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Spinocerebellar Ataxia Type 3

Synonyms: Azorean Ataxia, MJD, Machado-Joseph Disease, SCA 3
, MD, PhD
Professor, Department of Neurology
University of Michigan Medical School
Ann Arbor, Michigan

Initial Posting: ; Last Update: March 17, 2011.

Summary

Disease characteristics. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Neurologic findings tend to evolve as the disease progresses.

Diagnosis/testing. The diagnosis of SCA3 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in ATXN3. Affected individuals have alleles with 52 to 86 CAG trinucleotide repeats. Such testing detects 100% of affected individuals.

Management. Treatment of manifestations: Management is supportive as no medication slows the course of disease; restless legs syndrome and extrapyramidal syndromes resembling parkinsonism may respond to levodopa or dopamine agonists; spasticity, drooling, and sleep problems respond variably to lioresal, atropine-like drugs, and hypnotic agents; botulinum toxin has been used for dystonia and spasticity; daytime fatigue may respond to psychostimulants such as modafinil; accompanying depression should be treated. Affected individuals should remain active; canes and walkers help prevent falling; motorized scooters can help maintain independence; speech therapy and communication devices may benefit those with dysarthria and dietary modification those with dysphagia; weighted eating utensils and dressing hooks help to maintain independence.

Prevention of secondary complications: Modification of the home for safety; vitamin supplements if caloric intake is reduced; weight control to facilitate ambulation and mobility; caution with general anesthesia.

Surveillance: Annual or biannual assessment of speech, swallowing, and gait function.

Genetic counseling. SCA3 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the mutation. Prenatal testing is possible for pregnancies at increased risk if the diagnosis has been confirmed in an affected family member.

Diagnosis

Clinical Diagnosis

The diagnosis of spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is suggested in individuals with the following findings [Lima & Coutinho 1980, D’Abreu et al 2010]:

  • Progressive cerebellar ataxia and pyramidal signs associated to a variable degree with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy
  • Minor (but more specific) clinical signs such as progressive external ophthalmoplegia, dystonia, action-induced facial and lingual fasciculation-like movements, and bulging eyes
  • Family history consistent with autosomal dominant inheritance

Because the clinical findings are shared with many other dominantly inherited ataxias, diagnosis of SCA3 rests upon molecular genetic testing.

Molecular Genetic Testing

Gene. ATXN3 (known previously as MJD1) is the only gene in which mutations are known to cause SCA3. A polymorphic CAG repeat in ATXN3 is unstable and is expanded to an abnormal range in all individuals with SCA3. The CAG trinucleotide repeat in ATXN3 encodes a polyglutamine tract in the disease protein, ataxin-3 (see Table 2).

Allele sizes. The following allele sizes are observed in SCA3 [Potter N et al, unpublished; the Ataxia Molecular Diagnostics Testing Group; compiled October 2002, updated August 2005]:

Clinical testing

  • Targeted mutation analysis. Testing to determine the number of ATXN3 CAG repeats is performed typically by PCR amplification of the trinucleotide repeat region followed by gel or capillary electrophoresis. PCR analysis may be used to detect trinucleotide repeat expansions up to approximately 100 repeats; however, the upper limit of the size of the expansion detected may vary by laboratory.

Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 3

Gene SymbolTest MethodMutation Detected Mutation Detection Frequency by Test Method 1
ATXN3Targeted mutation analysisAbnormal number of CAG trinucleotide repeats100%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

Interpretation of test results. The presence of one disease-causing allele is diagnostic.

Testing Strategy

To confirm/establish the diagnosis in a proband requires identification of an abnormally expanded ATXN3 CAG repeat.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of an abnormally expanded CAG repeat in ATXN3 in an affected family member.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of an abnormally expanded CAG repeat in ATXN3 in an affected family member.

Clinical Description

Natural History

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized primarily by cerebellar ataxia and pyramidal signs variably associated with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy.

The age of onset of SCA3 is highly variable but most commonly in the second to fifth decade. In a large cohort of affected individuals from the Azores, the mean onset was age 37 years. The variable range of symptom onset largely reflects differences in the length of the CAG repeat.

