Spinocerebellar ataxia

Definition

The spinocerebellar ataxias (SCAs) are a group of inherited conditions that affect the brain and spinal cord, causing progressive difficulty with coordination. Some types of SCA also involve impairment of speech and eye movement.

Description

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 2005, at least 25 different types of SCA have been described. This group is numbered 1–26, 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.

Genetic profile

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 ), which 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 usually 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 DNA word is repeated a certain number of times. In most of the types of SCA, the DNA word that is repeated is CAG. So there is a part of the gene that reads CAGCAGCAGCAGCA G…and so on. In people who have SCA, this DNA segment is repeated too many times, making this section of the gene too big. This is called a trinucleotide repeat expansion. In SCA8, the DNA word that is repeated is CTG. In SCA10, the repeated DNA word is five DNA letters long and is ATTCT. This is called a pentanucleotide expansion. The actual number of DNA repeats that is normal or that causes SCA is different in each type of SCA.

In each type of SCA, there are a certain range or number of repeats that still fall within the normal range. People who have repeat numbers in the normal range will not develop SCA and cannot pass it to their children. There are 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 generalized 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 DNA expansion grows larger during the passing on of genes. This is called anticipation. Anticipation can result in an even earlier age of onset in children than in their affected parent. Anticipation does not occur in SCA6. However, significant anticipation can occur in SCA7. It is not unusual for a child with SCA7 to be affected before their parent or even grandparent begins to show symptoms. In most types of SCA, anticipation happens more often when a father passes SCA on to his children then when a mother passes it. However, in SCA8, the opposite is true; anticipation happens more often when a mother passes SCA8 to her children. Occasionally, repeat sizes stay the same or even get smaller when they are passed to a person's children.

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 on to 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 onto 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 definitive 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.

Demographics

SCA has been found in people from all over the world. However, some of the types of SCA are more common in certain areas and ethnic groups. SCA types 1, 2, 3, 6, 7, and 8 are the most commonly documented autosomal dominant SCA. SCA1 accounts for at least 25% of SCA cases in South Africa and Italy. SCA2 accounts for 25% of SCA cases in Singapore, India, and Italy. SCA3 appears to be the most common type and was first described in families from Portugal. SCA3 accounts for almost 100% of SCA cases in Brazil. SCA3 also accounts for the majority of SCA cases in Portugal, the Netherlands, Germany, China, and Singapore, and a significant proportion in Japan. SCA6 accounts for a significant proportion of SCA cases in the Netherlands, Germany, and Japan. In the United States, SCA2, SCA3, and SCA6 account for the majority of documented cases; these three types also account for 51% of worldwide cases. SCA1, SCA7, and SCA8 each account for less than 10% of SCA cases worldwide.

SCA types 4, 5, and 10 through 26 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 2005, SCA10 has only been described in Mexican families, SCA13 and 25 have each only been described in single French families, SCA14 and 16 have each only been described in single families from Japan, and SCA19 and 23 have each only been described in single Dutch families.

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 and 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 often a wheelchair. Because of the uncoordinated walking that develops, it is not uncommon for people with SCA to be mistaken for being intoxicated. Carrying around a note from their doctor explaining their medical condition can often be helpful.

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 may have slower eye movements; this does not usually interfere with a person's sight. People with SCA1 and 3 may develop problems with the peripheral nerves, which 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 may cause a loss of sensation, but affected individuals often have a normal lifespan. SCA5 often has an adult onset, and is slowly progressive, not affecting the lifespan. SCA6 often has a later onset, progresses very slowly, and does not shorten the lifespan. SCA7 involves progressive visual loss that eventually leads to blindness. SCA8 may cause sensory loss, but people have a normal lifespan. SCA10 may cause affected individuals to develop seizures. SCA11 is a relatively mild type, resulting in a normal lifespan for the affected person. SCA12 cases often develop a tremor as the first noticeable symptom and the people may eventually develop dementia. SCA13 may cause individuals to be shorter than average and have mild mental retardation. SCA14 may have an early onset, between 12 and 42 years of age, with an average of 28 years of age. SCA15 and 22 may be slow to progress, with SCA22 sometimes being early onset. SCA16 may involve tremors, SCA17 may involve mental deterioration, and SCA19 may involve both. SCA20 may result in calcification of some brain areas that shows up on brain imaging tests. SCA21 can be early onset, but involve only mild cognitive impairment. SCA23 is late onset and may involve sensory loss. SCA25 may also cause sensory loss. SCA26 may involve irregular eye movements.

Diagnosis

Genetic forms of ataxia must be distinguished from non-genetic causes of ataxia that may have their own, individual treatment. Non-genetic causes of ataxia are not types of SCA, and include alcoholism, vitamin deficiencies, multiple sclerosis, vascular disease, and some cancers. The genetic forms of ataxia, such as SCA, are diagnosed by family history, physical examination, and brain imaging.

An initial workup of people who are having symptoms of ataxia will include questions about a person's medical history and a physical examination. 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, which 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 is counted. As of early 2005, clinical testing is available to detect the mutations that cause SCA1, 2, 3, 6, 7, 8, 10, 12, 14, and 17. These tests may be offered as two sequential groups based on population frequency. Testing is often first performed for the more common ataxias, SCA1 through SCA7. Testing for the less common hereditary ataxias are often individualized as appropriate. Factors that may indicate testing for less common SCA types may include factors, such as ethnic background (SCA10 in the Mexican population), or specific symptoms, such as the presence of a tremor (SCA12). In these cases, testing can be performed for a single disease. 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. 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.

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 these visits 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.

If a child is having symptoms, it is appropriate to perform testing to confirm the cause of their symptoms. However, testing will not be performed on children who are at risk for developing SCA, but are not having symptoms. Children can make their own choice whether to know this information when they are old enough to make a mature decision. Testing a child who does not have symptoms could lead to possible problems with their future relationships, education, career, and insurance.

Testing a pregnant woman 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 between 10 and 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 fetus and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it. 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.

Treatment and management

Although there is a lot of ongoing research 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. Canes, walkers, and wheelchairs are often useful. A speech therapist may recommend devices that may make communication easier as speech progressively becomes affected. As swallowing becomes more difficult, a special swallow evaluation may lead to better strategies for eating and to help lessen the risk of choking.

Genetic counseling helps people and their families make decisions about their medical care, genetic testing, and having children. 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.

Prognosis

Most people with the SCAs do have progression of their symptoms that leads to fulltime 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.

Resources

PERIODICALS

Evidente, V. G. H., et al. "Hereditary Ataxias." Mayo Clinic Proceedings (2000): 475–490.

Zohgbi, H. Y., and H. T. Orr. "Glutamine Repeats and Neurodegeneration." Mayo Clinic Proceedings (2000): 217–247.

ORGANIZATIONS

National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 553-0167. E-mail: [email protected]. (April 23, 2005.) <http://www.ataxia.org>.

WE MOVE (Worldwide Education and Awareness for Movement Disorders). 204 E. 84th St., New York, NY 10024. (212) 875-8312 or (800) 437-MOV2. Fax: (212) 875-8389. E-mail: [email protected]. (April 23, 2005.) <http://www.wemove.org>.

WEBSITES

Hereditary Ataxia Overview. (April 23, 2005.) <http://www.geneclinics.org/profiles/ataxias/details.html>.

International Network of Ataxia Friends (INTERNAF). (April 23, 2005.) <http://www.internaf.org>.

Online Mendelian Inheritance in Man. (April 23, 2005.) <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM>.

Maria Basile, PhD