Definition
Spinocerebellar ataxia is a genetically inherited disorder characterized by abnormal brain function that represents a varied group of disorders. It is most commonly inherited as a dominant trait, which means that any individual who is a carrier of one of the many different gene mutations is affected. It also means that a carrier will have a 50% percent chance of having an affected offspring, regardless of the genetic background of the reproductive mate. In this group of disorders, the brain and spinal cord degenerate.
Description
Individuals affected with spinocerebellar ataxia develop a degenerative condition that affects a region in the base of the brain called the cerebellum located behind the brainstem. The primary function of the cerebellum is to coordinate the body's ability to move. Loss of this quintessential function leads to a progressive atrophy, or wasting away of muscles. The spine also atrophies and this can lead to spasticity.
Spinocerebellar ataxia can be physically devastating and the progressive loss of the ability to coordinate movements in emotional complications and significant lifestyle changes. The adverse effects involve the legs, hands, and the speech. Currently, there are 11 types of spinocerebellar ataxia. As there are many different genes mutations that cause this disease, there are different names for each type. The different types have numerical assignments as nomenclature. For example, Spinocerebellar ataxia type 1 is also known as SCA1. The numbers span from 1-25 (there is no SCA9) and are designated based on the time at which they were identified and characterized. Spinocerebellar ataxia is the same disease as spinal cerebellar ataxia.
Demographics
There are several gene mutations on different chromosomes that cause Spinocerebellar ataxia and the frequency of these gene within different populations varies considerably. In fact, due to the number of different types it is often difficult to estimate the incidence of a specific type in a specific population. In general, the incidence is thought to be approximately one to five per 100,000 people. There is no known predilection for sex. As with virtually all autosomal dominant disorders, males and females are equally likely to inherit a defective gene.
Causes and symptoms
Spinocerebellar ataxia is caused by a genetic defect that involves an expansion in the DNA sequence called a trinucleotide repeat expansion for SCA types 1-3, 6-10, 12, and 17. In general, the type of DNA expansion involves three DNA letters (nucleotides). In these cases, the sequence CAG (C=cytosine, A=adenine, G=guanine) is repeated above the normal repeat length. The normal repeat number differs for different types, as does the expanded repeat sizes. By repeating this sequence of DNA too many times, function of the protein it encodes can be disrupted. Other types of repeat expansions that cause SCA have been discovered. For example, SCA10 involves an ATTCT repeat expansion of the SCA10 gene and SCA8 involves an expansion in the SCA8 gene with the nucleotides CTG repeated. Finally, SCA14 involves a mutation in a gene that does not involve a trinucleotide repeat expansion.
The most common types are SCA1 (6%), SCA2 (14%), SCA3 (21%), SCA6 (15%), SCA7 (5%), and SCA8 (2–5%). Age of onset for all of these types is on average from 20–30 years of age except for SCA6, which usually occurs between the ages of 40 and 50. People with SCA8 usually develop symptoms between in their late 30s. SCA2 patients usually develop dementia and slow eye movements. SCA8, which has a normal lifespan, and SCA1 patients are both characterized as having active reflexes. SCA7 patients develop visual loss. SCA3 is also known as Machado-Joseph disease.
In SCA types 1–3 and 7, there can be an earlier age of onset with increased severity (called anticipation) as the defect is passed from one generation to the next. This means that children can be more severely affect at an earlier age than their affected parent. The size of the repeat of nucleotides in the affected genes is thought to correlate with the severity and age of onset in offspring. As the repeat size expands, the severity worsens and age of onset becomes earlier compared with the affected parent. However, repeat size does not predict the exact age of onset or the specific symptoms that will develop.
Penetrance refers to the likelihood that individuals with a genetic defect will develop the disease. In spinocerebellar ataxia, the penetrance is quite high; however, there are rare cases in which people do not develop symptoms. The reason for the lack of complete penetrance is currently unknown.
Affected individuals initially develop poor coordination of movement, which is the definition of ataxia. Developing poor movement coordination in patients is manifested clinically by difficulty in walking, abnormalities in hand or eye movements, and speech difficulties. Generally, the age of onset is usually after 18 years old, making it typically an adult-onset disorder. The severity of progressive degeneration depends primarily on the underlying defect.
