Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Azorean Ataxia, MJD, Machado-Joseph Disease, SCA 3]
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Author:
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Henry Paulson, MD, PhD
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Initial Posting:
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Last Update:
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Disease characteristics. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Neurologic findings tend to evolve as the disease progresses.
Diagnosis/testing. The diagnosis of SCA3 rests upon the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion of the ATXN3 gene. Affected individuals have alleles with 52 to 86 CAG trinucleotide repeats. Such testing detects 100% of cases and is available in clinical laboratories.
Management. Treatment of manifestations: Management is supportive as no medication slows the course of disease; restless legs syndrome and extrapyramidal syndromes resembling parkinsonism may respond to levodopa or dopamine agonists; spasticity, drooling, and sleep problems respond variably to lioresal, atropine-like drugs, and hypnotic agents; botulinum toxin has been used for dystonia and spasticity; daytime fatigue may respond to psychostimulants such as modafinil; depression should be treated. Affected individuals should remain active; canes and walkers help prevent falling; motorized scooters can help maintain independence; speech therapy and communication devices may benefit those with dysarthria and dietary modification those with dysphagia; weighted eating utensils and dressing hooks help to maintain independence. Prevention of secondary complications: modification of the home for safety; vitamin supplements if caloric intake is reduced; weight control to facilitate ambulation and mobility; caution with general anesthesia. Surveillance: annual or biannual assessment of speech, swallowing, and gait function.
Genetic counseling. SCA3 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the mutation. Prenatal testing is possible for fetuses at increased risk if the diagnosis has been confirmed in an affected family member.
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]:
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.
Gene. ATXN3 (MJD) is the only gene known to be associated with SCA3. A highly polymorphic CAG repeat in the ATXN3 gene is unstable and is expanded in all individuals with SCA3.
Allele sizes. The following allele sizes are observed in SCA3*:
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, resulting in a pathologic expansion in a subsequent generation [Maciel et al 2001].
Reduced penetrance allele: 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: 52 to 86 CAG repeats are associated with the SCA3 phenotype.
* N Potter for the Ataxia Molecular Diagnostics Testing Group; compiled October 2002, updated August 2005.
Clinical testing
Targeted mutation analysis. Testing to determine the number of CAG repeats in the ATXN3 gene is typically performed by PCR amplification of the SCA3 trinucleotide repeat region followed by gel electrophoresis. PCR analysis may be used to detect trinucleotide repeat expansions up to approximately 100 repeats.
Table 1
summarizes molecular genetic testing for this disorder.
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1.
Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
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Interpretation of test results. The presence of one disease-causing allele is diagnostic.
To establish the diagnosis in a proband requires identification of an expanded CAG repeat in ATXN3.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of an 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 expanded CAG repeat in ATXN3 in an affected family member.
No other phenotypes are associated with mutations in the ATXN3 gene.
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by cerebellar ataxia and pyramidal signs variably associated with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy.
The age of onset of SCA3 is 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.
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:
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 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 posturings 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 , Sequiros & Coutinho 1993].
Subtypes of SCA3. Occasionally, family members with mutations of the same 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. In some individuals one type can evolve into another during the course of disease [Fowler 1984].
A fourth disease type characterized by DOPA-responsive parkinsonism has also been described.
MRI. Brain imaging studies 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.
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].
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 [Rub et al 2002 ; Rub, Brunt et al 2004 ; Rub, Burk et al 2004 ; Rub et al 2006]. The cerebellum typically shows atrophy, but in some individuals Purkinje cells and inferior olivary neurons are relatively spared [Sequiros & Coutinho 1993].
Probands. As with other CAG 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. A loose correlation also appears to exist 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 size of 80, those with type II disease had a mean CAG repeat size of 76, and those with type III disease had a mean CAG repeat size of 73.
Some, but perhaps not all, observed anticipation in age of onset can be accounted for by the intergenerational expansion of the repeat size. 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 repeat sizes 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 Yemenese 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.
