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Spinocerebellar Ataxia Type 7

Synonym: SCA 7
, MD, PhD
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: December 20, 2012.

Summary

Clinical characteristics.

Spinocerebellar ataxia type 7 (SCA7) is characterized by progressive cerebellar ataxia, including dysarthria and dysphagia, and cone-rod and retinal dystrophy with progressive central visual loss resulting in blindness in affected adults. Onset in early childhood or infancy has an especially rapid and aggressive course often associated with failure to thrive and regression of motor milestones.

Diagnosis/testing.

The diagnosis of SCA7 is suspected in most adults based on clinical findings. ATXN7 is the only gene in which pathogenic variants cause SCA7. Molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in ATXN7 is used to confirm the diagnosis of SCA7 in adults and to establish the diagnosis in children. Affected individuals usually have greater than 36 CAG repeats, although individuals with fewer repeats may also present with symptoms.

Management.

Treatment of manifestations: For adults: use of canes and walkers to prevent falls, home modifications (e.g., grab bars, raised toilet seats, and ramps) for mobility, weighted eating utensils and dressing hooks for independence, speech therapy and communication devices for those with dysarthria, and feeding assessment for those with dysphagia; low-vision aids and mobility training for those with visual impairment.

Prevention of secondary complications: Weight control to facilitate ambulation and mobility.

Surveillance: Routine ophthalmologic examination.

Other: Tremor-controlling drugs are ineffective.

Genetic counseling.

SCA7 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the altered gene. Anticipation, resulting from further expansion of the CAG repeat on transmission from parent to child, occurs. Prenatal testing is possible for pregnancies at increased risk once the diagnosis has been confirmed by molecular genetic testing in an affected family member.

Diagnosis

Clinical Diagnosis

Although formal diagnostic criteria have not been established, the diagnosis of spinocerebellar ataxia type 7 (SCA7) can be established in adults who have the following findings:

  • Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia
  • Cone-rod retinal dystrophy with the following:
    • Abnormalities of rod and cone function on electroretinogram testing
    • A tritan-axis (blue/yellow) defect on detailed color vision testing
    • Macular changes on fundoscopic examination (late in the disease course)
  • Family history consistent with autosomal dominant inheritance

In children, the disease progression is often more rapid and aggressive than in adults. In infants, clinical diagnosis may be difficult because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings [Benton et al 1998].

Molecular Genetic Testing

Gene. ATXN7 is the only gene in which mutation is known to cause spinocerebellar ataxia type 7 (SCA7).

Allele sizes

  • Normal alleles. Approximately 75% of normal alleles have ten CAG repeats [Michalik et al 2004]. To date, no normal allele with greater than 19 CAG repeats has been reported. Thus, no data regarding the significance of alleles between 19 and 27 CAG repeats are available.
  • Alleles of uncertain significance. Whether alleles with 28-36 repeats are mutable normal alleles or alleles with reduced penetrance awaits long-term clinical follow up of individuals with this number of repeats [Stevanin et al 1998].
  • Mutable normal alleles. 28 to 33 CAG repeats [Lebre et al 2003]. Previously called "intermediate alleles," mutable normal alleles are meiotically unstable and not convincingly associated with an abnormal phenotype. Because of the instability of alleles in the mutable normal range, an asymptomatic individual with a mutable normal allele may be predisposed to having a child with an expanded allele [Mittal et al 2005].
  • Reduced-penetrance alleles. 34-36 CAG repeats may be provisionally defined as alleles with reduced penetrance (i.e., variably associated with disease manifestations). When they occur, symptoms are more likely to be later in onset and milder than average.
  • Full-penetrance alleles. Alleles of greater than 36 CAG repeats [Nardacchione et al 1999, Michalik et al 2004] to extreme expansions, e.g., 460 CAG repeats [van de Warrenburg et al 2001] are considered fully penetrant.

Note: The distinction between the allele size for reduced-penetrance alleles and for full-penetrance alleles is likely to remain unclear until more families are reported; nonetheless, regardless of the "descriptor" used for these alleles, they should be considered unstable and pathogenic.

