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 The following allele sizes are observed in SCA3 [Potter N et al, unpublished; the Ataxia Molecular Diagnostics Testing Group; compiled October 2002, updated August 2005]:

• Normal allele. Fewer than 44 CAG repeats [Padiath et al 2005]. Overall, 93.5% of normal alleles have fewer than 31 CAG repeats.
• Mutable normal allele (also called intermediate allele). Unknown. Mutable normal alleles have yet to be convincingly associated with a phenotype but can manifest meiotic instability, rarely resulting in a pathologic expansion in a subsequent generation [Maciel et al 2001].
• Reduced penetrance allele. Between 45 to 51 CAG repeats [Gu et al 2004, Padiath et al 2005]. Individuals with a reduced penetrance allele may or may not manifest the disorder during their lifetime.
• Abnormal allele with full penetrance. Alleles with 52 to 86 CAG repeats are associated with the SCA3 phenotype.

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.

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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in ATXN3.

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:

• Vocal cord paralysis, described in three of 19 persons with SCA3 [Isozaki et al 2002]
• Vestibular dysfunction [Yoshizawa et al 2004]
• Autonomic problems, including bladder and thermoregulation disturbances [Yeh et al 2005, França et al 2010]
• A disabling sleep disturbance, rapid eye movement behavior disorder [Friedman 2002, Friedman et al 2003], and restless legs syndrome [Schols et al 1998, Van Alfen et al 2001, D’Abreu et al 2009, Pedroso et al 2011].
• Chronic pain, often in the lumbosacral region, may precede onset of ataxia [França et al 2007]
• Individuals with SCA3 have been found to have impaired executive and emotional functioning that is unrelated to ataxia severity; however, these individuals do not meet the criteria for dementia [Zawacki et al 2002]. Verbal fluency and visual memory deficits have been noted [Kawai et al 2004].

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.

• Studies of affected families in the US found that approximately 10%-20% had an ATXN3 CAG expansion [Matilla et al 1995, Ranum et al 1995], a figure similar to the 28% prevalence found among 120 French families [Durr et al 1996].
• In a study by Silveira et al [1996], the prevalence of SCA3 among 67 families with autosomal dominant ataxia was 55%, and 84% among Portuguese families. A more recent study found that 58% of Portuguese families with dominantly inherited ataxia have SCA3 [Vale et al 2010].
• Studies on German, Japanese, and Chinese populations found that SCA3 accounted for 40%-72% of families with ataxia [Inoue et al 1996, Schols et al 1996, Zhao et al 2002, Gan et al 2010].
• Filla et al [1996] did not detect any ATXN3 mutations in 36 families from southern Italy, a result corroborated by a second study showing that SCA3 is very rare in the Italian population [Brusco et al 2004]. Similarly, no SCA3 was found among Czech families with dominantly inherited ataxia [Bauer et al 2005].

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].

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.

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.

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.

