Spinal muscular atrophy
Citation, DOI and article data
This disorder affects 1 in 6000-10000 infants 1.
Spinal muscular atrophy typically affects infants and young children, presenting with progressive, symmetrical, proximal-predominant muscle atrophy and weakness of varying severity 1,2. Although the lower extremities can have greater involvement, axial, intercostal, and bulbar musculature are also frequently involved 1,2.
In infants, the most common demographic affected, this classically manifests as difficulties sitting and rolling, assuming a frog-leg position, a weak cry, and increased respiratory effort with paradoxical breathing 1,3. Rarely is intellectual disability a feature 3.
Spinal muscular atrophy is classified into four types with decreasing clinical severity and increasing age of onset 1,2:
- type 1 (Werdnig-Hoffman disease): infantile form, most severe and most common form, onset before six months
- type 2: intermediate form, onset between six and twelve months
- type 3 (Kugelberg-Welander disease): juvenile form, onset after twelve months
- type 4: adult form
Some authors suggest an additional type 0, also termed 'severe infantile' form, with a prognosis (without novel therapy) of just a few weeks, although this has not been widely adopted in the literature 4.
Spinal muscular atrophy has an autosomal recessive mode of inheritance due to mutations to the SMN1 (survival motor neuron 1) gene on chromosome 5 1,2. This mutated gene has a carrier frequency of 1 in 40 1,2.
In muscles, the predominant features are those of muscle atrophy 5,6. Mild types tend to demonstrate fatty infiltration of muscular bundles with increased prominence of intramuscular fat planes 5,6. Intermediate forms may show ragged atrophy of muscles, while the severe forms often show gross atrophy 5,6.
In the spinal cord, MRI may reveal T2 hyperintensities in the anterior horns of the cervical cord, and to a lesser degree in the thoracolumbar cord, that are thought to correspond histopathologically to motor neuron loss in these regions 3. These features may resemble the owl's eye sign 3.
Treatment and prognosis
Although management was once considered to be mainly supportive, recent advances (as of June 2017) have led to the development of oligonucleotide drugs (e.g. nusinersen) and novel gene therapies (e.g. AVXS-101) which hold promise in improving the quality of life and prognosis of these patients 7-9.
History and etymology
Spinal muscular atrophy was originally described in two infant brothers by Austrian neurologist Guido Werdnig (1844-1919) in 1891, and in seven additional cases by German neurologist Johan Hoffmann (1857-1919) from 1893 to 1900 2.
- 1. Stephen J. Kolb, John T. Kissel. Spinal Muscular Atrophy: A Timely Review. Archives of Neurology. 68 (8): 979. doi:10.1001/archneurol.2011.74
- 2. Pearn J. Classification of spinal muscular atrophies. Lancet (London, England). 1 (8174): 919-22. Pubmed
- 3. Hsu CF, Chen CY, Yuh YS, Chen YH, Hsu YT, Zimmerman RA. MR findings of Werdnig-Hoffmann disease in two infants. American Journal of Neuroradiology. 19 (3): 550. Pubmed
- 4. Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 3 (2): 49-51. doi:10.1053/ejpn.1999.0181 - Pubmed
- 5. Chan WP, Liu GC. MR imaging of primary skeletal muscle diseases in children. AJR Am J Roentgenol. 2002;179 (4): 989-97. AJR Am J Roentgenol (full text) - Pubmed citation
- 6. Murphy WA, Totty WG, Carroll JE. MRI of normal and pathologic skeletal muscle. AJR Am J Roentgenol. 1986;146 (3): 565-74. AJR Am J Roentgenol (abstract) - Pubmed citation
- 7. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 86 (10): 890-7. doi:10.1212/WNL.0000000000002445 - Pubmed
- 8. Corey DR. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nature neuroscience. 20 (4): 497-499. doi:10.1038/nn.4508 - Pubmed
- 9. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT. Single-dose gene-replacement therapy for spinal muscular atrophy. (2017) New England Journal of Medicine. 2;377 (18): 1713-22. doi:10.1056/NEJMoa1706198