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Spinocerebellar Ataxia Type 1

[SCA 1]

Summary

Disease characteristics. Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later symptoms include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment, chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, althoufgh childhood onset has been reported. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed.

Diagnosis/testing. The diagnosis of SCA1 rests on the result of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in the ATXN1 gene. Affected individuals have alleles with 39 to 91 CAG trinucleotide repeats. Such testing detects 100% of cases and is available in clinical laboratories.

Management.  Treatment of manifestations: canes and walkers to help prevent falls; modification of the home with grab bars, raised toilet seats, and ramps for motorized chairs; speech therapy and communication devices for dysarthria; weighted eating utensils and dressing hooks to help maintain independence. Agents/circumstances to avoid: alcohol and medications (e.g., isoniazid) that are known to cause nerve damage.

Genetic counseling. SCA1 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the gene mutation. Prenatal diagnosis by molecular genetic testing is possible for at-risk pregnancies if the diagnosis have been confirmed by molecular genetic testing in an affected relative; however, requests for prenatal testing of typically adult-onset diseases are not common.

Diagnosis

Clinical Diagnosis

The phenotypic manifestations of spinocerebellar ataxia type 1 (SCA1) are not specific; thus, the diagnosis of SCA1 rests on molecular genetic testing.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   ATXN1 is the only gene known to be associated with SCA1.

Expansion of the CAG repeat in the ATXN1 gene is the mutational mechanism in all families with SCA1 examined to date [Matilla et al 1993 , Jodice et al 1994 , Ranum et al 1994 , Orr & Zoghbi 2001].

Allele sizes

• Normal alleles: 6-44 CAG repeats [Quan et al 1995 , Servadio et al 1995 , Goldfarb et al 1996]

  Note: (1) The repeat configuration in normal alleles with 21 or more repeats is interrupted by 1-3 CAT trinucleotides, whereas disease-causing alleles show a perfectly uninterrupted CAG repeat configuration [Chung et al 1993 , Chong et al 1995]. (2) Distinguishing normal interrupted alleles from mutable normal uninterrupted alleles in the 36-44 repeat range requires additional evaluation by Sfa NI restriction analysis [Chung et al 1993].

• Mutable normal (intermediate) alleles: 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms, but can expand into the abnormal range on transmission to offspring.

  Note: Distinguishing normal CAT-interrupted alleles from mutable normal uninterrupted alleles in the 36-44 repeat range requires additional evaluation by Sfa NI restriction analysis [Chung et al 1993].

• Reduced penetrance alleles: A woman with 44 CAG repeats with CAT repeat interruptions had an affected father but was herself asymptomatic at age 66 years [Goldfarb et al 1996]; thus, she may have reduced penetrance.

• Full penetrance alleles: 39-91 CAG repeats [Chong et al 1995 , Quan et al 1995 , Servadio et al 1995 , Goldfarb et al 1996]. An allele with 39 CAG repeats without the CAT repeat interruptions has the lowest number of repeats to be associated with symptoms [Zuhlke et al 2002]. Thus, alleles of 39-44 uninterrupted CAG repeats are considered abnormal and are likely associated with symptoms. An individual with juvenile-onset SCA1 was found to have a 91-CAG repeat expansion [Chong et al 1995].

Clinical testing

• Targeted mutation analysis by direct amplification of the ATXN1 CAG repeat identifies more than 99% of individuals with a disease-causing ATXN1 mutation.

  In some cases of infantile-onset SCA, direct amplification of the ATXN1 CAG repeat may not detect repeat sizes that are in the hundreds. Southern blot analysis and PCR analysis can be used to quantitate the CAG repeat number in suspected cases of infantile-onset SCA1.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in SCA1 Test Method Mutation Detected Mutation Detection Frequency  1 Test Availability Targeted mutation analysis (PCR) Up to ~100 CAG repeats in ATXN1 >99% Clinical Targeted mutation analysis (Southern blot) Greater than 100 CAG repeats in ATXN1 <1%

1. Proportion of affected individuals with a mutation(s) as classified by test method

Testing Strategy

Confirmation of the diagnosis in a proband requires molecular genetic testing to identify the ATXN1 CAG repeat expansion.

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family by molecular genetic testing.

Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis in the family by molecular genetic testing.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be caused by mutations in ATXN1.