Literature Cited

1. Alves S, Régulier E, Nascimento-Ferreira I, Hassig R, Dufour N, Koeppen A, Carvalho AL, Simões S, de Lima MC, Brouillet E, Gould VC, Déglon N, de Almeida LP. Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease. Hum Mol Genet. 2008;17:2071–83. [PubMed: 18385100]
2. Bauer PO, Zumrova A, Matoska V, Marikova T, Krilova S, Boday A, Singh B, Goetz P. Absence of spinocerebellar ataxia type 3/Machado-Joseph disease within ataxic patients in the Czech population. Eur J Neurol. 2005;12:851–7. [PubMed: 16241973]
3. Berke SJ, Chai Y, Marrs GL, Wen H, Paulson HL. Defining the role of ubiquitin-interacting motifs in the polyglutamine disease protein, ataxin-3. J Biol Chem. 2005;280:32026–34. [PubMed: 16040601]
4. Berke SJ, Schmied FA, Brunt ER, Ellerby LM, Paulson HL. Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem. 2004;89:908–18. [PubMed: 15140190]
5. Bichelmeier U, Schmidt T, Hübener J, Boy J, Rüttiger L, Häbig K, Poths S, Bonin M, Knipper M, Schmidt WJ, Wilbertz J, Wolburg H, Laccone F, Riess O. Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci. 2007;27:7418–28. [PubMed: 17626202]
6. Brusco A, Gellera C, Cagnoli C, Saluto A, Castucci A, Michielotto C, Fetoni V, Mariotti C, Migone N, Di Donato S, Taroni F. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol. 2004;61:727–33. [PubMed: 15148151]
7. Burk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, Didierjean O, Brice A, Klockgether T. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain. 1996;119(Pt 5):1497–505. [PubMed: 8931575]
8. Burnett B, Li F, Pittman RN. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet. 2003;12:3195–205. [PubMed: 14559776]
9. Burnett BG, Pittman RN. The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A. 2005;102:4330–5. [PMC free article: PMC555481] [PubMed: 15767577]
10. Cancel G, Abbas N, Stevanin G, Durr A, Chneiweiss H, Neri C, Duyckaerts C, Penet C, Cann HM, Agid Y. et al. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. Am J Hum Genet. 1995;57:809–16. [PMC free article: PMC1801502] [PubMed: 7573040]
11. Carvalho DR, La Rocque-Ferreira A, Rizzo IM, Imamura EU, Speck-Martins CE. Homozygosity enhances severity in spinocerebellar ataxia type 3. Pediatr Neurol. 2008;38:296–9. [PubMed: 18358414]
12. Cecchin CR, Pires AP, Rieder CR, Monte TL, Silveira I, Carvalho T, Saraiva-Pereira ML, Sequeiros J, Jardim LB. Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives. Community Genet. 2007;10:19–26. [PubMed: 17167246]
13. Cemal CK, Carroll CJ, Lawrence L, Lowrie MB, Ruddle P, Al-Mahdawi S, King RH, Pook MA, Huxley C, Chamberlain S. YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet. 2002;11:1075–94. [PubMed: 11978767]
14. Chai Y, Berke SS, Cohen RE, Paulson HL. Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem. 2004;279:3605–11. [PubMed: 14602712]
15. Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, Nukina N, Bezprozvanny I. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci. 2008;28:12713–24. [PMC free article: PMC2663415] [PubMed: 19036964]
16. Chow MK, Mackay JP, Whisstock JC, Scanlon MJ, Bottomley SP. Structural and functional analysis of the Josephin domain of the polyglutamine protein ataxin-3. Biochem Biophys Res Commun. 2004a;322:387–94. [PubMed: 15325242]
17. Chow MK, Paulson HL, Bottomley SP. Destabilization of a non-pathological variant of ataxin-3 results in fibrillogenesis via a partially folded intermediate: a model for misfolding in polyglutamine disease. J Mol Biol. 2004b;335:333–41. [PubMed: 14659761]
