Spinal Muscular Atrophy
- Author: Bryan Tsao, MD; Chief Editor: Amy Kao, MD more...
The spinal muscular atrophies (SMAs) comprise a group of autosomal-recessive disorders characterized by progressive weakness of the lower motor neurons.
In the early 1980s, Werdnig and Hoffman described a disorder of progressive muscular weakness beginning in infancy that resulted in early death, though the age of death was variable. In pathologic terms, the disease was characterized by loss of anterior horn cells. The central role of lower motor neuron degeneration was confirmed in subsequent pathologic studies demonstrating a loss of anterior horn cells in the spinal cord and cranial nerve nuclei.
Since then, several types of spinal muscular atrophies have been described based on age when accompanying clinical features appear. The most common types are acute infantile (SMA type I, or Werdnig-Hoffman disease), chronic infantile (SMA type II), chronic juvenile (SMA type III or Kugelberg-Welander disease), and adult onset (SMA type IV) forms.
The genetic defects associated with SMA types I-III are localized on chromosome 5q11.2-13.3.[2, 3, 4, 5]
Many classification systems have been proposed and include variants based on inheritance, clinical, and genetic criteria. Among these are the Emery , Pearn , and International SMA Consortium system . The ISMAC system is most widely accepted and is used in this review.
In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor neuron (SMN), was discovered. Each individual has 2 SMN genes, SMN1 and SMN2. More than 95% of patients with spinal muscular atrophy have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement. However, all patients with spinal muscular atrophy retain at least 1 copy of SMN2, which generates only 10% of the amount of full-length SMN protein versus SMN1. This genomic organization provides a therapeutic pathway to promote SMN2, existing in all patients, to function like the missing SMN1 gene.
The spinal muscular atrophies are the second most common autosomal-recessive inherited disorders after cystic fibrosis. The acute infantile-onset SMA (type I) affects approximately 1 per 10,000 live births; the chronic forms (types II and III) affect 1 per 24,000 births. SMA types I and III each account for about one fourth of cases, whereas SMA type II is the largest group and accounts for one half of all cases.
The incidence of spinal muscular atrophy is about 1 in 10,000 live births with a carrier frequency of approximately 1 in 50.[7, 12, 13]
The mortality and/or morbidity rates of spinal muscular atrophy are inversely correlated with the age at onset. High death rates are associated with early onset disease. In patients with SMA type I, the median survival is 7 months, with a mortality rate of 95% by age 18 months.
Respiratory infections account for most deaths.
In type II SMA, the age of death varies, but death is most often due to respiratory complications.
See Prognosis for more information.
Male individuals are most frequently affected, especially with the early-onset forms of spinal muscular atrophy, ie, types I and II.
The ISMAC classification system is based on the age of onset. See Background, History, and Physical for a review of the existing classification systems and a brief discussion of their relevancy to the role of age in spinal muscular atrophies.
According to the ISMAC system, the age of onset for spinal muscular atrophies is as follows:
SMA type I (acute infantile or Werdnig Hoffman): Onset is from birth to 6 months.
SMA type II (chronic infantile): Onset is between 6 and 18 months.
SMA type III (chronic juvenile): Onset is after 18 months.
SMA type IV (adult onset): Onset is in adulthood (mean onset, mid 30s).
Katirji B, Kaminski HJ, Preston DC. Spinal muscular atrophies. Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE, eds. Neuromuscular Disorders in Clinical Practice. Boston: Butterworth-Heinemann; 2002. 445-53.
Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. 2nd ed. Boston: Butterworth-Heinemann; 1996. 1829-43.
Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990 Apr 5. 344(6266):540-1. [Medline].
Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci. 1980 Mar. 45(2-3):337-48. [Medline].
Burlet P, Burglen L, Clermont O, et al. Large scale deletions of the 5q13 region are specific to Werdnig- Hoffmann disease. J Med Genet. 1996 Apr. 33(4):281-3. [Medline].
Emery AE. The nosology of the spinal muscular atrophies. J Med Genet. 1971 Dec. 8(4):481-95. [Medline].
Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26. 1(8174):919-22. [Medline].
Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992. 2(5-6):423-8. [Medline].
Burglen L, Lefebvre S, Clermont O, et al. Structure and organization of the human survival motor neurone (SMN) gene. Genomicx. 1996. 32:479-482.
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 21. 371(9630):2120-33. [Medline].
Harding AE. Inherited neuronal atrophy and degeneration predominantly of lower motor neurons. Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 3rd ed. Philadelphia: WB Saunders; 1993. 1051-64.
Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002 Jul 15. 110(4):301-7. [Medline].
Awater C, Zerres K, Rudnik-Schöneborn S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur J Obstet Gynecol Reprod Biol. 2012 Jun. 162(2):153-9. [Medline].
Hausmanowa-Petrusewicz I, Zaremba J, Borkowska J, Szirkowiec W. Chronic proximal spinal muscular atrophy of childhood and adolescence: sex influence. J Med Genet. 1984 Dec. 21(6):447-50. [Medline].
Walton JN. The limp child. J Neurol Neurosurg Psychiatry. 1957 May. 20(2):144-54. [Medline].
Rudnik-Schoneborn S, Forkert R, Hahnen E, et al. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics. 1996 Feb. 27(1):8-15. [Medline].
Fenichel GM. Clinical Pediatric Neurology. 3rd ed. WB Saunders: Philadelphia; 1997. 151-74.
Joynt R, Griggs R. Clinical Neurology. Philadelphia: Lippincott; 1997. Vol 4: 11-5.
Okamoto K, Saito K, Sato T, Ishigaki K, Funatsuka M, Osawa M. [A case of spinal muscular atrophy type 0 in Japan]. No To Hattatsu. 2012 Sep. 44(5):387-91. [Medline].
McShane MA, Boyd S, Harding B, et al. Progressive bulbar paralysis of childhood. A reappraisal of Fazio-Londe disease. Brain. 1992 Dec. 115 ( Pt 6):1889-900. [Medline].
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968 Jul. 18(7):671-80. [Medline].
Kaeser HE. Scapuloperoneal muscular atrophy. Brain. 1965 Jun. 88(2):407-18. [Medline].
Kondo K, Tsubaki T, Sakamoto F. The Ryukyuan muscular atrophy. An obscure heritable neuromuscular disease found in the islands of southern Japan. J Neurol Sci. 1970 Oct. 11(4):359-82. [Medline].
Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, et al. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology. 2013 Jan 29. 80(5):438-46. [Medline]. [Full Text].
Young ID, Harper PS. Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry. 1980 May. 43(5):413-08. [Medline].
Bertini E, Gadisseux JL, Palmieri G, et al. Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am J Med Genet. 1989 Jul. 33(3):328-35. [Medline].
Kamoshita S, Takei Y, Miyao M, Yanagisawa M, Kobayashi S, Saito K. Pontocerebellar hypoplasia associated with infantile motor neuron disease (Norman's disease). Pediatr Pathol. 1990. 10(1-2):133-42. [Medline].
Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, et al. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics. 2012 Jan. 129(1):e148-56. [Medline].
Penttilä S, Jokela M, Hackman P, Maija Saukkonen A, Toivanen J, Udd B. Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2. Eur J Hum Genet. 2012 Nov. 20(11):1193-6. [Medline]. [Full Text].
Rudnik-Schöneborn S, Arning L, Epplen JT, Zerres K. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord. 2012 Mar. 22(3):258-62. [Medline].
Frugier T, Nicole S, Cifuentes-Diaz C, Melki J. The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev. 2002 Jun. 12(3):294-8. [Medline].
Chen WJ, He J, Zhang QJ, Lin QF, Chen YF, Lin XZ, et al. Modification of phenotype by SMN2 copy numbers in two Chinese families with SMN1 deletion in two continuous generations. Clin Chim Acta. 2012 Nov 20. 413(23-24):1855-60. [Medline].