Diagnosis
The diagnosis of spinocerebellar ataxia is initially suspected by the adult-onset of symptoms. An MRI scan can detect atrophy (wasting) of the cerebellum, a typical finding in patients with spinocerebellar ataxia. A clinical evaluation involves an extensive neurological examination. Genetic testing is a critical component of the diagnosis, as symptoms among the various types of spinocerebellar ataxia are similar. A molecular genetic test to determine the gene that has the trinucleotide repeat expansion can be helpful in quickly identifying other carriers in the family. Once the genetic defect is characterized, family members can also be tested. Unfortunately, genetic testing is not always 100% informative. There are rare cases of spinocerebellar ataxia diagnosed clinically that cannot be explained by any of the known genetic defects. It is estimated that in approximately 50–60% of Caucasian persons with a dominant familial form of cerebellar ataxia, DNA testing can provide a definitive diagnosis.
Treatment team
For people who begin to show symptoms and are later diagnosed with spinocerebellar ataxia, a careful evaluation by a neurologist is usually required. Treatment is based on lessening the symptoms as they develop. A fulltime caretaker and nursing support will eventually be required in the later stages of the disease. Psychological counseling is often needed depending on the family, the patient, and their needs.
Treatment
There is no cure for spinocerebellar ataxia. There is also no treatment to slow the progression of the disease. Treatment, therefore, remains supportive. Drugs that help control tremors are not effective for treating cerebellar tremors. Although dietary factors are not proven to be helpful, vitamin supplementation is recommended.
Recovery and rehabilitation
Researchers assume that physical therapy does not slow the progression of loss of coordination or muscle wasting. However, people with spinocerebellar ataxias are encouraged to remain as active as possible. Occupational therapy can be helpful in developing ways to accommodate the patient in performing daily activities. Walkers and other devices can assist in allow the patient to have mobility. Other modifications such as ramps for a wheelchair, heavy eating utensils, and raised toilet seats can make patients more independent. Speech therapy and computerbased communication aids often help as the person loses his or her ability to speak.
Clinical trials
As of early 2004, there are no approved clinical trials for the treatment or cure of spinocerebellar ataxia. There is, however, a clinical trial to determine the maximum tolerated dose of a drug called idebenone in children, adolescents, and adults with Friedreich's Ataxia, a disorder related to spinocerebellar ataxia (contacts: Patient Recruitment and Public Liaison Office, Building 61, 10 Cloister Court, Bethesda, Maryland 20892-4754; toll free: 1-800-411-1222). Additionally, there is also an ongoing study to determine the efficacy of high-dose intravenous immunoglobulin therapy in patients with cerebellar degeneration that are already enrolled.
Prognosis
There are many factors that determine the prognosis of an affected individual. These factors depend on the type of genetic mutation, the size of the repeat expansion, anticipation, and the age at which symptoms develop. Although these factors can help determine the prognosis, the exact age of onset and the specific symptoms are difficult to determine, especially for carriers with no symptoms. Ultimately, as with all progressive degenerative disorders, the disease is fatal. In the case of spinocerebellar ataxia, persons usually die one to two decades after symptoms develop. The prognosis for SCA11 and SCA6 is typically less severe, with a very slow worsening of symptoms, and persons with SCA8 and SCA11 have a normal lifespan.
Special concerns
Genetic testing of at-risk family members can be performed when an affected individual has a known genetic mutation. Testing of high-risk family members without symptoms raises many issues. For example, individuals who test negative usually feel guilty that they did not inherit the genetic defect, and parents who are affected feel guilty that they passed on the gene defect. These experiences can have a significant impact on the family dynamics, particularly in adult-onset disorders. Additionally, it is often unclear when (or if) family members who test positive for the mutation will develop symptoms and how severe the symptoms will be. It is generally considered not useful to test children with no symptoms. These issues and others are usually carefully evaluated by family members with the help of a genetic counselor.
Resources
BOOKS
Pulst, Stefan, M. Neurogenetics. New York: Oxford University Press, 1999.
OTHER
"NINDS Ataxias and Cerebellar/Spinocerebellar Degeneration Information Page." National Institute of Neurological Disorders and Stroke. (February 11, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/ataxia.htm.
"Spinocerebellar ataxia." National Center for Biotechnology Information. (February 14, 2004). http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.218.
ORGANIZATIONS
National Ataxia Foundation (NAF). 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (612) 553-0020; Fax: (612) 553-0167. naf@mr.net. http://www.ataxia.org.
National Society of Genetic Counselors (NSGC). 233 Canterbury Drive, Wallingford, PA 19086-6617. (610) 872-7608; Fax: (610) 872-1192. nsgc@aol.com. http://www.nsgc.org.
WE MOVE (Worldwide Education and Awareness for Movement Disorders). 204 West 84th Street, New York, NY 10024. (212) 875-8389 or (800) 437-MOV2 (6683). wemove@wemove.org. http://www.wemove.org.
Bryan Richard Cobb, PhD