18. D'Abreu A, França M, Conz L, Friedman JH, Nucci AM, Cendes F, Lopes-Cendes I. Sleep symptoms and their clinical correlates in Machado-Joseph disease. Acta Neurol Scand. 2009;119:277–80. [PubMed: 18771522]
19. D'Abreu A, França MC, Paulson HL, Lopes-Cendes I. Caring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat Disord. 2010;16:2–7. [PMC free article: PMC2818316] [PubMed: 19811945]
20. Donaldson KM, Li W, Ching KA, Batalov S, Tsai CC, Joazeiro CA. Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci U S A. 2003;100:8892–7. [PMC free article: PMC166409] [PubMed: 12857950]
21. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K. Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol Cell Biol. 2003;23:6469–83. [PMC free article: PMC193705] [PubMed: 12944474]
22. Durcan TM, Kontogiannea M, Thorarinsdottir T, Fallon L, Williams AJ, Djarmati A, Fantaneanu T, Paulson HL, Fon EA. The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability. Hum Mol Genet. 2011;20:141–54. [PMC free article: PMC3005906] [PubMed: 20940148]
23. Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, Chneiweiss H, Benomar A, Lyon-Caen O, Julien J, Serdaru M, Penet C, Agid Y, Brice A. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996;39:490–9. [PubMed: 8619527]
24. Ellisdon AM, Pearce MC, Bottomley SP. Mechanisms of ataxin-3 misfolding and fibril formation: kinetic analysis of a disease-associated polyglutamine protein. J Mol Biol. 2007;368:595–605. [PubMed: 17362987]
25. Evert BO, Schelhaas J, Fleischer H, de Vos RA, Brunt ER, Stenzel W, Klockgether T, Wullner U. Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3. Clin Neuropathol. 2006;25:272–81. [PubMed: 17140157]
26. Evert BO, Wullner U, Schulz JB, Weller M, Groscurth P, Trottier Y, Brice A, Klockgether T. High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Hum Mol Genet. 1999;8:1169–76. [PubMed: 10369861]
27. Filla A, De Michele G, Campanella G, Perretti A, Santoro L, Serlenga L, Ragno M, Calabrese O, Castaldo I, De Joanna G, Cocozza S. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes. J Neurol Sci. 1996;142:140–7. [PubMed: 8902734]
28. Fowler HL. Machado-Joseph-Azorean disease. A ten-year study. Arch Neurol. 1984;41:921–5. [PubMed: 6477227]
29. França MC Jr, D'Abreu A, Friedman JH, Nucci A, Lopes-Cendes I. Chronic pain in Machado-Joseph disease: a frequent and disabling symptom. Arch Neurol. 2007;64:1767–70. [PubMed: 18071041]
30. França MC, D’Abreu A, Nucci A, Cendes F, Lopes-Cendes I. Prospective study of peripheral neuropathy in Machado-Joseph disease. Muscle Nerve. 2009;40:1012–8. [PubMed: 19802879]
31. França MC Jr, D'Abreu A, Nucci A, Lopes-Cendes I. Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease. Acta Neurol Scand. 2010;121:422–5. [PubMed: 20070275]
32. Freeman W, Wszolek Z. Botulinum Toxin Type A for Treatment of Spasticity in Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease). Mov Disord. 2005;20:644. [PubMed: 15747361]
33. Friedman JH. Presumed rapid eye movement behavior disorder in Machado-Joseph disease (spinocerebellar ataxia type 3). Mov Disord. 2002;17:1350–3. [PubMed: 12465081]
34. Friedman JH, Fernandez HH, Sudarsky LR. REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3). Mov Disord. 2003;18:1520–2. [PubMed: 14673890]
35. Gan SR, Shi SS, Wu JJ, Wang N, Zhao GX, Weng ST, Murong SX, Lu CZ, Wu ZY. High frequency of Machado-Joseph disease identified in southeastern Chinese kindreds with spinocerebellar ataxia. BMC Med Genet. 2010;11:47. [PMC free article: PMC2861663] [PubMed: 20334689]
36. Gan SR, Zhao K, Wu ZY, Wang N, Murong SX. Chinese patients with Machado-Joseph disease presenting with complicated hereditary spastic paraplegia. Eur J Neurol. 2009;16:953–6. [PubMed: 19453404]