Clinical Description

Natural History

Spinocerebellar ataxia type 1 (SCA1) is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions [Greenfield 1954 , Koeppen & Barron 1984 , Zoghbi & Ballabio 1995]. Onset is typically in the third or fourth decade, but early onset in childhood has been documented [Schut 1950 , Zoghbi et al 1988]. In adult-onset SCA1, the duration of illness from onset to death ranges from ten to 30 years; individuals with juvenile-onset disease (whose symptoms appear before age 13 years) show more rapid progression and more severe disease, and die before age 16 years [Zoghbi et al 1988].

The majority of affected individuals initially present with difficulties in gait; slurred speech is also common. They may first notice problems of balance in going down stairs or making sudden turns; athletic individuals may notice difficulties at an earlier stage of disease in the course of activities that require a high degree of control, such as skiing or dancing.

Affected individuals may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus in the early stages of disease. Mild dysphagia, indicated by choking on food and drink, may also occur early in the disease.

As the disease progresses, the saccadic velocity slows and an up-gaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities.

As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.

Optic nerve atrophy and variable degrees of ophthalmoparesis may be detected in some individuals.

Muscle atrophy, decreased or absent deep tendon reflexes, and loss of proprioception or vibration sense may occur in the middle or late stages of the disease [van de Warrenburg et al 2004].

Individuals may experience mild decline in memory and in verbal and nonverbal intelligence; the degree of cognitive impairment correlates with severity of disease. Executive dysfunction may also occur [Burk et al 2001 , Burk et al 2003].

Extrapyramidal signs tend to take the form of chorea and dystonia and occur in advanced disease [Wu et al 2004].

Bulbar dysfunction (atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia leading to frequent aspiration) become prominent in the final stages of the disease [Shiojiri et al 1999]. Affected individuals eventually develop respiratory failure, which is the main cause of death [Zoghbi & Ballabio 1995].

Electrophysiologic studies.   Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1 [Abele et al 1997].

Neuroimaging.  Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain reveal atrophy of the brachia pontis and anterior lobe of the cerebellum and enlargement of the fourth ventricle [Schut 1991 , Spadaro et al 1992 , Della Nave et al 2004 , Guerrini et al 2004].

Neuropathology.   Neuropathologic studies reveal cerebellar atrophy with definite loss of Purkinje cells and dentate nucleus neurons, eosinophilic spheres or "torpedoes" in the axons of degenerating Purkinje cells, and severe neuronal degeneration in the inferior olive. Additional features include mild neuronal loss in cranial nerve nuclei III, IV, IX, X, and XII, and demyelination of the restiform body and brachium conjunctivum, dorsal and ventral spinocerebellar tracts, and to a lesser degree the posterior columns [Schut & Haymaker 1951 , Currier et al 1972 , Nino et al 1980 , Bebin et al 1990 , Spadaro et al 1992].

Genotype-Phenotype Correlations

Probands.   A strong correlation exists between the number of CAG repeats and severity of disease: the larger the CAG repeat, the earlier the onset and more severe the disease [Ranum et al 1994]. However, the correlation is broad (e.g., a difference of seven repeats may lead to disease in one individual 20 years later than in another) and so is not useful clinically. The largest expansions of the CAG repeat tract are found in individuals with infantile- or juvenile-onset SCA1, who typically experience more rapid disease progression and are most commonly the offspring of affected males.

Some clinical signs (facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis) are more common with larger repeat size, independent of disease duration. Affected individuals with more than 52 CAG repeats tend to become significantly disabled five years after the onset of disease.

Individuals homozygous for two mutant ATXN1 alleles do not seem to develop disease that is more severe than that which can be predicted by the larger of their two alleles.

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

Penetrance

Penetrance is considered to be greater than 95%, but is age dependent. Onset after age 60 years has occasionally been reported [Sasaki et al 1996 , van de Warrenburg et al 2004].

Anticipation

Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1 [Schut 1950 , Zoghbi et al 1988]. The tendency of the ATXN1 CAG repeat to expand as it is transmitted provides a biologic explanation for the earlier age of onset in subsequent generations. Expansions are more likely to occur when the mutation is paternally transmitted, and contractions are more typical of maternal transmissions [Chung et al 1993 , Matilla et al 1993 , Jodice et al 1994]. Juvenile-onset SCA1 is characterized by severe brain stem dysfunction in addition to the cerebellar symptoms. This brain stem dysfunction occurs rapidly, leading to death within four to eight years of symptom onset.

Nomenclature

The nomenclature for the autosomal dominant hereditary ataxias has varied over the years. Terms no longer used to refer to SCA1 include Marie's ataxia, atypical Friedreich's ataxia, and olivopontocerebellar atrophy.

