What causes spinal muscle atrophy (SMA)?

Updated: May 04, 2020
  • Author: Ashish S Ranade, MBBS, MS, MRCS; Chief Editor: Jeffrey A Goldstein, MD  more...
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Patients with SMA have a homozygous deletion of the telomeric SMN gene SMN1, which is found in arm 5q13 (bands q11.2-13.3). [9]  This deletion has been demonstrated in as many as 98% of patients with SMA.

SMN1 encodes the SMN protein, which is part of a multiprotein complex required for the biogenesis of small nuclear ribonucleoproteins. [11, 12]  The SMN protein is critical to the health and survival of the nerve cells in the spinal cord that are responsible for muscle contraction (motor neurons). SMN1 has been linked to pre-mRNA splicing, spliceosome biogenesis, and the nucleolar protein fibrillarin. The absence or dysfunction of SMN is reflected by an enhanced neuronal death. A heterozygous deletion leads to an asymptomatic carrier state. [13]

A second gene also plays a role in producing the SMN protein—namely, SMN2, often called the SMA "backup gene." SMN2 is present in most individuals, including those with SMA. It is almost identical to SMN1, differing only by five nucleotides. Several versions of the SMN protein are produced by SMN2, but only one version (isoform d) is complete and functional. The other proteins produced by SMN2 are more labile and are unable to compensate fully for the absence of SMN1. [14]  Thus, only 10-15% of all functional SMN protein is produced from SMN2.

Most people have two copies of SMN1 and one or two copies of SMN2. The number of copies of SMN2 is variable, and some people have as many as eight copies. The severity of SMA is inversely related to the number of copies of SMN2. Most severely affected individuals will have fewer copies of this gene. [15]  The SMN2 gene copy number is related to, but not predictive of, disease severity, and care decisions should not be made on the basis of copy number alone. Other genetic modifiers, such as the protein plastin-3 (PLS3), may influence disease severity. [16]

A significant increase in nuclear DNA vulnerability was detected in fetuses with SMA at 12-15 weeks' gestational age. This reflected a decrease in the number of anterior horn neurons. This vulnerability is no longer seen in the rest of the antenatal or postnatal period. Abnormal cell morphology was seen only in the postnatal period. [17]

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