About spinal muscular atrophy

What is spinal muscular atrophy?
Spinal muscular atrophy is a term for a group of inherited neuromuscular diseases. All forms of the disease affect specialized nerve cells called motor neurons, which control the movement of voluntary muscles. SMA causes lower motor neurons in the base of the brain and the spinal cord to disintegrate, preventing them from delivering electrical and chemical signals that muscles depend on for normal function.
Involuntary muscles, such as those that control bladder and bowel function, are not affected in SMA. Hearing and vision are not affected, and intelligence is normal or above average. Investigators have noted that children with SMA can have very high intelligence.

What are the different forms of the disease?
The three major childhood-onset forms of SMA are now usually called type 1, type 2 and type 3. Types 1 and 3 are sometimes referred to by the names of the doctors who first described them. Werdnig-Hoffmann disease is sometimes used for type 1 SMA and Kugelberg-Welander disease for type 3.
All three types are also known as autosomal recessive SMA because of the way they are inherited. Both parents must pass on the defective gene in order for their children to inherit the disease.
Types 1, 2 and 3 appear to be variants of the same condition, because they all appear to arise from a defect in the same gene on chromosome 5 resulting in insufficient production of SMN protein (survival of motor neurons).
Occasionally, SMA is inherited as an autosomal dominant condition. In these cases, only one parent need have a genetic defect for a child to show the disease.
In addition, there is a form of the disease known as X-linked spinal-bulbar muscular atrophy (SBMA), also known as Kennedy's disease, that arises from a defect in a gene called the androgen receptor gene on the X chromosome.
Some doctors use the term SMA type 4 for adult-onset SMA, regardless of the inheritance pattern.

How do the forms of the disease differ?
They differ mostly in their time of onset and rate of progression. All forms affect the skeletal muscles of the trunk and limbs. In general, those muscles closer to the center of the body are more affected than those farther away.
SMA type 1 and SBMA affect the neurons controlling the mouth and throat muscles more and therefore involve more problems with chewing and swallowing.
Respiratory muscles are involved to varying degrees in all forms of the disease.
In SMA type 1, the most severe form, the onset of the disease is noted within the first 6 months of the child's life. Children with SMA type 1 are never able to sit without support, and death usually occurs within few years from the birth.
SMA type 2 is an intermediate form of the disease. Onset is between 7 and 18 months. Children with SMA type 2 generally do learn to sit without support but usually don't learn to stand or walk without aid. The child's survival depends in large part on the degree of respiratory and swallowing difficulties.
SMA type 3 is a milder form of this condition. Onset occurs after the age 18 months and is most often between the ages of 5 and 15 years. Weakness of the muscles of chewing and swallowing is rare, and respiratory effects are generally not as severe as in the first two forms. Respiratory complications, if they occur, pose the most serious threat to life.
It's important to note that these categories are somewhat arbitrary. Some children with early-onset disease do better than expected.
SMA type 4 is a term sometimes used to refer to SMA that begins in adulthood.
Autosomal dominant SMA forms differ from SMA types 1, 2 and 3 in their inheritance pattern and sometimes in the nerve cells and muscles affected. There have been reports of autosomal dominant SMA. It primarily affects certain muscle groups and mostly spares others.
X-linked spinal-bulbar muscular atrophy (SBMA) appears to be a rare disease and to affect only men. It begins in adulthood and arises from a defect in a gene on the X chromosome that changes the way cells use androgens, male hormones. The exact relationship between the androgen usage and the motor neuron damage is not yet understood.

How are the spinal muscular atrophies diagnosed?
An experienced physician makes a diagnosis by carefully evaluating the patient's medical history and by performing a thorough physical examination. The clinical diagnosis is then confirmed by a series of laboratory tests.

What if the diagnosis is unclear?
It's sometimes difficult to distinguish between SMA and other neuromuscular disorders. In these cases, physicians use tests to help them arrive at a diagnosis.

