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Spinocerebellar Ataxia Type 6

Synonym: SCA 6
, MD, PhD
Department of Neurology
University of Chicago
Chicago, Illinois

Initial Posting: ; Last Update: July 18, 2013.

Summary

Disease characteristics. Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Mean age of onset is 43 to 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved.

Diagnosis/testing. CACNA1A is the only gene in which mutation is known to cause SCA6. The diagnosis of SCA6 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in CACNA1A. Affected individuals have 20 to 33 CAG repeats. Molecular genetic testing reveals an expansion in more than 99% of affected individuals.

Management. Treatment of manifestations: Acetazolamide to eliminate episodes of ataxia; vestibular suppressants to reduce vertigo and/or osscilopsia; ophthalmology consultation for refractive or surgical management of diplopia; clonopin for REM sleep disorders; home modifications for safety and convenience; canes, walking sticks, and walkers to prevent falling; physical therapy to maximize compensation and strength; speech therapy and communication devices for dysarthria; weighted eating utensils and dressing hooks; video esophagrams to identify safest behaviors and consistency of food least likely to trigger aspiration; feeding assessment when dysphagia becomes troublesome; weight control, as obesity exacerbates ambulation and mobility difficulties; CPAP for sleep apnea.

Surveillance: Annual or semiannual evaluation by a neurologist; driving ability should be assessed by professionals periodically.

Agents/circumstances to avoid: Sedative hypnotics (ethanol or certain medications) that increase incoordination.

Other: Tremor-controlling drugs are not usually effective in reducing cerebellar tremors.

Genetic counseling. SCA6 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the CACNA1A mutation. Prenatal testing is possible for pregnancies at increased risk if the diagnosis has been confirmed in a family member; however, requests for prenatal diagnosis of (typically) adult-onset diseases are not common.

Diagnosis

Clinical Diagnosis

Spinocerebellar ataxia type 6 (SCA6) is suspected in individuals with adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Because the phenotypic manifestations of SCA6 are not specific, the diagnosis of SCA6 rests on molecular genetic testing.

Molecular Genetic Testing

Gene. CACNA1A is the only gene in which mutation is known to cause SCA6.

Allele sizes. A polymorphic CAG repeat in exon 47 of CACNA1A is unstable and is expanded in individuals with SCA6. The following are allele sizes for CACNA1A:

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in SCA6

Gene 1 Test MethodMutation Detected 2Mutation Detection Frequency by Test Method 3
CACNA1ATargeted mutation analysisCAG repeat expansion99%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

Testing Strategy

To confirm/establish the diagnosis in a proband, molecular genetic testing of CACNA1A must be performed to detect the CACNA1A CAG-repeat expansion. The test may be performed as a single gene test or as part of a multi-gene panel that evaluates for a variety of hereditary ataxia conditions.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the diagnosis in the family. See Related Genetic Counseling Issues.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior confirmation of the diagnosis in the family.

Clinical Description

Natural History

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 71 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [Gomez et al 1997, Jodice et al 1997].

Initial symptoms are gait unsteadiness, stumbling, and imbalance in approximately 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common.

Diplopia occurs in approximately 50% of individuals. Others experience visual disturbances related to difficulty fixating on moving objects, as well as horizontal gaze-evoked nystagmus (70%-100%) and vertical nystagmus (65%-83%), which is observed in fewer than 10% of those with other forms of SCA [Yabe et al 2003]. Other eye movement abnormalities, including periodic alternating nystagmus and rebound nystagmus, have also been described [Hashimoto et al 2003].

Hyperreflexia and extensor plantar responses occur in up to 40%-50% of individuals with SCA6.

Basal ganglia signs, such as dystonia and blepharospasm, are noted in up to 25% of individuals.

Mentation is generally preserved. Formal neuropsychological testing in one series revealed no significant cognitive deficits [Globas et al 2003].

Individuals with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy.

Life span is not shortened.

Pregnancy. The severity of the disease increases during pregnancy. No effect on the viability of the fetus has been reported.

Neuropathology. Neuropathologic studies in individuals with SCA6 have demonstrated either selective Purkinje cell degeneration or a combined degeneration of Purkinje cells and granule cells [Gomez et al 1997, Sasaki et al 1998].