Presenting features include gait problems, speech difficulties, clumsiness, and often visual blurring and diplopia. Progressive ataxia, hyperreflexia, nystagmus, and dysarthria may occur early in the disease. Upper motor neuron signs often become prominent early on, and in some families may resemble hereditary spastic paraplegia [Wang et al 2009, Gan et al 2009].

Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset. Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in up-gaze restriction. Disconjugate eye movements result in diplopia. At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions. Often, a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.

Other findings may include the following:

Later, evidence of a peripheral polyneuropathy [França et al 2009] may appear with loss of distal sensation, ankle reflexes, and sometimes other reflexes as well, and with some degree of muscle wasting. Severe ataxia of limbs and gait (with either hyperreflexia or areflexia) associated with muscle wasting is observed. Sitting posture is compromised, with affected individuals assuming various tilted positions.

Late in the disease course, individuals are wheelchair bound and have severe dysarthria, dysphagia, facial and temporal atrophy, poor cough, often dystonic posturing and ophthalmoparesis, and occasionally blepharospasm. The disease progresses relentlessly; death from pulmonary complications and cachexia occurs from six to 29 years after onset [Sudarsky et al 1992, Sequeiros & Coutinho 1993]. In a recent Brazilian study, the mean age of onset was 36 years with a 21-year mean survival after onset [Kieling et al 2007].

Subtypes of SCA3. Occasionally, family members with similar allele size may exhibit other clinical features such as a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy.

Individuals with later adult onset often have a disorder that combines ataxia, generalized areflexia, and muscle wasting.

Based on this phenotypic variability, Portuguese researchers classified SCA3 into several types, as reviewed recently [Riess et al 2008]. In some individuals one type can evolve into another during the course of disease [Fowler 1984]. Striving to place affected individuals into a specific SCA3 subtype has little clinical value, partly because the overlap across subtypes is considerable. The existence of subtypes, however, does illustrate the extreme clinical heterogeneity of SCA3.

  • Type I disease (13% of individuals) is characterized by onset at a young age and prominent spasticity, rigidity, and bradykinesia, often with little ataxia [Lu et al 2004]. Type I disease is associated with longer disease-causing repeat alleles.
  • Type II disease, the most common (57%), is characterized by ataxia and upper motor neuron signs. Spastic paraplegia can be part of the phenotype [Landau et al 2000]. Type II disease is associated with a wide range of disease-causing repeat alleles, the majority of which are in the middle of the disease range.
  • Type III disease (30%) manifests at a later age with ataxia and peripheral polyneuropathy. Type III disease is associated with shorter disease-causing repeat alleles.
  • Type IV disease is characterized by dopa-responsive parkinsonism; this type is not associated with any particular size disease-causing repeat alleles.
  • Type V disease resembling hereditary spastic paraplegia has been suggested by some observers [Wang et al 2009]; however, this designation has not been commonly accepted.

MRI. Brain imaging studies typically reveal pontocerebellar atrophy [Burk et al 1996]. The most commonly observed abnormality is enlargement of the fourth ventricle [Onodera et al 1998], which reflects atrophy of the cerebellum and brain stem. The degree of brain atrophy detectable by MRI varies greatly, consistent with the wide clinical variability observed. In a large European natural history study, clinical dysfunction in SCA3 correlated with the degree of total brain stem atrophy [Schulz et al 2010].

Abnormal linear high intensity of the globus pallidus interna on T2 and FLAIR images has also been observed [Yamada et al 2005].

NCV. Nerve conduction velocity studies often reveal evidence for involvement of the sensory nerves as well as the motor neurons [Lin & Soong 2002, França et al 2009].

Neuropathologic studies typically reveal neuronal loss in the pons, substantia nigra, thalamus, anterior horn cells and Clarke's column in the spinal cord, vestibular nucleus, many cranial motor nuclei, and other brain stem nuclei [Rüb et al 2002, Rüb et al 2004a, Rüb et al 2004b, Rüb et al 2006]. The cerebellum typically shows atrophy, but in some individuals Purkinje cells and inferior olivary neurons are relatively spared [Sequeiros & Coutinho 1993].