Prevalence

Approximately one to two individuals in 100,000 develop SCA1. SCA1 represents approximately 6% of individuals with autosomal dominant cerebellar ataxia, although this figure varies considerably based on geographic location and ethnic background. For example, SCA1 represented 6% of autosomal dominant ataxia in a North American study [Moseley et al 1998], 34% in Serbia [Dragasevic et al 2006], 22% in India [Mittal et al 2005], and no cases in a Korean study [Jin et al 1999]. (See also Ataxia Overview .)

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders that defy easy differentiation on the basis of clinical criteria alone. Inter- and intrafamilial variability is too great to permit definitive classification without molecular genetic testing. See also Ataxia Overview .

SCA2 and SCA3 (Machado-Joseph Disease , or MJD) have age of onset and neurologic signs similar to those seen in SCA1, although their phenotypes tend to be more heterogeneous. Individuals with SCA2, for example, show earlier and more severe abnormalities of saccade velocity, loss of deep tendon reflexes, and polyneuropathy than do individuals with SCA1. Individuals with SCA3 may display prominent extrapyramidal signs (parkinsonism , pill-rolling tremor, bradykinetic-rigid syndromes) in the early stages of disease and sometimes exhibit little ataxia. Nystagmus, gaze palsy, and abnormal vestibulo-ocular reflexes can also occur earlier and with greater frequency in individuals with SCA3, but the eye movement disorder of SCA1 overlaps with SCA2 and SCA3 [Burk et al 1999]. Generalized areflexia can be seen in SCA2, SCA3, and SCA4, but is uncommon in SCA1.

SCA5, SCA6 , and SCA8 tend to progress more slowly than SCA1 and to show more purely cerebellar signs, with fewer symptoms that reflect widespread neuropathology.

If an affected individual has macular degeneration, the most likely explanation is SCA7 , which can be tested for first. Note, however, that not all individuals with SCA7 have macular degeneration.

Friedreich ataxia is usually associated with childhood onset and depressed tendon reflexes. Inheritance is autosomal recessive.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 1 (SCA1), the following evaluations are recommended:

• Medical history
• Neurologic examination
• Molecular genetic testing

Treatment of Manifestations

Management of individuals with SCA1 remains supportive as no known therapy to delay or halt the progression of the disease exists. Affected persons should be followed by a neurologist with consultation from physiatrists and physical and occupational therapists.

Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.

Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.

Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.

Weighted eating utensils and dressing hooks help maintain a sense of independence.

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

When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.

Prevention of Primary Manifestations

See Therapies Under Investigation .

Prevention of Secondary Complications

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

Surveillance

Neurologic evaluation every three to six months is appropriate.

Agents/Circumstances to Avoid

Affected individuals should avoid alcohol as well as medications known to cause nerve damage (e.g., isoniazid).

Testing of Relatives at Risk

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

Therapies Under Investigation

Lithium [Watase et al 2007] and insulin-like growth factor 1 [Vig et al 2006] have improved neurologic function in a mouse model of SCA1.

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.

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

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.

Mode of Inheritance

Spinocerebellar ataxia type 1 (SCA1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SCA1 have an affected parent.
• A proband with SCA1 who appears to have SCA1 as the result of a de novo gene mutation may in fact have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-44 CAG repeats that are not interrupted by CAT sequences is not likely to display any symptoms of SCA1, but does have a "mutable normal" (intermediate) allele that can expand on transmission to any offspring (see Molecular Genetic Testing).
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include mutation analysis of ATXN1.

Note: Although most individuals diagnosed with SCA1 have an affected parent or parents with an intermediate expansion, 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 an affected person depends on the genetic status of the parents.
• If one parent has an expanded ATXN1 allele, the risk to each sib of inheriting an expanded ATXN1 allele is 50%.
• A parent with 36-44 CAG repeats that are not interrupted by CAT sequences is not likely to display any symptoms of SCA1, but does have a "mutable normal" (intermediate) allele that can expand on transmission to any offspring (see Molecular GeneticTesting).

Offspring of a proband

• Each child of an individual with SCA1 has a 50% chance of inheriting the expanded ATXN1 allele.
• CAG repeat tracts are unstable; they may contract by a few trinucleotides but tend to expand during transmission to offspring.

  Note: If the expansion is large to begin with, it may still be long enough to cause disease even after contraction to a shorter repeat length. See Anticipation .

Other family members of the proband.   The risk to other family members depends on the genetic status of the proband's parents. If a parent has the expanded ATXN1 allele, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults.   Testing of at-risk asymptomatic adults for SCA1 is available using the same techniques described in Molecular Genetic Testing . This 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 SCA1, an affected family member should be tested first to confirm that the disorder in the family is SCA1.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make 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 SCA1, 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.

