Spinal Muscular Atrophy (SMA)

Authors: Stephen J. Kolb, M.D., Ph.D., and John T. Kissel, M.D. Affiliation: Department of Neurology and Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH.

Key Points:

1. Incidence and Prevalence:
   • SMA has an incidence of 1:11,000 live births.
   • The carrier state prevalence is approximately 1 in 54.
2. Severity:
   • The clinical severity of SMA is inversely correlated with the SMN2 gene copy number.
   • It varies from extreme weakness and paraplegia in infancy to mild proximal weakness in adulthood.
3. Natural History:
   • SMA's natural history is complex and variable. Clinical subgroups have been defined based on motor function achievement during development:
   • Type 1 SMA: Infants never sit independently.
   • Type 2 SMA: Children sit at some point but never walk independently.
   • Type 3 SMA: Children and adults walk independently at some point.
4. Introduction:
   • SMA refers to genetic disorders characterized by anterior horn cell degeneration, leading to muscle atrophy and weakness.
   • Over 95% of SMA cases result from a homozygous deletion or mutation in the 5q13 survival of motor neuron (SMN) gene.
   • The severity of SMA is variable, with four main phenotypes based on age of onset and maximum motor function.
   • There's no cure, but understanding its molecular genetics has led to potential therapeutic approaches.
5. Clinical Features:
   • SMA's primary clinical features are muscle weakness and atrophy, with proximal muscles more affected than distal ones.
   • Clinical manifestations range from severe weakness in neonates (Type 0) to milder forms in adults (Type 4).
   • Type 0: Prenatal onset with severe weakness, leading to respiratory failure and death within 6 months.
   • Type 1 (Werdnig-Hoffman disease): Infants present with hypotonia, poor head control, and reduced reflexes before 6 months. They never sit unassisted and usually develop respiratory failure before 2 years.
   • Type 2: Children can sit but never walk independently. They experience progressive proximal leg weakness.
   • Type 3 (Kugelberg-Welander disease): Children and adults can walk unassisted at some point in their life. They have progressive proximal leg weakness.
   • Type 4: Represents less than 5% of SMA cases and is the mildest form. Onset is in adulthood, often after age 30.
6. Molecular Genetics:
   • The report touches upon the genetic etiology of SMA, but the provided data is incomplete in this section.