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Spinal muscular atrophy

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Your Question

My brother's daughter was recently diagnosed with spinal muscular atrophy. What can you you tell me about this condition, particularly as it relates to the SMN genes? Can this condition be treated? What is the prognosis?

Our Answer

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What is spinal muscular atrophy?

Spinal muscular atrophy is a group of inherited disorders that cause progressive muscle degeneration and weakness.[1][2] 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, the muscles used for breathing and swallowing are affected.[3][4] Spinal muscular atrophy is divided into subtypes based on the severity of the disease and the age when symptoms first appear.[1][3] It is usually inherited as an autosomal recessive trait.[1]

Last updated: 4/21/2010

What are the signs and symptoms of spinal muscular atrophy?

Spinal muscular atrophy (SMA) is chiefly characterized by progressive muscle weakness. Depending on the type, onset may range from before birth to adolescence or young adulthood.[5]

SMA type 0 (the prenatal form) is the most severe form and begins before birth. Usually, the first symptom of type 0 is reduced movement of the fetus that is first seen between 30 and 36 weeks of the pregnancy. After birth, these newborns have little movement and have difficulties with swallowing and breathing.[1] Life span is approximately 2-6 months.[5] 

There are 4 types of SMA that tend to affect children before the age of one (SMA type I, SMA type II, X-linked SMA and distal SMA type I). SMA I is a severe form that may be apparent at birth or the first few months of life. Features may include difficulty swallowing or breathing and inability to sit without support.[6] The life span is usually less than 2 years.[5] SMA II typically becomes apparent between 6 and 12 months of age; affected children may sit without support, although they cannot stand or walk unaided.[6] About 70% of individuals with this type live to be at least 25 years of age.[5] X-linked infantile SMA is similar to SMA I; additional features may include joint deformities (contractures) or being are born with broken bones in very severe cases. Signs and symptoms of distal SMA type I typically appear between 6 weeks and 6 months of age, although in rare cases affected individuals may not show symptoms until as late as adolescence. This type is characterized by progressive muscle weakness in the hands and feet that eventually spreads to the limbs, as well as paralysis of the diaphragm that leads to respiratory failure.[6]

Three other types of SMA can affect people in early childhood and adulthood.[6] SMA type III (called Kugelberg-Welander disease or juvenile type) is a milder form of spinal muscular atrophy than types 0, I or II. Symptoms appear between early childhood (older than age 1 year) and early adulthood. Individuals with type III are able to stand and walk without help. They usually lose their ability to stand and walk later in life.[1] SMA type IV and Finkel type occur in adulthood, usually after age 30. Symptoms of adult-onset SMA are usually mild to moderate and include muscle weakness, tremor and twitching.[1]
Last updated: 11/28/2011

What genes are related to spinal muscular atrophy?

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.[3]
Last updated: 4/21/2010

What can you tell me about the SMN genes and their relationship to 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, which are located in the spinal cord and the brainstem, 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.[3]

Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. Mutations in the SMN1 gene 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.[3]

Normally, each cell has two copies of the SMN1 gene and up to two copies of the SMN2 gene.[7][8]  In some cases, individuals have three or more copies of the SMN2 gene. In those with spinal muscular atrophy, additional copies of the SMN2 gene are associated with a milder course of the disease.[8] About 95 percent of individuals with spinal muscular atrophy have mutations that delete a section called exon 7 in both copies of this gene. As a result, little or no SMN protein is made.[7] Extra SMN2 genes can help replace some of the SMN protein that is lost due to mutations in the SMN1 genes. The symptoms of spinal muscular atrophy still occur, however, because only a small amount of the full-size SMN protein is produced from the SMN2 genes. In general, symptoms are less severe and begin later in life in affected individuals with three or more copies of the SMN2 gene compared with those who have two copies of this gene.[8]

It is unclear why motor neurons are particularly vulnerable to a shortage of the SMN protein. Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. Without mature mRNA, the production of proteins necessary for cell growth and function is disrupted. Research has indicated that motor neurons are particularly sensitive to this disruption and die prematurely. Some research findings indicate that a shortage of SMN protein impairs the formation and function of axons and dendrites, possibly leading to the death of neurons. While the cause of neuronal death is unclear, it is the loss of motor neurons that leads to the signs and symptoms of spinal muscular atrophy.[7]

Last updated: 4/21/2010

How is spinal muscular atrophy inherited?

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.[3]

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.[3]

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 striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.[3]

Last updated: 11/28/2011

How might spinal muscular atrophy be treated?

There is currently no specific cure for spinal muscular atrophy. Infants who have a severe form of the disease frequently die of respiratory failure due to weakness of the muscles that help with breathing. Children who have milder forms will live much longer but may need extensive medical support.[1]

The current treatment for spinal muscular atrophy involves prevention and management of the secondary effects of muscle weakness and loss. Respiratory, nutritional and rehabilitation care are available. In addition, several drugs have been identified in laboratory experiments that may help some patients. Some of the drugs that are currently being investigated include: Butyrates, valproic acid, hydroxyurea, and riluzole.[1]
Last updated: 11/28/2011

What is the prognosis for individuals with spinal muscular atrophy?

The lifespan in spinal muscular atrophy type 1 is seldom longer than 2 - 3 years. Survival time with type II is longer, but the disease takes the lives of most of those affected while they are still children. Children with type III disease may survive into early adulthood. However, people with all forms of the disease have worsening weakness and debility.[2] 
Last updated: 4/21/2010

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