Armendariz, B

    2018-01-01

    Geographic atrophy is characterized by severe visual deficit whose etiology and pathophysiology are yet to be elucidated. As a working hypothesis, oxidative damage could trigger a chronic inflammation in Bruch's membrane-RPE-choriocapillaris complex, mostly due to complement pathway overactivation. Some individuals with mutations in the complement system and other factors have diminished capacity in the modulation of the inflammatory response, which results in cell damage and waste accumulation. This accumulation of intracellular and extracellular waste products manifests as drusen and pigmentary changes that precede the atrophy of photoreceptors, RPE, choriocapillaris with an ischemic process with decreased choroid flow. All these processes can be detected as tomographic findings and autofluorescence signals that are useful in the evaluation of patients with atrophic AMD, which helps to establish an individualized prognosis. Anti-inflammatory, antioxidant and therapies that decrease the accumulation of toxins for the preservation of the RPE cells and photoreceptors are being investigated in order to slow down the progression of this disease. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

    Science.gov (United States)

    Sadda, Srinivas R; Guymer, Robyn; Holz, Frank G; Schmitz-Valckenberg, Steffen; Curcio, Christine A; Bird, Alan C; Blodi, Barbara A; Bottoni, Ferdinando; Chakravarthy, Usha; Chew, Emily Y; Csaky, Karl; Danis, Ronald P; Fleckenstein, Monika; Freund, K Bailey; Grunwald, Juan; Hoyng, Carel B; Jaffe, Glenn J; Liakopoulos, Sandra; Monés, Jordi M; Pauleikhoff, Daniel; Rosenfeld, Philip J; Sarraf, David; Spaide, Richard F; Tadayoni, Ramin; Tufail, Adnan; Wolf, Sebastian; Staurenghi, Giovanni

    2018-04-01

    To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). Consensus meeting. Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. A consensus classification system for atrophy and OCT-based criteria to identify atrophy. OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete

  13. Evaluating Alzheimer's disease progression using rate of regional hippocampal atrophy.

    Directory of Open Access Journals (Sweden)

    Edit Frankó

    Full Text Available Alzheimer's disease (AD is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects.

  14. Agreement between endoscopic and histological gastric atrophy scores

    NARCIS (Netherlands)

    Liu, Yi; Uemura, Naomi; Xiao, Shu-Dong; Tytgat, Guido N. J.; Kate, Fiebo J. W. Ten

    2005-01-01

    Background. This study was conducted to investigate the strength of agreement between the endoscopic atrophic border (EAB) and the histological score for atrophy. Methods. A series of 298 dyspeptic Japanese patients underwent upper endoscopy. The grade of gastric atrophy was estimated according to

  15. Detection of muscle atrophy on routine sonography of the shoulder.

    Science.gov (United States)

    Sofka, Carolyn M; Haddad, Ziyad K; Adler, Ronald S

    2004-08-01

    To describe the utility of sonography in visualizing muscle atrophy during routine sonographic examination of the shoulder for evaluation of the rotator cuff tendons. A retrospective review of 199 shoulder sonographic examinations performed by 2 musculoskeletal radiologists trained in musculoskeletal sonography with knowledge of the typical sonographic findings of muscle atrophy was performed. Reports were reviewed for the presence of muscle atrophy. If atrophy was present, the reports from those examinations were rereviewed for concomitant rotator cuff abnormalities. Forty-five examinations (23%) showed atrophy in at least 1 muscle on the basis of the criteria of increased echogenicity and decreased bulk. There were a total of 81 individual muscles that showed atrophy, with the following distribution: 16% supraspinatus (n = 13), 31% infraspinatus (n = 25), 36% teres minor (n = 29), 2% subscapularis (n = 2), and 6% biceps brachii (n = 5). In 34 of the 45 examinations with muscle atrophy, there were 57 concomitant full-thickness tendon tears: 64% supraspinatus (n = 29), 38% infraspinatus (n = 17), 7% subscapularis (n = 3), 0% teres minor (n = 0), 16% long head of biceps (n = 7), and 2% deltoid (n = 1). Although primary sonographic evaluation of the painful shoulder concentrates on the tendons of the rotator cuff, we suggest that examination of the muscles should become a standard component of the comprehensive shoulder sonographic examination, particularly given the potential clinical implications of muscle atrophy on the outcome of rotator cuff surgery.

  16. MRI study of degenerative process in multiple system atrophy

    International Nuclear Information System (INIS)

    Yagishita, Toshiyuki; Kojima, Shigeyuki; Hirayama, Keizo

    1995-01-01

    The characteristic morphological changes of the brainstem and cerebellar regions of multiple system atrophy (MSA) were studied by MRI in varing subtypes, that is olivoponto cerebellar atrophy (OPCA: 23 cases), striatonigral degeneration (SND: 7 cases) and Shy-Drager's syndrome (SDS: 9 cases). OPCA was characterized by atrophy of the entire regions of the brainstem and the cerebellum. SND and SDS tended to show atrophy similar in type but lessin extent to OPCA. The common lesions in MSA were atrophy of the pontine base and cerebellum, and dilation of the fourth ventricle. Atrophy of the pontine base was more dominant in the inferior part than in the superior part, and cerebellar atrophy was more dominant in the superior part than in the inferior part, indicating that degeneration of the pontocerebellar pathway proceeds principally along fibers connecting the inferior part of the pons and the superior part of the cerebellum. Dilation of the fourth ventricle indicated atrophy of the middle cerebellar peduncle. In almost all the cases of OPCA and about a half the cases of SND and SDS, the pontine base and the middle cerebellar peduncle appeared as high signal intensity on T 2 weighted image and as low intensity on T 1 , suggesting degeneration and demyelination. In a few cases of OPCA, the dorsolateral part of the putamen were demonstrated as low signal intensity on T 2 weighted image. (author)

  17. MRI study of degenerative process in multiple system atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Yagishita, Toshiyuki; Kojima, Shigeyuki; Hirayama, Keizo [Chiba Univ. (Japan). School of Medicine

    1995-02-01

    The characteristic morphological changes of the brainstem and cerebellar regions of multiple system atrophy (MSA) were studied by MRI in varing subtypes, that is olivoponto cerebellar atrophy (OPCA: 23 cases), striatonigral degeneration (SND: 7 cases) and Shy-Drager`s syndrome (SDS: 9 cases). OPCA was characterized by atrophy of the entire regions of the brainstem and the cerebellum. SND and SDS tended to show atrophy similar in type but lessin extent to OPCA. The common lesions in MSA were atrophy of the pontine base and cerebellum, and dilation of the fourth ventricle. Atrophy of the pontine base was more dominant in the inferior part than in the superior part, and cerebellar atrophy was more dominant in the superior part than in the inferior part, indicating that degeneration of the pontocerebellar pathway proceeds principally along fibers connecting the inferior part of the pons and the superior part of the cerebellum. Dilation of the fourth ventricle indicated atrophy of the middle cerebellar peduncle. In almost all the cases of OPCA and about a half the cases of SND and SDS, the pontine base and the middle cerebellar peduncle appeared as high signal intensity on T{sub 2} weighted image and as low intensity on T{sub 1}, suggesting degeneration and demyelination. In a few cases of OPCA, the dorsolateral part of the putamen were demonstrated as low signal intensity on T{sub 2} weighted image. (author).

  18. Corpus callosum atrophy in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Garde, Ellen; Skimminge, Arnold

    2011-01-01

    Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain......, such as age-related white matter changes (ARWMC) and progression of the disease....

  19. Deformation-Based Atrophy Estimation for Alzheimer’s Disease

    DEFF Research Database (Denmark)

    Pai, Akshay Sadananda Uppinakudru

    Alzheimer’s disease (AD) - the most common form of dementia, is a term used for accelerated memory loss and cognitive abilities enough to severely hamper day-to-day activities. One of the most globally accepted markers for AD is atrophy, in mainly the brain parenchyma. The goal of the PhD project...... is to develop a deformation-based atrophy estimation pipeline that is reliable and stable. We investigate the application of image registration using freeform deformation and stationary velocity fields in atrophy estimation. In the process, we propose a new multi-scale model for the transformation model...... and a new way to estimate atrophy from a deformation field. We demonstrate the performance of the proposed solution but applying it on the publicly available Alzheimer’s disease neuroimaging data (ADNI) initiative and compare to existing state-of-art atrophy estimation methods....

  20. CT findings of brain atrophy after chemotherapy in acute leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jun; Park, Seog Hee; Kim, Choon Yul; Bahk, Yong Whee [Catholic University Medicine College, Seoul (Korea, Republic of)

    1988-10-15

    A study was performed to evaluate the atrophic changes of the central nerve system after chemotherapy in the patients with acute leukemia. The computed tomographic findings and medical records of 20 proven acute leukemia patients under 35 years-old who developed various CNS symptoms and signs during and/or after 2 courses of chemotherapy were reviewed. The results were as follows: 1. Age distribution was from 14 to 5 years (mean was 26 years). Male was 15. 2. Presenting clinical symptoms and signs were headache (16/20), nausea and vomiting (11/20) and loss of consciousness (5/20). 3. Brain atrophy was noted in 16 patients including cortical and subcortical atrophy 15 cases and subcortical atrophy 1 case. 4. Two cases of hemorrhage, one each of intracranial hematoma and chronic subdural hematoma were found in addition to brain atrophy. This showed that chemotherapeutic agents cause brain atrophy in a considerable number of the patients with symptomatic acute leukemia.

  1. The golden retriever model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N

    2017-05-19

    Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about

  2. Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's disease

    NARCIS (Netherlands)

    Lehmann, M.; Koedam, E.L.G.E.; Barnes, J.; Bartlett, J.W.; Ryan, N.S.; Pijnenburg, Y.A.L.; Barkhof, F.; Wattjes, M.P.; Scheltens, P.; Fox, N.C.

    2012-01-01

    Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual

  3. Nanotherapy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nance, Michael E; Hakim, Chady H; Yang, N Nora; Duan, Dongsheng

    2018-03-01

    Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy. WIREs Nanomed Nanobiotechnol 2018, 10:e1472. doi: 10.1002/wnan.1472 This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies. © 2017 Wiley Periodicals, Inc.

  4. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

    Science.gov (United States)

    Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

    2015-01-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  5. Choroidal Round Hyporeflectivities in Geographic Atrophy.

    Directory of Open Access Journals (Sweden)

    Eleonora Corbelli

    Full Text Available In geographic atrophy (GA, choroidal vessels typically appear on structural optical coherence tomography (OCT as hyperreflective round areas with highly reflective borders. We observed that some GA eyes show choroidal round hyporeflectivities with highly reflective borders beneath the atrophy, and futher investigated the charcteristcs by comparing structural OCT, indocyanine green angiography (ICGA and OCT angiography (OCT-A.Round hyporeflectivities were individuated from a pool of patients with GA secondary to non-neovascular age-related macular degeneration consecutively presenting between October 2015 and March 2016 at the Medical Retina & Imaging Unit of the University Vita-Salute San Raffaele. Patients underwent a complete ophthalmologic examination including ICGA, structural OCT and OCT-A. The correspondence between choroidal round hyporeflectivities beneath GA on structural OCT and ICGA and OCT-A imaging were analyzed.Fifty eyes of 26 consecutive patients (17 females and 9 males; mean age 76.8±6.2 years with GA were included. Twenty-nine round hyporeflectivities have been found by OCT in choroidal layers in 21 eyes of 21 patients (42.0%; estimated prevalence of 57.7%. All 29 round hyporeflectivities showed constantly a hyperreflective border and a backscattering on structural OCT, and appeared as hypofluorescent in late phase ICGA and as dark foci with non detectable flow in the choroidal segmentation of OCT-A. Interestingly, the GA area was greater in eyes with compared to eyes without round hyporeflectivities (9.30±5.74 and 5.57±4.48mm2, respectively; p = 0.01.Our results suggest that most round hyporeflectivities beneath GA may represent non-perfused or hypo-perfused choroidal vessels with non-detectable flow.

