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Neurological Review |

Advances in Translational Research in Neuromuscular Diseases FREE

David Pleasure, MD
[+] Author Affiliations

Author Affiliation: Departments of Neurology and Pediatrics, and Institute for Pediatric Regenerative Medicine, UC Davis School of Medicine, Sacramento, California.


Author Affiliation: Departments of Neurology and Pediatrics, and Institute for Pediatric Regenerative Medicine, UC Davis School of Medicine, Sacramento, California.

More Author Information
Arch Neurol. 2011;68(4):429-433. doi:10.1001/archneurol.2011.44.
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New therapies developed over the past 3 years for previously intractable diseases of skeletal muscle, neuromuscular junctions, peripheral nerves, and motor neurons are now being incorporated into our standard neuromuscular clinical practice. The past 3 years were also marked by important advances in our understanding of the pathogenesis and pathophysiology of inherited and acquired neuromuscular diseases; these advances were acquired by the use of high-throughput nucleotide and protein analytic methods, novel animal models, and human-induced pluripotent stem cell–derived “diseases in a dish.” Over the next decade, we can reasonably anticipate that these insights, coupled with advances in our ability to modulate immune mechanisms, to modify the activity of mutant genes, and to perform gene replacement therapies with enhanced viral vector–based and stem cell–based delivery systems, will revolutionize our management of neuromuscular diseases.

Figures in this Article

Almost 2000 neurologists and an increasing number of neuroscientists now focus their interest primarily on neuromuscular disorders. Their combined efforts have delineated hundreds of diseases of motor neurons, peripheral nerves, neuromuscular junctions, or skeletal muscle and have generated more than 20 000 articles on these topics in the past 3 years alone. Effective new therapies have already resulted from these recent studies. Over the next decade, we can anticipate that gene replacement, gene modulation, and stem cell therapies, many already proven to be effective in animal models, will radically alter our practice of neuromuscular medicine. However, we have also been reminded of the need for caution in extrapolating therapeutic results in model systems to human neuromuscular diseases by the apparent failures of lithium carbonate therapy to ameliorate amyotrophic lateral sclerosis (ALS)1 and of vitamin C therapy to slow progression of deficits in patients with Charcot-Marie-Tooth disease type 1A.2

The past 3 years have also been marked by important advances in our capacity to diagnose and determine the pathophysiology of neuromuscular diseases, using high-throughput nucleotide sequencing, single-nucleotide polymorphism and protein expression arrays, novel animal models, and human induced pluripotent stem cell (IPSC)–based “diseases in a dish.”

Table 1 provides a sampling of recently tested therapies for neuromuscular disorders. Each has been reported to provide patients with significant symptomatic relief.

Table Graphic Jump LocationTable 1. New Drugs and New Indications for Old Drugs in Human Neuromuscular Disorders

It is seductive to contemplate definitive reversal of genetic neuromuscular diseases by engineering permanent expression of the normal gene in the affected tissue. The potential of this approach was recently illustrated by the continued improvement in vision in patients with Leber hereditary optic atrophy 18 months after subretinal administration of an adeno-associated viral vector–encoded normal allele of RPE65.12 The observation that adeno-associated viral vector–mediated transduction of α-sarcoglycan into extensor digitorum brevis in human limb-girdle muscular dystrophy type 2D restores the full sarcoglycan complex and increases muscle fiber size13 is also heartening. And the recent demonstration of the therapeutic efficacy of adeno-associated viral vector–mediated spinal cord SMN1 transduction in neonatal mice with mutant SMN1 spinal muscular atrophy14 argues that gene therapy could prove feasible for human motor neuron diseases as well.

