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Spinocerebellar Ataxia Type 3

Synonyms: Azorean Ataxia, Machado-Joseph Disease, MJD, SCA3

, MD, PhD.

Author Information

Initial Posting: ; Last Update: September 24, 2015.

Estimated reading time: 30 minutes


Clinical 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.


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.


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. Intensive coordinative training or a course of combined physical and occupational therapy focused on gait and incoordination can lead to symptom improvement. 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. Regular physical activity is recommended to help retain gait and coordination in the setting of a progressive degenerative disease.

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 abnormal CAG trinucleotide repeat expansion in ATXN3. Prenatal testing is possible for pregnancies at increased risk if the diagnosis has been confirmed in an affected family member.


Suggestive Findings

Diagnosis of spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), should be suspected 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

Establishing the Diagnosis

The diagnosis of SCA3 is established in a proband with identification of a pathogenic variant in ATXN3 (see Table 1). Because the clinical findings are shared with many other dominantly inherited ataxias, diagnosis of SCA3 rests on molecular genetic testing.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Targeted analysis for pathogenic variants to identify an abnormal number of CAG trinucleotide repeats
  • A multigene panel that includes ATXN3 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of SCA3.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Gene. ATXN3 (known previously as MJD1) is the only gene in which pathogenic variants 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 [Costa Mdo & Paulson 2012 and references therein]:

Table 1.

Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 3

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ATXN3Targeted analysis for pathogenic variants 2100%

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Detects abnormal number of CAG trinucleotide repeats. Note: Pathogenic variants included in a panel may vary by laboratory.

Clinical Characteristics

Clinical Description

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.

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].

Other findings may include the following:

Progression of disorder

  • 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.
  • Evidence of a peripheral polyneuropathy [França et al 2009] may appear later 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.

Life span. 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 [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 [Bürk 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].

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, later 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.

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


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 caused by trinucleotide expansion. However, rare intermediate-length alleles of 45 to approximately 60 CAG repeats may show reduced penetrance.


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 mutated alleles in offspring of affected males on the basis of meiotic instability in sperm [Ikeuchi et al 1996, Takiyama et al 1997].


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 variant 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 pathogenic variant.


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 variant. 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 [Schöls et al 2000]. In SCA3, however, most individuals manifesting with parkinsonian features also have some evidence of cerebellar involvement.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

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:

  • In particular, 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].

Clik here (pdf) for a review of clinical trials of medications that have not shown a definite benefit for those with SCA3.

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. Intensive coordinative training or a course of combined physical and occupational therapy focused on gait and incoordination can lead to symptomatic improvement [Ilg et al 2009, Miyai et al 2012]
  • 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.

Regular physical activity is recommended to help retain gait and coordination in the setting of a progressive degenerative disease.

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].


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 in the US and in Europe 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.

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.
  • The family history of some individuals diagnosed with SCA3 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

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 abnormal CAG trinucleotide repeat expansion in ATXN3, 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 abnormal CAG trinucleotide repeat expansion in ATXN3.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the abnormal CAG trinucleotide repeat expansion in ATXN3, 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 results of molecular genetic testing.

Testing of at-risk asymptomatic adult relatives of individuals with SCA3 is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. Predictive genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [Gonzalez et al 2004].

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

If the diagnosis of SCA3 has been established in the family, it is appropriate to consider testing of any symptomatic individual regardless of age.

For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the abnormal CAG trinucleotide repeat expansion in ATXN3 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SCA3 are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


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
  • 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)
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • Spanish Ataxia Federation (FEDAES)
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ATXN314q32​.12Ataxin-3ATXN3 databaseATXN3ATXN3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

607047ATAXIN 3; ATXN3

Gene structure. 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]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A normal variation in the CAG trinucleotide repeat encoding a polyglutamine repeat occurs within exon 10. The CAG repeat begins immediately following the sequence CAG, CAG, CAA, AAG, which encodes three glutamines followed by a lysine residue. The subsequent repeat is a perfect CAG repeat. Because it is embedded in the CAG repeat tract, the triplet encoding lysine is included in the length/number of CAG repeats that define an allele (see Table 2, footnote 1). A common variant c.916G>C occurs immediately 3’ of the CAG repeat, encoding p.Gly306 or p.Arg306. The c.916C allele is more common in expanded alleles (see Pathogenic variants). The results of clinical molecular genetic testing are usually given as simply number of CAG repeats, because testing determines repeat length and not repeat sequence.

The trinucleotide repeat length is highly variable in normal individuals with the (CAG)n in different alleles varying from 12 to 44 [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 Anglians (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.

Intermediate-length alleles. Alleles with 45 to approximately 60 repeats are difficult to categorize because they are rare and may be associated with phenotypes other than that of classic SCA3. Case reports of such alleles may be helpful [see Costa Mdo & Paulson 2012 and references therein].

Pathogenic variants. SCA3 (MJD) is caused by abnormally large number of CAG repeats, typically 60 or greater [Kawaguchi et al 1994, Cancel et al 1995, Maciel et al 1995, Matilla et al 1995, Ranum et al 1995, Takiyama et al 1995, Schöls 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 variant theory [Gaspar et al 1996]. Mittal et al [2005] found evidence for the single Portuguese founder allele in India.

Table 2.

Selected ATXN3 Variants

Variant ClassificationDNA Nucleotide Change
(__) 1
Predicted Protein ChangeReference Sequences
(≤44 CAG repeats)
(60 to 86 CAG repeats)

Note on variant classification: Variants listed in the table have been provided by the author. 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 (varnomen​ See Quick Reference for an explanation of nomenclature.


Reported simply as number of CAG repeats; does not take into consideration the imperfect repeats where a CAG unit is replaced by CAA, AAG, and CAA

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 [Costa Mdo & Paulson 2012, and references therein].

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, Matos et al 2011, Costa Mdo & Paulson 2012]. 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, Alves et al 2008, Chen et al 2008, Mueller et al 2009, Williams et al 2009, Boy et al 2010, 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 severely 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 mutated 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]. Studies in a fly model of disease [Jung et al 2009] and induced pluripotent stem cells [Koch et al 2011] further suggest that proteolysis contributes to pathogenesis.

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].


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 12-19-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2018. Accessed 12-19-18.

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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

  • 24 September 2015 (me) Comprehensive update posted live
  • 17 March 2011 (me) Comprehensive update posted live
  • 3 August 2007 (me) Comprehensive update posted live
  • 30 September 2003 (me) Comprehensive update posted live
  • 24 May 2001 (me) Comprehensive update posted live
  • 10 October 1998 (pb) Review posted live
  • 13 July 1998 (shs) Original submission
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