Genotype-Phenotype Correlations

Heterozygous individuals. Although the age of onset of symptoms of SCA6 correlates inversely with the length of the expanded CAG repeat, the same broad range of onset has been noted for individuals with 22 CAG repeats, the most common disease-associated allele [Gomez et al 1997, Schols et al 1998]. In the few individuals with (CAG)30 or (CAG)33, onset has been later than in individuals with (CAG)22 and (CAG)23 [Matsuyama et al 1997, Yabe et al 1998]. A recent retrospective study showed even closer correlation of age of onset with the sum of the two allele sizes [Takahashi et al 2004].

Homozygous individuals. Several individuals who are homozygous for an abnormal expansion in CACNA1A have been reported [Geschwind et al 1997, Ikeuchi et al 1997, Matsuyama et al 1997]. In three, the onset was earlier and symptoms appeared to be slightly more severe than in individuals who were heterozygous [Geschwind et al 1997, Ikeuchi et al 1997]; in one study age of onset correlated with the sum of two disease alleles [Takahashi et al 2004].

Penetrance

Penetrance is nearly 100%, although symptoms may not appear until the seventh decade.

Anticipation

Expansions of CACNA1A are not commonly observed in transmission from parent to child; thus, anticipation has not been observed in SCA6. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by the family history or CAG repeat size.

Nomenclature

Hereditary forms of ataxia once known as Holmes type of cerebellar cortical degeneration, and later as autosomal dominant cerebellar ataxia type III (pure cerebellar ataxia), may have included SCA6.

Prevalence

The prevalence of SCA6 appears to vary by geographic area, presumably relating to founder effects. Estimated as the fraction of all kindreds with autosomal dominant spinocerebellar ataxia, rates for SCA6 are 1%-2% in Spain and France, 3% in China, 12% in the US, 13% in Germany, and 31% in Japan.

The overall prevalence of autosomal dominant ataxia is estimated at 1:100,000. The prevalence of SCA6 is calculated to be 0.02:100,000 to 0.31:100,000 [Geschwind et al 1997, Ikeuchi et al 1997, Matsumura et al 1997, Matsuyama et al 1997, Riess et al 1997, Stevanin et al 1997, Schols et al 1998, Pujana et al 1999, Jiang et al 2005]. In the most accurate assessment to date, Craig et al [2004] used a large collection of non-selected samples of genomic DNA; they estimated the prevalence of the pathologic CACNA1A expansion in the United Kingdom at 5:100,000.

The frequency of CACNA1A expansions among individuals with ataxia and no known family history of ataxia was determined to be 5% in one study [Schols et al 1998] and 43% in another [Geschwind et al 1997]; however, premature death of parents may have hindered complete ascertainment of all cases (see Ataxia Overview).

Differential Diagnosis

Individuals with spinocerebellar ataxia type 6 (SCA6) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see Ataxia Overview).

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

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and proper management of an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the following evaluations are recommended:

  • Medical, neurologic, family and social history
  • Neurologic examination, including use of a rating scale to be used annually to assess progression
  • Brain MRI to gauge the extent of atrophy of cerebellum or other structures
  • Swallow evaluation for aspiration risk and counseling
  • PT evaluation to assess risk of falling, to determine whether assisted ambulation is necessary, and to advise regarding exercise.
  • Medical genetics consultation

Treatment of Manifestations

Management is supportive.

  • Vitamin supplements are recommended, particularly if caloric intake is reduced.
  • Acetazolamide may eliminate episodes of ataxia, but does not delay or slow the overall progression.
  • Vestibular suppressants may reduce vertigo and/or osscilopsia.
  • Ophthalmology consultation is indicated for refractive or surgical management of diplopia.
  • Although neither exercise nor physical therapy stems the progression of incoordination or muscle weakness, affected individuals should maintain activity. Physical therapy should be targeted to maximizing compensation and strength.
  • Canes, walking sticks, and walkers help prevent falling. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
  • Speech disturbances occasionally occur and may be managed as in other settings. 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.
  • Before dysphagia becomes troublesome, video esophagrams can identify safest behaviors and the consistency of food least likely to trigger aspiration.
  • Clonopin may be used for REM sleep behavior disorders (RBD) unless sedative effects increase imbalance in the morning. Note: RBD is rare in individuals with SCA6.
  • Continuous positive airway pressure may be used for sleep apnea.

