The spinocerebellar ataxias (SCAs) are a group of inherited conditions that affect the brain and spinal cord causing progressive difficulty with coordination.
The SCAs are named for the parts of the nervous system that are affected in this condition. Spino refers to the spinal cord and cerebellar refers to the cerebellum or back part of the brain. The cerebellum is the area of the brain that controls coordination. In people with SCA, the cerebellum often becomes atrophied or smaller. Symptoms of SCA usually begin in the 30s or 40s, but onset can be at any age. Onset from childhood through the 70s has been reported.
As of early 2001, at least 13 different types of SCA have been described. This group is numbered 1-14 and each is caused by mutations or changes in a different gene. Although the category of SCA9 has been reserved, there is no described condition for SCA9 and no gene has been found. Spinocerebellar ataxia has also been called olivopontocerebellar atrophy, Marie's ataxia, and cerebellar degeneration. SCA3 is sometimes called Machado-Joseph disease named after two of the first families described with this condition. All affected people in a family have the same type of SCA.
Although each of the SCAs is caused by mutations in different genes, the types of mutations are the same in all of the genes that have been found. Most genes come in pairs; one member of a pair comes from a person's mother and the other one comes from their father. The genes are made up of deoxyribonucleic acid (DNA) and the DNA is made up of chemical bases that are represented by the letters C, T, G, and A. This is the DNA alphabet. The letters are put together in three letter words. The arrangement of the words are what give the gene its meaning and therefore tells the body how to grow and develop.
In each of the genes that cause SCA, there is a section of the gene where a three letter word is repeated a certain number of times. In most of the types of SCA, the word that is repeated is CAG. So there is a part of the gene that reads CAGCAGCAGCAGCAG...and so on. In people who have SCA, this word is repeated too many times. Therefore, this section of the gene is too big. This is called a trinucleotide repeat expansion. In SCA8 the word that is repeated is CTG. In SCA10, the repeated word is five DNA letters long and is ATTCT. This is called a pentanucleotide expansion. The actual number of words that is normal or that causes SCA is different in each type of SCA.
In each type of SCA, there are a certain number of words that are normal (the normal range). People who have repeat numbers in the normal range will not develop SCA and cannot pass it to their children. There is also a certain number of repeats that cause SCA (the affected range). People who have repeat numbers in the affected range will go on to develop SCA sometime in their lifetime if they live long enough. People with repeat numbers in the affected range can pass SCA onto their children. Between the normal and affected ranges there is a gray range. People who have repeat numbers in the gray range may or may not develop SCA in their lifetime. Why some people with numbers in the gray zone develop SCA and others do not is not known. People with repeat numbers in the gray range can also pass SCA onto their children.
In general, the more repeats in the affected range that someone has, the earlier the age of onset of symptoms and the more severe the symptoms. However, this is a general rule. It is not possible to look at a person's repeat number and predict at what age they will begin to have symptoms or how their condition will progress.
Sometimes when a person who has repeat numbers in the affected or gray range has children, the expansion
The SCAs are passed on by autosomal dominant inheritance. This means that males and females are equally likely to be affected. It also means that only one gene in the pair needs to have the mutation in order for a person to become affected. Since a person only passes one copy of each gene onto their children, there is a 50% or one in two chance that a person who has SCA will pass it on to each of their children. A person who has repeat numbers in the gray range also has a 50% or one in two chance of passing the gene on to each of their children. However, whether or not their children will develop SCA depends on the number of their repeats. A person who has repeat numbers in the normal range cannot pass SCA onto their children.
Usually a person with SCA has a long family history of the condition. However, sometimes a person with SCA appears to be the only one affected in the family. This can be due to a couple of reasons. First, it is possible that one of their parents is or was affected, but died before they began to show symptoms. It is also possible that their parent had a mutation in the gray range and was not affected, but the mutation expanded into the affected range when it was passed on. Other family members may also have SCA but have been misdiagnosed with another condition or are having symptoms, but have no diagnosis. It is also possible that a person has a new mutation for SCA. New mutations are changes in the gene that happen for the first time in an affected person. Although a person with a new mutation may not have other affected family members, they still have a 50% or one in two chance of passing it on to their children.
SCA has been found in people from all over the world. However, some of the types of SCA may be more common in certain areas and ethnic groups. SCA types 1, 2, 3, 6, and 7 account for the majority of autosomal dominant SCA. SCA3 appears to be the most common type and was first described in families from Portugal. SCA3 also seems to be the most common type in Germany. SCA8 accounts for about 2-5% of all SCA. SCA types 4, 5, 10, 11, 12, 13, and 14 are rare and have each only been described in a few families. The first family described with SCA5 may have been distantly related to President Abraham Lincoln and was first called Lincoln ataxia. As of early 2001, SCA10 has only been described in Mexican families, SCA13 has only been described in one French family, and SCA14 has only been found in one family from Japan.
Signs and symptoms
Although different genes cause each of the SCAs, they all have similar symptoms. All people with SCA have ataxia or a lack of muscle coordination. Walking is affected and eventually the coordination of the arms, hands, and of the speech and swallowing is also affected. One of first symptoms of SCA is often problems with walking and difficulties with balance. The muscles that control speech and swallowing usually become affected. This results in dysarthria or slurred speech and difficulties with eating. Choking while eating can become a significant problem and can lead to a decrease in the number of calories a person can take in. The age of the onset of symptoms can vary greatly—anywhere from childhood through the seventh decade have been reported. The age of onset and severity of symptoms can also vary between people in the same family.