37. Gaspar C, Lopes-Cendes I, DeStefano AL, Maciel P, Silveira I, Coutinho P, MacLeod P, Sequeiros J, Farrer LA, Rouleau GA. Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins. Hum Genet. 1996;98:620–4. [PubMed: 8882886]
38. Gaspar C, Lopes-Cendes I, Hayes S, Goto J, Arvidsson K, Dias A, Silveira I, Maciel P, Coutinho P, Lima M, Zhou YX, Soong BW, Watanabe M, Giunti P, Stevanin G, Riess O, Sasaki H, Hsieh M, Nicholson GA, Brunt E, Higgins JJ, Lauritzen M, Tranebjaerg L, Volpini V, Wood N, Ranum L, Tsuji S, Brice A, Sequeiros J, Rouleau GA. Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study. Am J Hum Genet. 2001;68:523–8. [PMC free article: PMC1235286] [PubMed: 11133357]
39. Globas C, du Montcel ST, Baliko L, Boesch S, Depondt C, DiDonato S, Durr A, Filla A, Klockgether T, Mariotti C, Melegh B, Rakowicz M, Ribai P, Rola R, Schmitz-Hubsch T, Szymanski S, Timmann D, Van de Warrenburg BP, Bauer P, Schols L. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Mov Disord. 2008;23:2232–8. [PubMed: 18759344]
40. Gonzalez C, Lima M, Kay T, Silva C, Santos C, Santos J. Short-term psychological impact of predictive testing for Machado-Joseph disease: depression and anxiety levels in individuals at risk from the Azores (Portugal). Community Genet. 2004;7:196–201. [PubMed: 15692194]
41. Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haiem L, Jenkins NA, Copeland NG, Kakizuka A, Sharp AH, Ross CA, Mouton PR, Colomer V. A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci. 2004;24:10266–79. [PubMed: 15537899]
42. Gu W, Ma H, Wang K, Jin M, Zhou Y, Liu X, Wang G, Shen Y. The shortest expanded allele of the MJD1 gene in a Chinese MJD kindred with autonomic dysfunction. Eur Neurol. 2004;52:107–11. [PubMed: 15316156]
43. Hashida H, Goto J, Kurisaki H, Mizusawa H, Kanazawa I. Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado- Joseph disease, and spinocerebellar ataxia type 1. Ann Neurol. 1997;41:505–11. [PubMed: 9124808]
44. Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA, Sakaki Y, Kanazawa I. The genomic structure and expression of MJD, the Machado-Joseph disease gene. J Hum Genet. 2001;46:413–22. [PubMed: 11450850]
45. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet. 1996;13:196–202. [PubMed: 8640226]
46. Ikeuchi T, Igarashi S, Takiyama Y, Onodera O, Oyake M, Takano H, Koide R, Tanaka H, Tsuji S. Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis. Am J Hum Genet. 1996;58:730–3. [PMC free article: PMC1914673] [PubMed: 8644735]
47. Inoue K, Hanihara T, Yamada Y, Kosaka K, Katsuragi T, Iwabuchi K. Clinical and genetic evaluation of Japanese autosomal dominant cerebellar ataxias; is Machado-Joseph disease common in the Japanese? J Neurol Neurosurg Psychiatry. 1996;60:697–8. [PMC free article: PMC1073964] [PubMed: 8648347]
48. Isozaki E, Naito R, Kanda T, Mizutani T, Hirai S. Different mechanism of vocal cord paralysis between spinocerebellar ataxia (SCA 1 and SCA 3) and multiple system atrophy. J Neurol Sci. 2002;197:37–43. [PubMed: 11997064]
49. Jayadev S, Michelson S, Lipe H, Bird T. Cambodian founder effect for spinocerebellar ataxia type 3 (Machado-Joseph disease). J Neurol Sci. 2006;250:110–3. [PubMed: 17027034]
50. Jung J, Xu K, Lessing D, Bonini NM. Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet. 2009;18:4843–52. [PMC free article: PMC2778376] [PubMed: 19783548]
51. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I. et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8:221–8. [PubMed: 7874163]