  6. Choroidal Round Hyporeflectivities in Geographic Atrophy.

    Science.gov (United States)

    Corbelli, Eleonora; Sacconi, Riccardo; De Vitis, Luigi Antonio; Carnevali, Adriano; Rabiolo, Alessandro; Querques, Lea; Bandello, Francesco; Querques, Giuseppe

    2016-01-01

    In geographic atrophy (GA), choroidal vessels typically appear on structural optical coherence tomography (OCT) as hyperreflective round areas with highly reflective borders. We observed that some GA eyes show choroidal round hyporeflectivities with highly reflective borders beneath the atrophy, and futher investigated the charcteristcs by comparing structural OCT, indocyanine green angiography (ICGA) and OCT angiography (OCT-A). Round hyporeflectivities were individuated from a pool of patients with GA secondary to non-neovascular age-related macular degeneration consecutively presenting between October 2015 and March 2016 at the Medical Retina & Imaging Unit of the University Vita-Salute San Raffaele. Patients underwent a complete ophthalmologic examination including ICGA, structural OCT and OCT-A. The correspondence between choroidal round hyporeflectivities beneath GA on structural OCT and ICGA and OCT-A imaging were analyzed. Fifty eyes of 26 consecutive patients (17 females and 9 males; mean age 76.8±6.2 years) with GA were included. Twenty-nine round hyporeflectivities have been found by OCT in choroidal layers in 21 eyes of 21 patients (42.0%; estimated prevalence of 57.7%). All 29 round hyporeflectivities showed constantly a hyperreflective border and a backscattering on structural OCT, and appeared as hypofluorescent in late phase ICGA and as dark foci with non detectable flow in the choroidal segmentation of OCT-A. Interestingly, the GA area was greater in eyes with compared to eyes without round hyporeflectivities (9.30±5.74 and 5.57±4.48mm2, respectively; p = 0.01). Our results suggest that most round hyporeflectivities beneath GA may represent non-perfused or hypo-perfused choroidal vessels with non-detectable flow.

  7. Combined application of neuromuscular electrical stimulation and voluntary muscular contractions.

    Science.gov (United States)

    Paillard, Thierry

    2008-01-01

    Electromyostimulation (EMS) and voluntary muscle contraction (VC) constitute different modes of muscle activation and induce different acute physiological effects on the neuromuscular system. Long-term application of each mode of muscle activation can produce different muscle adaptations. It seems theoretically possible to completely or partially cumulate the muscle adaptations induced by each mode of muscle activation applied separately. This work consisted of examining the literature concerning the muscle adaptations induced by long-term application of the combined technique (CT) [i.e. EMS is combined with VC - non-simultaneously] compared with VC and/or EMS alone in healthy subjects and/or athletes and in post-operative knee-injured subjects. In general, CT induced greater muscular adaptations than VC whether in sports training or rehabilitation. This efficiency would be due to the fact that CT can facilitate cumulative effects of training completely or partially induced by VC and EMS practiced alone. CT also provides a greater improvement of the performance of complex dynamic movements than VC. However, EMS cannot improve coordination between different agonistic and antagonistic muscles and thus does not facilitate learning the specific coordination of complex movements. Hence, EMS should be combined with specific sport training to generate neuromuscular adaptations, but also allow the adjustment of motor control during a voluntary movement. Likewise, in a therapeutic context, CT was particularly efficient to accelerate recovery of muscle contractility during a rehabilitation programme. Strength loss and atrophy inherent in a traumatism and/or a surgical operation would be more efficiently compensated with CT than with VC. Furthermore, CT also restored more functional abilities than VC. Finally, in a rehabilitation context, EMS is complementary to voluntary exercise because in the early phase of rehabilitation it elicits a strength increase, which is necessary

  8. Assessment of Muscular Activity by Mechanomyogram(MMG

    Directory of Open Access Journals (Sweden)

    M. Saffar Dezfuli

    2006-10-01

    Full Text Available Background and aims   Recordings of electrical activity in the muscle and surface electromyography (EMG have been widely used in the field of applied physiology. In parallel to  recording of the EMG, the detectable low-frequency vibration signal generated by the skeletal  muscle has been known and well documented. As the nature of the signal has been progressively   revealed, the term of mechanomyography (MMG has been proposed by a recent review. The  main mechanism of the MMG generation has been considered to be sound pressure waves due to  the dimensional changes, i.e., lateral expansion of the activated muscle fibres.   Methods   Low-frequency vibrations produced by muscle fibres are clearly distinguishable from  the EMG, because MMG and EMG exhibit differences in response latency, spike duration, and  frequency. During voluntary contraction at constant force the MMG frequency content does not   change significantly.   Results   This suggests that the frequency of MMG signal is directly related to the absolute force level of the muscle, irrespective of fatigue phenomena. At low force contractions, in contrast to   EMG signal, the changes in the amplitude content of the MMG are more consistent with muscle  fatigue. This indicated that the amplitude of MMG signal might be recommended as a method to  improve the objective and reliable detection of muscle fatigue induced by low force contraction.   Conclusion   MMG is most likely a valuable supplement to EMG as a non-invasive method to  examine various aspects of muscle function including fatigue, electromechanical delay, muscle fibre type patterns, age related changes in muscular performance, muscle atrophy, and neuromuscular performance.

  9. Mechanisms of Botulinum Neurotoxin Induced Skeletal Muscle Atrophy

    Science.gov (United States)

    Hain, Brian A.

    Our previous research suggests that the mechanism of botulinum neurotoxintype A (BoNT/A)-induced atrophy does not occur via a NF-kappaB/Foxo-dependent process. We thus hypothesized that the primary mechanism would be activation of either the proteosomal or calpain pathways. BoNT/A injection induced elevations in proteolytic activity markers of the ubiquitin-proteasome-system (UPS) and calpain systems after 3 days of a single dose. Inhibition of the proteasome significantly attenuated BoNT/Ainduced atrophy 3-days post BoNT/A injection. Calpastatin overexpression prevented BoNT/A-induced calpain activity at 3 days, and but did not result in a significant attenuation of atrophy. Concurrent attenuation of the UPS and calpain systems was sufficient to attenuate all of the atrophy associated with BoNT/A induced atrophy. In conclusion, it appears that the UPS and calpain system work in an additive fashion with neurotoxin-induced muscle atrophy. Inhibiting both of these pathways while administering BoNT/A attenuates all of the observed muscle atrophy.

  10. Reviewing the options for local estrogen treatment of vaginal atrophy

    Directory of Open Access Journals (Sweden)

    Lindahl SH

    2014-03-01

    Full Text Available Sarah H Lindahl Sutter East Bay Medical Foundation, SEBMF – Diablo Division, Castro Valley, CA, USA Background: Vaginal atrophy is a chronic condition with symptoms that include vaginal dryness, pain during sex, itching, irritation, burning, and discharge, as well as various urinary problems. Up to 45% of postmenopausal women may be affected, but it often remains underreported and undertreated. This article aims to review the current recommendations for treatment of vaginal atrophy, and current data on the effectiveness and safety of local vaginal estrogen therapies. Methods: Literature regarding vaginal atrophy (2007–2012 was retrieved from PubMed and summarized, with emphasis on data related to the treatment of vaginal atrophy with local vaginal estrogen therapy. Results: Published data support the effectiveness and endometrial safety of low-dose local estrogen therapies. These results further support the general recommendation by the North American Menopause Society that a progestogen is not needed for endometrial protection in patients using low-dose local vaginal estrogen. Benefits of long-term therapy for vaginal atrophy include sustained relief of symptoms as well as physiological improvements (eg, decreased vaginal pH and increased blood flow, epithelial thickness, secretions. Conclusion: Currently available local vaginal estrogen therapies are well tolerated and effective in relieving symptoms of vaginal atrophy. Recent data support the endometrial safety of low-dose regimens for up to 1 year. Keywords: menopause, estrogen, local estrogen therapy, vaginal atrophy

  11. Mitochondrial disorders in progressive muscular dystrophies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

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

  12. Circulating Biomarkers for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-07-22

    Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput - omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products.

  13. Muscular pathology: echographic and NMR imaging aspects

    International Nuclear Information System (INIS)

    Pascal-Suisse, P.; Beaurain, P.; Mougniot, C.

    1995-01-01

    A comparison of echographic techniques and NMR imaging has been done for the diagnosis of muscular trauma and tumor pathologies. In traumatic pathology, the echographic analysis allows to determine the complete assessment of recent muscular injuries. NMR imaging can be used in granuloma or fibrous callosity appreciation and for the analysis of deep injury (muscles and muscles-tendon junctions) and of muscular aponeurosis. Echography must be used together with color coding Doppler technique in the diagnosis of tumor pathology and for the study of slow fluxes. The recently available energy Doppler technique seems to be powerful in the study of vascularization of small expansive formations, but their extension to adjacent bone or tissue can only be appreciated using NMR imaging. (J.S.)

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

    Directory of Open Access Journals (Sweden)

    Cynthia Kallás Bachur

    Full Text Available Introduction Duchenne Muscular Dystrophies (DMD is a genetic muscle disorder that causes degeneration and atrophy of skeletal muscle and heart. Objective The aim of this survey is accomplish an evaluation electrocardiographic and echocardiography in the patients bearers of Duchene Muscular Dystrophies (DMD, to observe which alterations, which the degree of cardiac compromising these patient present and the effectiveness of these exams in the evaluation cardiologic. Methods Nine patients of the sex male bearers of DMD, with medium age of 14.12 ± 4.19 years, varying of 7 to 23 years were appraised. All were submitted to the evaluation physiotherapy and the cardiologic: electrocardiogram and echocardiogram. Results The experimental conditions of the present survey we propitiate the observation of the alterations echocardiography, as well as: significant increase in the diastolic diameter of the left ventricular (LV, increase in the systolic diameter of the left atrium (LA, and significant decrease of the ejection fraction of the LV, characterizing global systolic function reduced, and of the alterations electrocardiographic suggested possible overload of RV, septum hypertrophy, blockade of left previous fascicle and overload of atrium left. Compatible alterations of hypertrophy left ventricular were not observed. Conclusion The evidences corroborate with the data described in the literature in the characterization of an important heart compromising that these patient present, like this the evaluation cardiologic, through the complemented exams of the echocardiography and electrocardiography provide important information for the prognostic, the accompaniment, and the treatment of patient bearers of DMD.

  15. Characteristic of muscle involvement evaluated by CT scans in early stages of progressive muscular dystrophy

    International Nuclear Information System (INIS)

    Arai, Yumi

    1993-01-01

    Muscle CT scans were performed in order to compare the characteristic distribution of progressive muscle involvement in the early stages of Duchenne type (DMD) and Fukuyama type muscular dystrophy (FCMD). Muscle images at the levels of the 3rd lumbar vertebra, thigh and calf were assessed by visual inspection, and mean CT numbers calculated for individual muscles were statistically analysed. On visual inspection, intramuscular low density areas and muscular atrophy were observed in the muscles of older patients with either disease. These changes were, however, more extensive at thigh level in DMD, and at calf level in FCMD. Nevertheless, the mean CT numbers of muscles in which only slight changes were grossly visible on CT scans displayed progressive decreases with increasing age. Moreover, a significant negative relationship was recognizable between age and mean CT number in almost all muscles examined. Comparison of the slopes of the regression lines revealed that the so-called selective pattern of muscle involvement characteristic of the symptomatic stage had already partially manifested in the preclinical or early stages of both diseases. In FCMD, the rates of decrease in CT numbers were extremely rapid for calf muscles as compared with those in DMD, indicating that this is one reason for FCMD patients never becoming ambulatory. However, for almost all of the other muscles, the CT numbers in FCMD decreased in parallel with the corresponding CT numbers in DMD; thus, these diseases displayed a similarity in the pattern of muscle involvement, despite their different pathogenetic mechanisms and inheritance patterns. (author)

  16. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Rojas

    2016-03-01

    Full Text Available ABSTRACT Multiple sclerosis (MS was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients.

  17. Visual impairment and posterior cortical atrophy preceding rapid progressive dementia.

    Science.gov (United States)

    Müller, Kai Ivar; Bekkelund, Svein Ivar

    2013-01-02

    Posterior cortical atrophy (PCA), also known as Benson's disease, has been previously reported as a variant of Alzheimer's disease (AD). We present a clinical picture and MRI findings of a patient with PCA who developed early right-sided homonymous haemianopia and marked atrophy of parieto-occipital regions of the brain before a cognitive decline appeared. This case demonstrates that PCA may appear with advanced brain atrophy at the onset of focal visual deficits before the development of progressive dementia, and adds to the knowledge of dementias with rapid progression.