Recent neuropathologic studies have established that degeneration is rather widespread in SCA3, not confined to the cerebellum, brain stem, and basal ganglia [Rüb et al 2008]. In general, however, the cerebral cortex is spared in disease.

Genotype-Phenotype Correlations

Probands. As with other CAG trinucleotide repeat expansion disorders, an inverse relationship exists between the age of onset and the number of CAG repeats in the abnormal allele, with the correlation coefficient ranging from -0.67 to -0.92 in a series of genotype-phenotype correlation studies performed in the 1990s. However, more recent analyses by European investigators found that only about 46%-48% of the variability in age of onset of SCA3 is accounted for by CAG repeat length, indicating that other genetic or non-genetic factors also contribute [van de Warrenburg et al 2005, Globas et al 2008]. A loose correlation also exists between the repeat number and the clinical phenotype.

Individuals classified as having type I disease (dystonic-rigid form) tend to have larger repeat sizes than individuals with type II disease (ataxia with pyramidal signs) or type III disease (peripheral amyotrophy). In general, individuals with type III disease have onset later in adulthood, more prominent polyneuropathy, and 73 or fewer CAG repeats. In the study by Sasaki et al [1995], individuals with type I disease had a mean CAG repeat length of 80, those with type II disease had a mean CAG repeat length of 76, and those with type III disease had a mean CAG repeat length of 73.

Some, but perhaps not all, observed anticipation in age of onset can be accounted for by the intergenerational expansion of the repeat length. Some of the largest expansions, reported by Zhou et al [1997] from China in two children with onset at age 11 and age five years, had CAG repeats of 83 and 86, respectively.

The severity of disease manifestations, although related to the age of disease onset, varies among families. An example is a Yemeni family in which two groups of affected individuals were distinguished by the age of onset [Lerer et al 1996]: an obligate heterozygote died at age 70 years having had no symptoms, and another person with 68 repeats was asymptomatic at age 66 years. More severe disease has been reported in homozygous individuals in a few other families [Lerer et al 1996, Carvalho et al 2008]. However, many of the homozygotes in the Yemeni family are no more severely affected than heterozygotes in other families.

Penetrance

A zone of CAG trinucleotide repeat lengths that displays reduced penetrance is less firmly established in individuals with SCA3 than in several other SCA disorders cause by trinucleotide expansion. However, rare alleles of 45 to 51 CAG repeats may show reduced penetrance.

In addition, the smallest disease-causing repeats occasionally manifest only, or primarily, as restless legs syndrome [Van Alfen et al 2001].

Anticipation

Instability of the CAG repeat has been documented in transmission of the repeat from parent to child. Overall, repeat expansion is more common than contraction; thus, anticipation (earlier age of onset and more severe disease manifestations in offspring) occurs in SCA3. The probability of expansion may be greater with paternal than with maternal transmission though the paternal bias is not pronounced (as, e.g., in Huntington disease).

Of note, Japanese investigators have provided limited evidence of distortion in favor of transmission of mutant alleles in offspring of affected males on the basis of meiotic instability in sperm [Ikeuchi et al 1996, Takiyama et al 1997].

Nomenclature

SCA3 is also known as Machado-Joseph disease (MJD). In fact, this autosomal dominant form of ataxia, which was first described among immigrants from the Portuguese Azorean islands, was initially known as MJD. In the early 1990s the pathogenic mutation for MJD was localized to chromosome 14 and identified as a CAG repeat expansion in MJD1 (now renamed ATXN3). During this same time, scientists mapped what was initially thought to be an unrelated ataxia, SCA3, to the same chromosomal region. Once the pathogenic expansion underlying MJD was discovered, it soon became clear that SCA3 was caused by the same mutation.

Prevalence

No accurate data are available regarding the prevalence of SCA3 in the general population, though in many populations SCA3 is the most common autosomal dominant ataxia. Overall, the dominantly inherited ataxias are rare.

