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Neuropediatrics 2017; 48(04): 273-281
DOI: 10.1055/s-0037-1603517
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Diagnosis and New Treatment Avenues in Spinal Muscular Atrophy

Astrid Pechmann
1   Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Janbernd Kirschner
1   Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Publikationsverlauf

23. März 2017

24. April 2017

Publikationsdatum:
01. Juni 2017 (online)

    Lizenzen und Reprints

Abstract

Spinal muscular atrophy (SMA) is an autosomal-recessive, neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, resulting in muscle atrophy and proximal muscle weakness. SMA is caused by a homozygous deletion in the survival motor neuron 1 (SMN1) gene on chromosome 5q13. The SMN gene region also comprises a centromeric copy containing the SMN2 gene. The severity of the disease correlates with age of onset and SMN2 copy number and varies from a severe muscle weakness with tetraplegia in infants to a mild proximal muscle weakness in ambulant children. Due to lack of a curative treatment, the care of children with SMA consists mostly of a multidisciplinary treatment including respiratory, nutritional, and orthopaedic management. During the past years, there has been a promising approach for the development of drugs intervening the pathophysiology of SMA with the main idea of upregulating the levels of functional SMN protein. Here, we summarize recent studies regarding diagnosis and treatment avenues in SMA.

Keywords

spinal muscular atrophy - survival motor neuron - floppy infant - muscle weakness
 