  18. Deformation-Based Atrophy Estimation for Alzheimer’s Disease

    DEFF Research Database (Denmark)

    Pai, Akshay Sadananda Uppinakudru

    Alzheimer’s disease (AD) - the most common form of dementia, is a term used for accelerated memory loss and cognitive abilities enough to severely hamper day-to-day activities. One of the most globally accepted markers for AD is atrophy, in mainly the brain parenchyma. The goal of the PhD project...... and a new way to estimate atrophy from a deformation field. We demonstrate the performance of the proposed solution but applying it on the publicly available Alzheimer’s disease neuroimaging data (ADNI) initiative and compare to existing state-of-art atrophy estimation methods....

  19. 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...

  20. Anoctamin 5 muscular dystrophy in Denmark

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Petri, Helle

    2013-01-01

    Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic...... mutations caused 11 % of our total cohort of LGMD2 cases making it the second most common LGMD2 etiology in Denmark. Eight patients complained of dysphagia and 3 dated symptoms of onset in childhood. Cardiac examinations revealed increased frequency of premature ventricular contractions. Four novel putative...

  1. The role of fibrosis in Duchenne muscular dystrophy

    OpenAIRE

    KLINGLER, WERNER; JURKAT-ROTT, KARIN; LEHMANN-HORN, FRANK; SCHLEIP, ROBERT

    2012-01-01

    Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical...

  2. 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.

  3. The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy.

    Science.gov (United States)

    Assereto, Stefania; Piccirillo, Rosanna; Baratto, Serena; Scudieri, Paolo; Fiorillo, Chiara; Massacesi, Manuela; Traverso, Monica; Galietta, Luis J; Bruno, Claudio; Minetti, Carlo; Zara, Federico; Gazzerro, Elisabetta

    2016-08-01

    Activation of the proteasome pathway is one of the secondary processes of cell damage, which ultimately lead to muscle degeneration and necrosis in Duchenne muscular dystrophy (DMD). In mdx mice, the proteasome inhibitor bortezomib up-regulates the membrane expression of members of the dystrophin complex and reduces the inflammatory reaction. However, chronic inhibition of the 26S proteasome may be toxic, as indicated by the systemic side-effects caused by this drug. Therefore, we sought to determine the components of the ubiquitin-proteasome pathway that are specifically activated in human dystrophin-deficient muscles. The analysis of a cohort of patients with genetically determined DMD or Becker muscular dystrophy (BMD) unveiled a selective up-regulation of the ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). The induction of TRIM32 was due to a transcriptional effect and it correlated with disease severity in BMD patients. In contrast, atrogin1 and muscle RING-finger protein-1 (MuRF-1), which are strongly increased in distinct types of muscular atrophy, were not affected by the DMD dystrophic process. Knock-out models showed that TRIM32 is involved in ubiquitination of muscle cytoskeletal proteins as well as of protein inhibitor of activated STAT protein gamma (Piasγ) and N-myc downstream-regulated gene, two inhibitors of satellite cell proliferation and differentiation. Accordingly, we showed that in DMD/BMD muscle tissue, TRIM32 induction was more pronounced in regenerating myofibers rather than in necrotic muscle cells, thus pointing out a role of this protein in the regulation of human myoblast cell fate. This finding highlights TRIM32 as a possible therapeutic target to favor skeletal muscle regeneration in DMD patients.

  4. Histopathologic Evolution of Cardiomyopathy in a Canine Model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Lygia M.M. Malvestio

    2015-07-01

    Full Text Available Duchenne muscular dystrophy (DMD is a recessive X-linked disorder characterized for mutation in dystrophin gene and manifested by progressive degeneration and necrosis of skeletal and cardiac muscle with replacement leading to generalized muscular weakness and atrophy. The dog Golden Retriever Muscular Dystrophy (GRMD is the best experimental model for DMD, with genotypic and phenotypic manifestations closely of human disease. Similar to patients with DMD, heart failure is a major cause of death in GRMD animals. The objective of this study was to evaluate the pathological progression of myocardial lesions from GRMD dogs in different ages in order to clarify the pathogenesis of Duchenne´s cardiomyopathy. Fragments of left and right ventricle and interventricular septum, from 18 GRMD dogs between 6 to 51 months were collected, fixed, dehydrated, clarified, and finally embedded in paraffin. Five micrometer thick serial sections were obtained and stained with Hematoxylin-Eosin (HE, Picrosirius red, and Von Kossa. Histological analyses were performed at the light microscopy. Myocardial lesions were observed in all GRMD dogs and the sequence of cardiac lesion classified according to according to the age included: abnormal calcium accumulation, myofibrillar necrosis, proliferation of granulation tissue, endomysial and perimysial fibrosis, and finally myocardial fatty infiltration. Interestingly, several Anitschkow cells, the hallmark of rheumatic carditis, were detected in inflammatory infiltrate present at granulation tissue. Our results demonstrate the sequence of cardiac lesions that determine the cardiomyopathy in Golden Retriever dogs affected by DMD and exhibit, for the first time, the Anitschkow cells in the histological findings of this cardiomyopathy. These results are relevant for to clarify the pathogenesis of cardiomyopathy in dogs and humans affected by DMD.

  5. Limb-girdle muscular dystrophy type 2D: clinical and genetic analysis of a family

    Directory of Open Access Journals (Sweden)

    Li-yu OU

    2017-09-01

    Full Text Available Objective To study the characteristics and diagnosis of limb-girdle muscular dystrophy type 2D (LGMD2D. Methods The clinical characteristics, EMG, muscle MRI and muscle pathological studies of 2 female patients in a family with LGMD2D were analyzed. Genetic analysis was used in the diagnosis of this disease. The cases were reported along with related literatures review. Results The onset of the proband and her younger sister occurred at 3 years old with progressive proximal muscle weakness of four limbs as the main clinical manifestation. The serum creatine kinase (CK was significantly high (> 50 × 10 3 U/L. EMG showed myogenic damage. Muscle MRI indicated partial muscle atrophy, fatness or fiber edema. Muscle pathological examination of the proband's younger sister revealed skeletal muscle necrosis and focal regeneration, partial striated muscle disappearance, and the muscle fibers in different sizes. Sequencing of all 10 coding exons of the SGCA gene in 2 patients revealed the same mutation: a c.262delT (p.Phe88SerfsX123 frameshift mutation in exon 3 and a c.409G > A (p.Glu137Lys missense mutation in exon 5. Their mother was a carrier of SGCA gene c.409G > A (p.Glu137Lys mutation. c.409G > A (p.Glu137Lys is a mutation already found, and c.262delT (p.Phe88SerfsX123 is a novel mutation. The proband's father did not take the genetic test for some reason. Conclusions In case of a female with Duchenne muscular dystrophy (DMD.like symptom, if she has been excluded from the DMD gene carrier, pedigree analysis and genetic analysis involving limb . girdle muscular dystrophy (LGMD should be conducted to facilitate the diagnosis of the LGMD and its subtypes. DOI: 10.3969/j.issn.1672-6731.2017.08.010

  6. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Falzarano, Maria Sofia; Passarelli, Chiara; Ferlini, Alessandra

    2014-02-01

    Antisense therapy is a powerful tool for inducing post-transcriptional modifications and thereby regulating target genes associated with disease. There are several classes of antisense oligonucleotides (AONs) with therapeutic use, such as double-stranded RNAs (interfering RNAs, utilized for gene silencing, and single-stranded AONs with various chemistries, which are useful for antisense targeting of micro-RNAs and mRNAs. In particular, the use of AONs for exon skipping, by targeting pre-mRNA, is proving to be a highly promising therapy for some genetic disorders like Duchenne muscular dystrophy and spinal muscular atrophy. However, AONs are unable to cross the plasma membrane unaided, and several other obstacles still remain to be overcome, in particular their instability due to their nuclease sensitivity and their lack of tissue specificity. Various drug delivery systems have been explored to improve the bioavailability of nucleic acids, and nanoparticles (NPs) have been suggested as potential vectors for DNA/RNA. This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy.

  7. Mechanisms of cisplatin-induced muscle atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  8. Mechanisms of cisplatin-induced muscle atrophy

    International Nuclear Information System (INIS)

    Sakai, Hiroyasu; Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara; Sato, Ken; Chiba, Yoshihiko; Yamazaki, Mitsuaki; Matoba, Motohiro; Narita, Minoru

    2014-01-01

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin

  9. Congenital monomelic muscular hypertrophy of the upper extremity.

    NARCIS (Netherlands)

    Gilhuis, H.J.; Zophel, O.T.; Lammens, M.M.Y.; Zwarts, M.J.

    2009-01-01

    Pathological muscular hypertrophy results from either muscular or neurogenic damage. Rarely, it is caused by a congenital malformation consisting of a unilateral muscular hyperplasia of the upper extremity. We report on a young woman with an enlargement of the right upper extremity. Electromyography

  10. Genetics Home Reference: gyrate atrophy of the choroid and retina

    Science.gov (United States)

    ... newborn period. Gyrate atrophy usually does not affect intelligence; however, abnormalities may be observed in brain imaging ... generated when protein is broken down by the body. In addition to its role in the urea ...

  11. Atrophy and hypertrophy of skeletal muscles: structural and functional aspects.

    Science.gov (United States)

    Boonyarom, O; Inui, K

    2006-10-01

    This review summarizes current information on structural and functional changes that occur during muscle atrophy and hypertrophy. Most published studies consider an increase in total mass of a muscle as hypertrophy, whereas a decrease in total mass of a muscle is referred to as atrophy. In hypertrophy, the rate of synthesis is much higher than the rate of degradation of muscle contractile proteins, leading to an increase in the size or volume of an organ due to enlargement of existing cells. When a muscle remains in disuse for a long period, the rate of degradation of contractile proteins becomes greater than the rate of replacement, resulting in muscle atrophy. This defect may occur as a result of lack of nutrition, loss of nerve supply, micro-gravity, ageing, systemic disease, prolonged immobilization or disuse. An understanding of the specific modifications that occur during muscle atrophy and hypertrophy may facilitate the development of novel techniques, as well as new therapies for affected muscles.

  12. Disease-Induced Skeletal Muscle Atrophy and Fatigue

    NARCIS (Netherlands)

    Powers, Scott K.; Lynch, Gordon S.; Murphy, Kate T.; Reid, Michael B.; Zijdewind, Inge

    2016-01-01

    Numerous health problems including acute critical illness, cancer, diseases associated with chronic inflammation, and neurological disorders often result in skeletal muscle weakness and fatigue. Disease-related muscle atrophy and fatigue is an important clinical problem because acquired skeletal

  13. Acquired alopecia, mental retardation, short stature, microcephaly, and optic atrophy

    NARCIS (Netherlands)

    Hennekam, R. C.; Renckens-Wennen, E. G.

    1990-01-01

    We report on a female patient who had acquired total alopecia, short stature, microcephaly, optic atrophy, severe myopia, and mental retardation. A survey of published reports failed to show an identical patient, despite various similar cases

  14. Multiple System Atrophy with Orthostatic Hypotension (Shy-Drager Syndrome)

    Science.gov (United States)

    ... or other vision disturbances, difficulty breathing and swallowing, sleep disturbances, and decreased sweating. Because the disease resembles others, a correct diagnosis may take years. × Definition Multiple system atrophy with orthostatic hypotension is the ...

  15. Facilitating text reading in posterior cortical atrophy.

    Science.gov (United States)

    Yong, Keir X X; Rajdev, Kishan; Shakespeare, Timothy J; Leff, Alexander P; Crutch, Sebastian J

    2015-07-28

    We report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA. Reading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2). Mean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy (PCA mean reading accuracy: single-word reading aid = 96%; individual patient improvement range: 6%-270%) and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA. These findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities. This study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy. © 2015 American Academy of Neurology.

  16. [Muscular hydatidosis. Apropos of 2 cases].

    Science.gov (United States)

    Meunier, Y; Danis, M; Nozais, J P; Gentilini, M

    1983-11-03

    Muscular hydatid disease is uncommon. It usually consists in a primary single cyst which remains asymptomatic. Diagnosis is made upon pathological examination after a surgical procedure carried out to establish the cause of a swelling. Indeed, in most cases serology is not helpful and, moreover, it rapidly becomes negative after surgery. We report two cases and discuss the features of this condition.

  17. Respiratory muscle training in Duchenne muscular dystrophy.

    OpenAIRE

    Rodillo, E; Noble-Jamieson, C M; Aber, V; Heckmatt, J Z; Muntoni, F; Dubowitz, V

    1989-01-01

    Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.