Dystrophin and dysferlin, the latter mutated in limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, are encoded by very large genes that cannot be packaged into present-day viral vectors. Although this delivery problem is potentially solvable (eg, by gene transfer in a human artificial chromosome),15 a promising alternative approach is to splice out mutated, nonessential, dystrophin or dysferlin exons by administration of antisense oligonucleotides, permitting translation of a near full-length, and functional, protein. Of the almost 900 known human dystrophin mutations, at least 60% are susceptible to mitigation by this exon-skipping approach,16 as are a substantial proportion of the more than 350 known dysferlin mutations.17 Some of these mutations can also be rescued by aminoglycoside-induced, premature termination codon “read through,”18 a tactic that has yielded a substantial decrease in serum creatine kinase levels in the first Duchenne cohorts thus far treated.19 Further advances in design and delivery of exon-skipping and premature termination codon–skipping reagents may permit clinically significant mitigation of these muscular dystrophies. Oligonucleotide reagents can also be used to displace aberrant mutant RNA × protein interactions, an approach that has already shown promise in a mouse triplet repeat expansion model of myotonic dystrophy type 1.20

An alternate therapeutic approach to loss-of-function genetic neuromuscular diseases is to induce overexpression of a functionally overlapping gene. In mice with mutant SMN1 spinal muscular atrophy, for example, weakness is diminished, and survival enhanced, by antisense oligonucleotide–mediated SMN2 exon skipping to elevate SMN2 protein expression21 or by administering a histone deacetylase inhibitor to enhance SMN2 transcription.22 Although an initial phase II trial of the US Food and Drug Administration–approved histone deacetylase inhibitor valproate failed to show therapeutic efficacy in spinal muscular atrophy,23 results of a recent human trial showed that histone deacetylase inhibitor–mediated induction of ABCD2 can ameliorate the oxidative protein damage that is believed to contribute to neural inflammation in mutant ABCD1 adrenomyeloneuropathy.24

Recent animal studies have suggested strategies to diminish downstream deleterious effects of mutant proteins, including administration of a cyclophilin inhibitor or a ryanodine receptor stabilizer to prevent calcium overload–induced myofiber necrosis in the muscular dystrophies,25,26 administration of cystamine to suppress polyalanine expansion toxicity in oculopharyngeal muscular dystrophy,27 and administration of sialic acid metabolites to slow progression of distal myopathy with rimmed vacuoles-hereditary inclusion body myopathy.28

Stem cells can both self-renew and generate differentiated daughter cells. Skeletal muscle satellite cells are an example of tissue-specific stem cells. When stimulated to proliferate as a result of muscle injury, these cells generate myocytes that fuse to and repair damaged multinucleate myofibers.29 Animal studies have shown that transplantation of skeletal muscle satellite cells from a normal donor or satellite cell autografts from an affected individual after their engineering to express full-length or near full-length dystrophin can rescue Duchenne myofibers.30 Although generating sufficient numbers of fusion-competent myocytes to globally repair dystrophic muscle remains problematic, this might be accomplished by genetic manipulations that transiently induce terminally differentiated skeletal muscle to reenter the cell cycle and enhance the survival of the resulting myocytes.31,32

Human embryonic stem cells (HESCs) and IPSCs may provide alternate sources for fusion-competent myocytes and can also be used to generate motor neurons33 or Schwann cells.34 The use of IPSCs avoids ethical concerns related to HESC harvesting and, because autografts could be derived by genetically engineering the patient's own IPSCs, would diminish the need for long-term graft recipient immunosuppression.

Safety concerns need to be surmounted before HESC or IPSC transplants become integrated into the practice of neuromuscular medicine; these concerns include teratoma formation, which is an intrinsic property of stem cells, and malignant transformation as a consequence of alterations in the genome of the grafted cells. The efficacy of stem cell–derived motor neurons for ALS or spinal muscular atrophy will also require development of methods for broad dissemination to the central nervous system and for enhancing appropriate upstream and downstream synaptic interactions by the grafted cells. And, of course, stem cell–derived motor neuron transplants would be of limited utility in those motor neuron diseases in which, as in mutant SOD1 familial ALS, motor neuron loss is at least in part a consequence of a neuroglial defect.35,36