  • References

  • 1 Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet 1978; 15 (06) 409-413
    CrossrefPubMedGoogle Scholar
  • 2 Prior TW, Snyder PJ, Rink BD. , et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 2010; 152A (07) 1608-1616
    CrossrefPubMedGoogle Scholar
  • 3 Oskoui M, Levy G, Garland CJ. , et al. The changing natural history of spinal muscular atrophy type 1. Neurology 2007; 69 (20) 1931-1936
    CrossrefPubMedGoogle Scholar
  • 4 Finkel RS, McDermott MP, Kaufmann P. , et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014; 83 (09) 810-817
    CrossrefPubMedGoogle Scholar
  • 5 De Sanctis R, Coratti G, Pasternak A. , et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord 2016; 26 (11) 754-759
    CrossrefPubMedGoogle Scholar
  • 6 Zerres K, Rudnik-Schöneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995; 52 (05) 518-523
    CrossrefPubMedGoogle Scholar
  • 7 Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Eur J Paediatr Neurol 1999; 3 (02) 49-51
    CrossrefPubMedGoogle Scholar
  • 8 Lefebvre S, Bürglen L, Reboullet S. , et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80 (01) 155-165
    CrossrefPubMedGoogle Scholar
  • 9 Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 2000; 9 (02) 259-265
    CrossrefPubMedGoogle Scholar
  • 10 Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci 2016; 3: 7
    PubMedGoogle Scholar
  • 11 Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A 2004; 130A (03) 307-310
    CrossrefPubMedGoogle Scholar
  • 12 Mailman MD, Heinz JW, Papp AC. , et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 2002; 4 (01) 20-26
    CrossrefPubMedGoogle Scholar
  • 13 Oprea GE, Kröber S, McWhorter ML. , et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008; 320 (5875): 524-527
    CrossrefPubMedGoogle Scholar
  • 14 Riessland M, Kaczmarek A, Schneider S. , et al. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am J Hum Genet 2017; 100 (02) 297-315
    CrossrefPubMedGoogle Scholar
  • 15 Swoboda KJ, Prior TW, Scott CB. , et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol 2005; 57 (05) 704-712
    CrossrefPubMedGoogle Scholar
  • 16 Pyatt RE, Mihal DC, Prior TW. Assessment of liquid microbead arrays for the screening of newborns for spinal muscular atrophy. Clin Chem 2007; 53 (11) 1879-1885
    CrossrefPubMedGoogle Scholar
  • 17 Dobrowolski SF, Pham HT, Downes FP, Prior TW, Naylor EW, Swoboda KJ. Newborn screening for spinal muscular atrophy by calibrated short-amplicon melt profiling. Clin Chem 2012; 58 (06) 1033-1039
    CrossrefPubMedGoogle Scholar
  • 18 Taylor JL, Lee FK, Yazdanpanah GK. , et al. Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency. Clin Chem 2015; 61 (02) 412-419
    CrossrefPubMedGoogle Scholar
  • 19 Sugarman EA, Nagan N, Zhu H. , et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012; 20 (01) 27-32
    CrossrefPubMedGoogle Scholar
  • 20 Su Y-N, Hung C-C, Lin S-Y. , et al. Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study. PLoS One 2011; 6 (02) e17067
    CrossrefPubMedGoogle Scholar
  • 21 Feng Y, Ge X, Meng L. , et al. The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med 2017; (e-pub ahead of print) DOI: 10.1038/gim.2016.215.
    CrossrefPubMedGoogle Scholar
  • 22 Wood SL, Brewer F, Ellison R, Biggio JR, Edwards RK. Prenatal carrier screening for spinal muscular atrophy. Am J Perinatol 2016; 33 (12) 1211-1217
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 23 Carré A, Empey C. Review of spinal muscular atrophy (SMA) for prenatal and pediatric genetic counselors. J Genet Couns 2016; 25 (01) 32-43
    CrossrefPubMedGoogle Scholar
  • 24 McClaren BJ, Delatycki MB, Collins V, Metcalfe SA, Aitken M. ‘It is not in my world’: an exploration of attitudes and influences associated with cystic fibrosis carrier screening. Eur J Hum Genet 2008; 16 (04) 435-444
    CrossrefPubMedGoogle Scholar
  • 25 Moultrie RR, Kish-Doto J, Peay H, Lewis MA. A review on spinal muscular atrophy: awareness, knowledge, and attitudes. J Genet Couns 2016; 25 (05) 892-900
    CrossrefPubMedGoogle Scholar
  • 26 Boardman FK, Young PJ, Griffiths FE. Population screening for spinal muscular atrophy: A mixed methods study of the views of affected families. Am J Med Genet A 2017; 173 (02) 421-434
    CrossrefPubMedGoogle Scholar
  • 27 Wang CH, Finkel RS, Bertini ES. , et al; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007; 22 (08) 1027-1049
    CrossrefPubMedGoogle Scholar
  • 28 Bladen CL, Thompson R, Jackson JM. , et al. Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. J Neurol 2014; 261 (01) 152-163
    CrossrefPubMedGoogle Scholar
  • 29 Schroth MK. Special considerations in the respiratory management of spinal muscular atrophy. Pediatrics 2009; 123 (Suppl. 04) S245-S249
    CrossrefPubMedGoogle Scholar
  • 30 Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E. Long-term survival in Werdnig-Hoffmann disease. Am J Phys Med Rehabil 2007; 86 (05) 339-345 , quiz 346–348, 379