  18. Brain Function in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

  19. A Drosophila model for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Plas, Mariska Cathelijne van der

    2008-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal

  20. Duchenne muscular dystrophy - a molecular service

    African Journals Online (AJOL)

    In 1987 a carrier detection and prenatal diagnostic service for. Duchenne muscular dystrophy using molecular technology was instituted at the Department of Human Genetics, Uni- versity of Cape Town, to serve affe.cted families in southern. Africa. DNA samples from 100 affected male subjects and. 350 of their relatives ...

  1. Merosin/laminin-2 and muscular dystrophy

    DEFF Research Database (Denmark)

    Wewer, U M; Engvall, E

    1996-01-01

    and skin. Merosin is the collective name for laminins that share a common subunit, the laminin alpha 2 chain. Merosin-deficient congenital muscular dystrophy (CMD) is caused by mutations in the laminin alpha 2 chain gene. The skin disease Herlitz junctional epidermolysis bullosa is caused by mutations...

  2. Respiratory function in facioscapulohumeral muscular dystrophy 1.

    Science.gov (United States)

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

    2017-06-01

    To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  4. Prevalence of congenital muscular dystrophy in Italy

    Science.gov (United States)

    Graziano, Alessandra; Bianco, Flaviana; D'Amico, Adele; Moroni, Isabella; Messina, Sonia; Bruno, Claudio; Pegoraro, Elena; Mora, Marina; Astrea, Guja; Magri, Francesca; Comi, Giacomo P.; Berardinelli, Angela; Moggio, Maurizio; Morandi, Lucia; Pini, Antonella; Petillo, Roberta; Tasca, Giorgio; Monforte, Mauro; Minetti, Carlo; Mongini, Tiziana; Ricci, Enzo; Gorni, Ksenija; Battini, Roberta; Villanova, Marcello; Politano, Luisa; Gualandi, Francesca; Ferlini, Alessandra; Muntoni, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; Pane, Marika

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  5. Lesiones musculares en el mundo del deporte. [Muscular injuries in the world of the sport

    Directory of Open Access Journals (Sweden)

    María Ángeles Cardero Durán

    2009-12-01

    Full Text Available Resumen En el mundo del deporte y no solo en este, sino en toda la práctica de una actividad física, son muy frecuentes las lesiones musculares. Hay muchos tipos de lesiones musculares de los que hablaremos más adelante, como pueden ser desgarros musculares, calambres, contracturas etc., que tienen mayor incidencia en la musculatura poli-articular, por condiciones de acumulación de fatiga, trabajo no realizado correctamente, o condiciones ambientales desfavorables. Es importante el diagnóstico y el tratamiento precoz, para poder intervenir y conseguir que el deportista vuelva lo antes posible a su actividad y al proceso de competición. En este artículo hablaremos de los distintos tipos de lesiones musculares, de las causas y mecanismos de producción, así como del tratamiento fisioterápico que se emplea en un deportista en estos casos. Palabras claves: Lesión, músculo, deporte. Abstract In the world of the sport and not only in this one, but in the whole practice of a physical activity, the muscular injuries are very frequent. There are many types of muscular injuries about which we are going to speak later, like can be muscular tears, cramps, contractions etc. That have major incident in the musculature poly-articulate, because of conditions of accumulation of fatigue, the work not done correctly, or  unfavorable environmental conditions.  The diagnosis and the precocious treatment is important, to be able to intervene and achieve that the sportsman come back as soon as possible to the activity and to the process of competition.  In this article we are going to speak about the different types of muscular injuries, about the reasons and mechanisms of production, as well as about the physical therapy diagnosed in these cases.  Key words: Injury, muscle, sport

  6. Photoreceptor atrophy in acute zonal occult outer retinopathy

    DEFF Research Database (Denmark)

    Zibrandtsen, N.; Munch, I.C.; Klemp, K.

    2008-01-01

    appearance were examined using optical coherence tomography (OCT), automated perimetry and electroretinography (ERG). RESULTS: Both patients demonstrated photoreceptor atrophy corresponding to partial or complete scotomata with reduced or extinct electroretinographic responses. Attenuation or complete loss...... dysfunction. The field loss was more extensive than the area of photoreceptor loss. CONCLUSION: Photoreceptor atrophy can be demonstrated in AZOOR without ophthalmoscopically visible fundus lesions Udgivelsesdato: 2008/12...

  7. Steroid-induced Kager's fat pad atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Taneja, Atul K. [Hospital Israelita Albert Einstein, Musculoskeletal Radiology Division, Imaging Department, Sao Paulo (Brazil); Musculoskeletal Imaging, Diagnostic Center, Hospital do Coracao (HCor) and Teleimagem, Sao Paulo, SP (Brazil); Santos, Durval C.B. [Hospital Israelita Albert Einstein, Musculoskeletal Radiology Division, Imaging Department, Sao Paulo (Brazil)

    2014-08-15

    We report a rare case of Kager's fat pad atrophy and fibrosis in a 60-year-old woman 1 year after a steroid injection for Achilles tendinopathy. There are few published reports of steroid-induced atrophy affecting deeper layers of fat tissue. To our knowledge, this case report is the first to illustrate its features using magnetic resonance imaging. A review of the scientific literature is also presented. (orig.)

  8. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.

    Science.gov (United States)

    Reinson, Karit; Õiglane-Shlik, Eve; Talvik, Inga; Vaher, Ulvi; Õunapuu, Anne; Ennok, Margus; Teek, Rita; Pajusalu, Sander; Murumets, Ülle; Tomberg, Tiiu; Puusepp, Sanna; Piirsoo, Andres; Reimand, Tiia; Õunap, Katrin

    2016-08-01

    The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. An association with epilepsy and CACNA1A mutations has also been described. However, the link with epileptic encephalopathies has emerged only recently. Here we describe two patients, sister and brother, with compound heterozygous mutations in CACNA1A. Exome sequencing detected biallelic mutations in CACNA1A: A missense mutation c.4315T>A (p.Trp1439Arg) in exon 27, and a seven base pair deletion c.472_478delGCCTTCC (p.Ala158Thrfs*6) in exon 3. Both patients were normal at birth, but developed daily recurrent seizures in early infancy with concomitant extreme muscular hypotonia, hypokinesia, and global developmental delay. The brain MRI images showed progressive cerebral, cerebellar, and optic nerve atrophy. At the age of 5, both patients were blind and bedridden with a profound developmental delay. The elder sister died at that age. Their parents and two siblings were heterozygotes for one of those pathogenic mutations and expressed a milder phenotype. Both of them have intellectual disability and in addition the mother has adult onset cerebellar ataxia with a slowly progressive cerebellar atrophy. Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Rectus abdominis atrophy after ventral abdominal incisions: midline versus chevron.

    Science.gov (United States)

    Vigneswaran, Y; Poli, E; Talamonti, M S; Haggerty, S P; Linn, J G; Ujiki, M B

    2017-08-01

    Although many outcomes have been compared between a midline and chevron incision, this is the first study to examine rectus abdominis atrophy after these two types of incisions. Patients undergoing open pancreaticobiliary surgery between 2007 and 2011 at our single institution were included in this study. Rectus abdominis muscle thickness was measured on both preoperative and follow-up computed tomography (CT) scans to calculate percent atrophy of the muscle after surgery. At average follow-up of 24.5 and 19.0 months, respectively, rectus abdominis atrophy was 18.9% greater in the chevron (n = 30) than in the midline (n = 180) group (21.8 vs. 2.9%, p 20% atrophy at follow-up compared with 10% with a midline incision [odds ratio (OR) 9.0, p atrophy of the rectus abdominis compared with midline incisions. The long-term effects of transecting the rectus abdominis and disrupting its innervation creates challenging abdominal wall pathology. Atrophy of the abdominal wall can not be readily fixed with an operation, and this significant side effect of a transverse incision should be factored into the surgeon's decision-making process when choosing a transverse over a midline incision.

  10. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice.

    Science.gov (United States)

    Porporato, Paolo E; Filigheddu, Nicoletta; Reano, Simone; Ferrara, Michele; Angelino, Elia; Gnocchi, Viola F; Prodam, Flavia; Ronchi, Giulia; Fagoonee, Sharmila; Fornaro, Michele; Chianale, Federica; Baldanzi, Gianluca; Surico, Nicola; Sinigaglia, Fabiola; Perroteau, Isabelle; Smith, Roy G; Sun, Yuxiang; Geuna, Stefano; Graziani, Andrea

    2013-02-01

    Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

  11. FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

    Directory of Open Access Journals (Sweden)

    Gerrard Dave

    2007-04-01

    Full Text Available Abstract Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight.

  12. Brain atrophy and dementia from the aspect of CT

    International Nuclear Information System (INIS)

    Ohkuni, Michiko

    1979-01-01

    Two major causes of dementia in the elderly are reported to be the degeneration of brain and cerebrovascular diseases. Recently, CT findings of cerebrovascular diseases and brain atrophy have been noticed, because they rather clearly show these changes. The authors examined the view of atrophy frequently observed on the dementia in the elderly. The results obtained are as follows: 1) In accordance with the increase of age the appearance of the view of atrophy increased in frequency and that of extreme brain atrophy also increased. 2) As the age increased, the average value of the width of the 3rd ventricle tended to increase. 3) In the cases accompanied with the view of cerebrovascular diseases remarkable ventricular dilatation was frequently observed, and in the very old dilatations of cerebral sulci, central fissure and Sylvian fissure were observed of all cases. 4) Of the group of severe dementia the view of extreme brain atrophy was observed in the major. However, there was no significant difference on the lesion of atrophy between the cases. The results mentioned above include some exceptional points respectively, so further investigation will be necessary from the qualitative and quantitative points of view. (author)

  13. Generation of GZKHQi001-A and GZWWTi001-A, two induced pluripotent stem cell lines derived from peripheral blood mononuclear cells of Duchenne muscular dystrophy patients

    Directory of Open Access Journals (Sweden)

    Xie Yuhuan

    2018-04-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked disease caused by mutations in the DMD gene, which spans ~2.4 Mb of genomic sequence at locus Xp21. This mutation results in the loss of the protein dystrophin. DMD patients die in their second or third decade due to either respiratory failure or cardiomyopathy, as the absence of dystrophin leads to myofiber membrane fragility and necrosis, eventually resulting in muscle atrophy and contractures. Currently, there is no effective treatment for DMD, therefore induced pluripotent stem cells from DMD patients would be a powerful tool for studying disease mechanisms.

  14. Cardiac involvement in children with neuro-muscular disorders

    Directory of Open Access Journals (Sweden)

    E. N. Arkhipova

    2015-01-01

    Full Text Available Many inherited neuromuscular disorders include cardiac involvement as a typical clinical feature. Among the most common of them is the group of muscular dystrophies. Dilated cardiomyopathy, ventricular arrhythmias, atrial fibrillations, atrioventricular and intraventricular conduction abnormalities, and sudden cardiac death are well known pathological findings in Duchenne muscular dystrophies, myotonic dystrophy type I and 2, Emery-Dreifuss muscular dystrophies and different types of limb-girdle muscular dystrophies and other disorders. Detection of cardiac pathology in patients with different muscular dystrophies is possible with ECG, echocardiography and cardiovascular magnetic resonance imaging, which are recommended for screening and early cardioprotective treatment.

  15. [Muscular strength in patients with fibromyalgia. A literature review

    DEFF Research Database (Denmark)

    Dombernowsky, T.; Dreyer, L.; Bartels, E.M.

    2008-01-01

    Do patients with fibromyalgia (FM) have reduced muscular strength? We examined 22 articles and conclude from the results of these that FM patients have reduced muscular strength in their hands and quadriceps. The material also suggests generalised reduced muscular strength. However, the studies...... have several methodological shortcomings and future studies should be carefully designed with respect to patients as well as the control group and should be larger. To avoid CNS influence from e.g. fatigue and pain, muscular electro-stimulation may be used to ensure that the actual maximal muscular...

  16. Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study.

