Spinal muscular atrophy
- Olaf A Bodamer, MD, PhD, FAAP, FACMG
Olaf A Bodamer, MD, PhD, FAAP, FACMG
- Park Gerald Chair in Genetics and Genomics
- Associate Chief, Genetics and Genomics
- Boston Children’s Hospital/Harvard Medical School
- Section Editors
- Douglas R Nordli, Jr, MD
Douglas R Nordli, Jr, MD
- Section Editor — Pediatric Neurology
- Chief of Neurology
- Children’s Hospital Los Angeles
- Vice Chair of Neurology
- USC Keck School of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
- Richard Martin, MD
Richard Martin, MD
- Section Editor — Neonatology
- Professor, Pediatrics, Reproductive Biology, and Physiology & Biophysics
- Case Western Reserve University School of Medicine
Neuromuscular disorders that present in the newborn period with hypotonia and weakness are caused by a variety of conditions that affect the central nervous system (brain or spinal cord), peripheral nervous system, or skeletal muscle. Conditions that affect the anterior horn cells of the spinal cord are listed in the table (table 1).
This topic will review clinical aspects of spinal muscular atrophy (SMA).
SMA disorders are characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. These diseases are classified as types 1 through 4 depending upon the age of onset and clinical course.
Classification — SMA type 1, also known as infantile spinal muscular atrophy or Werdnig-Hoffmann disease, is the most common and severe type of SMA. It typically presents in the neonatal period. However, mothers of affected patients may recognize a decrease or loss of fetal movement in late pregnancy. Some experts classify prenatal onset as SMA type 0 [2,3]. In these neonatal forms, symptoms progress rapidly, and the majority of infants die before one year of age from respiratory failure [4,5]. Nevertheless, long-term survivors have been reported [6-8]. This is perhaps due, in part, to advances in the care of chronic respiratory insufficiency and to more aggressive care. (See 'Management' below.)
- Prior TW, Russman BS. Spinal muscular atrophy. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1352/ (Accessed on November 03, 2014).
- Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol 2012; 11:443.
- Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord 1992; 2:423.
- Thomas NH, Dubowitz V. The natural history of type I (severe) spinal muscular atrophy. Neuromuscul Disord 1994; 4:497.
- Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr 2013; 162:155.
- Chung BH, Wong VC, Ip P. Spinal muscular atrophy: survival pattern and functional status. Pediatrics 2004; 114:e548.
- 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; 52:518.
- Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy type 1. Neurology 2007; 69:1931.
- Lefebvre S, Bürglen L, Frézal J, et al. The role of the SMN gene in proximal spinal muscular atrophy. Hum Mol Genet 1998; 7:1531.
- Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology 2012; 79:1889.
- Kroksmark AK, Beckung E, Tulinius M. Muscle strength and motor function in children and adolescents with spinal muscular atrophy II and III. Eur J Paediatr Neurol 2001; 5:191.
- Rudnik-Schöneborn S, Hausmanowa-Petrusewicz I, Borkowska J, Zerres K. The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III. Eur Neurol 2001; 45:174.
- Brahe C, Servidei S, Zappata S, et al. Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 1995; 346:741.
- Clermont O, Burlet P, Lefebvre S, et al. SMN gene deletions in adult-onset spinal muscular atrophy. Lancet 1995; 346:1712.
- Zerres K, Rudnik-Schöneborn S, Forkert R, Wirth B. Genetic basis of adult-onset spinal muscular atrophy. Lancet 1995; 346:1162.
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 2015; 51:157.
- Ioos C, Leclair-Richard D, Mrad S, et al. Respiratory capacity course in patients with infantile spinal muscular atrophy. Chest 2004; 126:831.
- 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; 45:635.
- Menke LA, Poll-The BT, Clur SA, et al. Congenital heart defects in spinal muscular atrophy type I: a clinical report of two siblings and a review of the literature. Am J Med Genet A 2008; 146A:740.
- Takahashi N, Shimada T, Ishibashi Y, et al. Cardiac involvement in Kugelberg-Welander disease: a case report and review. Am J Med Sci 2006; 332:354.
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am 2015; 62:743.
- Palladino A, Passamano L, Taglia A, et al. Cardiac involvement in patients with spinal muscular atrophies. Acta Myol 2011; 30:175.
- Bianco F, Pane M, D'Amico A, et al. Cardiac function in types II and III spinal muscular atrophy: should we change standards of care? Neuropediatrics 2015; 46:33.
- Scheffer H, Cobben JM, Matthijs G, Wirth B. Best practice guidelines for molecular analysis in spinal muscular atrophy. Eur J Hum Genet 2001; 9:484.
- Schmalbruch H, Haase G. Spinal muscular atrophy: present state. Brain Pathol 2001; 11:231.
- Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 1998; 95:615.
- Cuscó I, Barceló MJ, del Río E, et al. Detection of novel mutations in the SMN Tudor domain in type I SMA patients. Neurology 2004; 63:146.
- Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet 2002; 111:477.
- Friesen WJ, Massenet S, Paushkin S, et al. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol Cell 2001; 7:1111.
- Kerr DA, Nery JP, Traystman RJ, et al. Survival motor neuron protein modulates neuron-specific apoptosis. Proc Natl Acad Sci U S A 2000; 97:13312.
- Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16:265.
- Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80:155.
- Hsieh-Li HM, Chang JG, Jong YJ, et al. A mouse model for spinal muscular atrophy. Nat Genet 2000; 24:66.
- Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 2002; 4:20.