Molecular genetic testing of at-risk asymptomatic individuals younger than age 18 years is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. Genetic testing is always indicated in affected or symptomatic individuals in a family with established SCA1 regardless of age.

For more information, see 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).

Family planning.  The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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.

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 methodology 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 laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at increased risk for SCA1 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The expanded ATXN1 allele of an affected family member should be identified 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 SCA1 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).   Preimplantation genetic diagnosis may be available for families in which the ATXN1 expansion has been identified. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The ATXN1 gene spans an estimated 450 kb of DNA and consists of nine exons. The coding region is 2448 bp long. The 5' untranslated region is found in the first seven exons, and the region encoding the ataxin-1 protein is located within the large exons 8 and 9, which are 2079 and 7805 bp respectively. Both the 5' untranslated and 3' untranslated region of the ATXN1 transcript are extremely long at 935 bp and 7000 bp, respectively. Normal alleles may contain six to 44 CAG repeats and are interrupted with one to three CAT trinucleotides.

Pathologic allelic variants: Alleles of 39 or more uninterrupted CAG repeats are associated with disease. Somatic instability has been observed for the ATXN1 CAG repeats, particularly in tissues that have higher mitotic potential, such as peripheral blood cells and sperm [Chong et al 1995]. The presence of the CAT interruption within the CAG repeat tract has demonstrated a stabilizing effect in somatic tissues. Comparative analysis of a large normal allele (39 repeats with CAT interruptions) with a small expanded allele (40 uninterrupted repeats) revealed that the interrupted allele was somatically stable, whereas the allele with an uninterrupted CAG tract was unstable [Chong et al 1995].

Normal gene product: The CAG repeat encodes a glutamine tract in ataxin-1, a nuclear protein of unknown function. The transcript expressed from the ATXN1 gene is approximately 11 kb and is found in a wide variety of different cell and tissue types. Normal ataxin-1 has 792 to 829 amino acids, depending on the number of CAG repeats that encode the polyglutamine tract within the protein. Ataxin-1 has been postulated to have several functions in the nucleus, such as transcription regulation and RNA processing. Deletion of ATXN1 leads to mild impairment of spatial learning in mice. But no SCA1-like phenotypes were produced by complete deletion of ATXN1, arguing against a loss-of-function mechanism in SCA1 pathogenesis.

Abnormal gene product: In SCA1, as in several other polyglutamine diseases, the mutant protein accumulates in the nucleus into a single aggregate, often referred to as a nuclear inclusion (NI). Because these NI also accumulate portions of the cell's protein refolding and degradation machinery — chaperones, ubiquitin, and proteasomal subunits — it is thought that impaired protein clearance underlies the pathogenesis of SCA1 and related diseases. At least three lines of evidence support this hypothesis:

• Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [Cummings et al 1999].
• Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [Fernandez-Funez et al 2000 , Cummings et al 2001].
• Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [Park et al 2005].

Studies revealed that serine 776 in ataxin-1, which is phosphorylated by Akt kinase, mediates specific protein-protein interactions and is critical for pathogenicity of mutant ataxin-1 [Chen et al 2003 , Emamian et al 2003].

Genetic studies in Drosophila revealed that components of the PI3K-Akt signaling pathway are modifiers of ataxin-1-induced degeneration and that reduction of Akt activity subdues ataxin-1 toxicity.

An analysis of the genomic expression profile in SCA1 transgenic mice showed consistently altered levels of mRNA from five genes forming a biologic cohort centered on glutamate signaling pathways in Purkinje cells [Serra et al 2004]. These new findings identify this pathway as a target to investigate potential therapies in animal models.

More recent molecular studies suggested that both normal and mutant ataxin-1 interacts with the transcription repressor Capicua in its native complex, and this interaction seems to be important for the neurotoxicity of mutant ataxin-1 [Lam et al 2006]. Moreover, it is shown that duplication of ATXN1L, a paralog gene of ATXN1, suppresses SCA1 neuropathology by decreasing incorporation of mutant ataxin-1 into this native complex containing Capicua [Bowman et al 2007]. These studies suggest that SCA1 pathogenesis is mediated at least in part by modulating in part of the normal activity of ataxin-1.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.
  
  
• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents (pdf; Genetic Testing)

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Suggested Readings

• Zoghbi HY and Orr HT (revised 2002) Spinocerebellar Ataxias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 226. www.ommbid.com
  
  

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