Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

Abstract

Proximal spinal muscular atrophy (SMA) is a progressive neurodegenerative disease associated with the loss of alpha motor neurons in the lumbar spinal cord. The loss of these motor neurons leads to the progressive atrophy of the associated proximal muscles, eventual respiratory distress, and death. SMA occurs in about 1 in 6,000 to 10,000 live births and is a leading genetic cause of infant mortality (Burnett et al. 2009). SMA is subdivided into several groupings based on disease onset, severity, and outcome. The most severe form of SMA is referred to as type 0, or embryonic SMA, wherein patients are born with severe muscle atrophy and have expected lifespans of less than 6 months. The most common type of SMA is type I, which is characterized by disease onset within 6 months and mortality by age 2. Children with SMA type I often fail to sit unaided or walk, have difficulty breathing, and often require respiratory assistance. SMA type II children experience disease onset between 6 to 18 months and will not gain the ability to walk. Two forms of SMA are characterized by disease onset later in life and have unaltered life expectancies: juvenile and adult onset SMA, or type III and IV, respectively. Juvenile onset SMA type III is distinguished by disease onset after the age of 2, but there is variability of onset that can extend to early teen years. Type III children are often able to walk, and the ability to remain ambulatory throughout life can further subdivide this juvenile onset SMA. The least severe form of SMA is adult onset SMA type IV. This form of SMA does not emerge until the adult years and often presents with difficulty in performing previously attainable activities, such as climbing stairs (Zerres et al. 1995; Zerres et al. 1997; Zerres et al. 1997). In SMA disease progression, the inability to achieve normal motor function is often the primary indication of disease. The level of motor function decline in SMA disease progression can be measured by the loss of functional motor units in SMA patients. In severe forms of SMA, there is a rapid loss of motor neurons innervating proximal muscles. This measure of reduced motor units can be observed by evaluating the Compound Motor Action Potential (CMAP) and Motor Unit Number Estimation (MUNE). The total number of innervated motor units is reduced in SMA disease as measured by these two tests and is correlated with age, severity of disease, and disease progression (Swoboda et al. 2005). The loss of motor neurons early in the onset of disease argues for the significance of motor neurons in disease, although additional components of the disease may provide for the