Clinical testing – Targeted analysis for pathogenic variants

  • PCR analysis may be used to detect trinucleotide repeat expansions in the first exon of ATXN7 that are up to approximately 100 repeats [Fu et al 1991]. PCR analysis may show either two heterozygous normal-sized alleles or a single normal-sized allele. In the latter case, it may be necessary to perform Southern analysis to determine if the two alleles are the same size and within normal range or if one of the alleles is expanded and therefore not detectable by the PCR analysis.
  • Southern analysis may be necessary to detect repeat expansions of more than approximately 100 CAG repeats.

Table 1.

Summary of Molecular Genetic Testing Used in the Diagnosis of SCA7

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
ATXN7Targeted analysis for pathogenic variants: PCR amplificationCAG trinucleotide repeat expansions of ≤~100 repeats~100%
Targeted analysis for pathogenic variants: Southern analysisHighly expanded CAG trinucleotide repeat expansions (>100 repeats)
1.
2.

See Molecular Genetics for information on allelic variants.

3.

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

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Use targeted analysis for pathogenic variants to determine the number of CAG trinucleotide repeats.

2.

If a single normal-sized allele is identified, determine if there is a family history of SCA7 and/or autosomal dominant cerebellar ataxia with retinal degeneration. Based on the family history and the age of onset in the proband, determine if Southern blot analysis to detect very large ATXN7 CAG repeat expansions is appropriate for the proband or another family member.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

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

Clinical Characteristics

Clinical Description

The onset of spinocerebellar ataxia type 7 (SCA7) ranges from infancy (with an accelerated course and early death) to the fifth or occasionally sixth decade (with slowly progressive retinal degeneration and cerebellar ataxia) [Giunti et al 1999].

In infancy or early childhood, ataxia may not be obvious but muscle wasting, weakness, and hypotonia are common [Enevoldson et al 1994]. Two infants with severe disease and expansions of more than 200 and 306 CAG repeats had neonatal hypotonia, developmental delay, poor feeding, dysphagia, congestive heart failure, cerebral and cerebellar atrophy, and retinal disease [Babovic-Vuksanovic et al 1998, Benton et al 1998]. Ansorge et al [2004] reported a child with 180 CAG repeats dying in infancy.

In those with infantile-onset disease, the cerebellar and brain stem degeneration is so rapid that retinal degeneration and related vision loss may not be evident.

When initial symptoms occur at or before adolescence, blindness from retinal degeneration can occur within a few years. Individuals showing symptoms in their teens may be blind within a decade or less.

In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) may precede, but usually follows, the onset of visual symptoms. While the rate of progression varies, the eventual result is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.

Brisk tendon reflexes and spasticity become evident as the disease progresses. Ocular saccades may become markedly slowed.

Cognitive decline and psychosis have been reported [Benton et al 1998]. Neuropsychiatric testing of some individuals with SCA7 has revealed selective deficits in social cognition [Sokolovsky et al 2010].

The retinal degeneration is a progressive, cone-rod dystrophy that results in total blindness [To et al 1993, Aleman et al 2002, Ahn et al 2005, Hugosson et al 2009]. The onset of retinal degeneration is often characterized in the late teens or early 20s by hemeralopia (inability to see clearly in bright light), photophobia (extreme sensitivity to light), and abnormalities in color vision and central visual acuity [Miller et al 2009].

During the earliest stages of retinal degeneration, young adults may have no symptoms, but may have subtle granular changes in the macula and make errors in the tritan (blue-yellow) axis on detailed color vision testing using the Farnsworth dichromatous (D15) test. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [Miller et al 2009].

As cone function decreases over time, central visual acuity decreases to the 20/200 (legally blind) range, more prominent macular changes appear (see Figure 1), all color discrimination is lost, and eventually all vision.

Figure 1. . Funduscopic photo shows extreme macular degeneration of late-stage SCA7.

Figure 1.

Funduscopic photo shows extreme macular degeneration of late-stage SCA7.