What are some common diagnostic tests?
Studying a small piece of muscle tissue taken from an individual during a muscle biopsy often enables a pathologist to determine whether a disorder is one of the spinal muscular atrophies.
Another diagnostic test is the electromyogram (EMG). By placing small electrodes in muscle, this test creates a graph of muscle contractions.
Blood tests are administered to evaluate the levels of certain enzymes, helping to distinguish the spinal muscular atrophies from other neuromuscular diseases.
Genetic tests using blood samples can be done to identify carriers of SMA as well as someone with the disease.

Is there any treatment for SMA?
At present, there is no known treatment that will stop or reverse any form of SMA.

Can something be done to alleviate the symptoms?
Yes. Physical therapy and orthopedic devices can help preserve walking longer. Orthopedic devices or surgery may also help to counteract scoliosis, or curvature of the spine.

Is SMA contagious?
No.Genetic disorders aren't contagious.

What causes SMA?
All of the spinal muscular atrophies are caused by one or more gene defects. Humans have an estimated 100,000 genes.

How does a gene defect cause SMA?
When genes are defective, they are unable to properly produce proteins that are necessary for a cell to function. A destructive chain of events can be triggered when a protein is absent, when there is too little or too much of it, or if it doesn't work properly for any reason. In the case of spinal muscular atrophy, protein abnormalities prevent the normal functioning of motor neurons, leading to their deterioration and muscle degeneration.
Early in 1995, Alex MacKenzie at Children's Hospital of Eastern Ontario in Ottawa, Canada, was part of an international team that discovered an association between flaws in a certain gene on chromosome 5 and SMA. They called their gene a neuronal apoptosis inhibitory protein, or NAIP, gene. Their hypothesis is that the protein made from this gene's instructions may help protect cells from a type of cell death known as apoptosis.
At the same time, a French group under Arnold Munnich and Judith Melki at the INSERM at the Hopital des Enfants Malades in Paris identified defects in another gene within the same chromosome 5 region that also seemed to play a role in causing SMA. The French named their discovery the SMN, or survival of motor neurons, gene. The lack of SMN affects cell's ability to produce proteins. The presence of an intact NAIP gene may lessen the impact of a defect in the SMN gene.
The cause of X-linked spinal-bulbar muscular atrophy has been identified by MDA-supported researchers as a defect in a gene for an androgen receptor. This gene, which is on the X chromosome, contains information for production of an androgen receptor protein. Androgens (male hormones), after attaching to androgen receptors, normally act in the cell's nucleus to "turn on" or "turn off" certain genes. Just how a flawed androgen receptor might cause SBMA is not yet known.

How is SMA inherited?
Humans have 23 pairs of chromosomes - 22 pairs of autosomes, which are the same in both sexes, and one pair of sex chromosomes. Females have two X chromosomes, while males have one X and one Y chromosome. Diseases are said to be "autosomal" when they're inherited on one of the 22 non-sex chromosomes. They're called sex-linked when they're inherited on the X or Y chromosome. SMA types 1, 2 and 3 are thought to be inherited in an autosomal recessive pattern. This means that the inheritance is not sex-linked; that is, not on an X or Y chromosome. The term "recessive" means that two defective genes, one from each parent, are necessary to produce disease symptoms.
Autosomal dominant SMA is also inherited on a chromosome other than the X or Y. However, unlike recessive SMA, it requires a genetic defect from only one parent to produce disease symptoms.
X-linked SBMA is carried on the X chromosome. X-linked recessive diseases usually only affect males. Females are somewhat protected by having two copies of the X chromosome, one of which usually contains a normal version of the gene. Men have only one X chromosome, so the effect of any X chromosome defect is not offset by a normal version of the gene from a second X chromosome. Women and girls sometimes show a mild form of an X-linked disease.

Is there a carrier-detection test for SMA?
Yes. A few medical centers and private laboratories will do genetic testing for those affected and for carriers in SMA types 1, 2 and 3, and in X-linked SBMA.

(sources: FSMA and UILDM websites)