    Science.gov (United States)

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

    2015-10-24

    The clinical features of SMA, which range along a spectrum of severity, are relatively well described. In contrast, the literature on how individuals with SMA and their families experience this condition is limited. To address this gap, we undertook a qualitative study with individuals affected by SMA Types I, II and III, parents of those affected, and clinicians. We completed 16 focus group sessions and 37 interviews in the US with 96 participants including: 21 with individuals with SMA; 64 parents of individuals affected by SMA; and 11 clinicians who specialize in the care of SMA patients. The Diagnostic Journey: Families reported substantial diagnostic delays owing to: 1) lack of awareness and knowledge about SMA; 2) the difficulty of distinguishing normal from abnormal development; and 3) the challenge of differential diagnosis. Lack of sensitivity in how clinicians communicated this potentially devastating diagnosis compounded parents' negative impressions. Newborn Screening: Parents generally held positive views about adding SMA to newborn screening panels. For example, it would: 1) enable earlier access to care; 2) shorten the diagnostic journey; and 3) give families more time to prepare to care for a disabled child. Some noted negative outcomes such as prematurely affecting a parent's relationship with a child before symptoms are evident. The Psychosocial Impact of Living with SMA: Ten thematic areas characterized the impact: 1) confronting premature death; 2) making difficult treatment choices; 3) fearing the loss of functional ability; 4) coming to terms with lost expectations; 5) loss of sleep and stress; 6) stigma; 7) limitations on social activities; 8) independence; 9) uncertainty and helplessness; and 10) family finances. The results of this study suggest high levels of burden experienced by individuals with SMA and their families. The difficulties of living with SMA begin with the long and often arduous process of finding a diagnosis for their child. Newborn screening for SMA is seen as an important step toward shortening this journey. The psychosocial effects of coping with SMA are substantial and wide ranging both for the individual living with this condition and family members of affected individuals.

  17. Contribution of white matter hyperintensities, medial temporal lobe atrophy and cortical atrophy on outcome, seven to twelve years after ECT in severely depressed geriatric patients

    NARCIS (Netherlands)

    Oudega, M.L.; Dols, A.; Adelerhof, I.; Rozing, M.; Wattjes, M.P.; Comijs, H.C.; Barkhof, F.; Eikelenboom, P.; Stek, M.L.; van Exel, E.

    2015-01-01

    Background Depression and cognitive decline are highly prevalent and often coexisting, however, the association between depression and dementia remains unclear. White matter hyperintensities (WMH), medial temporal lobe atrophy (MTA) and global cortical atrophy (GCA) are associated with depression,

  18. Calculation of brain atrophy using computed tomography and a new atrophy measurement tool

    Science.gov (United States)

    Bin Zahid, Abdullah; Mikheev, Artem; Yang, Andrew Il; Samadani, Uzma; Rusinek, Henry

    2015-03-01

    Purpose: To determine if brain atrophy can be calculated by performing volumetric analysis on conventional computed tomography (CT) scans in spite of relatively low contrast for this modality. Materials & Method: CTs for 73 patients from the local Veteran Affairs database were selected. Exclusion criteria: AD, NPH, tumor, and alcohol abuse. Protocol: conventional clinical acquisition (Toshiba; helical, 120 kVp, X-ray tube current 300mA, slice thickness 3-5mm). Locally developed, automatic algorithm was used to segment intracranial cavity (ICC) using (a) white matter seed (b) constrained growth, limited by inner skull layer and (c) topological connectivity. ICC was further segmented into CSF and brain parenchyma using a threshold of 16 Hu. Results: Age distribution: 25-95yrs; (Mean 67+/-17.5yrs.). Significant correlation was found between age and CSF/ICC(r=0.695, patrophy among elderly VA patients is attributable to the presence of other comorbidities. Conclusion: Brain atrophy can be reliably calculated using automated software and conventional CT. Compared to MRI, CT is more widely available, cheaper, and less affected by head motion due to ~100 times shorter scan time. Work is in progress to improve the precision of the measurements, possibly leading to assessment of longitudinal changes within the patient.

  19. Visual neglect in posterior cortical atrophy

    Directory of Open Access Journals (Sweden)

    Andrade Katia

    2010-08-01

    Full Text Available Abstract Background In posterior cortical atrophy (PCA, there is a progressive impairment of high-level visual functions and parietal damage, which might predict the occurrence of visual neglect. However, neglect may pass undetected if not assessed with specific tests, and might therefore be underestimated in PCA. In this prospective study, we aimed at establishing the side, the frequency and the severity of visual neglect, visual extinction, and primary visual field defects in an unselected sample of PCA patients. Methods Twenty-four right-handed PCA patients underwent a standardized battery of neglect tests. Visual fields were examined clinically by the confrontation method. Results Sixteen of the 24 patients (66% had signs of visual neglect on at least one test, and fourteen (58% also had visual extinction or hemianopia. Five patients (21% had neither neglect nor visual field defects. As expected, left-sided neglect was more severe than right-sided neglect. However, right-sided neglect resulted more frequently in this population (29% than in previous studies on focal brain lesions. Conclusion When assessed with specific visuospatial tests, visual neglect is frequent in patients with PCA. Diagnosis of neglect is important because of its negative impact on daily activities. Clinicians should consider the routine use of neglect tests to screen patients with high-level visual deficits. The relatively high frequency of right-sided neglect in neurodegenerative patients supports the hypothesis that bilateral brain damage is necessary for right-sided neglect signs to occur, perhaps because of the presence in the right hemisphere of crucial structures whose damage contributes to neglect.

  20. Cerebellar atrophy in neurodegeneration-a meta-analysis.

    Science.gov (United States)

    Gellersen, Helena M; Guo, Christine C; O'Callaghan, Claire; Tan, Rachel H; Sami, Saber; Hornberger, Michael

    2017-09-01

    The cerebellum has strong cortical and subcortical connectivity, but is rarely taken into account for clinical diagnosis in many neurodegenerative conditions, particularly in the absence of clinical ataxia. The current meta-analysis aims to assess patterns of cerebellar grey matter atrophy in seven neurodegenerative conditions (Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (MSP)). We carried out a systematic search in PubMed (any date: 14 July 2016) and a hand search of references from pertinent articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The authors were contacted to provide missing coordinate data. Peer-reviewed studies with direct comparison of patient and control groups, and availability of coordinate data of grey matter cerebellar atrophy in patients were included. These coordinates were used in an anatomical likelihood estimation meta-analysis. Across 54 studies, clusters of cerebellar atrophy were found for AD, ALS, FTD, MSA, and PSP. Atrophy patterns were largely disease-specific, with overlap in certain areas of the cerebellar hemisphere, which showed marked atrophy in AD, ALS, FTD and PSP (Crus I/II), and MSA and PSP (lobules I-IV), respectively. Atrophy colocated with cerebellar areas implicated for motor (PSP, MSA) or cognitive symptoms (FTD, ALS, PSP) in the diseases. Our findings suggest that cerebellar changes are largely disease-specific and correspond to cortical or subcortical changes in neurodegenerative conditions. High clinical variability in PD and HD samples may explain the absence of findings for consistent grey matter loss across studies. Our results have clinical implications for diagnosis and cerebellar neuroimaging referencing approaches. © Article author(s) (or their employer(s) unless otherwise stated

  1. Imagem radiográfica da cavidade torácica de cães Golden Retriever acometidos pela distrofia muscular Radiologic images of the thoracic cavity of Golden Retriever dogs affected by muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Flávio R. Alves

    2009-02-01

    Full Text Available A distrofia muscular de Duchenne (DMD é uma doença de origem genética, cuja principal manifestação clínica é enfraquecimento e atrofia progressiva dos músculos. Os cães da raça Golden Retriever podem apresentar distrofia muscular, com características genotípicas e fenotípicas muito próximas à distrofia muscular humana, sendo considerado o modelo animal mais apropriado para o estudo da DMD. Foram realizadas radiografias torácicas látero-laterais e dorsoventrais de 10 cães Golden Retriever afetados pela distrofia muscular, com o objetivo de relatar as alterações radiográficas associadas a essa patologia. O exame radiográfico da cavidade torácica evidenciou: (a padrão pulmonar intersticial e alveolar predominante, (b um quadro de pneumonia e edema pulmonar em fase inicial, (c a cardiomegalia como o principal achado de comprometimento circulatório na cavidade torácica, (d O megaesôfago torácico foi observado deslocando a traquéia e silhueta cardíaca ventralmente e, (e a cúpula diafragmática apresentou modificação morfológica, mostrando protrusão para o interior da cavidade torácica e hérnia hiatal, com deslocamento do estômago para o espaço mediastino caudal. Os achados de necropsia evidenciaram efusão pleural e enfisema pulmonar e lesões compatíveis com processos degenerativos e metaplásicos da musculatura diafragmática e intercostal. A avaliação radiográfica constituiu-se como um meio diagnóstico auxiliar essencial na identificação de doença cardíaca e respiratória em cães Golden Retriever acometidos pela Distrofia Muscular, capaz de identificar processos pneumônicos primários, permitindo o estabelecimento de terapêutica adequada de tratamento, com prognóstico reservado nos estágios mais avançados desta alteração.Duchenne Muscular Dystrophy (DMD is a genetic disorder with clinical signs of muscular weaknesses and progressive atrophy. Golden Retriever dogs show similar genotypic and

  2. Pain characterization in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Talita Dias da Silva

    Full Text Available ABSTRACT Duchenne muscular dystrophy (DMD is an X-linked recessive disorder, characterized by progressive muscle weakness. Historically, pain has not been considered to be a major symptom in DMD. Objective To investigate the relationship between DMD and pain. Methods We conducted a systematic review in Medline/PubMed and BVS (virtual library in health databases. We searched for articles that showed the terms “Muscular Dystrophy, Duchenne” and “Pain” in all fields. All studies included boys diagnosed with DMD and the occurrence/amount of pain on this population. Results Initially, there were 175 studies. 167 articles were excluded for not meeting the inclusion criteria. The remaining eight eligible studies, involving pain assessment in DMD, were analyzed. Conclusion Pain is a frequent problem in this population and this symptom is potentially tractable. Studies conclude that pain can directly influence the quality of life of this population.

  3. Sleep Disordered Breathing in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    LoMauro, Antonella; D'Angelo, Maria Grazia; Aliverti, Andrea

    2017-05-01

    This review aims to explain the inevitable imbalance between respiratory load, drive, and muscular force that occurs in the natural aging of Duchenne muscular dystrophy and that predisposes these patients to sleep disordered breathing (SDB). In DMD, SDB is characterized by oxygen desaturation, apneas, hypercapnia, and hypoventilation during sleep and ultimately develops into respiratory failure during wakefulness. It can be present in all age groups. Young patients risk obstructive apneas because of weight gain, secondary to progressive physical inactivity and prolonged corticosteroid therapy; older patients hypoventilate and desaturate because of respiratory muscle weakness, in particular the diaphragm. These conditions are further exacerbated during REM sleep, the phase of maximal muscle hypotonia during which the diaphragm has to provide most of the ventilation. Evidence is given to the daytime predictors of early symptoms of SDB, important indicators for the proper time to initiate mechanical ventilation.

  4. A lesão muscular na miastenia grave: estudo de 17 casos com histoquimica muscular

    Directory of Open Access Journals (Sweden)

    Lineu Cesar Werneck

    1982-03-01

    Full Text Available Estudo de 17 biópsias musculares de pacientes com miastenia grave, utilizando técnicas de coloração a fresco e histoquímica muscular. Foram encontradas 15 biópsias musculares anormais, sendo que as principais alterações foram fibras musculares angulares escuras atróficas, excesso de gotículas de gordura na membrana externa das fibras, variação no diâmetro das fibras e atrofia de fibras do tipo II. Os achados foram interpretados como denervação em 11 biópsias, atrofia de fibras do tipo II em 7, infiltrado linfocitário em 4, necrose de fibras musculares com fagocitose em 1 e em 2 biópsias não foi encontrada qualquer anormalidade. Quanto maior o tempo de doença, mais severa foi a anormalidade encontrada. Dois pacientes apresentavam timoma, um miastenia grave congênita, um artrite reumatoide, um neurite hipertrófica intersticial, um tireoidite de Hashimoto e um com síndrome miastênica concomitante. São discutidos os achados anatomopatológicos e sua possível explicação.

  5. Rehabilitation therapy of Duchenne muscular dystrophy

    OpenAIRE

    ZHANG Cheng; YANG Juan

    2012-01-01

    It is very important that the rehabilitation therapy of Duchenne muscular dystrophy (DMD) can improve the quality of life and delay the disease progression. There are the guidelines for DMD rehabilitation therapy in some countries, but it is not emphasized by clinical doctors in our country. According to our experiences to DMD rehabilitation therapy, we reviewed the progress of DMD rehabilitation therapy. It includes the clinical stages and characteristics of DMD, the general principle and th...

