Dominant Spinocerebellar Ataxias (SCA)
There are many different types of Spinocerebellar Ataxia (SCA). These ataxias are all characterized by autosomal dominant inheritance. The primary feature of these disorders is ataxia (problems with balance, speech, and eye movements). The spinocerebellar ataxias are labeled using the acronym “SCA” and then numbered in the order of their discovery.
SCA1 was the first genetic form of dominant ataxia that was discovered in 1993 in two large families from Minnesota and Texas. SCA1 is an autosomal dominant form of ataxia that is caused by a repeat expansion. While symptoms most often develop in the mid 30’s, they can begin in childhood or late in life. The first symptoms are usually problems with walking and coordinating hand movements. Normal repeat numbers in both copies of this gene are usually less than 36. If one gene has 45 or more repeats, the person will develop SCA1. If one gene has between 36-44 repeats, then additional testing may be required to interpret the result.
SCA-2 is sometimes called “Cuban ataxia” because some of the first described families were from Cuba. This form of ataxia was the second form of dominant ataxia described. The inheritance pattern is autosomal dominant and it is caused by a repeat expansion. One common feature of SCA2 is slowness and paralysis of eye movements. Some individuals may have peripheral neuropathy or reduced reflexes. SCA2 can cause problems with memory in some individuals. Repeat numbers in both copies of the SCA2 gene are usually 31 or smaller. If one gene has 32 or more repeats, then the person will develop SCA2. Smaller repeat numbers (32 or 33) may be associated with later onset, while larger repeats (100 or more) may be seen in infants with SCA2.
SCA-3 is also known as Machado-Joseph disease—named after affected families of Azorean ancestry who were descendants of William Machado (Portuguese immigrants living in England) and Antone Joseph (Portuguese sailors who came to California in
1845). The disease has also been identified in other ethnic groups, nationalities, and races.
SCA-3 is an autosomal dominant form of ataxia caused by a repeat expansion. SCA3 can show a variety of symptoms beside ataxia including tremor and stiff muscles (resembling Parkinson disease) and neuropathy. Some individuals may have twitching movements of the face and tongue (resembling Lou Gherig's disease or ALS). There may be abnormal movements of the eye. SCA3 is the most common dominant ataxia in many parts of the world.
If both copies of the gene have 44 or fewer repeats, then the individual will not develop SCA3. If one copy of the SCA3 genes has 45-51 repeats, the individual might develop SCA3. All individuals who have 52 or more repeats will develop SCA3. The repeat number may predict, to a limited degree, the type of symptoms that an individual experiences (ataxia vs. neuropathy vs. Parkinsonism).
SCA-4 was first described in an American family from Utah. This family had Scandinavian ancestry. Since that time, the disease has also been described in a large German family. The hallmarks of this disease are late age of onset, difficulty with coordinating arms and legs, difficulty with speaking, and peripheral neuropathy. While this is one of the first ataxias that was mapped, the exact genetic cause has still not been determined. That is why there is currently no gene test for SCA4. Because the SCA4 and the SCA31 genes are located very close to one another in the genome, scientists have wondered whether or not these may be different forms of the same condition. At the present time, it appears that these are two distinct diseases that are caused by different genes that just happen to be located very closely to one another in our genome.
SCA5 (Lincoln’s ataxia)
This form of ataxia was found in one branch of Abraham Lincoln’s family. It is not known whether or not Abraham Lincoln actually had the disease gene. SCA5 is an autosomal dominant condition caused by sequence changes in a gene called “SPTBN2.” SCA5 is often associated with a young age of onset and slowly progressive symptoms. SCA5 is usually described as a “pure cerebellar ataxia” because other neurological problems are not commonly seen. Results of genetic testing for SCA5 need to be very carefully interpreted because the testing may identify sequence variations of unknown significance.
SCA-6 is an autosomal dominant progressive cerebellar ataxia characterized by slurred speech, changes in eye movements, and lack of coordination in gait and extremities. Age of onset varies considerably, even within the same family, and ranges from 19 to 71 years of age. SCA6 may initially present as an episodic disorder (symptoms occur intermittently) and may be associated with migraine headaches. Treatment with acetazolamide (Diamox) or topiramate (Topamax) may help in the episodic phase of the disease. SCA6 is caused by a repeat expansion. Individuals who have 18 or fewer repeats in both copies of the gene do not have SCA6. If one repeat number is 20 or more, then the individual will develop SCA6. If one or both copies of the gene have 19 repeats, these results may be difficult to interpret.
SCA-7 is an autosomal dominant ataxia caused by a repeat expansion. One of the most striking features of SCA7 is the vision-loss, which often begins in the late teens or early 20’s. Visual symptoms often begin with decreased visual acuity and decreased color vision. Progressive ataxia usually follows the onset of visual symptoms. Patients should be evaluated for the use of medications to treat eye symptoms and use of dark glasses to limit retinal damage from ultraviolet light. If both copies of the gene have 19 or fewer repeats, then the individual does not have SCA7. If one copy of the gene has more than 36 repeats, then an individual will develop SCA7. Borderline repeat numbers between 28-36 repeats may be difficult to interpret. The size of the repeat sometimes grows dramatically in SCA7, leading to younger ages of onset in each generation. Infantile onset SCA7 has been reported in several families with as many as 460 repeats reported.
