Funded by the NIH  •  Developed at the University of Washington, Seattle

Spinocerebellar Ataxia Type 7

[SCA 7]

Summary

Disease 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 (SCA7) is the only gene associated with SCA7. Molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in the ATXN7 gene 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, 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 by molecular genetic testing is possible for pregnancies at risk once the diagnosis has been confirmed 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 (ERG) 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

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.   ATXN7 (SCA7) is the only gene known to be associated with spinocerebellar ataxia type 7 (SCA7).

Allele sizes

• Normal alleles: 19 or fewer CAG repeats. To date, no normal allele with greater than 19 CAG repeats has been reported. Approximately 75% of normal alleles have ten CAG repeats.

• 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 a 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 present in an individual with a reduced penetrance allele, symptoms are more likely to be later in onset and milder than average.

  • A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [Nardacchione et al 1999].
  • Koob et al (1998) described a symptomatic individual with 35 CAG repeats. This number contrasts with the 35 CAG repeats described in asymptomatic adults by David et al (1998) and Stevanin et al (1998).
  • An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [Nardacchione et al 1999].

• Full penetrance alleles: Greater than 36 [Nardacchione et al 1999] to 460 [van de Warrenburg et al 2001] CAG repeats

  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 pathologic.

• Alleles of questionable significance: Whether alleles with 27-35 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].

Clinical testing

• Diagnostic testing (in young individuals with an atypical phenotype)
• Confirmatory diagnostic testing (in individuals with the typical phenotype)
• Prenatal diagnosis
• Preimplantation genetic diagnosis

Clinical testing

• Targeted mutation analysis

  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 trinucleotide repeats.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in the Diagnosis of SCA7

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Targeted mutation analysis: PCR amplification	ATXN7 CAG trinucleotide repeat expansions of up to ~100 repeats	~100%	Clinical
Targeted mutation analysis: Southern	Highly expanded ATXN7 CAG trinucleotide repeat expansions (>100 repeats)

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related (Allelic) Disorders

No other phenotypes have been associated with mutations in the ATXN7 gene.

Clinical Description

Natural History

The phenotype of spinocerebellar ataxia type 7 (SCA7) ranges from onset in infancy with an accelerated course and early death to onset in 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 dying in infancy with 180 CAG repeats.

Retinal degeneration in adults is characterized by abnormalities in color vision and central visual acuity, often presenting in the late teens or early 20's before the onset of cerebellar findings. The retinal degeneration is a progressive, cone-rod dystrophy that results in blindness [Aleman et al 2002]. During the earliest stages of retinal degeneration, 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 (ERG) shows a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response. 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), and all color discrimination is lost. Eventually, blindness is total [To et al 1993 , Ahn et al 2005].

When initial symptoms occur at or before adolescence, blindness can occur within a few years. Individuals showing symptoms in their teens may be blind within a decade or less. In infantile onset, the cerebellar and brainstem degeneration is so rapid that retinal degeneration and related vision loss may not be evident.

Progressive cerebellar ataxia in adults (i.e., dysmetria, dysdiadochokinesia, and poor coordination) may precede, but usually follow, the onset of visual symptoms. While the rate of progression varies, the a 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 are not common but have been reported [Benton et al 1998].

Pathology.  Neuronal loss and gliosis are observed in the cerebellum (especially Purkinje cells), inferior olivary and dentate nucleus and pontine nuclei, and to a lesser extent in the globus pallidus, substantia nigra, and red nucleus. Nuclear inclusion aggregates, containing mutant ataxin-7 in neurons from both degenerating and spared areas, are largely absent from Purkinje cells [Michalik & Broeckhoven 2003]. Degeneration is evident in the posterior columns and spinocebellar 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]. Ansorge et al (2004) doscribed a severely affected infant who had ataxin-7 nuclear inclusions in the hippocampus and many non-nervous system tissues including the intestine, pancreas, and the cardiovascular system.

Genotype-Phenotype Correlations

A correlation between 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 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].

Penetrance

See Molecular Genetic Testing .

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 the gene 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].

Differential Diagnosis

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

While many of the clinical and pathologic findings of the other spinocerebellar ataxias (SCA) 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 DNA testing, by pattern of inheritance (maternal rather than autosomal dominant), 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 in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7), the following evaluations are recommended:

• Medical history
• Neurologic examination
• Eye examination
• Brain MRI

Treatment of Manifestations

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

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.

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.

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

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

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

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 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 an 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 the ATXN7 allele.

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 allele, the risk to each sib of inheriting the expanded ATXN7 allele is 50%. The risk to the individual who inherits an expanded allele of developing the SCA7 phenotype depends on the size of the expanded allele.

Offspring of a proband.  Offspring of an affected individual have a 50% chance of inheriting the altered ATXN7 gene at conception. The risk to the individual who inherits an expanded allele 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 upon the genetic status of the proband's parents. If a parent is found to have an expanded allele, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. 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 individuals.   Testing of at-risk adults for SCA7 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 SCA7, an affected family member should be tested first to confirm that the disorder in the family is actually SCA7. It should be remembered that 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 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 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 children 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 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 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 a list of laboratories offering this service.