Surveillance

Affected individuals should be followed annually or semiannually by a neurologist, with consultations as needed by physiatrist and physical and/or occupational therapist. Driving ability should be assessed by professionals periodically.

Agents/Circumstances to Avoid

Agents with sedative/hypnotic properties such as ethanol or certain medications may produce marked increases in incoordination.

Evaluation of Relatives at Risk

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

Pregnancy Management

Although the disease rarely manifests during years of fertility, measures to support imbalance should by enhanced in symptomatic pregnant women.

Therapies Under Investigation

Gazulla & Tintore [2007] suggested gabapentin and pregabalin as potential therapeutic agents.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Tremor-controlling drugs are not usually effective in reducing cerebellar tremors.

Patients and their families should be informed about natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources.

Genetic Counseling

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

Mode of Inheritance

Spinocerebellar ataxia type 6 (SCA6) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Because penetrance is 100%, most individuals diagnosed with SCA6 have an affected parent.
  • A proband with SCA6 may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo gene mutations is unknown.
  • Recommendations for the evaluation of parents of an individual with SCA6 and no known family history of SCA6 include clinical evaluation and molecular genetic testing.

Note: 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 individual depends on the genetic status of the proband's parents.
  • If one parent has an expanded CACNA1A allele or another mutation, the risk to each sib of inheriting the disease-causing CACNA1A allele and developing the disease is 50%.
  • If neither biologic parent of the proband has a disease-causing CACNA1A allele detectable in DNA, it is presumed that the proband has a de novo gene mutation and the risk to the sibs of the proband depends on the probability of germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Offspring of affected individuals have a 50% chance of inheriting the altered CACNA1A allele, and developing the disease.

Changes in repeat size. Although repeat size changes can occur in SCA6 alleles in subsequent generations, they are much rarer than those in other repeat expansion disorders.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent has the disease-causing CACNA1A allele, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults. Testing of adults at risk for SCA6 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 SCA6, an affected family member should be tested first to confirm the diagnosis of SCA6. Testing for the disease-causing mutation in the absence of definite symptoms or signs 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 SCA6, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about 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.

Testing of at-risk asymptomatic individuals during childhood. Consensus holds that individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals before age 18 years are that it removes their 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.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or evidence of the disorder, it is possible that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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.

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 disease-causing mutation has been identified in an affected family member, prenatal testing 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 diagnosis of (typically) adult-onset diseases 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 or 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 disease-causing mutation/expansion has been identified.

Resources

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

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

Molecular Genetics

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

Table A. Spinocerebellar Ataxia Type 6: Genes and Databases

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

Table B. OMIM Entries for Spinocerebellar Ataxia Type 6 (View All in OMIM)

183086SPINOCEREBELLAR ATAXIA 6; SCA6
601011CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A

Normal allelic variants. CACNA1A consists of 47 exons. A polymorphic CAG repeat in the 3' end of the gene occurs within a portion of the gene previously thought to be only non-coding. The identification of expansions of this CAG repeat associated with autosomal dominant ataxia was accompanied by the recognition of a novel long splice form of the alpha 1A mRNA in which the reading frame includes the CAG repeat translated into glutamine residues. The CAG repeats range from (CAG)4 to (CAG)18.

Pathologic allelic variants. Disease-associated CAG-repeat alleles ranging from (CAG)21 to (CAG)33 have been reported. The most common allele is (CAG)22. One individual with a (CAG)20 allele has episodic ataxia [Jodice et al 1997].

Normal gene product. CACNA1A encodes two distinct proteins, an α1A subunit that serves as the pore-forming subunit of a voltage-dependent P/Q-type calcium channel (reviewed in Greenberg [1997]), and a transcription factor, α1ACT, that translocates to the nucleus and acts to enhance expression of several neuronally expressed genes [Du et al 2013]. Both Alpha-1A (some splice-forms) and α1ACT bear the polymorphic CAG repeat that is expanded in SCA6.