It is important to note that in adult-onset disease visual loss from retinal degeneration may precede, accompany, or follow the onset of ataxia [Miller et al 2009] and that profound visual loss can be accompanied by minimal ophthalmoscopic findings and minimal ataxia [Thurtell et al 2009].

Pathology. Neuronal loss, loss of myelinated fibers, and gliosis are observed in the cerebellum (especially Purkinje cells); inferior olivary, dentate, and pontine nuclei; and to a lesser extent in cerebral cortex, basal ganglia, thalamus and midbrain [Rüb et al 2008, Seidel et al 2012].

In a detailed pathoanatomical study, Rüb et al [2008] correlated the widespread pattern of brain neuronal degeneration with the variable clinical phenotype, comparing degeneration in 18 different regions with various clinical manifestations such as ataxia, pyramidal signs, visual loss, diplopia, and impaired hearing.

Nuclear inclusion aggregates, containing mutated ataxin-7 in neurons from both degenerating and spared areas, are largely absent from Purkinje cells [Michalik & Van Broeckhoven 2003]. In a severely affected infant, Ansorge et al [2004] identified ataxin-7 nuclear inclusions in the hippocampus and many non-nervous system tissues including the intestine, pancreas, and cardiovascular system. Abnormal mitochondria have also been observed in biopsies from skeletal muscle and liver [Han et al 2010a].

Degeneration is evident in the posterior columns and spinocerebellar tracks of the spinal cord [Martin et al 1994, Lebre et al 2003, Koeppen 2005].

Degeneration of photoreceptors and bipolar and granular cells is evident in the retina, especially in the foveal and parafoveal regions [Martin et al 1994].

Genotype-Phenotype Correlations

A correlation between CAG repeat length and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease. Despite observations correlating CAG repeat length with age of onset, disease severity, and course, current consensus is that ATXN7 allele size cannot provide sufficient predictive value for clinical prognosis [Andrew et al 1997].

Anticipation

In families with a disease-causing ATXN7 allele, repeat length tends to expand with transmission to successive generations, with more marked expansions seen in affected offspring of affected males [Gouw et al 1998]. This explains, at the genetic level, the marked anticipation seen in families with SCA7, now regarded as the most unstable of the disorders with CAG repeats. Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be a sporadic neurodegenerative disease years before a parent or grandparent with an ATXN7 CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004].

Nomenclature

The association of retinal degeneration with cerebellar ataxia has been recognized for many decades [Havener 1951, Carpenter & Schumacher 1966, Weiner et al 1967, Konigsmark & Weiner 1970, Anttinen et al 1986, Gouw et al 1994]. Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and OPCA type II.

Prevalence

The prevalence is less than 1:100,000 population. In several studies, SCA7 represented 2% of all SCAs [Filla et al 2000, Storey et al 2000].

No individuals with SCA7 were reported from population studies in Hokkaido, Japan [Sasaki et al 2000, Jardim et al 2001, Kim et al 2001] and mainland China [Tang et al 2000]. However, another study reported four families with SCA7 from Beijing, China [Gu et al 2000] and one from Taiwan [Tsai et al 2004]. Han et al [2010b] reviewed seven reports describing 14 families with SCA7 in Southeast Asia (three from mainland China, one from Taiwan, two from Japan, and eight from Korea). The clinical and genetic features of these families were typical of SCA7 in Western countries.

Differential Diagnosis

While many of the clinical and pathologic findings of the other spinocerebellar ataxias (SCAs) overlap with SCA7, retinal degeneration is the distinguishing feature of SCA7 (see Ataxia Overview).

A few individuals with SCA1 have been reported to have progressive visual loss [Illarioshkin et al 1996, Abe et al 1997].

The SCA7 phenotype may be confused with acquired ataxia associated with other forms of visual loss such as diabetic retinopathy, multiple sclerosis, or age-related macular degeneration.

Mitochondrial encephalopathies such as Leber hereditary optic neuropathy (LHON) can present with ataxia and, in some cases, concomitant visual degeneration; these mitochondrially based ataxias can be distinguished from SCA7 by molecular genetic testing, by pattern of inheritance (maternal inheritance rather than autosomal dominant inheritance), and by the absence of anticipation, which is normally seen in SCA7 (see Mitochondrial Diseases Overview).

