Q 2.29. Spinal Muscular Atrophy (SMA)

1. Definition and Background:

   • SMA is an autosomal recessive inherited disease that primarily affects anterior horn cells in the spinal cord.
   • The estimated incidence is 1 in 6,000 to 10,000 live births.
   • Clinically, patients present with hypotonia and progressive symmetric, proximal weakness, typically sparing the facial muscles and diaphragm.
   • Most individuals with SMA have a homozygous deletion of at least exon 7 on the SMN1 gene on chromosome 5q, leading to SMN protein deficiency.
   • In rare cases, pathogenic single nucleotide variants have been found in SMN1.
   • There are also other rare SMA subtypes associated with different genes, collectively known as non-5q SMA.

2. Genetics and Molecular Basis:

   • The SMN1 and SMN2 genes differ by only a few nucleotides and both encode identical full-length SMN proteins.
   • However, the dominant isoform of SMN2 tends to exclude exon 7, resulting in a truncated SMN protein in 90% to 95% of cases.
   • Because SMN2 produces only a small amount of full-length SMN protein, it can only partially compensate for SMN1 deficiency.
   • The severity of SMA symptoms partially correlates with the number of copies of the SMN2 gene.

3. Diagnosis:

   • Diagnosis of SMA is based on clinical evaluation and molecular genetic testing.
   • Supportive diagnostic tests such as EMG and muscle biopsy are now employed more selectively.
   • Newborn screening for SMA has been added to the Recommended Uniform Screening Panel (RUSP) in the US, allowing early initiation of treatment.

4. Clinical Manifestations:

   • There are 5 subtypes of SMA, classified by the greatest motor milestone achieved:
     • SMA type 0: Prenatal onset, most severe phenotype, profound weakness, and hypotonia. Life expectancy is limited to 6 months or less without treatment.
     • SMA type 1 (previously known as Werdnig-Hofmann disease): Presents during infancy with hypotonia, weakness, and delayed motor milestones.

In summary, SMA is a genetic disorder characterized by motor neuron loss, muscle weakness, and progressive degeneration. Early diagnosis and intervention are crucial for better outcomes.

References:
1 practicalneurology.com

2 hopkinsmedicine.org

3 genome.gov

4 mda.org