    CrossrefPubMedGoogle Scholar
  • 31 Benson RC, Hardy KA, Gildengorin G, Hsia D. International survey of physician recommendation for tracheostomy for Spinal Muscular Atrophy Type I. Pediatr Pulmonol 2012; 47 (06) 606-611
    CrossrefPubMedGoogle Scholar
  • 32 Hardart MK, Burns JP, Truog RD. Respiratory support in spinal muscular atrophy type I: a survey of physician practices and attitudes. Pediatrics 2002; 110 (2 Pt 1): e24
    CrossrefPubMedGoogle Scholar
  • 33 Moore GE, Lindenmayer AW, McConchie GA, Ryan MM, Davidson ZE. Describing nutrition in spinal muscular atrophy: A systematic review. Neuromuscul Disord 2016; 26 (07) 395-404
    CrossrefPubMedGoogle Scholar
  • 34 Sproule DM, Montes J, Montgomery M. , et al. Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy. Neuromuscul Disord 2009; 19 (06) 391-396
    CrossrefPubMedGoogle Scholar
  • 35 Sproule DM, Montes J, Dunaway S. , et al. Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy. Neuromuscul Disord 2010; 20 (07) 448-452
    CrossrefPubMedGoogle Scholar
  • 36 Kinali M, Banks LM, Mercuri E, Manzur AY, Muntoni F. Bone mineral density in a paediatric spinal muscular atrophy population. Neuropediatrics 2004; 35 (06) 325-328
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 37 Rodillo E, Marini ML, Heckmatt JZ, Dubowitz V. Scoliosis in spinal muscular atrophy: review of 63 cases. J Child Neurol 1989; 4 (02) 118-123
    CrossrefPubMedGoogle Scholar
  • 38 Fujak A, Raab W, Schuh A, Kreß A, Forst R, Forst J. Operative treatment of scoliosis in proximal spinal muscular atrophy: results of 41 patients. Arch Orthop Trauma Surg 2012; 132 (12) 1697-1706
    CrossrefPubMedGoogle Scholar
  • 39 Granata C, Cervellati S, Ballestrazzi A, Corbascio M, Merlini L. Spine surgery in spinal muscular atrophy: long-term results. Neuromuscul Disord 1993; 3 (03) 207-215
    CrossrefPubMedGoogle Scholar
  • 40 Fujak A, Forst R, Forst J. Aktuelle Strategien der konservativen und operativen Therapie der häufigsten Muskelerkrankungen. Orthopade 2010; 39 (01) 38-52
    CrossrefPubMedGoogle Scholar
  • 41 Chandran S, McCarthy J, Noonan K, Mann D, Nemeth B, Guiliani T. Early treatment of scoliosis with growing rods in children with severe spinal muscular atrophy: a preliminary report. J Pediatr Orthop 2011; 31 (04) 450-454
    CrossrefPubMedGoogle Scholar
  • 42 McElroy MJ, Shaner AC, Crawford TO. , et al. Growing rods for scoliosis in spinal muscular atrophy: structural effects, complications, and hospital stays. Spine 2011; 36 (16) 1305-1311
    CrossrefPubMedGoogle Scholar
  • 43 Furumasu J, Swank SM, Brown JC, Gilgoff I, Warath S, Zeller J. Functional activities in spinal muscular atrophy patients after spinal fusion. Spine 1989; 14 (07) 771-775
    CrossrefPubMedGoogle Scholar
  • 44 Chou S-H, Lin G-T, Shen P-C. , et al. The effect of scoliosis surgery on pulmonary function in spinal muscular atrophy type II patients. Eur Spine J 2016 (e-pub ahead of print)
    PubMedGoogle Scholar
  • 45 Chua K, Tan CY, Chen Z. , et al. Long-term follow-up of pulmonary function and scoliosis in patients with Duchenne's muscular dystrophy and spinal muscular atrophy. J Pediatr Orthop 2016; 36 (01) 63-69
    CrossrefPubMedGoogle Scholar
  • 46 Ørngreen MC, Zacho M, Hebert A, Laub M, Vissing J. Patients with severe muscle wasting are prone to develop hypoglycemia during fasting. Neurology 2003; 61 (07) 997-1000
    CrossrefPubMedGoogle Scholar
  • 47 Rudnik-Schöneborn S, Heller R, Berg C. , et al. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J Med Genet 2008; 45 (10) 635-638
    CrossrefPubMedGoogle Scholar
  • 48 Bowerman M, Swoboda KJ, Michalski J-P. , et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol 2012; 72 (02) 256-268
    CrossrefPubMedGoogle Scholar
  • 49 Davis RH, Miller EA, Zhang RZ, Swoboda KJ. Responses to fasting and glucose loading in a cohort of well children with spinal muscular atrophy type II. J Pediatr 2015; 167 (06) 1362-8.e1
    CrossrefPubMedGoogle Scholar
  • 50 Madsen KL, Hansen RS, Preisler N, Thøgersen F, Berthelsen MP, Vissing J. Training improves oxidative capacity, but not function, in spinal muscular atrophy type III. Muscle Nerve 2015; 52 (02) 240-244
    CrossrefPubMedGoogle Scholar
  • 51 Abresch RT, Carter GT, Han JJ, McDonald CM. Exercise in neuromuscular diseases. Phys Med Rehabil Clin N Am 2012; 23 (03) 653-673
    CrossrefPubMedGoogle Scholar
  • 52 Glanzman AM, Mazzone E, Main M. , et al. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord 2010; 20 (03) 155-161
    CrossrefPubMedGoogle Scholar
  • 53 Haataja L, Mercuri E, Regev R. , et al. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr 1999; 135 (2 Pt 1): 153-161
    CrossrefPubMedGoogle Scholar
  • 54 Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol 2003; 7 (04) 155-159
    CrossrefPubMedGoogle Scholar
  • 55 O'Hagen JM, Glanzman AM, McDermott MP. , et al. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord 2007; 17 (9-10): 693-697