Although human stem cell–derived oligodendroglial progenitors have received approval from the US Food and Drug Administration and are already being tested in the United States for patients with spinal cord trauma and Pelizaeus-Merzbacher disease, efficacy trials of embryonic stem cell–derived or IPSC-derived cell transplants for human neuromuscular diseases have not yet been initiated. However, HESC and IPSC technologies have already proven their worth by permitting the development of human “disease in a dish” models for familial dysautonomia,37 spinal muscular atrophy,38 mutant SOD1 familial ALS,35,36 and Duchenne dystrophy15 (Table 2). These human cell–based models facilitate exploration of pathogenetic mechanisms and can also be used for rapid screening of drug candidates38 (Figure).

Place holder to copy figure label and caption
Figure.

Human induced pluripotent stem cell colonies (original magnification ×4) stained in red (ie, vital stain) for the pluripotency marker TRA-1-60. This image was kindly provided by Bonnie Barrilleaux, PhD, and Paul Knoepfler, PhD, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Human Embryonic Stem Cell Culture Model and Induced Pluripotent Stem Cell Culture Models of Neuromuscular Diseases

Advances in sequencing of large chromosomal segments and in single-nucleotide polymorphism analysis have revolutionized the workup of familial neuromuscular diseases, permitting rapid identification of neuromuscular disease–causing gene mutations and revealing unexpected genetic relationships between phenotypically diverse syndromes. For example, single-nucleotide polymorphisms in what was previously considered a multiply repeated, untranscribed gene on chromosome 4q35 now appear to be the cause of facioscapulohumeral muscular dystrophy,39 and scapuloperoneal spinal muscular atrophy and Charcot-Marie-Tooth disease type 2C have proven to be allelic mutations of TRPV4, both of which increase TRPV4 channel calcium permeability.40 The potential importance of analyzing even very large genes (eg, dystrophin) for mutations susceptible to therapeutic remediation16 has already been mentioned. Even whole genome sequencing has now become economically feasible, permitting definitive diagnosis of neuromuscular disorders caused by the cumulative effects of several rare recessive mutations.41

Modern methods for nucleotide analysis can also reveal genetic susceptibilities to acquired neuromuscular disorders. Examples include the detection of mutations in a previously undiscovered potassium channel–encoding gene in patients with thyrotoxic hypokalemic periodic paralysis42 and the detection of genetic polymorphisms that alter the rate of progression of sporadic ALS43 or modulate peripheral pain perception.44 Also, an important outcome of recognizing the many more rare mutations linked to familial ALS during the past 3 years has been the highlighting of metabolic pathways in which these genes participate and in which they may be perturbed in sporadic forms of ALS, including aberrant activation of nuclear factor κB45 and dysregulation of neural D-serine homeostasis.46 These pathways may provide opportunities for therapeutic intervention.

Our understanding of nongenetic neuromuscular diseases has also been enhanced during the past 3 years. To cite a few examples, protein microarray analysis, coupled with immunohistology, demonstrated a tight linkage between dermatomyositis and upregulation of the type 1 interferon-inducible protein ISG15,47 anti-GD1a antibodies were shown to induce electrophysiological dysfunction at motor nodes of Ranvier by activating calpain and complement,48 and combined epidemiological and immunological studies provided a link between an outbreak of polyradiculoneuropathy and workplace exposure to aerosolized porcine neural tissue.49

Studies completed during the past 3 years have demonstrated the substantial benefits of new drugs (eg, rituximab for immune-mediated neuromuscular diseases) and new indications for old drugs (eg, ephedrine for mutant DOK7 congenital myasthenia). During the same period, the experimental infrastructure required for the design of human trials of gene replacement, RNA exon skipping and premature termination codon skipping, and stem cell transplantation has been strengthened, and advances in analytic technologies have vastly increased our ability to diagnose and evaluate the pathophysiology of neuromuscular diseases. However, many challenges remain: no new therapies for ALS have come on line since riluzole; we still lack effective treatments for most of the inherited polyneuropathies; and there have been no recent advances in our understanding of the most common of all neuromuscular diseases in developed countries (ie, diabetic polyneuropathy).