  6. Urological manifestations of Duchenne muscular dystrophy.

    Science.gov (United States)

    Askeland, Eric J; Arlen, Angela M; Erickson, Bradley A; Mathews, Katherine D; Cooper, Christopher S

    2013-10-01

    Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  7. Muscular cysticercosis: Case report and imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Olmo, Neide Regina Simoes; Fiorio, Ulysses Ferreira; Clemente, Marcel Andreazza, E-mail: neideolmo@yahoo.com.br [Clinica Mult Imagem, Santos, SP (Brazil); Bastos, Eder Amaral [Universidade Metropolitana de Santos (UNIMES), Santos, SP (Brazil); Mendes, Gustavo Gomes [AC Camargo Cancer Center, Sao Paulo, SP (Brazil)

    2016-11-15

    Cysticercosis is a parasitic disease caused by a worm of the Cestoda class. The most prevalent form affects the nervous system. This case report is from a 78-year old female patient evaluated at Clinica Mult Imagem, in the city of Santos, Brazil, who presented a form of the disease that differed from the classic neurocysticercosis, in this case muscular cysticercosis. This and other forms of manifestation justify further studies to ensure adequate recognition, diagnosis and treatment of this parasitic disease. (author)

  8. A case of dentato-rubro-pallido-luysian atrophy

    International Nuclear Information System (INIS)

    Usui, Sadanari; Komiya, Tadatoshi

    1988-01-01

    A clinical case of dentato-rubro-pallido-luysian atrophy (DRPLA) was reported. We established several aspects on the basis of MRI findings and a neuro-otological study. A 47-year-old woman had gait disturbance, involuntary movements, speech disturbance, and memory disturbance at the age of 42. She was admitted to the hospital because of worsening of the gait disturbance. Neurological examinations showed choreo-athetosis of the face, neck and upper extremities, mental disturbance, and scanning speech. However, she had neither ocular disturbance nor epilepsy or myoclonus. On the MRI-CT, an atrophy of midbrain and pontine tegmentum was observed. The neuro-otological study showed gaze nystagmus at the horizontal gaze, rebound nystagmus, hypometria of the saccade, saccadic pursuit, reduction of the optokinetic nystagmus, and increase in caloric nystagmus by means of visual input. A severe atrophy of the brainstem tegmentum and a mild atrophy of the cerebellar hemisphere and cerebral cortex are regarded as neuro-radiological features of DRPLA. Moreover, tegmental atrophy is related to ocular disturbance as a clinical feature. Various neuro-otological findings reveal many systems of ocular movements, i.e., a smooth pursuit system, a saccade system, and a vestibulo-ocular reflex system, involving flocculus. DRPLA can be clinically diagnosed by means of clinical features, MRI findings, and neuro-otological findings. A variety of neuro-otological abnormalities may indicate a progression of the ocular disturbance and a variety of lesions. (author)

  9. Significance of type II fiber atrophy in chronic alcoholic myopathy.

    Science.gov (United States)

    Fernández-Solá, J; Sacanella, E; Estruch, R; Nicolás, J M; Grau, J M; Urbano-Márquez, A

    1995-05-01

    To determine the significance of type II fiber atrophy in alcoholic myopathy and its relationship with ethanol-related diseases a prospective study was carried out in 100 chronic alcoholics who showed clinical suspicion of skeletal myopathy. Measurement of muscle strength, laboratory analysis, nutritional assessment and open biopsy of deltoid muscle were performed in each case, as well as electrophysiological testing for peripheral neuropathy. Hepatic ultrasonography and liver biopsy, echocardiography and radionuclide cardiac scanning were carried out in selected subjects. According to histomorphometric analysis, type II fiber atrophy was found in 33 cases (33%), being selective for type II B fiber in 23 (70%). Skeletal myopathy was diagnosed in 61 cases, alcoholic cardiomyopathy in 26, peripheral neuropathy in 23 and cirrhosis in 12. Patients with type II fiber atrophy had a significantly higher total lifetime dose of ethanol, presented a greater incidence of skeletal myopathy and peripheral neuropathy, and exhibited significantly lower values of percentage of ideal body weight and lean body mass than their counterparts. However, the only independent factors for developing type II fiber atrophy were the coexistence of caloric malnutrition (p = 0.004) and the presence of skeletal myopathy (p = 0.043). Selective type II fiber atrophy is a non-specific finding in alcohol-induced muscle damage appearing, overall, in the patients with caloric malnutrition as well as in those with histologic evidence of myopathy.

  10. [Quantitative echographic assessment of muscular physiopathology].

    Science.gov (United States)

    Talia, B; Casini, A; Fabbri, F; Lotti, F; Masotti, L

    1993-05-01

    The evaluation of muscular contraction is one of the main variables in muscular reeducation treatment protocols. US depicts muscular structure and size, as well as changes in both. A real-time US unit with 5/7.5 MHz probes and a computer with advanced software were used; the US unit was modified so as to reduce scanning times and to yield a high number of images/second (about 45). During endoscopy, a higher number of intermediate positions can thus be found between rest and contraction, which yields more statistically significant results. The US unit is connected to a video-recorder and to an electrostimulator to obtain isometric and isotonic contractions; the latter unit is connected to the US unit so that the electric and the US energies can be emitted simultaneously and the synchronism of the contraction and of the beginning of the electric stimulation can be assessed. Besides normal control subjects, patients with hypotrophic recto-femoral muscle were examined: the results were collected in a databank useful to choose the most appropriate treatment, to follow patients during therapy, to evaluate the final results and finally to be used in sports activities.

  11. Management of myocardial damage in muscular dystrophy

    International Nuclear Information System (INIS)

    Tamura, Takuhisa

    2011-01-01

    Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future. (author)

  12. Gene therapy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Verhaart, Ingrid E C; Aartsma-Rus, Annemieke

    2012-10-01

    Duchenne muscular dystrophy is a severe neuromuscular disorder for which there is currently no cure. Years of research have come to fruition during the past 18 months with publications on clinical trials for several gene therapy approaches for Duchenne muscular dystrophy. This review covers the present status of these approaches. The exon skipping approach is most advanced in the process of clinical application. Encouraging results have been obtained in two systemic clinical trials and further optimization has increased delivery to the heart in animal models. Limitations of the approach are the mutation-specificity and the anticipated requirement for lifelong treatment. Gene therapy by means of gene transfer holds the promise of more long-lasting effects. Results of a first, early-stage gene therapy trial, using viral vectors to deliver a minidystrophin gene, were reported. Animal studies suggest that it may be possible to overcome the main challenges currently facing gene therapy (immunogenicity of the vector and systemic body-wide delivery). Significant steps have been made in the development of gene therapy approaches for Duchenne muscular dystrophy. These approaches aim to slow down disease progression, requiring robust outcome measures to assess efficacy.

  13. Exposure to microgravity for 30 days onboard Bion M1 caused muscle atrophy and impaired regeneration in murine femoral Quadriceps

    Science.gov (United States)

    Radugina, E. A.; Almeida, E. A. C.; Blaber, E.; Poplinskaya, V. A.; Markitantova, Y. V.; Grigoryan, E. N.

    2018-02-01

    Mechanical unloading in microgravity during spaceflight is known to cause muscular atrophy, changes in muscle fiber composition, gene expression, and reduction in regenerative muscle growth. Although some limited data exists for long-term effects of microgravity in human muscle, these processes have mostly been studied in rodents for short periods of time. Here we report on how long-term (30-day long) mechanical unloading in microgravity affects murine muscles of the femoral Quadriceps group. To conduct these studies we used muscle tissue from 6 microgravity mice, in comparison to habitat (7), and vivarium (14) ground control mice from the NASA Biospecimen Sharing Program conducted in collaboration with the Institute for Biomedical Problems of the Russian Academy of Sciences, during the Russian Bion M1 biosatellite mission in 2013. Muscle histomorphology from microgravity specimens showed signs of extensive atrophy and regenerative hypoplasia relative to ground controls. Specifically, we observed a two-fold decrease in the number of myonuclei, compared to vivarium and ground controls, and central location of myonuclei, low density of myofibers in the tissue, and of myofibrils within a fiber, as well as fragmentation and swelling of myofibers. Despite obvious atrophy, muscle regeneration nevertheless appeared to have continued after 30 days in microgravity as evidenced by thin and short newly formed myofibers. Many of them, however, showed evidence of apoptotic cells and myofibril degradation, suggesting that long-term unloading in microgravity may affect late stages of myofiber differentiation. Ground asynchronous and vivarium control animals demonstrated normal, well-developed tissue structure with sufficient blood and nerve supply and evidence of regenerative formation of new myofibers free of apoptotic nuclei. Regenerative activity of satellite cells in muscles was observed both in microgravity and ground control groups, using Pax7 and Myogenin

  14. Exposure to microgravity for 30 days onboard Bion M1 caused muscle atrophy and decreased regeneration in the mouse femoral Quadriceps

    Science.gov (United States)

    Grigoryan, Eleonora; Radugina, Elena A.; Almeida, Eduardo; Blaber, Elizabeth; Poplinskaya, Valentina; Markitantova, Yulia

    Mechanical unloading of muscle during spaceflight in microgravity is known to cause muscular atrophy, changes in muscle fiber type composition, gene expression, and reductions in regenerative muscle growth. Although limited data exists for long-term effects of microgravity in human muscle, these processes have mostly been studied in rodents for short periods of time, up to two weeks of spaceflight. Here we report on how 30-day, long-term, mechanical unloading in microgravity affects mouse muscle of the femoral Quadriceps group. To conduct these studies we used muscle tissue from 6 mice from the NASA Biospecimen Sharing Program conducted in collaboration with the Institute for Biomedical Problems of the Russian Academy of Sciences, during the Russian Bion M1 biosatellite mission in 2013. Muscle morphology observed in histological sections shows signs of extensive atrophy and regenerative hypoplasia. Specifically, we observed a two-fold decrease in the number of myonuclei and low density of myofibrils, their separation and fragmentation. Despite obvious atrophy, muscle regeneration nevertheless appears to have continued after 30 days in microgravity as evidenced by thin and short newly formed muscle fibers. Many of them however showed evidence of apoptosis and degradation of synthesized fibrils, suggesting long-term unloading in microgravity affects late stages of myofiber differentiation. Ground asynchronous and vivarium control animals showed normal, well-developed tissue structure with sufficient blood and nerve supply and evidence of regenerative formation of new muscle fibers free of apoptotic nuclei. Myofiber nuclei stress responses in spaceflight animals was detected by positive nuclear immunolocalization of c-jun and c-myc proteins. Regenerative activity of satellite cells in muscle was localized with pax-7, MyoD and MCad immunostaining, and did not appear altered in microgravity. In summary, long-term spaceflight in microgravity causes significant atrophy

  15. Threatened masculinity and muscularity: an experimental examination of multiple aspects of muscularity in men.

    Science.gov (United States)

    Hunt, Christopher John; Gonsalkorale, Karen; Murray, Stuart B

    2013-06-01

    Two studies examined the threatened masculinity theory of male body dissatisfaction, which posits that threats to masculinity result in increased muscle dissatisfaction. In Study 1, a masculinity threat was followed by tasks examining confidence in physical ability and perceptions of current and ideal body shapes. Results showed that men who experienced a masculinity threat reported lower confidence in their physical ability and perceived themselves as less muscular than men who experienced an affirmation of their masculinity. In Study 2, men were asked to report their intention to increase muscularity and their appearance anxiety following a threat to masculinity. Results showed that men reported lower appearance anxiety and drive for muscularity when their masculinity was threatened than when their masculinity was affirmed. This apparent contradiction can be explained by noting that men may be motivated to deny appearance concerns following a threat to masculinity, as such concerns are equated with femininity. Copyright © 2013. Published by Elsevier Ltd.