Prenatal Testing

Prenatal testing 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 ATXN7 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.

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 .

Molecular Genetics

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

Normal allelic variants: The ATXN7 gene is 136,094 bp in length encoding an 892-amino acid protein. 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.

Pathologic allelic variants: The ATXN7 mutation is caused by an abnormal (CAG)_n trinucleotide repeat expansion in the coding region of the protein [David et al 1997]. Disease-causing alleles have from 36 to more than 450 CAG repeats.

Normal gene product: Ataxin-7, the gene product of ATXN7 is expected to be about 95 kd. The function of ataxin-7 is currently unknown, although evidence indicates that it may have a nuclear localization and could act at a transcriptional level. 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 the ATXN7 gene 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]. In SCA7 transgenic mice, expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina [Yvert et al 2000]. Abnormal Bergmann glia in the cerebellum may cause degeneration by way of impaired glutamate transport [Custer et al 2006].

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

• 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)
  
  
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders

Literature Cited

• Abe T, Abe K, Aoki M, Itoyama Y, Tamai M (1997) Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene. Arch Ophthalmol 115:231-6 [Medline]
  
  
• Ahn JK, Seo JM, Chung H, Yu HG (2005) Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol 139:923-5 [Medline]
  
  
• Aleman TS, Cideciyan AV, Volpe NJ, Stevanin G, Brice A, Jacobson SG (2002) Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res 74:737-45 [Medline]
  
  
• Andrew SE, Goldberg YP, Hayden MR (1997) Rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum Mol Genet 6:2005-10 [Medline]
  
  
• Ansorge O, Giunti P, Michalik A, Van Broeckhoven C, Harding B, Wood N, Scaravilli F (2004) Ataxin-7 aggregation and ubiquitination in infantile SCA7 with 180 CAG repeats. Ann Neurol 56:448-52 [Medline]
  
  
• Anttinen A, Nikoskelainen E, Marttila RJ, Grenman R, Falck B, Aarnisalo E, Kalimo H (1986) Familial olivopontocerebellar atrophy with macular degeneration: a separate entity among the olivopontocerebellar atrophies. Acta Neurol Scand 73:180-90 [Medline]
  
  
• Babovic-Vuksanovic D, Snow K, Patterson MC, Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-7 [Medline]
  
  
• Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY (1998) Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 51:1081-6 [Medline]
  
  
• Bloch M and Hayden MR (1990) Opinion: predictive testing for Huntington disease in childhood: challenges and implications. Am J Hum Genet 46:1-4 [Medline]
  
  
• Cancel G, Duyckaerts C, Holmberg M, Zander C, Yvert G, Lebre AS, Ruberg M, Faucheux B, Agid Y, Hirsch E, Brice A (2000) Distribution of ataxin-7 in normal human brain and retina. Brain 123 (Pt 12):2519-30 [Medline]
  
  
• Carpenter S and Schumacher GA (1966) Familial infantile cerebellar atrophy associated with retinal degeneration. Arch Neurol 14:82-94 [Medline]
  
  
• Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, Guyenet SJ, Deller T, Westrum LE, Sopher BL, La Spada AR (2006) Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 9:1302-11 [Medline]
  
  
• David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, Agid Y, Mandel JL, Brice A (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65-70 [Medline]
  
  
• David G, Durr A, Stevanin G, Cancel G, Abbas N, Benomar A, Belal S, Lebre AS, Abada-Bendib M, Grid D, Holmberg M, Yahyaoui M, Hentati F, Chkili T, Agid Y, Brice A (1998) Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet 7:165-70 [Medline]
  
  
• Del-Favero J, Krols L, Michalik A, Theuns J, Lofgren A, Goossens D, Wehnert A, Van den Bossche D, Van Zand K, Backhovens H, van Regenmorter N, Martin JJ, Van Broeckhoven C (1998) Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion. Hum Mol Genet 7:177-86 [Medline]
  
  
• Enevoldson TP, Sanders MD, Harding AE (1994) Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain 117 (Pt 3):445-60 [Medline]
  
  
• Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, Calabrese O, Salvatore E, De Michele G, Riggio MC, Pareyson D, Gellera C, Di Donato S (2000) Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 44:31-6 [Medline]
  
  
• Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, et al. (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047-58 [Medline]
  
  
• Giunti P, Stevanin G, Worth PF, David G, Brice A, Wood NW (1999) Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet 64:1594-603 [Medline]
  
  
• Gouw LG, Castaneda MA, McKenna CK, Digre KB, Pulst SM, Perlman S, Lee MS, Gomez C, Fischbeck K, Gagnon D, Storey E, Bird T, Jeri FR, Ptacek LJ (1998) Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Hum Mol Genet 7:525-32 [Medline]
  
  
• Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ (1994) Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 44:1441-7 [Medline]
  