SCA-8 is a slowly progressive ataxia resulting in poor coordination of limbs, especially lower extremities, and poor coordination of gait and speech. SCA-8 is officially described as an autosomal dominant ataxia, however, many people who inherit abnormal SCA8 genes never develop the disease. This is called reduced penetrance. It is not known why some people develop ataxia and others do not. SCA8 is caused by a repeat expansion. Repeat numbers larger than 71 are considered abnormal, but it is important to remember that many people with abnormal repeat numbers do not develop ataxia.
Evidence for SCA-9 was first reported in 1997. Scientists described a large family and traced the ataxia back to a British couple who emigrated to the United States in 1685. The clinical findings in this family were reported to be similar to SCA3 families. Some individuals had symptoms similar to Parkinson disease or multiple sclerosis. No other work has been published on SCA9 since1997. Therefore, the gene that causes SCA9 is unknown and genetic testing is not available for this condition.
SCA-10 is a slowly progressive ataxia, that is found primarily in people with Mexican, or Brazlian ancestry. In addition to the typical symptoms of ataxia, patients with SCA-10 may also develop epilepsy (seizures), weakness, and loss of sensation. SCA-10 is an autosomal dominant condition that is caused by a repeat expansion. If both copies of the gene have 10-29 repeats, then the individual will not develop SCA10. If one copy of the gene has more than 800 repeats, then the individual will develop SCA10. Additional interpretation may be required if one of the repeat numbers is between 29 and 800. Some, but not all, individuals in this range will develop SCA10. Management includes anti-seizure medications to control seizures.
SCA11 has been genetically confirmed in a family from England and in a family from Pakistan. SCA11 appears to be caused by sequence changes in a gene called “TTBK2.” Individuals with SCA11 have difficulties with balance and eye movements. The symptoms begin in later adulthood and appear to progress more slowly than other types of ataxia. Genetic testing for this type of ataxia is not currently available in the United States.
SCA12 is a very rare form of autosomal dominant ataxia that has been described in families with German, American, or Asian-Indian ancestry. The first symptoms are often tremor, rather than true ataxia. Patients later develop symptoms of ataxia. Patients may also develop slowness of movement, similar to Parkinson’s disease, and exaggerated tendon reflexes and loss of sensation. Tremor in SCA-12 might respond to medications used for essential tremor. SCA12 is caused by a repeat expansion. If both genes have 4-32 repeats, then the individual does not have SCA12. If one repeat has 51-78 repeats in one copy of the SCA12 gene, then they will develop SCA12. If one gene has 32-50 repeats, it is not clear if the person will develop SCA12.
SCA13 is a very variable form of ataxia. In some families, the disease may begin in childhood and be accompanied by mental subnormality. In other families, the disease may have a very late age of onset without cognitive manifestations. SCA13 is inherited in an autosomal dominant pattern and it is caused by sequence changes in a gene called “KCNC3.” Sometimes, testing for SCA13 may show a variation of unknown significance. It is important that these types of results be interpreted very carefully because they do not necessarily mean that the individual has SCA13.
SCA14 is a rare form of autosomal dominant ataxia and it is caused by sequence changes in a gene called “PRKCG.” Commonly, testing for SCA14 gene may show a "variation of unknown significance". It is important that these types of results be interpreted very carefully because they do not mean that the individual has SCA14 in most cases.
SCA-14 is characterized by poor coordination of the arms, legs, gait, and speech and jerky movements that affect the trunk of the body. The jerky movements are called myoclonus. Tremor, sensory loss, twitches of facial muscles, and slowness and stiffness similar to that seen in Parkinson’s disease have been observed in SCA-14.
SCA15 was first described in an Australian family. It has since been described in families from Great Britain and Japan. This type of ataxia appears to be a slowly progressive form of ataxia. Symptoms may begin as early as childhood, or as late as the 60’s. There are usually no other neurological symptoms, with the exception of occasional tremors. SCA15 is caused by either sequence changes or deletions of a gene called “ITPR1.” Gene testing for SCA15 is currently not available in the United States.
SCA16 was first described in Japanese families. It was later discovered that SCA16 and SCA15 are actually the same disease.
SCA-17 is associated with abnormal movements twitching/fidgety movements (chorea) and abnormal posturing (dystonia), as well as problems with memory and ataxia. Patients may also develop mental health problems such as mood disorders. Many patients also have features resembling Parkinson’s disease, including muscle stiffness and tremor. Age of onset is between 3 to 55 years. SCA17 is an autosomal dominant condition caused by a repeat expansion. If both genes have repeat numbers between 25-42, then the individual will not develop SCA17. If one copy of the gene has between 43-48 repeats, then that individual might develop SCA17 i.e. some individuals with 43-48 repeats do not develop SCA17. If one copy of the gene has 49 or more repeats, then the individual will develop SCA17. Specific treatment for mental health problems and seizures is recommended. Treatment for dystonia (such as botulinum toxin injections) and stiffness can also be given.