  16. Surgery for scoliosis in Duchenne muscular dystrophy.

    Science.gov (United States)

    Cheuk, Daniel K L; Wong, Virginia; Wraige, Elizabeth; Baxter, Peter; Cole, Ashley

    2013-02-28

    Scoliosis in people with Duchenne muscular dystrophy is usually progressive and treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most people with Duchenne muscular dystrophy and scoliosis. This is an updated review and an updated search was undertaken in which no new studies were found. To determine the effectiveness and safety of spinal surgery in people with Duchenne muscular dystrophy with scoliosis. We intended to test whether spinal surgery is effective in increasing survival, improving respiratory function, improving quality of life and overall functioning; and whether spinal surgery is associated with severe adverse effects. We searched the specialized registers of the Cochrane Neuromuscular Disease Group (31 July 2012), MEDLINE (January 1966 to July 2012), EMBASE (January 1947 to July 2012), CENTRAL (2012, Issue 7 in the Cochrane Library), CINAHL Plus(January 1937 to July 2012), Proquest Dissertation and Thesis Database (January 1980 to July 2012), and the National Institute of Health Clinical Trials Database (July 2012). No language restrictions were imposed. We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in people with Duchenne muscular dystrophy in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. Two authors independently examined the search results and evaluated the study characteristics against inclusion criteria to decide which ones would be included in the review. On searching, 47 studies were relevant but none met the inclusion criteria for the review, because they were not clinical trials but prospective or retrospective reviews of case series. Since there were no randomized controlled clinical trials available to evaluate the effectiveness of

  17. Disease-Induced Skeletal Muscle Atrophy and Fatigue

    Science.gov (United States)

    Powers, Scott K.; Lynch, Gordon S.; Murphy, Kate T.; Reid, Michael B.; Zijdewind, Inge

    2016-01-01

    Numerous health problems including acute critical illness, cancer, diseases associated with chronic inflammation, and neurological disorders often result in skeletal muscle weakness and fatigue. Disease-related muscle atrophy and fatigue is an important clinical problem because acquired skeletal muscle weakness can increase the duration of hospitalization, result in exercise limitation, and contribute to a poor quality of life. Importantly, skeletal muscle atrophy is also associated with increased morbidity and mortality of patients. Therefore, improving our understanding of the mechanism(s) responsible for skeletal muscle weakness and fatigue in patients is a required first step to develop clinical protocols to prevent these skeletal muscle problems. This review will highlight the consequences and potential mechanisms responsible for skeletal muscle atrophy and fatigue in patients suffering from acute critical illness, cancer, chronic inflammatory diseases, and neurological disorders. PMID:27128663

  18. Can endurance exercise preconditioning prevention disuse muscle atrophy?

    Directory of Open Access Journals (Sweden)

    Michael P Wiggs

    2015-03-01

    Full Text Available Emerging evidence suggests that exercise training can provide a level of protection against disuse muscle atrophy. Endurance exercise training imposes oxidative, metabolic, and heat stress on skeletal muscle which activates a variety of cellular signaling pathways that ultimately leads to the increased expression of proteins that have been demonstrated to protect muscle from inactivity –induced atrophy. This review will highlight the effect of exercise-induced oxidative stress on endogenous enzymatic antioxidant capacity (i.e., superoxide dismutase, glutathione peroxidase, and catalase, the role of oxidative and metabolic stress on PGC1-α, and finally highlight the effect heat stress and HSP70 induction. Finally, this review will discuss the supporting scientific evidence that these proteins can attenuate muscle atrophy through exercise preconditioning.

  19. Distrofia muscular de Emery-Dreifuss: relato de caso Emery-Dreifuss muscular dystrophy: case report

    Directory of Open Access Journals (Sweden)

    Ana Lucila Moreira Carsten

    2006-06-01

    Full Text Available A distrofia muscular de Emery-Dreifuss é uma forma de distrofia muscular freqüentemente associada a contraturas articulares e defeitos de condução cardíaca, que pode ser causada pela deficiência da proteína emerina na membrana nuclear interna das fibras musculares. Descrevemos o caso de um homem de 19 anos com diminuição de força muscular, hipotrofia nas cinturas escapular e pélvica, disfagia, contraturas articulares em cotovelos e tornozelos, apresentando história familiar compatível com herança ligada ao cromossomo X. A investigação mostrou creatinaquinase sérica elevada, eletrocardiograma com bloqueio atrioventricular de primeiro grau e bloqueio de ramo direito, eletroneuromiografia normal, biópsia muscular com alterações miopáticas e a análise por imuno-histoquímica mostrou deficiência de emerina. São discutidas as manifestações clínicas e genéticas, alterações laboratoriais e eletroneuromiográficas, bem como, a importância do estudo do padrão de herança no aconselhamento genético destas famílias.The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that frequently presents early contractures and cardiac conduction defects, caused by emerin deficiency in the inner nuclear membrane of the muscular fibers. A 19-years-old man it presented muscle weakness and hypotrophy in the proximal upper and lower limbs, dysphagia and early contractures in elbows and ankles, with familiar history compatible with X-linked inheritance form. The investigation showed increased serum creatinekinase levels electrocardiogram had a first degree atrioventricular block and right bundle branch block normal electromyography and nerve conduction study muscle biopsy disclosed myopathic characteristics and nuclear protein immunohystochemical analysis showed deficiency of emerin. The clinical and genetics manifestations, laboratorial and electromyography changes, as well as, the study of the pattern of inheritance for

  20. Identification of three distinguishable phenotypes in golden retriever muscular dystrophy

    OpenAIRE

    AMBROSIO, C. E.; FADEL, L.; GAIAD, T. P.; MARTINS, D. S.; ARAUJO, K. P. C.; ZUCCONI, E.; BROLIO, M. P.; GIGLIO, R. F.; MORINI, A. C.; JAZEDJE, T.; FROES, T. R.; FEITOSA, M. L. T.; VALADARES, M. C.; BELTRAO-BRAGA, P. C. B.; MEIRELLES, F. V.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a human disease characterized by progressive and irreversible skeletal muscle degeneration caused by mutations in genes coding for important muscle proteins. Unfortunately, there is no efficient treatment for this disease; it causes progressive loss of motor and muscular ability until death. The canine model (golden retriever muscular dystrophy) is similar to DMD, showing similar clinical signs. Fifteen dogs were followed from birth and closely observed fo...

  1. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of Duchenne muscular dystrophy. © The Author(s) 2015.

  2. Atrophy of the corpus callosum correlates with white matter lesions in patients with cerebral ischaemia

    International Nuclear Information System (INIS)

    Meguro, K.; Yamadori, A.; Constans, J.M.; Courtheoux, P.; Theron, J.; Viader, F.

    2000-01-01

    Many studies of white matter high signal (WMHS) on T2-weighted MRI have disclosed that it is related to cerebral ischaemia and to brain atrophy. Atrophy of the corpus callosum (CC) has also been studied in relation to ischaemia. Our objective was to test the hypothesis that CC atrophy could be due to ischaemia. We therefore assessed CC, WMHS and brain atrophy in patients with risk factors without strokes (the risk factor group) and in those with infarcts (the infarct group), to investigate the relationships between these factors. We studied 30 patients in the infarct group, 14 in the risk factor group, and 29 normal subjects. Using axial T1-weighted MRI, cortical atrophy and ventricular enlargement (brain atrophy) were visually rated. Using axial T2-weighted MRI, WMHS was assessed in three categories: periventricular symmetrical, periventricular asymmetrical and subcortical. Using the mid-sagittal T1-weighted image, the CC was measured in its anterior, posterior, midanterior and midposterior portions. In the normal group, no correlations were noted between parameters. In the infarct group, there were significant correlations between CC and brain atrophy, and between CC atrophy and WMHS. After removing the effects of age, gender and brain atrophy, significant correlations were noted between some CC measures and subcortical WMHS. In the risk factor group, there were significant correlations between CC and brain atrophy and between CC atrophy and WMHS. After allowance for age, gender and brain atrophy, significant correlations between some CC measures and periventricular WMHS remained. The hypothesis that CC atrophy could be due to cerebral ischaemia was supported by other analyses. Namely, for correlations between the extent of infarcts and partial CC atrophy in patients with anterior middle cerebral artery (MCA) and with posterior MCA infarcts, there were significant correlations between the extent of infarct and midanterior CC atrophy in the former, and posterior

  3. Atrophy of the corpus callosum correlates with white matter lesions in patients with cerebral ischaemia

    Energy Technology Data Exchange (ETDEWEB)

    Meguro, K.; Yamadori, A. [Section of Neuropsychology, Division of Disability Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, 980-8575 Sendai (Japan); Constans, J.M.; Courtheoux, P.; Theron, J. [MR Unit, University of Caen School of Medicine, Caen (France); Viader, F. [Department of Neuroradiology, University of Caen School of Medicine, Caen (France)

    2000-06-01

    Many studies of white matter high signal (WMHS) on T2-weighted MRI have disclosed that it is related to cerebral ischaemia and to brain atrophy. Atrophy of the corpus callosum (CC) has also been studied in relation to ischaemia. Our objective was to test the hypothesis that CC atrophy could be due to ischaemia. We therefore assessed CC, WMHS and brain atrophy in patients with risk factors without strokes (the risk factor group) and in those with infarcts (the infarct group), to investigate the relationships between these factors. We studied 30 patients in the infarct group, 14 in the risk factor group, and 29 normal subjects. Using axial T1-weighted MRI, cortical atrophy and ventricular enlargement (brain atrophy) were visually rated. Using axial T2-weighted MRI, WMHS was assessed in three categories: periventricular symmetrical, periventricular asymmetrical and subcortical. Using the mid-sagittal T1-weighted image, the CC was measured in its anterior, posterior, midanterior and midposterior portions. In the normal group, no correlations were noted between parameters. In the infarct group, there were significant correlations between CC and brain atrophy, and between CC atrophy and WMHS. After removing the effects of age, gender and brain atrophy, significant correlations were noted between some CC measures and subcortical WMHS. In the risk factor group, there were significant correlations between CC and brain atrophy and between CC atrophy and WMHS. After allowance for age, gender and brain atrophy, significant correlations between some CC measures and periventricular WMHS remained. The hypothesis that CC atrophy could be due to cerebral ischaemia was supported by other analyses. Namely, for correlations between the extent of infarcts and partial CC atrophy in patients with anterior middle cerebral artery (MCA) and with posterior MCA infarcts, there were significant correlations between the extent of infarct and midanterior CC atrophy in the former, and posterior

  4. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Sluimer, Jasper D. [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Diagnostic Radiology and Alzheimer Centre, PO Box 7057, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); Karas, Giorgos B.; Barkhof, Frederik [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); Schijndel, Ronald van [VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Informatics, Amsterdam (Netherlands); Barnes, Josephine; Boyes, Richard G. [UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Cover, Keith S. [VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands); Olabarriaga, Silvia D. [University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam (Netherlands); Fox, Nick C. [VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Vrenken, Hugo [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands)

    2009-12-15

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 {+-} 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  5. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    International Nuclear Information System (INIS)

    Sluimer, Jasper D.; Flier, Wiesje M. van der; Scheltens, Philip; Karas, Giorgos B.; Barkhof, Frederik; Schijndel, Ronald van; Barnes, Josephine; Boyes, Richard G.; Cover, Keith S.; Olabarriaga, Silvia D.; Fox, Nick C.; Vrenken, Hugo

    2009-01-01

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  6. [Urogenital atrophy and recurrent urinary tract infection in elderly patients].

    Science.gov (United States)

    Salvat, J; Capilna, M; Schmidt, M H

    1997-08-13

    Postmenopausal lower urinary tract atrophy and its relations to recurrent urinary infections in elderly women are studied. Clinical aspects, functional and histological aspects and hypothetic mechanisms of atrophy are reported, epidemiologic data, mechanisms of urinary infections and of estrogen effects are reviewed and reports on the results of local or systemic use of drugs from the literature are presented. Local administration of estrogen seems to be efficient on the urinary tract. Local treatment is less dangerous and cheaper than systemic treatment. Hormonal treatment is one of the preventive measures against recurrent urinary infections in elderly women.

  7. Dyke–Davidoff–Masson syndrome with crossed cerebellar atrophy

    Directory of Open Access Journals (Sweden)

    Sanjay M. Khaladkar

    2017-01-01

    Full Text Available Dyke–Davidoff–Masson syndrome is a rare condition with classical, clinical and radiological changes – mental retardation, hemiparesis, facial asymmetry, seizures and cerebral hemiatrophy with calvarial changes. Contralateral cerebellar atrophy is rare and occurs if insult occurs after 1 month of age. We report a case of a 6-year-old female child presenting with right-sided hemiparesis, convulsions and left cerebral hemiatrophy with an old infarct in left middle cerebral artery (MCA territory, ipsilateral calvarial thickening and right (crossed cerebellar atrophy.