Finkel RS, Crawford TO, Swoboda KJ, Kaufmann P, Juhasz P, Li X, et al. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS One. 2012. 7(4):e35462. [Medline]. [Full Text].
Anderson K, Talbot K. Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol. 2003 Oct. 16(5):595-9. [Medline].
Hausmanowa-Petrusewicz I, Vrbova G. Spinal muscular atrophy: a delayed development hypothesis. Neuroreport. 2005 May 12. 16(7):657-61. [Medline].
Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995 Jan 13. 80(1):167-78. [Medline].
Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med. 1996 Oct. 74(10):555-62. [Medline].
[Guideline] Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol. 2012 May. 11(5):443-52. [Medline].
Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015 Feb. 51 (2):157-67. [Medline].
Palladino A, Passamano L, Taglia A, D'Ambrosio P, Scutifero M, Cecio MR, et al. Cardiac involvement in patients with spinal muscular atrophies. Acta Myol. 2011 Dec. 30(3):175-8. [Medline]. [Full Text].
Hausmanowa-Petrusewicz I, Karwanska A. Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy. Muscle Nerve. 1986 Jan. 9(1):37-46. [Medline].
Krivickas LS. Electrodiagnosis in neuromuscular disease. Phys Med Rehabil Clin N Am. 1998 Feb. 9(1):83-114, vi. [Medline].
Buchthal F, Olsen PZ. Electromyography and muscle biopsy in infantile spinal muscular atrophy. Brain. 1970. 93(1):15-30. [Medline].
Dubowitz V. Muscle disorders in childhood. Major Probl Clin Pediatr. 1978. 16:iii-xiii, 1-282. [Medline].
Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, et al. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011. 6(7):e21296. [Medline]. [Full Text].
Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010 Aug 19. 5(8):e12140. [Medline]. [Full Text].
Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST, et al. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev. 2012 Apr 18. 4:CD006282. [Medline].
Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST, et al. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev. 2012 Apr 18. 4:CD006281. [Medline].
Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb. 10(2):140-7. [Medline].
van Bruggen HW, van den Engel-Hoek L, van der Pol WL, de Wijer A, de Groot IJ, Steenks MH. Impaired mandibular function in spinal muscular atrophy type II: need for early recognition. J Child Neurol. 2011 Nov. 26(11):1392-6. [Medline].
Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. 3rd ed. Loma Linda, Calif: 2000. 18. [Full Text].
Mesfin A, Sponseller PD, Leet AI. Spinal muscular atrophy: manifestations and management. J Am Acad Orthop Surg. 2012 Jun. 20(6):393-401. [Medline].
Birnkrant DJ, Pope JF, Martin JE, et al. Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding. Pediatr Neurol. 1998 May. 18(5):407-10. [Medline].
Montes J, McIsaac TL, Dunaway S, Kamil-Rosenberg S, Sproule D, Garber CE, et al. Falls and spinal muscular atrophy: exploring cause and prevention. Muscle Nerve. 2013 Jan. 47(1):118-23. [Medline].
Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, 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 Jan. 20(1):27-32. [Medline]. [Full Text].
Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995 May. 52(5):518-23. [Medline].
Ge X, Bai J, Lu Y, Qu Y, Song F. The natural history of infant spinal muscular atrophy in China: a study of 237 patients. J Child Neurol. 2012 Apr. 27(4):471-7. [Medline].
Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr. 2013 Jan. 162(1):155-9. [Medline].
Lemoine TJ, Swoboda KJ, Bratton SL, Holubkov R, Mundorff M, Srivastava R. Spinal muscular atrophy type 1: are proactive respiratory interventions associated with longer survival?. Pediatr Crit Care Med. 2012 May. 13(3):e161-5. [Medline].
Manson JI, Thong YH. Immunological abnormalities in the syndrome of poliomyelitis-like illness associated with acute bronchial asthma (Hopkin's syndrome). Arch Dis Child. 1980 Jan. 55(1):26-32. [Medline].
Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann Neurol. 2006 Jun. 59(6):970-5. [Medline].
Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. 2006 Aug 8. 67(3):500-1. [Medline].