A more severe disease has been reported in several homozygous individuals in the family described by Lerer et al (1996) as well as in a few other families. However, many of the homozygotes in the Yemenese family are no more severely affected than heterozygotes in other families.
A zone of repeat lengths that displays reduced penetrance is less firmly established in individuals with SCA3 than in some other repeat expansion SCAs. However, rare CAG repeat sizes of 44 to 52 may be incompletely penetrant. In addition, the smallest disease-causing repeats occasionally manifest only or primarily with restless legs syndrome [Van Alfen et al 2001].
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. 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 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].
SCA3 is also known as Machado-Joseph disease (MJD). In fact, this 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 the MJD1 gene, now renamed the ATXN3 gene. 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.
No accurate data are available regarding the prevalence of SCA3 in the general population. Overall, the dominantly inherited ataxias are rare.
The proportion of SCA3 among the dominantly inherited ataxias has been variable. Studies of affected families in the US found that approximately 10%-20% had the ATXN3 mutation [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 overall prevalence of SCA3 among 67 families with dominant ataxia was 55%; among Portuguese families it was 84%. Studies on German, Japanese, and Chinese populations found that SCA3 accounted for 40%-50% of families with ataxia [Inoue et al 1996 , Schols et al 1996 , Zhao et al 2002]. In contrast, Filla et al (1996) did not detect any ATXN3 gene mutations in 36 families from southern Italy. 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 ffrom the 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].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Progressive ataxia, often associated with evidence of upper motor neuron dysfunction such as brisk tendon reflexes and extensor plantar responses, can be seen in individuals with spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), as well as in many other dominantly inherited ataxias (see Ataxia Overview).
Findings suggestive of SCA3 include occurrence of variant clinical features in members of the same family, such as an akinetic-rigid syndrome (often responsive to dopaminergic agonists) or cerebellar ataxia associated with significant peripheral amyotrophy and generalized areflexia.
The presence of dystonia and parkinsonian features, including a beneficial response to levodopa or dopamine agonists, can cause diagnostic confusion with dopa-responsive dystonia and Parkinson disease , [Schols et al 2000]. In SCA3, however, most individuals manifesting with parkinsonian features also have some evidence of cerebellar involvement.
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
Management of individuals with SCA3 remains supportive as no medication has been proven to slow the course of disease.
However, some symptoms 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 [Cecchin et al 2007].
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 [Takei et al 2004]; a larger, double blind 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.
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].
Speech, swallowing, and gait function should be monitored annually or biannually to assess need for assistive devices.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Tremor-controlling drugs do not work well for cerebellar tremors.
No dietary factor has been shown to curtail symptoms.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is inherited in an autosomal dominant manner.
Parents of a proband
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
Offspring of a proband. Each sib of an affected individual has a 50% chance of inheriting the altered ATXN3 gene.
Other family members. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to have the expanded ATXN3 allele, his or her family members are at risk.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
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 available using the same 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 resolution on genetic testing of children 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 (pdf; Genetic Testing).
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methods and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The presence of an expanded ATXN3 allele in an affected family member must be confirmed before prenatal testing can be performed.
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, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD)
may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see
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Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
ATXN3 | 14q24.3-q31 | Ataxin-3 |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Gene Symbol | Entrez Gene | HGMD |
ATXN3 |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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Normal allelic variants:
The
ATXN3 gene consists of 11 exons within a 1776-base pair coding region with one long open reading frame [Kawaguchi et al 1994
, Ichikawa et al 2001]. A polymorphic CAG repeat encoding the glutamine repeat occurs within exon 10. Variations in the (CAG)n sequence exist. In many alleles examined, the third, fourth, and sixth CAG unit is replaced by CAA, AAG, and CAA, respectively. These variant triplets were commonly found both in normal and abnormal alleles. The CAG repeat is highly polymorphic in normal individuals with the (CAG)n in different alleles varying from 12 to 43 [Cancel et al 1995
, Maciel et el 1995
, Matilla et al 1995
, Ranum et al 1995
, Sasaki et al 1995
, Takiyama et al 1995
, Limprasert et al 1996
, Matsumura et al 1996]. 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 chromosomes 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 sizes 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 repeat numbers were 20 or 21, the guanine was replaced with cytosine. In addition, cytosine occurred in 54.5% of normal alleles with 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. It appears that cytosine at this point may play a role in determining the instability of polyglutamine tracts. Overall, 93.5% of normal chromosomes carry fewer than 31 repeat numbers.