  8. Recommendations for the management of postmenopausal vaginal atrophy

    DEFF Research Database (Denmark)

    Sturdee, D W; Panay, N; Ulrich, Lian

    2010-01-01

    for hormone replacement therapy (HRT) over recent years that has suggested an increased risk of breast cancer, heart disease and stroke. But, regardless of whether these scares are justified, local treatment of vaginal atrophy is not associated with these possible risks of systemic HRT. Other reasons...... dryness can be helped by simple lubricants but the best and most logical treatment for urogenital atrophy is to use local estrogen. This is safe, effective and with few contraindications. It is hoped that these guidelines and recommendations, produced to coincide with World Menopause Day 2010, will help...

  9. Homocysteine, Liver Function Derangement and Brain Atrophy in Alcoholics.

    Science.gov (United States)

    Fernández-Rodríguez, Camino; González-Reimers, Emilio; Quintero-Platt, Geraldine; de la Vega-Prieto, María José; Pérez-Hernández, Onán; Martín-González, Candelaria; Espelosín-Ortega, Elisa; Romero-Acevedo, Lucía; Santolaria-Fernández, Francisco

    2016-11-01

    Hyperhomocysteinemia may be involved in the development of brain atrophy in alcoholics. Its pathogenesis is multifactorial. In the present study, we analyse the relationship between homocysteine levels and brain atrophy, and the relative weight of co-existing factors such as liver function impairment, the amount of ethanol consumed, serum vitamin B12, B6, and folic acid levels on homocysteine levels and brain alterations in alcoholic patients. We included 59 patients admitted to this hospital for major withdrawal symptoms and 24 controls. The mini-mental state examination test and a brain computed tomography (CT) scan were performed and several indices were calculated. Serum levels of homocysteine, folic acid, vitamin B6 and vitamin B12 were determined. Liver function was assessed by Child-Pugh score. The daily consumption of ethanol in grams per day and years of addiction were recorded. A total of 83.6% and 80% of the patients showed cerebellar or frontal atrophy, respectively. Patients showed altered values of brain indices, higher levels of homocysteine and vitamin B12, but lower levels of folic acid, compared with controls. Homocysteine, B12 and liver function variables showed significant correlations with brain CT indices. Multivariate analyses disclosed that Pugh's score, albumin and bilirubin were independently related to cerebellar atrophy, frontal atrophy, cella index or ventricular index. Serum vitamin B12 was the only factor independently related to Evans index. It was also related to cella index, but after bilirubin. Homocysteine levels were independently related to ventricular index, but after bilirubin. Vitamin B12 and homocysteine levels are higher among alcoholics. Liver function derangement, vitamin B12 and homocysteine are all independently related to brain atrophy, although not to cognitive alterations. Hyperhomocysteinemia has been described in alcoholics and may be related to brain atrophy, a reversible condition with an obscure pathogenesis

  10. Dyke–Davidoff–Masson syndrome with crossed cerebellar atrophy

    Directory of Open Access Journals (Sweden)

    Sanjay M. Khaladkar

    2017-09-01

    Full Text Available Dyke–Davidoff–Masson syndrome is a rare condition with classical, clinical and radiological changes – mental retardation, hemiparesis, facial asymmetry, seizures and cerebral hemiatrophy with calvarial changes. Contralateral cerebellar atrophy is rare and occurs if insult occurs after 1 month of age. We report a case of a 6-year-old female child presenting with right-sided hemiparesis, convulsions and left cerebral hemiatrophy with an old infarct in left middle cerebral artery (MCA territory, ipsilateral calvarial thickening and right (crossed cerebellar atrophy.

  11. Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone

    International Nuclear Information System (INIS)

    Matsuda, Hiroshi; Imabayashi, Etsuko; Kuji, Ichiei; Seto, Akira; Ito, Kimiteru; Kikuta, Daisuke; Yamada, Minoru; Shimano, Yasumasa; Sato, Noriko

    2010-01-01

    Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT) images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM) to SPECT. After linear spatial normalization of brain perfusion SPECT using 99m Tc-ethyl cysteinate dimer ( 99m Tc-ECD) to a Talairach space, high-dimension-warping was done using an original 99m Tc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2) between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C) patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images. SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99m Tc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT

  12. Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone

    Directory of Open Access Journals (Sweden)

    Matsuda Hiroshi

    2010-08-01

    Full Text Available Abstract Background Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM to SPECT. Methods After linear spatial normalization of brain perfusion SPECT using 99mTc-ethyl cysteinate dimer (99mTc-ECD to a Talairach space, high-dimension-warping was done using an original 99mTc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2 between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images. Results SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99mTc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. Conclusions The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT

  13. Report of 3 Cases of Emery-Dreifuss Muscular Dystrophy in a Family

    Directory of Open Access Journals (Sweden)

    P. Yazdanpanah

    2004-01-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMDcan be seen in the middle childhood and the genetic patterns of them are X-linked recessive, autosomal dominant or recessive. The classic triad of this disease are: 1-early contractures, particularly of the elbows, achilles tendons, and posterior cervical muscles; 2-cardiac conduction defects ;and 3- a slowly progressive weakness and atrophy in a humeroperoneal distribution. The early onset of contractures before the onset of any significant weakness is unique to this disease. This case study was done in two 12 and 3.5 years old brothers and their 8 years old sister in a family. The first one referred to the medical center because of his weakness muscles of shoulders and arms. The second case was referred with tip toe walking which has been started 8 months ago. The third case was referred with difficulties in walking and sitting and surgery on achilles tendons for her and the first case was performed at 4 and 8 years ago respectively. In physical examination contractures of achilles tendons , weakness of pelvic girdle muscles, positive gowers sign and tip toe walking were observed in all three cases . Echocardiogram in both boys and CK enzyme in all 3 patients were normal. In ECGs atrial flutter with 3:1 AV block was seen in all 3 individuals. Muscle biopsy was nonspecific in the first case and mild focal atrophy was seen in the second case. Findings of myopathic patterns in electromyography were seen in all 3 patients. The genetic pattern of EDMD in this family is autosomal dominant. Stretching exercises and modalities such as ultrasound and hot pack were applied for these cases. The second was not responded and surgery of achilles tendons release was recommended for him.

  14. Integrins, muscle agrin and sarcoglycans during muscular inactivity conditions: an immunohistochemical study

    Directory of Open Access Journals (Sweden)

    G Anastasi

    2009-06-01

    Full Text Available Sarcoglycans are transmembrane proteins that seem to be functionally and pathologically as important as dystrophin. Sarcoglycans cluster together to form a complex, which is localized in the cell membrane of skeletal, cardiac, and smooth muscle. It has been proposed that the dystrophin-glycoprotein complex (DGC links the actin cytoskeleton with the extracellular matrix and the proper maintenance of this connection is thought to be crucial to the mechanical stability of the sarcolemma. The integrins are a family of heterodimeric cell surface receptors which play a crucial role in cell adhesion including cell-matrix and intracellular interactions and therefore are involved in various biological phenomena, including cell migration, and differentiation tissue repair. Sarcoglycans and integrins play a mechanical and signaling role stabilizing the systems during cycles of contraction and relaxation.Several studies suggested the possibility that integrins might play a role in muscle agrin signalling. On these basis, we performed an immunohistochemical analyzing sarcoglycans, integrins and agrin, on human skeletal muscle affected by sensitive-motor polyneuropathy, in order to better define the correlation between these proteins and neurogenic atrophy due to peripheral neuropathy. Our results showed the existence of a cascade mechanism which provoke a loss of regulatory effects of muscle activity on costameres, due to loss of muscle and neural agrin.This cascade mechanism could determine a quantitative modification of transmembrane receptors and loss of ?7B could be replaced and reinforced by enhanced expression of the ?7A integrin to restore muscle fiber viability. Second, it is possible that the reduced cycles of contraction and relaxation of muscle fibers, during muscular atrophy, provoke a loss of mechanical stresses transmitted over cell surface receptors that physically couple the cytoskeleton to extracellular matrix. Consequently, these mechanical

  15. Quantitative assessment of gastric antrum atrophy shows restitution to normal histology after Helicobacter pylori eradication

    NARCIS (Netherlands)

    van Grieken, Nicole C. T.; Meijer, Gerrit A.; Kale, Ilse; Bloemena, Elisabeth; Lindeman, Jan; Offerhaus, G. Johan A.; Meuwissen, Stefan G. M.; Baak, Jan P. A.; Kuipers, Ernst J.

    2004-01-01

    Background/Aims: Grading gastric mucosal atrophy in antrum biopsy specimens remains a controversial subject because of limitations in interobserver agreement. We previously described a reliable, quantitative method for grading atrophy of the corpus mucosa with excellent reproducibility and good

  16. Brain atrophy and lesion load predict long term disability in multiple sclerosis

    DEFF Research Database (Denmark)

    Popescu, Veronica; Agosta, Federica; Hulst, Hanneke E

    2013-01-01

    To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS).......To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS)....

  17. Muscular response to the first three months of deflazacort treatment in boys with Duchenne muscular dystrophy

    DEFF Research Database (Denmark)

    Jensen, L; Petersson, S J; Illum, N O

    2017-01-01

    OBJECTIVE: Duchenne muscular dystrophy (DMD) patients are often treated with glucocorticoids; yet their precise molecular action remains unknown. METHODS: We investigated muscle biopsies from nine boys with DMD (aged: 7,6±2,8 yrs.) collected before and after three months of deflazacort treatment...

  18. Muscular anatomy of the Podocoryna carnea hydrorhiza.

    Science.gov (United States)

    Buss, Leo W; Anderson, Christopher; Bolton, Edward W

    2013-01-01

    The muscular anatomy of the athecate hydroid Podocoryna carnea hydrorhiza is elucidated. The polyp-stolon junction is characterized by an opening, here called the chloe, in the otherwise continuous hydrorhizal perisarc. The chloe is elliptical when the polyp first arises, but takes on a more complex outline as multiple stolons anastomose to communicate with that polyp. Surrounding the polyp base are spots, here called anchors, which autofluoresce at the same wavelengths as perisarc and which, like perisarc, contain chitin as assessed by Calcofluor White, Congo Red and wheat germ agglutinin staining. Anchors remain after living tissues are digested using KOH. Collagen IV staining indicates that the mesoglea is pegged to the anchors and rhodamine phallodin staining detects cytoskeletal F-actin fibers of the basal epidermis surrounding the anchors. Longitudinal muscle fibers of the polyp broaden at the polyp base and are inserted into the mesoglea of the underlying stolon, but were neither observed to extend along the stolonal axis nor to attach to the anchors. Circular muscular fibers of the polyp extend into stolons as a dense collection of strands running along the proximal-distal axis of the stolon. These gastrodermal axial muscular fibers extend to the stolon tip. Epidermal cells at the stolon tip and the polyp bud display a regular apical latticework of F-actin staining. A similar meshwork of F-actin staining was found in the extreme basal epidermis of all stolons. Immunohistochemical staining for tubulin revealed nerves at stolon tips, but at no other hydrorhizal locations. These studies bear on the mechanisms by which the stolon tip and polyp bud pulsate, the manner in which the stolon lumen closes, and on the developmental origin of the basal epidermis of the hydrorhiza.

  19. Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy*

    OpenAIRE

    Tando, Toshimi; Hirayama, Akiyoshi; Furukawa, Mitsuru; Sato, Yuiko; Kobayashi, Tami; Funayama, Atsushi; Kanaji, Arihiko; Hao, Wu; Watanabe, Ryuichi; Morita, Mayu; Oike, Takatsugu; Miyamoto, Kana; Soga, Tomoyoshi; Nomura, Masatoshi; Yoshimura, Akihiko

    2016-01-01

    Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice ex...

  20. Muscular cysticercosis: Case report and imaging findings

    Directory of Open Access Journals (Sweden)

    Neide Regina Simões Olmo

    Full Text Available Summary Cysticercosis is a parasitic disease caused by a worm of the Cestoda class. The most prevalent form affects the nervous system. This case report is from a 78-year-old female patient evaluated at Clínica Mult Imagem, in the city of Santos, Brazil, who presented a form of the disease that differed from the classic neurocysticercosis, in this case muscular cysticercosis. This and other forms of manifestation justify further studies to ensure adequate recognition, diagnosis and treatment of this parasitic disease.