SCA18 is more commonly called “sensory/motor neuropathy with ataxia” (SMNA). This type of ataxia was described in a large Irish-American family. In addition to ataxia, individuals with this condition have problems with the nerves in their arms and legs (peripheral nerves). These peripheral nerve problems include weakness and problems with sensation. In 2009, researchers reported that they may have found the gene that causes SMNA, but further research is needed to confirm this finding. Until that time, testing for SCA18 (SMNA) is not available in the United States.
SCA19 was first described in a large Dutch family. Symptoms usually begin between the ages of 20 and 45. In addition to ataxia, individuals with SCA19 may have myoclonus (very fast jerking movements) and cognitive changes (problems with memory). The gene causing SCA19 has not yet been discovered. Therefore, testing for SCA19 is not available in the United States. SCA19 and SCA22 may actually be the same disease, but this is not yet clear.
SCA20 has only been described in a single Australian family with ancestry in the British Isles. In addition to ataxia, problems with speaking are very prominent in SCA20. Individuals with SCA20 often have a tremor in their palate (the roof of the mouth). A genetic change was recently identified in the Australian family, but it is not yet clear if this genetic change is truly causing the ataxia. This genetic change is a large duplication of a piece of genetic code. Until the exact cause of SCA20 is confirmed, there will not be genetic testing for this condition in the United States.
SCA21 is characterized by a young age of onset compared to some other dominant forms of ataxia (age 6-30 years). SCA21 was first reported in a large family from France. In addition to ataxia, individuals with SCA21 may have some symptoms similar to Parkinson disease (tremor and stiffness). The gene that causes SCA21 has not been identified. Genetic testing for this condition is not available.
This form of ataxia was first described in a large Chinese family. It is now suspected that SCA22 and SCA19 are actually the same condition. The Chinese family with SCA22 did not have some of the features reported in the SCA19 family (myoclonus and cognitive changes). Therefore, it is not completely clear that SCA19 and SCA22 are the same disease.
SCA23 has been described in a single Dutch family. Symptoms generally began in the 40’s and 50’s. In addition to typical symptoms of ataxia, there are pronounced problems with eye movements. The exact gene that causes SCA23 has not been identified. Therefore, there is no genetic testing for this condition at the present time.
This condition is no longer called SCA24. The autosomal recessive pattern of inheritance is different from the other SCA’s. SCA24 is now called spinocerebellar ataxia autosomal recessive type 4 (SCAR4). It is also called “spinocerebellar ataxia with saccadic intrusions.” This condition was first described in a family from Slovenia and the most striking feature is the unusual sudden fast eye movements (saccades). There is no genetic testing for this condition at the present time.
SCA25 has been described in a single family from South-Eastern France. The gene that causes this condition has not yet been identified. Symptoms typically begin between the ages of 17 and 39. There is no genetic testing for this condition at the present time.
SCA26 has been described in a single family from the Upper-Midwest region of the United States. The family had Norwegian ancestry. On average, symptoms started in the 40’s. Besides the typical problems associated with ataxia (balance, speech, eye movements), affected individuals had no other neurological symptoms. There is no genetic testing for this condition at the present time but will likely be available soon.
SCA27 was originally described in a Dutch family. Several other families or individuals with SCA27 have now been identified. SCA27 is caused by sequence changes in a gene called “FGF14.” In addition to ataxia, individuals with SCA27 may have developmental delays or mental retardation. Testing for SCA27 is not yet available in the United States.
SCA28 was first described in an Italian family, and later in a German family. SCA28 is caused by sequence changes in a gene called “AFG3L2.” Symptoms of SCA28 often begin in childhood. In addition to problems with balance, individuals with SCA28 can have paralysis of the muscles that move the eyes. Clinical testing for SCA28 is not yet available in the United States.
SCA29 is a type of ataxia that presents very early in life, but is not progressive. That means that the symptoms do not appear to grow worse over time. A specific gene for SCA29 has not yet been found.
At the time this booklet was written, no information has yet been published in the medical literature about SCA30. The name SCA30 has been reserved, which means that a group of scientists believes that they found a family with a unique genetic form of SCA.
The gene that causes SCA31 is very close to the gene that is believed to cause SCA4. There has been some discussion as to whether these might be the same condition. SCA31 is caused by a repeat expansion. Due to the very recent discovery of the SCA31 gene, the range of normal and abnormal repeat numbers is not yet known. Genetic testing is not yet available.
The gene for SCA32 has now been identified in a family from the Upper-Midwest region of the United States. Information about SCA32 has not been published at the time this pamphlet was written.
Other forms of SCA
There are now at least 32 different forms of SCA (and counting). As new genes are discovered, tests for these new types of SCA will become available in laboratories. Even after new genes are discovered, it may take many years for scientists to understand the gene well enough to offer testing to patients. That is why there are many SCA’s for which clinical testing is currently not available in the United States. It is important to remember that as many as half of SCA families will have normal genetic testing (as of 2010). This means that there are many more genes to be discovered. If your testing has not identified the cause of ataxia in your family, it is important to continue to check in with your clinic to see if new tests become available.