    CrossrefPubMedGoogle Scholar
  • 56 Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol 2006; 26 (04) 1333-1346
    CrossrefPubMedGoogle Scholar
  • 57 Rigo F, Hua Y, Krainer AR, Bennett CF. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol 2012; 199 (01) 21-25
    CrossrefPubMedGoogle Scholar
  • 58 Passini MA, Bu J, Richards AM. , et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 2011; 3 (72) 72ra18
    PubMedGoogle Scholar
  • 59 Chiriboga CA, Swoboda KJ, Darras BT. , et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016; 86 (10) 890-897
    CrossrefPubMedGoogle Scholar
  • 60 Finkel RS, Chiriboga CA, Vajsar J. , et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388 (10063): 3017-3026
    CrossrefPubMedGoogle Scholar
  • 61 Naryshkin NA, Weetall M, Dakka A. , et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345 (6197): 688-693
    CrossrefPubMedGoogle Scholar
  • 62 Palacino J, Swalley SE, Song C. , et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol 2015; 11 (07) 511-517
    CrossrefPubMedGoogle Scholar
  • 63 Ratni H, Karp GM, Weetall M. , et al. Specific correction of alternative survival motor neuron 2 splicing by small molecules: discovery of a potential novel medicine to treat spinal muscular atrophy. J Med Chem 2016; 59 (13) 6086-6100
    CrossrefPubMedGoogle Scholar
  • 64 Gogliotti RG, Cardona H, Singh J. , et al. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. Hum Mol Genet 2013; 22 (20) 4084-4101
    CrossrefPubMedGoogle Scholar
  • 65 Dayton RD, Wang DB, Klein RL. The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin Biol Ther 2012; 12 (06) 757-766
    CrossrefPubMedGoogle Scholar
  • 66 Valori CF, Ning K, Wyles M. , et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med 2010; 2 (35) 35ra42
    PubMedGoogle Scholar
  • 67 Foust KD, Wang X, McGovern VL. , et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010; 28 (03) 271-274
    CrossrefPubMedGoogle Scholar
  • 68 Snyder BR, Gray SJ, Quach ET. , et al. Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Hum Gene Ther 2011; 22 (09) 1129-1135
    CrossrefPubMedGoogle Scholar
  • 69 Federici T, Taub JS, Baum GR. , et al. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 2012; 19 (08) 852-859
    CrossrefPubMedGoogle Scholar
  • 70 Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 2009; 27 (01) 59-65
    CrossrefPubMedGoogle Scholar
  • 71 Robbins KL, Glascock JJ, Osman EY, Miller MR, Lorson CL. Defining the therapeutic window in a severe animal model of spinal muscular atrophy. Hum Mol Genet 2014; 23 (17) 4559-4568
    CrossrefPubMedGoogle Scholar
  • 72 Mendell J. AveXis Reports Interim Data from Ongoing Phase 1 Clinical Trial of AVXS-101 in Spinal Muscular Atrophy Type 1 as Presented at the International Annual Congress of the World Muscle Society. Available at http://www.businesswire.com/news/home/20161008005041/en/AveXis-Reports-Interim-Data-Ongoing-Phase-1 . Accessed October 8, 2016
    PubMedGoogle Scholar
  • 73 Hayhurst M, Wagner AK, Cerletti M, Wagers AJ, Rubin LL. A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. Dev Biol 2012; 368 (02) 323-334
    CrossrefPubMedGoogle Scholar
  • 74 Bricceno KV, Martinez T, Leikina E. , et al. Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Genet 2014; 23 (18) 4745-4757
    CrossrefPubMedGoogle Scholar
  • 75 Hansen R, Saikali KG, Chou W. , et al. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 2014; 50 (06) 925-931
    CrossrefPubMedGoogle Scholar
  • 76 Russell AJ, Hartman JJ, Hinken AC. , et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 2012; 18 (03) 452-455
    CrossrefPubMedGoogle Scholar
  • 77 Hwee DT, Kennedy A, Ryans J. , et al. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS One 2014; 9 (05) e96921
    CrossrefPubMedGoogle Scholar
  • 78 Shefner JM, Wolff AA, Meng L. , et al; ON BEHALF OF THE BENEFIT-ALS STUDY GROUP. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2016; 17 (5-6): 426-435
    CrossrefPubMedGoogle Scholar
  • 79 Bordet T, Berna P, Abitbol J-L, Pruss RM. Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound. Pharmaceuticals (Basel) 2010; 3 (02) 345-368
    CrossrefPubMedGoogle Scholar
  • 80 Dessaud E, André C, Scherrer B. , et al. G.O.19. Neuromuscul Disord 2014; 24 (9–10): 920-921
    PubMedGoogle Scholar
  • 81 Kariya S, Obis T, Garone C. , et al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J Clin Invest 2014; 124 (02) 785-800
    CrossrefPubMedGoogle Scholar
  • 82 Hua Y, Sahashi K, Rigo F. , et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011; 478 (7367): 123-126
    CrossrefPubMedGoogle Scholar
  • 83 Dominguez E, Marais T, Chatauret N. , et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet 2011; 20 (04) 681-693
    CrossrefPubMedGoogle Scholar
  • 84 Wirth B, Barkats M, Martinat C, Sendtner M, Gillingwater TH. Moving towards treatments for spinal muscular atrophy: hopes and limits. Expert Opin Emerg Drugs 2015; 20 (03) 353-356
    CrossrefPubMedGoogle Scholar