What causes spinal muscle atrophy (SMA)?

Updated: Nov 05, 2018
  • 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 5q (bands q11.2-13.3). [10]  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. [12, 13]  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. [14]

There is a second gene that also plays a role in producing the SMN protein—namely, SMN2, often called the SMA "backup gene." The protein produced by SMN2 is more labile and is unable to compensate fully for the absence of SMN1. [15]  The severity of SMA is dependent on the number of copies of SMN2. Most severely affected individuals will have fewer copies of this gene. [16]

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

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