The proportion of SCA3 among the dominantly inherited ataxias differs greatly by population.

A founder effect in Cambodian families has been reported [Jayadev et al 2006]. Thus, some geographic variation exists in the occurrence of SCA3.

A large international genetic study has shown that a single intragenic haplotype is shared by a majority of the families studied (including those from the Azorean island of Flores), suggesting a single founder mutation. However, at least two other haplotypes have been found in the Portuguese population [Gaspar et al 2001, Verbeek et al 2004].

Differential Diagnosis

Progressive ataxia, often associated with evidence of upper motor neuron dysfunction including brisk tendon reflexes and extensor plantar responses, can be seen in individuals with spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), as well as in many other dominantly inherited ataxias (see Ataxia Overview).

Findings suggestive of SCA3 include occurrence of variant clinical features in members of the same family, such as an akinetic-rigid syndrome (often responsive to dopaminergic agonists) or cerebellar ataxia associated with significant peripheral amyotrophy and generalized areflexia.

The presence of dystonia and parkinsonian features, including a beneficial response to levodopa or dopamine agonists, can cause diagnostic confusion with dopa-responsive dystonia and Parkinson disease [Schols et al 2000]. In SCA3, however, most individuals manifesting with parkinsonian features also have some evidence of cerebellar involvement.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), the following evaluations are recommended if specific symptoms are present:

  • MRI of the brain and spinal cord if there are cognitive problems or unusually severe ataxia, motor, or sensory findings
  • Speech and swallowing assessment if dysarthria and/or dysphagia are present
  • Gait assessment
  • EMG/NCV if peripheral symptoms are present to assess the degree of involvement of the peripheral nervous system

Treatment of Manifestations

Management of individuals with SCA3 remains supportive as no medication has been proven to slow the course of disease [D’Abreu et al 2010].

However, some symptoms may respond — in some cases dramatically — to certain drugs:

  • Particularly the extrapyramidal syndromes resembling parkinsonism may benefit from levodopa or dopamine agonist [Subramony et al 1993, Nandagopal & Moorthy 2004].
  • Symptoms of restless legs syndrome may respond to these agents.
  • Other manifestations, including spasticity, drooling, and sleep problems, also respond variably to appropriate agents such as lioresal, atropine-like drugs, and hypnotic agents.
  • Botulinum toxin has been used for dystonia and spasticity [Freeman & Wszolek 2005].
  • Daytime fatigue, a common problem in individuals with SCA3, may respond to psychostimulants used in narcolepsy such as modafinil.

Depression is common in individuals with SCA3 and should be treated with antidepressants [Cecchin et al 2007]. A trial of occupational therapy in SCA3 showed that depression scores improved as a consequence of therapy, underscoring the fact that non-pharmacologic measures may also improve affective disorder in SCA3 [Silva et al 2010].

Of note, relatively few clinical trials of medications have been performed in SCA3, and none has yet been confirmed to shown a definite benefit:

  • A small study of six individuals with SCA3 suggested that lamotrigine may improve balance; however, benefit was not confirmed during the withdrawal phase of the trial [Liu et al 2005].
  • While an earlier study suggested that tremethoprim-sulfamethoxazole may be beneficial in treating SCA3 [Sakai et al 1995], a larger study of 22 persons failed to show any benefit [Schulte et al 2001], leading the authors to conclude that long-term therapy with this drug combination is not recommended.
  • A study of fluoxetine failed to show benefit for motor symptoms [Monte et al 2003].
  • A study of the 5-HT1A agonist, tandospirone, in ten persons suggested improvement in depressive symptoms, ataxia, insomnia, and leg pain in a subset of individuals [Takei et al 2004]. A subsequent open-label four-week symptomatic study by the same investigators tested tandospirone in a variety of degenerative ataxias, including 14 persons with SCA3. Four of 14 showed improved scores in an ataxia rating scale [Takei et al 2010]. A larger, double blind placebo-controlled study is needed to confirm such benefits.