Correspondence: David Pleasure MD, Departments of Neurology and Pediatrics, and Institute for Pediatric Regenerative Medicine, UC Davis School of Medicine, 2425 Stockton Blvd, Sacramento, CA 95817 (david.pleasure@ucdmc.ucdavis.edu).

Accepted for Publication: August 31, 2011.

Financial Disclosure: None reported.

Funding/Support: This review was supported by National Institutes of Health grant RO1 NS025044 and by the Shriners Hospitals for Children.

Chiò  ABorghero  GCalvo  A  et al. LITALS Study Group, Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 2010;75 (7) 619- 625
PubMed
Burns  JOuvrier  RAYiu  EM  et al.  Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial. Lancet Neurol 2009;8 (6) 537- 544
PubMed
Dalakas  MCRakocevic  GSalajegheh  M  et al.  Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol 2009;65 (3) 286- 293
PubMed
Maddison  P McConville  JFarruia  ME  et al.  The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome [published online ahead of print April 14, 2010]. J Neurol Neurosurg Psychiatry 10.1136/jnnp.2009.197632
Lashley  DPalace  JJayawant  SRobb  SBeeson  D Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7Neurology 2010;74 (19) 1517- 1523
PubMed
Logigian  ELMartens  WBMoxley  RT  IV  et al.  Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology 2010;74 (18) 1441- 1448
PubMed
Matthews  EFialho  DTan  SV  et al. CINCH Investigators, The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 2010;133 (pt 1) 9- 22
PubMed
Platt  DGriggs  R Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias. Curr Opin Neurol 2009;22 (5) 524- 531
PubMed
Banno  HKatsuno  MSuzuki  K  et al.  Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 2009;65 (2) 140- 150
PubMed
Jeppesen  TDDunø  MSchwartz  M  et al.  Short- and long-term effects of endurance training in patients with mitochondrial myopathy. Eur J Neurol 2009;16 (12) 1336- 1339
PubMed
van der Ploeg  ATClemens  PRCorzo  D  et al.  A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med 2010;362 (15) 1396- 1406
PubMed
Simonelli  FMaguire  AMTesta  F  et al.  Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010;18 (3) 643- 650
PubMed
Mendell  JRRodino-Klapac  LRRosales-Quintero  X  et al.  Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. Ann Neurol 2009;66 (3) 290- 297
PubMed
Passini  MABu  JRoskelley  EM  et al.  CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 2010;120 (4) 1253- 1264
PubMed
Kazuki  YHiratsuka  MTakiguchi  M  et al.  Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol Ther 2010;18 (2) 386- 393
PubMed
Flanigan  KMDunn  DMvon Niederhausern  A  et al. United Dystrophinopathy Project Consortium, Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat 2009;30 (12) 1657- 1666
PubMed
Wein  NAvril  ABartoli  M  et al.  Efficient bypass of mutations in dysferlin deficient patient cells by antisense-induced exon skipping. Hum Mutat 2010;31 (2) 136- 142
PubMed
Dietz  HC New therapeutic approaches to mendelian disorders. N Engl J Med 2010;363 (9) 852- 863
PubMed
Malik  VRodino-Klapac  LRViollet  L  et al.  Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol 2010;67 (6) 771- 780
PubMed
Wheeler  TMSobczak  KLueck  JD  et al.  Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 2009;325 (5938) 336- 339
PubMed
Hua  YSahashi  KHung  G  et al.  Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 2010;24 (15) 1634- 1644
PubMed
Narver  HLKong  LBurnett  BG  et al.  Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol 2008;64 (4) 465- 470
PubMed
Swoboda  KJScott  CBReyna  SP  et al.  Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009;4 (5) e5268
PubMed
Fourcade  SRuiz  MGuilera  C  et al.  Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 2010;19 (10) 2005- 2014
PubMed
Millay  DPSargent  MAOsinska  H  et al.  Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 2008;14 (4) 442- 447
PubMed
