Mutations in the SMN1, UBA1, DYNC1H1, and VAPB genes cause spinal muscular atrophy. Extra copies of the SMN2 gene modify the severity of spinal muscular atrophy.  The SMN1 and SMN2 genes provide instructions for making a protein called the survival motor neuron (SMN) protein. The SMN protein is important for the maintenance of specialized nerve cells called motor neurons. Motor neurons are located in the spinal cord and the brainstem; they control muscle movement. Most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is full size and functional.  Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. SMN1 gene mutations lead to a shortage of the SMN protein. Without SMN protein, motor neurons die, and nerve impulses are not passed between the brain and muscles. As a result, some muscles cannot perform their normal functions, leading to weakness and impaired movement.  Some people with type II, III, or IV spinal muscular atrophy have three or more copies of the SMN2 gene in each cell. Having multiple copies of the SMN2 gene can modify the course of spinal muscular atrophy. The additional SMN proteins produced from the extra copies of the SMN2 gene can help replace some of the SMN protein that is lost due to mutations in the SMN1 gene. In general, symptoms are less severe and begin later in life as the number of copies of the SMN2 gene increases.  Mutations in the UBA1 gene cause X-linked spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is involved in a process that targets proteins to be broken down (degraded) within cells. UBA1 gene mutations lead to reduced or absent levels of functional enzyme, which disrupts the process of protein degradation. A buildup of proteins in the cell can cause it to die; motor neurons are particularly susceptible to damage from protein buildup.  The DYNC1H1 gene provides instructions for making a protein that is part of a group (complex) of proteins called dynein. This complex is found in the fluid inside cells (cytoplasm), where it is part of a network that moves proteins and other materials. In neurons, dynein moves cellular materials away from the junctions between neurons (synapses) to the center of the cell. This process helps transmit chemical messages from one neuron to another. DYNC1H1 gene mutations that cause SMA-LED disrupt the function of the dynein complex. As a result, the movement of proteins, cellular structures, and other materials within cells are impaired. A decrease in chemical messaging between neurons that control muscle movement is thought to contribute to the muscle weakness experienced by people with SMA-LED. It is unclear why this condition affects only the lower extremities.  The adult-onset form of spinal muscular atrophy is caused by a mutation in the VAPB gene. The VAPB gene provides instructions for making a protein that is found in cells throughout the body. Researchers suggest that this protein may play a role in preventing the buildup of unfolded or misfolded proteins within cells. It is unclear how a VAPB gene mutation leads to the loss of motor neurons. An impaired VAPB protein might cause misfolded and unfolded proteins to accumulate and impair the normal function of motor neurons.  Other types of spinal muscular atrophy that primarily affect the lower legs and feet and the lower arms and hands are caused by the dysfunction of neurons in the spinal cord. When spinal muscular atrophy shows this pattern of signs and symptoms, it is also known as distal hereditary motor neuropathy. The various types of this condition are caused by mutations in other genes.