Non-pharmacologic therapy is important in SCA3:

  • Although neither exercise nor physical therapy slows the progression of incoordination or muscle weakness, affected individuals should maintain activity. Canes and walkers help prevent falling, and motorized scooters later in disease can help maintain independence.
  • Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.
  • When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.
  • Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
  • Weighted eating utensils and dressing hooks help maintain a sense of independence.

Prevention of Secondary Complications

Vitamin supplements are recommended, particularly if caloric intake is reduced.

Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

General anesthesia may be problematic; experience with local anesthesia has been reported [Teo et al 2004].

Surveillance

Speech, swallowing, and gait function should be monitored annually or biannually to assess need for assistive devices.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Tremor-controlling drugs do not work well for cerebellar tremors.

No dietary factor has been shown to curtail symptoms.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed as having SCA3 have an affected parent.
  • Recommendations for the evaluation of parents of a proband include physical examination and consideration of ATXN3 molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with SCA3 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the parents.
  • If one parent has an expanded ATXN3 allele, the risk to each sib of inheriting the expanded ATXN3 allele is 50%.

Offspring of a proband. Each sib of an affected individual has a 50% chance of inheriting an expanded ATXN3 allele.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent has the expanded ATXN3 allele, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

At-risk individuals. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by the family history or molecular genetic testing.

Testing of at-risk asymptomatic adults. Testing of asymptomatic adults at risk for SCA3 is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for SCA3, an affected family member should be tested first to confirm that the disorder in the family is actually SCA3.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing and needs to be approached with a well-thought-out genetic counseling plan. Predictive testing occurs when at-risk asymptomatic adult family members seek testing in order to clarify their risk of developing the disease. Often they are making personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations, including simply "the need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA3, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations. Predictive genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [Gonzalez et al 2004].

Testing of at-risk individuals during childhood. Consensus holds that asymptomatic individuals younger than age 18 who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against such testing are that it removes the individual's choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the presence of an expanded ATXN3 allele in an affected family member has been confirmed, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as SCA3 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the diagnosis has been confirmed by molecular genetic testing.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Ataxia MJD Research Project, Inc.
    1425 Alvarado Avenue
    Burlingame CA 94010-5547
    Email: info@ataxiamjd.org
  • NCBI Genes and Disease
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Spinocerebellar Ataxia Type 3: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ATXN314q32​.12Ataxin-3ATXN3 homepage - Mendelian genesATXN3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Spinocerebellar Ataxia Type 3 (View All in OMIM)

109150MACHADO-JOSEPH DISEASE; MJD
607047ATAXIN 3; ATXN3

Normal allelic variants. ATXN3 consists of 11 exons within a 1776-base pair coding region with one long open reading frame [Kawaguchi et al 1994, Ichikawa et al 2001]. A normal variation in the CAG trinucleotide repeat encoding a polyglutamine repeat occurs within exon 10. Variations in the (CAG)n sequence exist. It can be an imperfect repeat in many alleles examined, where the third, fourth, and sixth CAG unit is replaced by CAA, AAG, and CAA, respectively. These variant triplets were commonly found both in normal and abnormal alleles.

The CAG repeat is highly variable in normal individuals with the (CAG)n in different alleles varying from 12 to 43 [Cancel et al 1995, Maciel et al 1995, Matilla et al 1995, Ranum et al 1995, Sasaki et al 1995, Takiyama et al 1995, Limprasert et al 1996, Matsumura et al 1996a. In many studies, the distribution of CAG repeat numbers in normal alleles has shown a bimodal or trimodal pattern with peaks around 14, 22-24, and 27. Rubinsztein et al [1995] looked at 748 normal alleles from individuals of eight different ethnic backgrounds who had spinocerebellar ataxia type 3 (SCA3, MJD) and found a similar bimodal distribution of normal CAG repeat numbers with peaks at 14 and 21-23. The proportion of heterozygotes varied among populations, with higher figures among Melanesians (98%), Polynesians (92%), and African blacks (88%), and the fewest among East Anglicans (58%).

