Spinal muscular atrophy

Spinal muscular atrophy is a disorder that affects the control of muscle movement. It is caused by a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The loss of motor neurons leads to weakness and wasting (atrophy) of muscles used for activities such as crawling, walking, sitting up, and controlling head movement. In severe cases of spinal muscular atrophy, the muscles used for breathing and swallowing are affected. Spinal muscular atrophy is divided into subtypes based on the severity of the disease and the age when symptoms appear.

Four types of spinal muscular atrophy affect children before the age of 1. Type I spinal muscular atrophy (also called Werdnig-Hoffman disease) is a severe form of the disorder that is evident at birth or within the first few months of life. Typically, affected infants have difficulty breathing and swallowing and are unable to sit without support.

Type II spinal muscular atrophy is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with type II can sit without support, although they cannot stand or walk unaided.

X-linked infantile spinal muscular atrophy has features that are very similar to type I, except that children with this type are typically born with joint deformities (contractures) that impair movement. In severe cases, affected infants are born with broken bones. Poor muscle tone before birth may contribute to the contractures and broken bones seen in these children.

The fourth type of spinal muscular atrophy that appears in infancy is called distal spinal muscular atrophy type 1. This form of the disorder is characterized by progressive muscle weakness in the hands and feet that eventually spreads to the limbs. Affected individuals also develop paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm), which leads to respiratory failure. The signs and symptoms of distal spinal muscular atrophy type 1 typically appear between ages 6 weeks and 6 months. Rarely, people with this condition do not show symptoms until late childhood or adolescence.

Three other types of spinal muscular atrophy can affect people in early childhood and adulthood. Type III spinal muscular atrophy (also called Kugelberg-Welander disease or juvenile type) is a milder form of the disorder than types I or II, or the X-linked form. Symptoms appear between early childhood and early adulthood. Individuals with type III spinal muscular atrophy can stand and walk unaided, but usually lose this ability later in life. Two types of spinal muscular atrophy, type IV and Finkel type, usually occur after age 30. Symptoms of these adult-onset types of spinal muscular atrophy are typically mild to moderate and include muscle weakness, tremor, and twitching.

Spinal muscular atrophy affects 1 in 6,000 to 1 in 10,000 people.

Mutations in the SMN1, UBA1, VAPB, and IGHMBP2 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.

Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is full size and functional. Most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene.

Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. SMN1 mutations lead to a shortage of the SMN protein, which is needed for the survival of motor neurons. 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. These multiple copies of the SMN2 gene can modify the course of spinal muscular atrophy. Extra SMN2 genes can help replace some of the SMN protein that is lost due to mutations in the SMN1 genes. 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 infantile 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 disrupt the process of protein degradation. A buildup of proteins in cells can cause the cell to die; motor neurons are particularly susceptible to damage from protein buildup.

Finkel type 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. Little is known about the function of the VAPB protein. 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.

Mutations in the IGHMBP2 gene cause distal spinal muscular atrophy type 1. The IGHMBP2 gene provides instructions for making a protein that is thought to be involved in copying (replicating) DNA; producing RNA, a chemical cousin of DNA; and producing proteins. IGHMBP2 gene mutations that cause distal spinal muscular atrophy type 1 interfere with the protein's ability to aid in DNA replication and RNA and protein production. Alpha-motor neurons, which are motor neurons located in the brainstem and spinal cord, are particularly sensitive to a disruption in IGHMBP2 protein function. Over time, these neurons become damaged and die, leading to the progressive muscle weakness seen in people with distal spinal muscular atrophy type 1.

Read more about the IGHMBP2, SMN1, SMN2, UBA1, and VAPB genes.

Spinal muscular atrophy types I, II, III, IV and distal spinal muscular atrophy type 1 are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Finkel type spinal muscular atrophy is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

X-linked infantile spinal muscular atrophy is inherited in an X-linked pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.