52. Kawai Y, Takeda A, Abe Y, Washimi Y, Tanaka F, Sobue G. Cognitive impairments in Machado-Joseph disease. Arch Neurol. 2004;61:1757–60. [PubMed: 15534186]
53. Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival estimates for patients with Machado-Joseph disease (SCA3). Clin Genet. 2007;72:543–5. [PubMed: 17894834]
54. Landau WM, Schmidt RE, McGlennen RC, Reich SG. Hereditary spastic paraplegia and hereditary ataxia, Part 2: A family demonstrating various phenotypic manifestations with the SCA3 genotype. Arch Neurol. 2000;57:733–9. [PubMed: 10815141]
55. Lerer I, Merims D, Abeliovich D, Zlotogora J, Gadoth N. Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet. 1996;4:3–7. [PubMed: 8800925]
56. Li LB, Yu Z, Teng X, Bonini NM. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature. 2008;453:1107–11. [PMC free article: PMC2574630] [PubMed: 18449188]
57. Lima L, Coutinho P. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorena Portuguese family. Neurology. 1980;30:319–22. [PubMed: 7189034]
58. Limprasert P, Nouri N, Heyman RA, Nopparatana C, Kamonsilp M, Deininger PL, Keats BJ. Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet. 1996;5:207–13. [PubMed: 8824876]
59. Lin KP, Soong BW. Peripheral neuropathy of Machado-Joseph disease in Taiwan: a morphometric and genetic study. Eur Neurol. 2002;48:210–7. [PubMed: 12422070]
60. Liu CS, Hsu HM, Cheng WL, Hsieh M. Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy. Acta Neurol Scand. 2005;111:385–90. [PubMed: 15876340]
61. Lu CS, Chang HC, Kuo PC, Liu YL, Wu WS, Weng YH, Yen TC, Chou YH. The parkinsonian phenotype of spinocerebellar ataxia type 3 in a Taiwanese family. Parkinsonism Relat Disord. 2004;10:369–73. [PubMed: 15261879]
62. Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, Barros J, Rouleau GA, Coutinho P, Sequeiros J. Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol. 2001;58:1821–7. [PubMed: 11708990]
63. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JE. et al. Correlation between CAG repeat length and clinical features in Machado- Joseph disease. Am J Hum Genet. 1995;57:54–61. [PMC free article: PMC1801255] [PubMed: 7611296]
64. Masino L, Nicastro G, Menon RP, Dal Piaz F, Calder L, Pastore A. Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3. J Mol Biol. 2004;344:1021–35. [PubMed: 15544810]
65. Matilla T, McCall A, Subramony SH, Zoghbi HY. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol. 1995;38:68–72. [PubMed: 7611728]
66. Matsumura R, Takayanagi T, Fujimoto Y, Murata K, Mano Y, Horikawa H, Chuma T. The relationship between trinucleotide repeat length and phenotypic variation in Machado-Joseph disease. J Neurol Sci. 1996a;139:52–7. [PubMed: 8836972]
67. Matsumura R, Takayanagi T, Murata K, Futamura N, Hirano M, Ueno S. Relationship of (CAG)nC configuration to repeat instability of the Machado-Joseph disease gene. Hum Genet. 1996b;98:643–5. [PubMed: 8931692]
68. Mittal U, Srivastava AK, Jain S, Jain S, Mukerji M. Founder haplotype for Machado-Joseph disease in the Indian population: novel insights from history and polymorphism studies. Arch Neurol. 2005;62:637–40. [PubMed: 15824265]
69. Monte TL, Rieder CR, Tort AB, Rockenback I, Pereira ML, Silveira I, Ferro A, Sequeiros J, Jardim LB. Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study. Acta Neurol Scand. 2003;107:207–10. [PubMed: 12614314]
70. Mueller T, Breuer P, Schmitt I, Walter J, Evert BO, Wüllner U. CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3. Hum Mol Genet. 2009;18:3334–43. [PubMed: 19542537]
71. Nandagopal R, Moorthy SG. Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J. 2004;80:363–5. [PMC free article: PMC1743016] [PubMed: 15192175]
72. Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A. The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A. 2005;102:10493–8. [PMC free article: PMC1180765] [PubMed: 16020535]
73. Onodera O, Idezuka J, Igarashi S, Takiyama Y, Endo K, Takano H, Oyake M, Tanaka H, Inuzuka T, Hayashi T, Yuasa T, Ito J, Miyatake T, Tsuji S. Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease. Ann Neurol. 1998;43:288–96. [PubMed: 9506544]
74. Padiath QS, Srivastava AK, Roy S, Jain S, Brahmachari SK. Identification of a novel 45 repeat unstable allele associated with a disease phenotype at the MJD1/SCA3 locus. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:124–6. [PubMed: 15457499]
75. Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol. 1997a;41:453–62. [PubMed: 9124802]
76. Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997b;19:333–44. [PubMed: 9292723]
77. Pedroso JL, Braga-Neto P, Felício AC, Dutra LA, Santos WA, do Prado GF, Barsottini OG. Sleep Disorders in Machado-Joseph Disease: Frequency, Discriminative Thresholds, Predictive Values, and Correlation with Ataxia-Related Motor and Non-Motor Features. Cerebellum. 2011;10:291–5. [PubMed: 21287304]
78. Ranum LP, Lundgren JK, Schut LJ, Ahrens MJ, Perlman S, Aita J, Bird TD, Gomez C, Orr HT. Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet. 1995;57:603–8. [PMC free article: PMC1801263] [PubMed: 7668288]
79. Reina CP, Zhong X, Pittman RN. Proteotoxic stress increases nuclear localization of ataxin-3. Hum Mol Genet. 2010;19:235–49. [PMC free article: PMC2796889] [PubMed: 19843543]
80. Riess O, Rüb U, Pastore A, Bauer P, Schöls L. SCA3: neurological features, pathogenesis and animal models. Cerebellum. 2008;7:125–37. [PubMed: 18418689]
81. Rüb U, Brunt ER, de Vos RA, Del Turco D, Del Tredici K, Gierga K, Schultz C, Ghebremedhin E, Burk K, Auburger G, Braak H. Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance. Neuropathol Appl Neurobiol. 2004a;30:402–14. [PubMed: 15305986]
82. Rüb U, Brunt ER, Deller T. New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol. 2008;21:111–6. [PubMed: 18317266]
83. Rüb U, Burk K, Schols L, Brunt ER, de Vos RA, Diaz GO, Gierga K, Ghebremedhin E, Schultz C, Del Turco D, Mittelbronn M, Auburger G, Deller T, Braak H. Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3. Neurology. 2004b;63:1258–63. [PubMed: 15477548]
84. Rüb U, de Vos RA, Brunt ER, Sebesteny T, Schols L, Auburger G, Bohl J, Ghebremedhin E, Gierga K, Seidel K, den Dunnen W, Heinsen H, Paulson H, Deller T. Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions. Brain Pathol. 2006;16:218–27. [PubMed: 16911479]
85. Rüb U, de Vos RA, Schultz C, Brunt ER, Paulson H, Braak H. Spinocerebellar ataxia type 3 (Machado-Joseph disease): severe destruction of the lateral reticular nucleus. Brain. 2002;125:2115–24. [PubMed: 12183356]
86. Rubinsztein DC, Leggo J, Coetzee GA, Irvine RA, Buckley M, Ferguson-Smith MA. Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes. Hum Mol Genet. 1995;4:1585–90. [PubMed: 8541843]
87. Sakai T, Matsuishi T, Yamada S, Komori H, Iwashita H. Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Joseph disease: sulfamethoxazole- trimethoprim increases cerebrospinal fluid level of biopterin. J Neural Transm Gen Sect. 1995;102:159–72. [PubMed: 8748680]
88. Sasaki H, Wakisaka A, Fukazawa T, Iwabuchi K, Hamada T, Takada A, Mukai E, Matsuura T, Yoshiki T, Tashiro K. CAG repeat expansion of Machado-Joseph disease in the Japanese: analysis of the repeat instability for parental transmission, and correlation with disease phenotype. J Neurol Sci. 1995;133:128–33. [PubMed: 8583215]
89. Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, Rechsteiner M, Riess O, Landwehrmeyer GB. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol. 2002;51:302–10. [PubMed: 11891825]
90. Schols L, Amoiridis G, Epplen JT, Langkafel M, Przuntek H, Riess O. Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. J Neurol Neurosurg Psychiatry. 1996;61:466–70. [PMC free article: PMC1074043] [PubMed: 8937340]
91. Schols L, Haan J, Riess O, Amoiridis G, Przuntek H. Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology. 1998;51:1603–7. [PubMed: 9855509]
92. Schols L, Peters S, Szymanski S, Kruger R, Lange S, Hardt C, Riess O, Przuntek H. Extrapyramidal motor signs in degenerative ataxias. Arch Neurol. 2000;57:1495–500. [PubMed: 11030803]
93. Schulte T, Mattern R, Berger K, Szymanski S, Klotz P, Kraus PH, Przuntek H, Schols L. Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease. Arch Neurol. 2001;58:1451–7. [PubMed: 11559318]
94. Schulz JB, Borkert J, Wolf S, Schmitz-Hübsch T, Rakowicz M, Mariotti C, Schöls L, Timmann D, van de Warrenburg B, Dürr A, Pandolfo M, Kang JS, Mandly AG, Nägele T, Grisoli M, Boguslawska R, Bauer P, Klockgether T, Hauser TK. Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6. Neuroimage. 2010;49:158–68. [PubMed: 19631275]
95. Seidel K, den Dunnen WF, Schultz C, Paulson H, Frank S, de Vos RA, Brunt ER, Deller T, Kampinga HH, Rüb U. Axonal inclusions in spinocerebellar ataxia type 3. Acta Neuropathol. 2010;120:449–60. [PMC free article: PMC2923324] [PubMed: 20635090]
96. Sequeiros J, Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. Adv Neurol. 1993;61:139–53. [PubMed: 8421964]
97. Silva RC, Saute JA, Silva AC, Coutinho AC, Saraiva-Pereira ML, Jardim LB. Occupational therapy in spinocerebellar ataxia type 3: an open-label trial. Braz J Med Biol Res. 2010;43:537–42. [PubMed: 20414586]
98. Silveira I, Lopes-Cendes I, Kish S, Maciel P, Gaspar C, Coutinho P, Botez MI, Teive H, Arruda W, Steiner CE, Pinto-Junior W, Maciel JA, Jerin S, Sack G, Andermann E, Sudarsky L, Rosenberg R, MacLeod P, Chitayat D, Babul R, Sequeiros J, Rouleau GA. Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology. 1996;46:214–8. [PubMed: 8559378]
99. Subramony SH, Bock HG, Smith SC, Currier RD, et al. Presumed Machado-Joseph disease: four kindreds from Mississippi. In: Lechentenberg R, ed. Handbook of Cerebellar Diseases. New York, NY: Marcel Dekker Inc; 1993:353-62.
100. Sudarsky L, Corwin L, Dawson DM. Machado-Joseph disease in New England: clinical description and distinction from the olivopontocerebellar atrophies. Mov Disord. 1992;7:204–8. [PubMed: 1620136]
101. Takei A, Fukazawa T, Hamada T, Sohma H, Yabe I, Sasaki H, Tashiro K. Effects of tandospirone on "5-HT1A receptor-associated symptoms" in patients with Machado-Joseph disease: an open-label study. Clin Neuropharmacol. 2004;27:9–13. [PubMed: 15090930]
102. Takei A, Hamada S, Homma S, Hamada K, Tashiro K, Hamada T. Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study. Cerebellum. 2010;9:567–70. [PubMed: 20809107]
103. Takiyama Y, Igarashi S, Rogaeva EA, Endo K, Rogaev EI, Tanaka H, Sherrington R, Sanpei K, Liang Y, Saito M. et al. Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease. Hum Mol Genet. 1995;4:1137–46. [PubMed: 8528200]
104. Takiyama Y, Sakoe K, Soutome M, Namekawa M, Ogawa T, Nakano I, Igarashi S, Oyake M, Tanaka H, Tsuji S, Nishizawa M. Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability. Hum Mol Genet. 1997;6:1063–8. [PubMed: 9215676]
