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. Spinal muscular atrophy (SMA) is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy. This topic will review clinical aspects of spinal muscular atrophy (SMA), with a focus on SMN1-related SMA.
The inheritance pattern of 5q-related SMA is autosomal recessive . The different forms of 5q-SMA are caused by biallelic deletions or mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q13.2, resulting in deficiency of the SMN1 protein [2-5]. The most common mutation of the SMN1 gene is a deletion of exon 7 . Approximately 94 percent of patients with clinically typical SMA carry homozygous deletions of exon 7. SMN protein appears to play a role in mRNA synthesis in motor neurons and also may inhibit apoptosis [7,8].
The differences in SMN protein and phenotypic expression appear to be related in part to a modifying gene, called SMN2. The SMN1 and SMN2 genes are more than 99 percent identical and lie within an inverted duplication on chromosome 5q13.2 . The SMN1 gene lies telomeric of the SMN2 gene. The main difference between them is a C to T transition in exon 7 of the SMN2 gene [9,10]. This change leads to production of a truncated, nonfunctional SMN protein from the majority of SMN2-derived mRNAs. However, about 10 to 15 percent of mRNAs from SMN2 contain exon 7 and can produce some functional, full-length SMN protein . Thus, loss of the SMN1 protein is partially compensated by SMN2 protein synthesis (figure 1), a mechanism that explains some but not all of the phenotypic variability in patients with SMA . Disease severity in SMA generally correlates inversely with SMN2 gene copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein [11,13-16]. The presence of three or more copies of SMN2 is associated with a milder phenotype [1,14].
While the most common forms of SMA are caused by deletions or mutations in the SMN1 gene on chromosome 5q (ie, 5q SMAs), there are a number of rare non-5q spinal muscular atrophies [15,17,18]. The non-5q SMAs are genetically and clinically heterogeneous (table 1).
The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease-causing SMN1 mutations ranges from 1/90 to 1/47 [1,19-22]. SMA is the most common monogenic cause of infant mortality .
Subscribers log in hereLiterature review current through: Sep 2017. | This topic last updated: Mar 29, 2017.References
- Prior TW, Finanger E. Spinal muscular atrophy.GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1352/ (Accessed on March 03, 2017).
- 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.
- Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80:155.
- 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.
- Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 1999; 96:6307.
- Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8:1177.
- Butchbach ME. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front Mol Biosci 2016; 3:7.
- Hsieh-Li HM, Chang JG, Jong YJ, et al. A mouse model for spinal muscular atrophy. Nat Genet 2000; 24:66.
- Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16:265.
- 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.
- Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology 2011; 77:312.
- Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin 2015; 33:831.
- 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.
- Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain 2014; 137:2879.
- 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; 20:27.
- Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet 1978; 15:409.
- Mostacciuolo ML, Danieli GA, Trevisan C, et al. Epidemiology of spinal muscular atrophies in a sample of the Italian population. Neuroepidemiology 1992; 11:34.
- Thieme A, Mitulla B, Schulze F, Spiegler AW. Epidemiological data on Werdnig-Hoffmann disease in Germany (West-Thüringen). Hum Genet 1993; 91:295.
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am 2015; 62:743.
- von Gontard A, Zerres K, Backes M, et al. Intelligence and cognitive function in children and adolescents with spinal muscular atrophy. Neuromuscul Disord 2002; 12:130.
- 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.
- Pera MC, Romeo DM, Graziano A, et al. Sleep disorders in spinal muscular atrophy. Sleep Med 2017; 30:160.
- 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.
- 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.
- 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.
- Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol 2012; 11:443.
- Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Eur J Paediatr Neurol 1999; 3:49.
- MacLeod MJ, Taylor JE, Lunt PW, et al. Prenatal onset spinal muscular atrophy. Eur J Paediatr Neurol 1999; 3:65.
- Grotto S, Cuisset JM, Marret S, et al. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients. J Neuromuscul Dis 2016; 3:487.
- 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.
- González De Dios J, Martínez Frías ML, Arroyo Carrera I, et al. [Role of signs of fetal hypokinesia in the diagnosis of spinal muscular atrophy of neonatal onset]. An Esp Pediatr 2002; 56:233.
- 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.
- 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.
- Moosa A, Dubowitz V. Spinal muscular atrophy in childhood. Two clues to clinical diagnosis. Arch Dis Child 1973; 48:386.
- Piepers S, van den Berg LH, Brugman F, et al. A natural history study of late onset spinal muscular atrophy types 3b and 4. J Neurol 2008; 255:1400.
- 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.
- 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.
- 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.
- Baumbach-Reardon L, Sacharow S, Ahearn ME. Spinal muscular atrophy, X-linked infantile. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK2594/ (Accessed on March 07, 2017).
- 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.
- 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.
- Kaback MM, Desnick RJ. Hexosaminidase A deficiency. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1218/ (Accessed on March 07, 2017).
- Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007; 22:1027.
- Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol 2017; 81:355.
- 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.
- 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.
- 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; 86:890.
- 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; 388:3017.
- FDA approves first drug for spinal muscular atrophy. U.S. Food & Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm (Accessed on January 03, 2017).
- Prescribing information, SPINRAZA (nusinersen) injection, for intrathecal use. www.accessdata.fda.gov/drugsatfda_docs/label/2016/209531lbl.pdf (Accessed on January 03, 2017).
- A study to assess the efficacy and safety of IONIS-SMN Rx in patients with later-onset spinal muscular atrophy. https://clinicaltrials.gov/ct2/show/NCT02292537 (Accessed on January 23, 2017).
- Biogen and Ionis Pharmaceuticals announce SPINRAZA (nusinersen) meets primary endpoint at interim analysis of phase 3 CHERISH study in later-onset spinal muscular atrophy. http://media.biogen.com/press-release/corporate/biogen-and-ionis-pharmaceuticals-announce-spinraza-nusinersen-meets-primary- (Accessed on January 23, 2017).
- 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.
- 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.
- Committee on Genetics. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol 2017; 129:e41.
- CLINICAL FEATURES
- SMA type 0
- SMA type 1
- SMA type 2
- SMA type 3
- SMA type 4
- DIFFERENTIAL DIAGNOSIS
- Onset from prenatal to six months of age
- - X-linked infantile spinal muscular atrophy
- - Spinal muscular atrophy with respiratory distress type 1
- - Other neuromuscular disorders
- - Multisystem disorders
- - Arthrogryposis multiplex congenita
- Onset six months to childhood
- Adult onset
- Supportive therapy
- - Pulmonary
- - Nutrition and gastrointestinal
- - Orthopedic and musculoskeletal
- Genetic counseling
- SUMMARY AND RECOMMENDATIONS