Infantile and childhood-onset SCA7 may be confused with lipid storage diseases and the neuronal ceroid-lipofuscinoses.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with spinocerebellar ataxia type 7 (SCA7), the following evaluations are recommended:

  • Medical history
  • Neurologic examination
  • Ophthalmologic examination including assessment of visual acuity, visual fields, and color vision
  • Clinical genetics consultation

Treatment of Manifestations

Management of affected individuals remains supportive as no known therapy to delay or halt the progression of the disease exists.

Cerebellar ataxia. Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals with spinocerebellar ataxia type 7 (SCA7) 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.

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

Note: Tremor-controlling drugs do not work well for cerebellar tremors.

Retinal degeneration. Use of sunglasses and limitation of UV exposure are encouraged in order to limit damage to the retina.

Various optical aids have been proposed for individuals with peripheral visual loss and preserved central vision, although all have drawbacks.

Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.

Wide-field, high-intensity flashlights produce a bright wide beam of light and improve the nighttime mobility of individuals with retinal degeneration. They are inexpensive and allow binocular viewing, but are large, heavy, and conspicuous.

Prevention of Secondary Complications

No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.

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

Surveillance

Routine follow up by an ophthalmologist is appropriate to measure visual acuity and visual fields and to help identify appropriate visual aids.

Evaluation of Relatives at Risk

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

Pregnancy Management

Walking during pregnancy may be more difficult than usual because of the ataxia.

Therapies Under Investigation

Scholefield et al [2009] have suggested allele-specific RNA interference as a therapeutic approach for SCA7.

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.

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 7 (SCA7) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed as having SCA7 have an affected parent.
  • A proband with SCA7 may have the disorder as the result of expansion of a reduced-penetrance allele (34-36 CAG repeats) or a mutable normal allele (28-33 CAG repeats) inherited from an unaffected parent.
  • Recommendations for the evaluation of parents of a proband include clinical evaluation and molecular genetic testing of ATXN7.

Note: Although most individuals diagnosed with SCA7 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of an affected person depends on the genetic status of the parents: if one parent has an expanded ATXN7 CAG repeat, the risk to each sib of inheriting the expanded CAG repeat is 50%.
  • The risk to the individual who inherits an expanded allele of developing the SCA7 phenotype depends on the size of the CAG repeat.

Offspring of a proband. Offspring of an affected individual have a 50% chance of inheriting the expanded CAG repeat at conception. The risk to the individual who inherits an expanded CAG repeat of developing the SCA7 phenotype depends on the size of the expanded allele.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parent: if a parent has an expanded CAG repeat, his or her family members are at risk.

Related Genetic Counseling Issues

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 individuals. Testing of at-risk adults for SCA7 is possible using the 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 SCA7, an affected family member should be tested first to confirm the molecular diagnosis. It should be remembered that testing for the pathogenic variant 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 SCA7, 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 positive test results need arrangements for long-term follow up and evaluations.

Testing of at-risk individuals younger than age 18 years. 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 younger than 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 [Bloch & Hayden 1990, Harper & Clarke 1990]. 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 Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the expanded ATXN7 CAG repeat has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for SCA7 are possible.

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
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • 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
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: sanfordresearch@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 7: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
ATXN73p14​.1Ataxin-7ATXN7 databaseATXN7

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 7 (View All in OMIM)

164500SPINOCEREBELLAR ATAXIA 7; SCA7
607640ATAXIN 7; ATXN7

Gene structure. ATXN7 is 136,094 bp in length encoding an 892-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A polymorphic CAG repeat tract occurs in the first exon; normal alleles have between four and 19 CAG repeats. In unaffected, unrelated reference populations, (CAG)10 was the most common allele and alleles larger than 19 repeats were not observed [Del-Favero et al 1998, Gouw et al 1998]. Splice variants appear to exist, although their significance is unknown.