Pathologic allelic variants: SCA3 (MJD) is caused by the unstable expansion of a CAG repeat sequence [Kawaguchi et al 1994 , Cancel et al 1995 , Maciel et al 1995 , Matilla et al 1995 , Ranum et al 1995 , Takiyama et al 1995 , Schols et al 1996 , Silveira et al 1996 , Takiyama et al 1997]. Both somatic and gametic instability of the repeat have been reported [Hashida et al 1997]. Typically, spermatozoa contain a larger repeat size than leukocytes in the same individuals [Watanabe et al 1996]. In the CNS, cerebellar tissues often tend to have smaller repeat sizes than other regions of the brain. Haplotype analysis has revealed that individuals with SCA3 from different populations often shared the same haplotype, suggesting presence of a founder effect [Takiyama et al 1995]. However, in the restricted populations of the Azores, two distinct haplotypes have been found, a fact that could overrule the one founder mutation theory [Gaspar et al 1996]. Mittal et al (2005) found evidence for the single Portuguese founder allele in India.
Normal gene product:
Ataxin-3, the protein encoded by
ATXN3, is a novel protein 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, Das et al 1997].
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 primarily to its globular Josephin domain [Chow, Mackay et al 2004
; Chow, Paulson et al 2004
; Masino et al 2004]. Normal human ataxin-3 is a potent suppressor of polyglutamine neurodenergation in Drosophila [Warrick et al 2005] and a supporter of aggresome formation [Burnett & Pittman 2005]; the carboxy-terminal portion of the protein, which contains the polyglutamine tract, forms a flexible, extended structure. 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 [Burnett & Pittman 2005] as well as the degradation of proteins sent from the endoplasmic reticulum. Taken together with the enzymatic properties of ataxin-3, these facts suggest that ataxin-3 normally participates in protein quality control pathways in the cell.
Abnormal gene product:
Most evidence favors a toxic protein mechanism of disease in which expansion of the polyglutamine tract in ataxin-3 makes the protein highly susceptible to misfolding and subsequent aggregation. This process has been successfully modeled in in vitro studies employing recombinant protein and in various cellular models and transgenic animal models [Paulson, Perez et al 1997
, Warrick et al 1998
, Evert et al 1999
, Cemal et al 2002
, Evert et al 2006]. In humans with SCA3, normal and expanded (i.e., pathogenic) ataxin-3 is widely expressed both in the brain and in all other, unaffected organ systems [Paulson, Perez et al 1997]. 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, Perez et al 1997]. 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 certain heat shock molecular chaperones and proteasomal subunits, suggesting that they are repositories for aberrantly folded, aggregated protein [Schmidt et al 2002]. Current evidence, including recent neuropathologic studies [Rub et al 2006], suggest that inclusions are not directly pathogenic structures and may rather by the byproduct of neuronal efforts to wall off abnormal proteins in a nontoxic manner. At the very least, inclusions are a biomarker of abnormal protein accumulation and impaired protein clearance. The disease protein also forms abnormal deposits outside the cell nucleus, including in neuronal projections; whether these are direly pathogenic is also unknown.
In several other polyglutamine disorders, 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 in flies and mice expressing the full-length mutant protein [Ikeda et al 1996
, Warrick et al 1998
, Warrick et al 2005]. Moreover, a putative cleavage fragment has been shown to accumulate in one mouse model of disease [Goti et al 2004], and a specific cleavage fragment also accumulates in cells undergoing apoptosis [Berke et al 2004]. 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.
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