Limprasert et al [1996] found 14 and 23 (CAG)n repeat lengths to be the most common across populations. Furthermore, in analyzing the (CAG)n tracts in different species, including humans, it was observed that usually the CAG repeat was flanked with a guanine, but when the alleles had 20 or 21 CAG repeats, the guanine was replaced with cytosine. In addition, cytosine occurred in 54.5% of normal alleles with CAG repeat numbers between 27 and 40, with a frequency distribution of 23%-100% among different ethnic populations. All expanded alleles also contained cytosine at the first nucleic acid residue following the (CAG)n tracts. Cytosine at this point may play a role in determining the instability of polyglutamine tracts [Matsumura et al 1996b]. Overall, 93.5% of normal chromosomes have fewer than 31 CAG repeats.

Pathologic allelic variants. SCA3 (MJD) is caused by abnormally large number of CAG repeats [Kawaguchi et al 1994, Cancel et al 1995, Maciel et al 1995, Matilla et al 1995, Ranum et al 1995, Takiyama et al 1995, Schols et al 1996, Silveira et al 1996, Takiyama et al 1997].

Alleles with an abnormal number of CAG repeats may display both somatic and gametic instability of the repeat [Hashida et al 1997]. Typically, spermatozoa contain a larger repeat length than leukocytes in the same individuals [Watanabe et al 1996]. In the CNS, cerebellar tissues often tend to have slightly smaller repeat lengths than other regions of the brain.

Haplotype analysis has revealed that individuals with SCA3 from different populations often shared the same haplotype, suggesting presence of a founder effect [Takiyama et al 1995]. However, in the restricted populations of the Azores, two distinct haplotypes have been found, a fact that could overrule the one founder mutation theory [Gaspar et al 1996]. Mittal et al [2005] found evidence for the single Portuguese founder allele in India.

Table 2. Selected ATXN3 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
Normalc.886_888CAG(<44)
(<44 CAG repeats)
p.Gln296(<44)NM_004993​.5
NP_004984​.2
Reduced penetrancec.886_888CAG(45_51)
(45 to 51 CAG repeats)
p.Gln296(45_51)
Pathologicc.886_888CAG(52_86)
(52 to 86 CAG repeats)
p.Gln296(52_86)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Ataxin-3, the protein encoded by ATXN3, is a de-ubiquitinating enzyme with a predicted molecular weight of approximately 42 kd. It is widely expressed in the brain and throughout the body, existing both in the cytoplasm and nucleus of various cell types. In neurons, ataxin-3 is predominantly a cytoplasmic protein [Paulson et al 1997a], but the protein readily shuttles in and out of the nucleus.

Ataxin-3 is a ubiquitin-specific protease that binds and cleaves ubiquitin chains [Burnett et al 2003, Donaldson et al 2003, Doss-Pepe et al 2003, Chai et al 2004, Berke et al 2005]. A highly conserved amino-terminal "josephin" domain contains the catalytic triad of amino acids found in cysteine proteases [Nicastro et al 2005]. The carboxy-terminal region of the protein contains several ubiquitin-interacting motifs (UIMs) through which the protein binds tightly to polyubiquitin chains. The polyglutamine tract resides between UIMs 2 and 3, but how the polyglutamine tract affects the enzymatic function of the protein (if at all) is unknown. Studies suggest that ataxin-3 is intrinsically prone to self-associate. The stability and aggregating properties of ataxin-3 are related both to its globular josephin domain [Chow et al 2004a, Chow et al 2004b, Masino et al 2004, Ellisdon et al 2007] and to the polyglutamine domain that is expanded in disease.

Normal human ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila through a mechanism that requires its ubiquitin-associated functions [Warrick et al 2005]. Ataxin-3 also regulates aggresome formation, the degradation of proteins sent from the endoplasmic reticulum and the activity of some ubiquitin ligases [Burnett & Pittman 2005, Durcan et al 2011]. Taken together with the enzymatic properties of ataxin-3, these facts suggest that ataxin-3 normally participates in various ubiquitin-dependent protein quality control pathways in the cell.