Voltage-dependent calcium channels are made up of beta and gamma-δ accessory subunits. α1A subunits are membrane glycoproteins of approximately 2400 amino acids in length in which primary structure predicts the presence of four homologous domains, each consisting of six transmembrane domains and a pore-forming P loop. P/Q-type calcium channels are high-voltage-activated calcium channels found primarily on neurons and expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. The α1 (2.1), formerly α1A, subunit is the major pore-forming subunit of the CaV2.1 (P-Q type) voltage-gated calcium channel. CACNA1A gives rise to several alternatively spliced mRNAs of approximately 7-8 kb [Ophoff et al 1996]. The predicted polypeptides range from 195 to 270 kd and vary in sequence internally and in the carboxy terminus. The discovery of the polymorphic CAG repeat in the 3' end of the gene was associated with the identification of a novel long splice form of the α1A mRNA [Zhuchenko et al 1997]. In the long splice form, inclusion of additional nucleotides at the end of exon 46 eliminates a stop codon and places an additional 237 nucleotides of 3' sequence, including the polymorphic CAG repeat, in translational frame. The CAG repeat encodes a tract of glutamine residues, in which wild type alleles range from four to 18 glutamates in length. The function of the different splice forms of the CACNA1A gene products remains to be demonstrated, although differences have been measured in phosphorylation acceptor sites.

α1ACT is encoded as a separate protein within the 3’ portion of the long splice form of α1A subunit mRNA. The α1ACT polypeptide is translated from the α1A mRNA as a separate protein under the control of a cellular internal ribosomal entry site (IRES). α1ACT is a transcriptional protein that is translocated to nuclei and binds and enhances expression via a conserved AT-rich motif on several genes expressed in Purkinje cells. α1ACT expressed without α1A subunits accelerates neurite outgrowth in cultured neuronal cells and normalizes Purkinje cell dendrites and innervation when expressed in α1A knockout mice. α1ACT polypeptide bears the polymorphic polyglutamine tract [Du et al 2013].

Abnormal gene product. The expanded CAG repeat in CACNA1A in SCA6 codes for an expanded polyglutamine tract present in both the carboxy terminus of a long splice form of the α1A subunit of the P/Q-type calcium channel [Zhuchenko et al 1997] and the α1ACT protein. While there is no consistent effect of the expanded polyglutamine tract on P/Q channel function, the polyqlutamine expansion alters gene binding, impairs transcription factor function and is toxic to cells expressing the α1ACT.

The allelic disorder, autosomal dominant cerebellar ataxia associated with CACNA1A mutations (including p.Gly293Arg in the P loop of the first domain, p.Ala454Thr in the I-II loop, and p.Arg1664Gln), has a very similar phenotype to that of SCA6 associated with CAG-repeat expansions [Yue et al 1997, Tonelli et al 2006, Cricchi et al 2007]. As these mutations do not act through nuclear translocation of an expanded polyglutamine tract in the C terminus, the disease presumably occurs through perturbed calcium channel function caused by the abnormal allele [Chen & Piedras-Renteria 2007, Kordasiewicz & Gomez 2007].

References

Published Guidelines/ Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 6-13-13. [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 6-13-13.

Literature Cited

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Suggested Reading

  1. Zoghbi HY, Orr HT. Spinocerebellar ataxias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 226. Available online. Accessed 6-14-13.

Chapter Notes

Revision History

  • 18 July 2013 (me) Comprehensive update posted live
  • 16 June 2008 (cd) Revision: mutation scanning/sequence analysis no longer available clinically
  • 21 September 2007 (me) Comprehensive update posted to live Web site
  • 8 January 2007 (cd) Revision: errata, Genotype-Phenotype Correlations, Heterozygous individuals
  • 12 May 2005 (me) Comprehensive update posted to live Web site
  • 11 April 2003 (me) Comprehensive update posted to live Web site
  • 25 July 2000 (me) Comprehensive update posted to live Web site
  • 23 October 1998 (pb) Review posted to live Web site
  • 7 April 1998 (cg) Original submission
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