105. Teo AY, Goy RW, Woon YS. Combined spinal-epidural technique for vaginal hysterectomy in a patient with Machado-Joseph disease. Reg Anesth Pain Med. 2004;29:352–4. [PubMed: 15305255]
106. Toulouse A, Au-Yeung F, Gaspar C, Roussel J, Dion P, Rouleau GA. Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts. Hum Mol Genet. 2005;14:2649–60. [PubMed: 16087686]
107. Vale J, Bugalho P, Silveira I, Sequeiros J, Guimarães J, Coutinho P. Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal. Eur J Neurol. 2010;17:124–8. [PubMed: 19659750]
108. van Alfen N, Sinke RJ, Zwarts MJ, Gabreels-Festen A, Praamstra P, Kremer BP, Horstink MW. Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype. Ann Neurol. 2001;49:805–7. [PubMed: 11409435]
109. van de Warrenburg BP, Hendriks H, Dürr A, van Zuijlen MC, Stevanin G, Camuzat A, Sinke RJ, Brice A, Kremer BP. Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort. Ann Neurol. 2005;57:505–12. [PubMed: 15747371]
110. Verbeek DS, Piersma SJ, Hennekam EF, Ippel EF, Pearson PL, Sinke RJ. Haplotype study in Dutch SCA3 and SCA6 families: evidence for common founder mutations. Eur J Hum Genet. 2004;12:441–6. [PubMed: 15026782]
111. Wang YG, Du J, Wang JL, Chen J, Chen C, Luo YY, Xiao ZQ, Jiang H, Yan XX, Xia K, Pan Q, Tang BS, Shen L. Six cases of SCA3/MJD patients that mimic hereditary spastic paraplegia in clinic. J Neurol Sci. 2009;285:121–4. [PubMed: 19608203]
112. Warrick JM, Morabito LM, Bilen J, Gordesky-Gold B, Faust LZ, Paulson HL, Bonini NM. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell. 2005;18:37–48. [PubMed: 15808507]
113. Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, Bonini NM. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell. 1998;93:939–49. [PubMed: 9635424]
114. Watanabe M, Abe K, Aoki M, Kameya T, Kaneko J, Shoji M, Ikeda M, Shizuka M, Ikeda Y, Iizuka T, Hirai S, Itoyama Y. Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease. J Neurol Sci. 1996;136:101–7. [PubMed: 8815156]
115. Williams AJ, Knutson TM, Colomer Gould VF, Paulson HL. In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis. Neurobiol Dis. 2009;33:342–53. [PMC free article: PMC2662361] [PubMed: 19084066]
116. Williams AJ, Paulson HL. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci. 2008;31:521–8. [PMC free article: PMC2580745] [PubMed: 18778858]
117. Yamada S, Nishimiya J, Nakajima T, Taketazu F. Linear high intensity area along the medial margin of the internal segment of the globus pallidus in Machado-Joseph disease patients. J Neurol Neurosurg Psychiatry. 2005;76:573–5. [PMC free article: PMC1739610] [PubMed: 15774449]
118. Yeh TH, Lu CS, Chou YH, Chong CC, Wu T, Han NH, Chen RS. Autonomic dysfunction in Machado-Joseph disease. Arch Neurol. 2005;62:630–6. [PubMed: 15824264]
119. Yoshizawa T, Nakamagoe K, Ueno T, Furusho K, Shoji S. Early vestibular dysfunction in Machado-Joseph disease detected by caloric test. J Neurol Sci. 2004;221:109–11. [PubMed: 15178224]
120. Zawacki TM, Grace J, Friedman JH, Sudarsky L. Executive and emotional dysfunction in Machado-Joseph disease. Mov Disord. 2002;17:1004–10. [PubMed: 12360550]
121. Zhao Y, Tan EK, Law HY, Yoon CS, Wong MC, Ng I. Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet. 2002;62:478–81. [PubMed: 12485197]
122. Zhou YX, Takiyama Y, Igarashi S, Li YF, Zhou BY, Gui DC, Endo K, Tanaka H, Chen ZH, Zhou LS, Fan MZ, Yang BX, Weissenbach J, Wang GX, Tsuji S. Machado-Joseph disease in four Chinese pedigrees: molecular analysis of 15 patients including two juvenile cases and clinical correlations. Neurology. 1997;48:482–5. [PubMed: 9040742]

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