Abnormal gene product. Most evidence favors a toxic protein mechanism of disease in which expansion of the polyglutamine tract in ataxin-3 makes the protein highly susceptible to misfolding and aggregation [Williams & Paulson 2008]. This process has been successfully modeled in in vitro studies employing recombinant protein and in various cellular models and transgenic animal models [Paulson et al 1997b, Warrick et al 1998, Evert et al 1999, Cemal et al 2002, Evert et al 2006, Bichelmeier et al 2007, Chen et al 2008, Alves et al 2008, Williams et al 2009, Boy et al 2009, Mueller et al 2009, Reina et al 2010]. In humans with SCA3, normal and expanded (i.e., pathogenic) ataxin-3 are widely expressed both in the brain and in other unaffected organ systems [Paulson et al 1997b].

The subcellular distribution of ataxin-3 differs in disease brain versus normal brain: normally a predominantly cytoplasmic protein in neurons, ataxin-3 becomes concentrated in the nucleus of neurons during disease. Moreover, in many brain regions, ataxin-3 forms intranuclear inclusions [Paulson et al 1997b]. These neuronal inclusions, which are also found in other polyglutamine disorders, are particularly abundant in pontine neurons but are also seen in several other brain regions. Inclusions are heavily ubiquitinated and contain heat shock molecular chaperones and proteasomal subunits, suggesting that they are repositories for aberrantly folded, aggregated protein [Schmidt et al 2002]. Axonal inclusions have also been noted [Seidel et al 2010]. Current evidence, including recent neuropathologic studies [Rüb et al 2006], suggest that inclusions are not directly pathogenic structures and may instead be the byproduct of neuronal efforts to wall off abnormal proteins [Williams & Paulson 2008]. At the very least, inclusions are a biomarker of abnormal protein accumulation and impaired protein clearance. The disease protein also forms abnormal deposits outside the cell nucleus, including in neuronal projections; whether these are direly pathogenic is also unknown.

In several other disorders caused by polyglutamine expansions, cleavage of the disease protein to produce a "toxic fragment" has been postulated to contribute to pathogenesis. In SCA3, some findings support this view. For example, transgenic mice or flies expressing an ataxin-3 polyglutamine fragment show marked degeneration, much more so than flies and mice expressing the full-length mutant protein [Ikeda et al 1996, Warrick et al 1998, Warrick et al 2005]. Moreover, a putative cleavage fragment has been shown to accumulate in one mouse model of disease [Goti et al 2004], and a specific cleavage fragment also accumulates in cells undergoing apoptosis [Berke et al 2004]. Recent studies in a fly model of disease further suggest that proteolysis contributes to pathogenesis [Jung et al 2009].

Although expanded polyglutamine is favored as the primary toxic element in disease, it is possible that CAG expansion promotes ribosomal frameshifting during translation of the disease protein [Toulouse et al 2005], potentially leading to alternative protein sequences containing polyalanine tracts instead of polyglutamine tracts. Studies in Drosophila further suggest that, independent of proteotoxic effects, the expanded CAG repeat also may exert toxicity at the RNA level [Li et al 2008].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 6-26-12. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 6-26-12.

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Chapter Notes

Author History

D Olga McDaniel, PhD; University of Missippi Medical Center (1998-2006)
Henry Paulson, MD, PhD (2006-present)
Stephanie C Smith, MS; University of Mississippi Medical Center (1998-2006)
SH Subramony, MD; University of Mississippi Medical Center (1998-2006)
Parminder JS Vig, PhD; University of Mississippi Medical Center (1998-2006)

Revision History

  • 17 March 2011 (me) Comprehensive update posted live
  • 3 August 2007 (me) Comprehensive update posted to live Web site
  • 30 September 2003 (me) Comprehensive update posted to live Web site
  • 24 May 2001 (me) Comprehensive update posted to live Web site
  • 10 October 1998 (pb) Review posted to live Web site
  • 13 July 1998 (shs) Original submission
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