Spinal Muscular Atrophy 

  • Author: Bryan Tsao, MD; Chief Editor: Amy Kao, MD   more...
 
Updated: Mar 8, 2011
 

Background

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.[1]

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[6] , Pearn[7] , and International SMA Consortium system[8] . The ISMAC system is most widely accepted and is used in this review.

Next

Pathophysiology

In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor neuron (SMN), was discovered.[9] 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.[10]

Previous
Next

Epidemiology

Frequency

United States

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.[11]

International

The incidence of spinal muscular atrophy is about 1 in 10,000 live births with a carrier frequency of 1 in 50.[7, 12]

Mortality/Morbidity

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.

Sex

Male individuals are most frequently affected, especially with the early-onset forms of spinal muscular atrophy, ie, types I and II.[13]

Age

The ISMAC classification system is based on the age of onset.[8] 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).
Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Bryan Tsao, MD  Associate Professor, Department of Neurology, Loma Linda University; Chair and Service Chief, Department of Neurology, Loma Linda University Medical Center

Bryan Tsao, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Carmel Armon, MD, MSc, MHS  Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Avanir Pharmaceuticals Consulting fee Consulting

Specialty Editor Board

Robert J Baumann, MD  Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine

Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, and Child Neurology Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Kenneth J Mack, MD, PhD  Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Amy Kao, MD  Attending Neurologist, Children's National Medical Center, Washington DC

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose.

References

  1. Katirji B, Kaminski HJ, Preston DC. Spinal muscular atrophies. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE, eds. Neuromuscular Disorders in Clinical Practice. Boston: Butterworth-Heinemann; 2002:445-53.

  2. Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. 2nd ed. Boston: Butterworth-Heinemann; 1996:1829-43.

  3. Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. Apr 5 1990;344(6266):540-1. [Medline].

  4. Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci. Mar 1980;45(2-3):337-48. [Medline].

  5. Burlet P, Burglen L, Clermont O, et al. Large scale deletions of the 5q13 region are specific to Werdnig- Hoffmann disease. J Med Genet. Apr 1996;33(4):281-3. [Medline].

  6. Emery AE. The nosology of the spinal muscular atrophies. J Med Genet. Dec 1971;8(4):481-95. [Medline].

  7. Pearn J. Classification of spinal muscular atrophies. Lancet. Apr 26 1980;1(8174):919-22. [Medline].

  8. Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(5-6):423-8. [Medline].

  9. Burglen L, Lefebvre S, Clermont O, et al. Structure and organization of the human survival motor neurone (SMN) gene. Genomicx. 1996;32:479-482.

  10. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. Jun 21 2008;371(9630):2120-33. [Medline].

  11. Harding AE. Inherited neuronal atrophy and degeneration predominantly of lower motor neurons. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 3rd ed. Philadelphia: WB Saunders; 1993:1051-64.

  12. Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. Jul 15 2002;110(4):301-7. [Medline].

  13. Hausmanowa-Petrusewicz I, Zaremba J, Borkowska J, Szirkowiec W. Chronic proximal spinal muscular atrophy of childhood and adolescence: sex influence. J Med Genet. Dec 1984;21(6):447-50. [Medline].

  14. Walton JN. The limp child. J Neurol Neurosurg Psychiatry. May 1957;20(2):144-54. [Medline].

  15. 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. Feb 1996;27(1):8-15. [Medline].

  16. Fenichel GM. Clinical Pediatric Neurology. 3rd ed. WB Saunders: Philadelphia; 1997:151-74.

  17. Joynt R, Griggs R. Clinical Neurology. Vol 4. Philadelphia: Lippincott; 1997:11-5.

  18. McShane MA, Boyd S, Harding B, et al. Progressive bulbar paralysis of childhood. A reappraisal of Fazio-Londe disease. Brain. Dec 1992;115 ( Pt 6):1889-900. [Medline].

  19. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. Jul 1968;18(7):671-80. [Medline].

  20. Kaeser HE. Scapuloperoneal muscular atrophy. Brain. Jun 1965;88(2):407-18. [Medline].

  21. 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. Oct 1970;11(4):359-82. [Medline].

  22. Young ID, Harper PS. Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry. May 1980;43(5):413-08. [Medline].

  23. 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. Jul 1989;33(3):328-35. [Medline].

  24. 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].

  25. Frugier T, Nicole S, Cifuentes-Diaz C, Melki J. The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev. Jun 2002;12(3):294-8. [Medline].

  26. Anderson K, Talbot K. Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol. Oct 2003;16(5):595-9. [Medline].

  27. Hausmanowa-Petrusewicz I, Vrbova G. Spinal muscular atrophy: a delayed development hypothesis. Neuroreport. May 12 2005;16(7):657-61. [Medline].

  28. 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. Jan 13 1995;80(1):167-78. [Medline].

  29. Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med. Oct 1996;74(10):555-62. [Medline].

  30. Hausmanowa-Petrusewicz I, Karwanska A. Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy. Muscle Nerve. Jan 1986;9(1):37-46. [Medline].

  31. Krivickas LS. Electrodiagnosis in neuromuscular disease. Phys Med Rehabil Clin N Am. Feb 1998;9(1):83-114, vi. [Medline].

  32. Buchthal F, Olsen PZ. Electromyography and muscle biopsy in infantile spinal muscular atrophy. Brain. 1970;93(1):15-30. [Medline].

  33. Dubowitz V. Muscle disorders in childhood. Major Probl Clin Pediatr. 1978;16:iii-xiii, 1-282. [Medline].

  34. 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. Jun 2006;59(6):970-5. [Medline].

  35. Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. Aug 8 2006;67(3):500-1. [Medline].

  36. 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. Feb 2011;10(2):140-7. [Medline].

  37. 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].

  38. Birnkrant DJ, Pope JF, Martin JE, et al. Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding. Pediatr Neurol. May 1998;18(5):407-10. [Medline].

  39. 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. May 1995;52(5):518-23. [Medline].

  40. Manson JI, Thong YH. Immunological abnormalities in the syndrome of poliomyelitis-like illness associated with acute bronchial asthma (Hopkin's syndrome). Arch Dis Child. Jan 1980;55(1):26-32. [Medline].

  41. de Leon GA, Grover WD, D'Cruz CA. Amyotrophic cerebellar hypoplasia: a specific form of infantile spinal atrophy. Acta Neuropathol. 1984;63(4):282-6. [Medline].

  42. Fidzianska A, Goebel HH, Warlo I. Acute infantile spinal muscular atrophy. Muscle apoptosis as a proposed pathogenetic mechanism. Brain. Apr 1990;113 ( Pt 2):433-45. [Medline].

  43. Hausmanowa-Petrusewicz I. Spinal Muscular Atrophy: Infantile and Juvenile Type. Springfield, Va: National Library of Medicine;. 1978.

  44. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. Jul 4 1991;352(6330):77-9. [Medline].

  45. MacLean HE, Choi WT, Rekaris G, Warne GL, Zajac JD. Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy). J Clin Endocrinol Metab. Feb 1995;80(2):508-16. [Medline].

  46. Meister G, Eggert C, Fischer U. SMN-mediated assembly of RNPs: a complex story. Trends Cell Biol. Oct 2002;12(10):472-8. [Medline].

  47. Norman RM. Cerebellar hypoplasia in Werdnig-Hoffmann disease. Arch Dis Child. Feb 1961;36:96-101. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.