Bellinger  AMReiken  SCarlson  C  et al.  Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 2009;15 (3) 325- 330
PubMed
Davies  JERose  CSarkar  SRubinsztein  DC Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy. Sci Transl Med 2010;2 (34) 34ra40
PubMed
Malicdan  MCVNoguchi  SHayashi  YKNonaka  INishino  I Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 2009;15 (6) 690- 695
PubMed
Tedesco  FSDellavalle  ADiaz-Manera  JMessina  GCossu  G Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest 2010;120 (1) 11- 19
PubMed
Benchaouir  RMeregalli  MFarini  A  et al.  Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice. Cell Stem Cell 2007;1 (6) 646- 657
PubMed
Pajcini  KVCorbel  SYSage  JPomerantz  JHBlau  HM Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 2010;7 (2) 198- 213
PubMed
Fakhfakh  RMichaud  ATremblay  JP Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice [published online ahead of print August 10, 2010]. Mol Ther 10.1038/mt.2010.171
Zeng  HGuo  MMartins-Taylor  K  et al.  Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One 2010;5 (7) e11853
PubMed
Lee  GChambers  SMTomishima  MJStuder  L Derivation of neural crest cells from human pluripotent stem cells. Nat Protoc 2010;5 (4) 688- 701
PubMed
Di Giorgio  FPBoulting  GLBobrowicz  SEggan  KC Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 2008;3 (6) 637- 648
PubMed
Marchetto  MCNMuotri  ARMu  YSmith  AMCezar  GGGage  FH Non-cell-autonomous effect of human SOD1G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 2008;3 (6) 649- 657
PubMed
Lee  GPapapetrou  EPKim  H  et al.  Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009;461 (7262) 402- 406
PubMed
Ebert  ADSvendsen  CN Stem cell model of spinal muscular atrophy. Arch Neurol 2010;67 (6) 665- 669
PubMed
Lemmers  RJLFvan der Vliet  PJKlooster  R  et al.  A unifying genetic model for facioscapulohumeral muscular dystrophy [published online ahead of print August 10, 2010]. Science 10.1126/science.1189044
Deng  HXKlein  CJYan  J  et al.  Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 2010;42 (2) 165- 169
PubMed
Lupski  JRReid  JGGonzaga-Jauregui  C  et al.  Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 2010;362 (13) 1181- 1191
PubMed
Ryan  DPda Silva  MRSoong  TW  et al.  Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 2010;140 (1) 88- 98
PubMed
Landers  JEMelki  JMeininger  V  et al.  Reduced expression of the kinesin-associated protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2009;106 (22) 9004- 9009
PubMed
Estacion  MHarty  TPChoi  JSTyrrell  LDib-Hajj  SDWaxman  SG A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Ann Neurol 2009;66 (6) 862- 866
PubMed
Maruyama  HMorino  HIto  H  et al.  Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010;465 (7295) 223- 226
PubMed
Mitchell  JPaul  PChen  HJ  et al.  Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc Natl Acad Sci U S A 2010;107 (16) 7556- 7561
PubMed
Salajegheh  MKong  SWPinkus  JL  et al.  Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol 2010;67 (1) 53- 63
PubMed
McGonigal  RRowan  EGGreenshields  KN  et al.  Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain 2010;133 (Pt 7) 1944- 1960
PubMed
Lachance  DHLennon  VAPittock  SJ  et al.  An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study. Lancet Neurol 2010;9 (1) 55- 66
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Human induced pluripotent stem cell colonies (original magnification ×4) stained in red (ie, vital stain) for the pluripotency marker TRA-1-60. This image was kindly provided by Bonnie Barrilleaux, PhD, and Paul Knoepfler, PhD, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. New Drugs and New Indications for Old Drugs in Human Neuromuscular Disorders
Table Graphic Jump LocationTable 2. Human Embryonic Stem Cell Culture Model and Induced Pluripotent Stem Cell Culture Models of Neuromuscular Diseases