As the condition progresses, walking becomes more difficult and it is necessary to use a cane, walker, and eventually a wheelchair. Because of the uncoordinated walking that develops, it is not uncommon for people with SCA to be mistaken for being intoxicated. Carrying
Some of the SCA types can also have other symptoms, although not all of these are seen in every person with that particular type. SCA2: People with this type may have slower eye movements. This does not usually interfere with a person's sight. SCA3: In this type people may develop problems with the peripheral nerves—those nerves that carry information to and from the spinal cord. This can lead to decreased sensation and weakness in the hands and feet. In SCA3 people may also have twitching in the face and tongue, and bulging eyes. SCA4: People with this type may have a loss of sensation but often have a normal lifespan. SCA5: This type often has an adult onset and is slowly progressive, not affecting a person's lifespan. SCA6: This type often has a later onset, progresses very slowly and does not shorten a person's life. SCA7: Progressive visual loss that eventually leads to blindness always happens with this type. SCA10: A few people with this type have had seizures. SCA11: This type is relatively mild and people have a normal lifespan. SCA12: People often have a tremor as the first noticeable symptom and may eventually develop dementia. SCA13: Some people with this type are shorter than average and have mild mental retardation.
An initial workup of people who are having symptoms of ataxia will include questions about a person's medical history and a physical examination. Blood work to rule out other causes of the ataxia such as vitamin deficiencies may also be done. Magnetic resonance imaging (MRI) of the brain in people with SCA will usually show degeneration or atrophy of the cerebellum and may be helpful in suggesting a diagnosis of SCA. A thorough family history should be taken to determine if others in the family have similar symptoms and the inheritance pattern in the family.
Since there is so much overlap between symptoms in the different types of SCA, it is not usually possible to tell the different types apart based on clinical symptoms. The only way to definitively diagnose SCA and determine a specific subtype is by genetic testing. This involves drawing a small amount of blood. The DNA in the blood cells is then examined and the number of CAG repeats in each of the SCA genes are counted. As of early 2001, clinical testing is available to detect the mutations that cause SCA1, 2, 3, 6, 7, 8, and 10.
If genetic testing is negative for the available testing, it does not mean that a person does not have SCA. It could mean that they have a type of SCA for which genetic testing is not yet available.
It is possible to test someone who is at risk for developing SCA before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms, or the course of the disease. The decision to undergo this testing is a very personal decision and one that a person can only make for his or her self. Some people choose to have testing so that they can make decisions about having children or about their future education, career, or finances. Protocols for predictive testing have been developed, and only certain centers perform this testing. Most centers require that the diagnosis of SCA has been confirmed by genetic testing in another family member. It is also strongly suggested that a person have a support person, either a spouse or close friend, be with them at all visits.
A person who is interested in testing will be seen by a team of specialists over the course of a few visits. Often they will meet a neurologist who will perform a neurological examination to see if they may be showing early signs of the condition. If a person is having symptoms, testing may be performed to confirm the diagnosis. The person will also meet with a genetic counselor to talk about SCA, how it is inherited, and what testing can and cannot tell someone. They will also explore reasons for testing and what impact the results may have on their life, their family, their job and their insurance. Most centers also require a person going through predictive testing to meet a few times with a psychologist. The purpose of this visit is to make sure that the person has thought through the decision to be tested and is prepared to deal with whatever the results may be. These visits also allow a person to make contact with someone who can help him or her deal with the results if necessary. All centers require that results are given in person and usually require that a person come in for a few follow-up visits, regardless of the testing results.
These protocols are not in place to make people go through endless steps to get testing. Rather they have been developed to make sure that people make the best decision for themselves, their life, and their family and that they are prepared to cope with the results, whatever the outcome. Once the results are given, it is not possible to give them back or forget them. People should therefore take the testing process seriously and give a great deal of consideration to making the decision to be tested.
If a child is having symptoms, it is appropriate to perform testing to confirm the cause of their symptoms.
Testing a pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a certain type of SCA. This can be done at 10-12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor. Continuing a pregnancy that is found to be affected is like performing predictive testing on a child. Therefore couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.
There is also another procedure, called preimplantation diagnosis that allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.
Treatment and management
Although there is a lot of ongoing research to try to learn more about SCA and develop treatments, no cure currently exists for the SCAs. Although vitamin supplements are not a cure or treatment for SCA, they may be recommended if a person is taking in fewer calories because of feeding difficulties. Different types of therapy might be useful to help people maintain as independent a lifestyle as possible. An occupational therapist may be able to suggest adaptive devices to make the activities of daily living easier. For example they may suggest installing bars to use in the bathroom or shower or special utensils for eating. A speech therapist might be able to make recommendations for devices that might make communication easier as the speech becomes affected. As swallowing becomes more difficult, a special swallow evaluation may lead to better strategies for eating and to lessen the risk of choking.
Genetic counseling helps people and their families to make decisions about their medical care, genetic testing, and having children by providing information and support. It can also help people to deal with the medical and emotional issues that arise when there is a genetic condition diagnosed in the family.
Most people with the SCAs do have progression of their symptoms that leads to full time use of a wheelchair. The duration of the disease after the onset of symptoms is about 10-30 years, but can vary depending in part to the number of trinucleotide repeats and age of onset. In general, people with a larger number of repeats have an earlier age of onset and more severe symptoms. Choking can be a major hazard because if food gets into the lungs, a life-threatening pneumonia can result. As the condition progresses, it can become difficult for people to cough and clear secretions. Most people die from respiratory failure or pulmonary complications.
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Karen M. Krajewski, MS