- Zerres K, Rudnik-Schöneborn S. 93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) - clinical picture (6-8 April 2001, Naarden, The Netherlands). Neuromuscul Disord 2003; 13:179.
- Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology 2011; 77:312.
- Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain 2014; 137:2879.
- ACOG Committee on Genetics. ACOG committee opinion No. 432: spinal muscular atrophy. Obstet Gynecol 2009; 113:1194.
- Prior TW, Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med 2008; 10:840.
- Prior TW. Spinal muscular atrophy: a time for screening. Curr Opin Pediatr 2010; 22:696.
- Buchthal F, Olsen PZ. Electromyography and muscle biopsy in infantile spinal muscular atrophy. Brain 1970; 93:15.
- Hausmanowa-Petrusewicz I, Karwańska A. Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy. Muscle Nerve 1986; 9:37.
- Gordon N. Arthrogryposis multiplex congenita. Brain Dev 1998; 20:507.
- O'Flaherty P. Arthrogryposis multiplex congenita. Neonatal Netw 2001; 20:13.
- Banker BQ. Arthrogryposis multiplex congenita: spectrum of pathologic changes. Hum Pathol 1986; 17:656.
- Bianchi DW, Van Marter LJ. An approach to ventilator-dependent neonates with arthrogryposis. Pediatrics 1994; 94:682.
- Bürglen L, Amiel J, Viollet L, et al. Survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association. J Clin Invest 1996; 98:1130.
- Bingham PM, Shen N, Rennert H, et al. Arthrogryposis due to infantile neuronal degeneration associated with deletion of the SMNT gene. Neurology 1997; 49:848.
- Kobayashi H, Baumbach L, Matise TC, et al. A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11.3-q11.2. Hum Mol Genet 1995; 4:1213.
- Reardon LB, Sacharow S, Ahearn ME. Spinal muscular atrophy, X-linked infantile. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK2594/ (Accessed on January 24, 2011).
- Dressman D, Ahearn ME, Yariz KO, et al. X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping. Genet Med 2007; 9:52.
- Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol 2003; 54:719.
- Eckart M, Guenther UP, Idkowiak J, et al. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics 2012; 129:e148.
- Clancy RR, Sladky JT, Rorke LB. Hypoxic-ischemic spinal cord injury following perinatal asphyxia. Ann Neurol 1989; 25:185.
- Tangsrud SE, Carlsen KC, Lund-Petersen I, Carlsen KH. Lung function measurements in young children with spinal muscle atrophy; a cross sectional survey on the effect of position and bracing. Arch Dis Child 2001; 84:521.
- Schroth MK. Special considerations in the respiratory management of spinal muscular atrophy. Pediatrics 2009; 123 Suppl 4:S245.
- Bach JR, Niranjan V, Weaver B. Spinal muscular atrophy type 1: A noninvasive respiratory management approach. Chest 2000; 117:1100.
- Chatwin M, Bush A, Simonds AK. Outcome of goal-directed non-invasive ventilation and mechanical insufflation/exsufflation in spinal muscular atrophy type I. Arch Dis Child 2011; 96:426.
- Hardart MK, Truog RD. Spinal muscular atrophy--type I. Arch Dis Child 2003; 88:848.
- Mulcahy PJ, Iremonger K, Karyka E, et al. Gene therapy: a promising approach to treating spinal muscular atrophy. Hum Gene Ther 2014; 25:575.
- Passini MA, Bu J, Roskelley EM, et al. CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 2010; 120:1253.
- Porensky PN, Mitrpant C, McGovern VL, et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 2012; 21:1625.
- 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; 478:123.
- MacKenzie A. Sense in antisense therapy for spinal muscular atrophy. N Engl J Med 2012; 366:761.
- 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; 345:688.
- Swoboda KJ. Romancing the spliceosome to fight spinal muscular atrophy. N Engl J Med 2014; 371:1752.
- Argov Z, de Visser M. What we do not know about pregnancy in hereditary neuromuscular disorders. Neuromuscul Disord 2009; 19:675.
- Rudnik-Schöneborn S, Zerres K, Ignatius J, Rietschel M. Pregnancy and spinal muscular atrophy. J Neurol 1992; 239:26.
- Carter GT, Bonekat HW, Milio L. Successful pregnancies in the presence of spinal muscular atrophy: two case reports. Arch Phys Med Rehabil 1994; 75:229.
- Pugh CP, Healey SK, Crane JM, Young D. Successful pregnancy and spinal muscular atrophy. Obstet Gynecol 2000; 95:1034.
- Rudnik-Schöneborn S, Breuer C, Zerres K. Stable motor and lung function throughout pregnancy in a patient with infantile spinal muscular atrophy type II. Neuromuscul Disord 2002; 12:137.
- Yim R, Kirschner K, Murphy E, et al. Successful pregnancy in a patient with spinal muscular atrophy and severe kyphoscoliosis. Am J Phys Med Rehabil 2003; 82:222.
- CLINICAL FEATURES
- Genetic counseling
- Muscle biopsy
- DIFFERENTIAL DIAGNOSIS
- Arthrogryposis multiplex congenita
- X-linked infantile spinal muscular atrophy
- Spinal muscular atrophy with respiratory distress type 1
- Congenital myasthenic syndromes
- Congenital myopathies
- Hypoxic-ischemic myelopathy
- Glycogen storage disease II
- Prader-Willi syndrome
- Traumatic myelopathy
- Zellweger syndrome
- SUMMARY AND RECOMMENDATIONS