References

Chiò  ABorghero  GCalvo  A  et al. LITALS Study Group, Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 2010;75 (7) 619- 625
PubMed
Burns  JOuvrier  RAYiu  EM  et al.  Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial. Lancet Neurol 2009;8 (6) 537- 544
PubMed
Dalakas  MCRakocevic  GSalajegheh  M  et al.  Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol 2009;65 (3) 286- 293
PubMed
Maddison  P McConville  JFarruia  ME  et al.  The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome [published online ahead of print April 14, 2010]. J Neurol Neurosurg Psychiatry 10.1136/jnnp.2009.197632
Lashley  DPalace  JJayawant  SRobb  SBeeson  D Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7Neurology 2010;74 (19) 1517- 1523
PubMed
Logigian  ELMartens  WBMoxley  RT  IV  et al.  Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology 2010;74 (18) 1441- 1448
PubMed
Matthews  EFialho  DTan  SV  et al. CINCH Investigators, The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 2010;133 (pt 1) 9- 22
PubMed
Platt  DGriggs  R Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias. Curr Opin Neurol 2009;22 (5) 524- 531
PubMed
Banno  HKatsuno  MSuzuki  K  et al.  Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 2009;65 (2) 140- 150
PubMed
Jeppesen  TDDunø  MSchwartz  M  et al.  Short- and long-term effects of endurance training in patients with mitochondrial myopathy. Eur J Neurol 2009;16 (12) 1336- 1339
PubMed
van der Ploeg  ATClemens  PRCorzo  D  et al.  A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med 2010;362 (15) 1396- 1406
PubMed
Simonelli  FMaguire  AMTesta  F  et al.  Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010;18 (3) 643- 650
PubMed
Mendell  JRRodino-Klapac  LRRosales-Quintero  X  et al.  Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. Ann Neurol 2009;66 (3) 290- 297
PubMed
Passini  MABu  JRoskelley  EM  et al.  CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 2010;120 (4) 1253- 1264
PubMed
Kazuki  YHiratsuka  MTakiguchi  M  et al.  Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol Ther 2010;18 (2) 386- 393
PubMed
Flanigan  KMDunn  DMvon Niederhausern  A  et al. United Dystrophinopathy Project Consortium, Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat 2009;30 (12) 1657- 1666
PubMed
Wein  NAvril  ABartoli  M  et al.  Efficient bypass of mutations in dysferlin deficient patient cells by antisense-induced exon skipping. Hum Mutat 2010;31 (2) 136- 142
PubMed
Dietz  HC New therapeutic approaches to mendelian disorders. N Engl J Med 2010;363 (9) 852- 863
PubMed
Malik  VRodino-Klapac  LRViollet  L  et al.  Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol 2010;67 (6) 771- 780
PubMed
Wheeler  TMSobczak  KLueck  JD  et al.  Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 2009;325 (5938) 336- 339
PubMed
Hua  YSahashi  KHung  G  et al.  Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 2010;24 (15) 1634- 1644
PubMed
Narver  HLKong  LBurnett  BG  et al.  Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol 2008;64 (4) 465- 470
PubMed
Swoboda  KJScott  CBReyna  SP  et al.  Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009;4 (5) e5268
PubMed
Fourcade  SRuiz  MGuilera  C  et al.  Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 2010;19 (10) 2005- 2014
PubMed
Millay  DPSargent  MAOsinska  H  et al.  Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med 2008;14 (4) 442- 447
PubMed
Bellinger  AMReiken  SCarlson  C  et al.  Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 2009;15 (3) 325- 330
PubMed
Davies  JERose  CSarkar  SRubinsztein  DC Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy. Sci Transl Med 2010;2 (34) 34ra40
PubMed
Malicdan  MCVNoguchi  SHayashi  YKNonaka  INishino  I Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 2009;15 (6) 690- 695
PubMed
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