Pathogenic variants. The ATXN7 pathogenic variant is an abnormal (CAG)n trinucleotide repeat expansion in the coding region of the protein [David et al 1997]. Pathogenic alleles range from 36 to more than 450 CAG repeats [Michalik et al 2004]. Alleles with 28-36 CAG repeats are of uncertain significance (see Molecular Genetic Testing).

Normal gene product. Ataxin-7, the gene product of ATXN7, is expected to be about 95 kd. The protein is predominantly nuclear, but shuttles between the nucleus and cytoplasm. One function of ataxin-7 is as a core component of a transcription co-activator complex called STAGA [Garden & LaSpada 2008]. Ataxin-7 also has a cytoplasmic role in stabilizing microtubules [Nakamura et al 2012]. The normal distribution of ataxin-7 in human brain and retina has been described [Cancel et al 2000].

Abnormal gene product. The CAG repeats in ATXN7 code for a run of glutamines. In unaffected individuals, the polyglutamine tract is from four to 19 amino acids long. Abnormal proteins have an expanded polyglutamine tract of 37 or more amino acids. Protein from an affected individual has been detected in the nuclear fraction and appears to run at approximately 130 kd [Trottier et al 1995]. CAG repeat expansions in ATXN7 suppress transcription of an antisense non-coding RNA that promotes repressive chromatin modification of the ataxin-7 promoter [Sopher et al 2011], leading to increased expression of the mutated protein.

The precise molecular mechanism by which mutated ataxin-7 causes neurodegeneration is not well defined. In a cell culture model, Ajayi et al [2012] report that mutated ataxin-7 leads to increased production of reactive oxygen species, which contribute to toxicity. Both Mookerjee et al [2009] and Janer et al [2010] noted that post-translational modification of lysine 257 in ataxin-7 is important in pathogenesis.

In an SCA7 transgenic mouse model, expanded polyglutamine tracts induce neurodegeneration and transneuronal alterations in cerebellum and retina [Yvert et al 2000]. Deletion of Gcn5, an enzymatic component of the STAGA complex, worsens cerebellar and retinal pathology [Chen et al 2012]. Abnormal Bergmann glia in the cerebellum may cause degeneration by way of impaired glutamate transport resulting in non-cell autonomous degeneration of cerebellar Purkinje cells [Garden et al 2002, Custer et al 2006]. Neurons in the inferior olive that project climbing fibers to the cerebellum also appear to play a role in SCA7 pathogenesis. Deletion of the mutated gene from three cell types – Bergmann glia, inferior olive neurons, and Purkinje cells – doubled the presymptomatic period in transgenic mice [Furrer et al 2011]. Suppression of mutated protein expression by 50% in transgenic mice reverses several aspects of the mouse SCA7 phenotype, suggesting avenues for potential therapy [Furrer et al 2013].

References

Published Guidelines/Consensus Statements

  1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-7-17. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 2-7-17.

Literature Cited

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Suggested Reading

  1. Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptácek LJ. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet. 1995;10:89–93. [PubMed: 7647799]
  2. Zoghbi HY, Orr HT. Spinocerebellar ataxias. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chapter 226. McGraw-Hill. Available online. Accessed 5-4-16.

Chapter Notes

Author History

Thomas D Bird, MD; University of Washington (2007-2012)
Gwenn Garden, MD, PhD (2012-present)
Launce G-C Gouw, MD, PhD; University of Utah School of Medicine (1998-2007)
Albert R La Spada, MD, PhD; University of California, San Diego (2007-2012)
Roberta A Pagon, MD, University of Washington (2007-2012)
Louis J Ptacek, MD; University of California at San Francisco (1998-2007)

Revision History

  • 20 December 2012 (me) Comprehensive update posted live
  • 6 September 2007 (tb) Revision: Natural History (Clinical Description)
  • 9 February 2007 (me) Comprehensive update posted to live Web site
  • 11 December 2003 (me) Comprehensive update posted to live Web site
  • 20 June 2001 (me) Comprehensive update posted to live Web site
  • 27 August 1998 (pb) Review posted to live Web site
  • 1 June 1998 (lg) Original submission
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