  
• Gu W, Wang Y, Liu X, Zhou B, Zhou Y, Wang G (2000) Molecular and clinical study of spinocerebellar ataxia type 7 in Chinese kindreds. Arch Neurol 57:1513-8 [Medline]
  
  
• Harper PS and Clarke A (1990) Should we test children for "adult" genetic diseases? Lancet 335:1205-6 [Medline]
  
  
• HAVENER WH (1951) Cerebellar-macular abiotrophy. AMA Arch Ophthalmol 45:40-3 [Medline]
  
  
• Illarioshkin SN, Slominsky PA, Ovchinnikov IV, Markova ED, Miklina NI, Klyushnikov SA, Shadrina M, Vereshchagin NV, Limborskaya SA, Ivanova-Smolenskaya IA (1996) Spinocerebellar ataxia type 1 in Russia. J Neurol 243:506-10 [Medline]
  
  
• Jardim LB, Silveira I, Pereira ML, Ferro A, Alonso I, do Ceu Moreira M, Mendonca P, Ferreirinha F, Sequeiros J, Giugliani R (2001) A survey of spinocerebellar ataxia in South Br J Neurol 248:870-6 [Medline]
  
  
• Kim JY, Park SS, Joo SI, Kim JM, Jeon BS (2001) Molecular analysis of Spinocerebellar ataxias in Koreans: frequencies and reference ranges of SCA1, SCA2, SCA3, SCA6, and SCA7. Mol Cells 12:336-41 [Medline]
  
  
• Koeppen AH (2005) The pathogenesis of spinocerebellar ataxia. Cerebellum 4:62-73 [Medline]
  
  
• Konigsmark BW and Weiner LP (1970) The olivopontocerebellar atrophies: a review. Medicine (Baltimore) 49:227-41 [Medline]
  
  
• Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LP (1998) Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA. Nat Genet 18:72-5 [Medline]
  
  
• Lebre AS, Stevanin G, Brice A (2003) Spinocerebellar ataxia 7 (SCA7). In: Pulst SM (ed) Genetics of Movement Disorders. Academic Press, pp 85-94
  
  
• Martin JJ, Van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, Evrard P, Ceuterick C, Tassignon MJ, Smet-Dieleman H, et al. (1994) On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol (Berl) 88:277-86 [Medline]
  
  
• Michalik A, Van Broeckhoven C (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 12 Spec No 2:R173-86 [Medline]
  
  
• Mittal U, Roy S, Jain S, Srivastava AK, Mukerji M (2005) Post-zygotic de novo trinucleotide repeat expansion at spinocerebellar ataxia type 7 locus: evidence from an Indian family. J Hum Genet 50:155-7 [Medline]
  
  
• Nardacchione A, Orsi L, Brusco A, Franco A, Grosso E, Dragone E, Mortara P, Schiffer D, De Marchi M (1999) Definition of the smallest pathological CAG expansion in SCA7. Clin Genet 56:232-4 [Medline]
  
  
• Sasaki H, Yabe I, Yamashita I, Tashiro K (2000) Prevalence of triplet repeat expansion in ataxia patients from Hokkaido, the northernmost island of Japan. J Neurol Sci 175:45-51 [Medline]
  
  
• Stevanin G, Giunti P, Belal GD, Durr A, Ruberg M, Wood N, Brice A (1998) De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet 7:1809-13 [Medline]
  
  
• Storey E, du Sart D, Shaw JH, Lorentzos P, Kelly L, McKinley Gardner RJ, Forrest SM, Biros I, Nicholson GA (2000) Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet 95:351-7 [Medline]
  
  
• Tang B, Liu C, Shen L, Dai H, Pan Q, Jing L, Ouyang S, Xia J (2000) Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol 57:540-4 [Medline]
  
  
• To KW, Adamian M, Jakobiec FA, Berson EL (1993) Olivopontocerebellar atrophy with retinal degeneration. An electroretinographic and histopathologic investigation. Ophthalmology 100:15-23 [Medline]
  
  
• Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, et al (1995) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378:403-6 [Medline]
  
  
• Tsai HF, Liu CS, Leu TM, Wen FC, Lin SJ, Liu CC, Yang DK, Li C, Hsieh M (2004) Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan. Acta Neurol Scand 109:355-60 [Medline]
  
  
• van de Warrenburg BP, Frenken CW, Ausems MG, Kleefstra T, Sinke RJ, Knoers NV, Kremer HP (2001) Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype. J Neurol 248:911-4 [Medline]
  
  
• Weiner LP, Konigsmark BW, Stoll J Jr, Magladery JW (1967) Hereditary olivopontocerebellar atrophy with retinal degeneration. Report of a family through six generations. Arch Neurol 16:364-76 [Medline]
  
  
• Yvert G, Lindenberg KS, Picaud S, Landwehrmeyer GB, Sahel JA, Mandel JL (2000) Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet 9:2491-506 [Medline]
  
  

Suggested Readings

• Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ (1994) Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 44:1441-7 [Medline]
  
  
• Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptacek LJ (1995) Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 10:89-93 [Medline]
  
  
• 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
  
  

Author Information