Clinical characteristics.

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control.

Diagnosis/testing.

The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care involves supportive treatment of: neurologic manifestations – physical and occupational therapy to help maintain mobility and function, and pharmacologic treatment to reduce symptoms; dysarthria – speech and language therapy and alternative communication methods; dysphagia – feeding therapy to improve nutrition and reduce the risk of aspiration; and reduced vision – use of low vision aids and consultation with agencies for the visually impaired.

Surveillance: Routine follow up with multidisciplinary care providers.

Agents/circumstances to avoid: Avoid: alcohol intake (especially if excessive) as it can further impair cerebellar function; foods identified by a registered dietitian as possible causes of dizziness or disorientation.

Therapies under investigation: Several ongoing clinical trials for medications used as treatment for ataxia.

Genetic counseling.

SCA7 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG repeat expansion in ATXN7. Once an ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA7 are possible.

Suggestive Findings

Spinocerebellar ataxia type 7 (SCA7) should be suspected in individuals with the following clinical findings (by age) and family history.

Establishing the Diagnosis

The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing (see Table 1).

Note: Pathogenic (CAG)_n repeat expansions in ATXN7 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Repeat sizes

• Normal. 7-27 CAG repeats
• Mutable normal. 28-33 CAG repeats [Lebre et al 2003]. Repeats in this range are meiotically unstable, but not associated with an abnormal phenotype. A mutable normal repeat may expand to the pathogenic range in one generation [Mittal et al 2005].
• Pathogenic. The distinction between reduced-penetrance CAG repeat size and full-penetrance CAG repeat size is likely to remain unclear until more families are reported; nonetheless, regardless of the "descriptor" used for these CAG repeats, they should be considered unstable and pathogenic:
  • Pathogenic reduced penetrance. 34-36 CAG repeats. When manifestations occur, they are more likely to be later onset and milder than average. (See case reports in Genotype-Phenotype Correlations.)
  • Pathogenic full penetrance. 37-460 CAG repeats [Nardacchione et al 1999, van de Warrenburg et al 2001, Michalik et al 2004].

Molecular genetic testing relies on targeted analysis to characterize the number of ATXN7 CAG repeats (see Table 8).

Clinical Description

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy with progressive central visual loss to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death [Giunti et al 1999].

One important aspect of SCA7 clinical manifestations is their extreme variability with respect to age of onset and rate of progression. Affected individuals may present in infancy, childhood, adolescence, young adulthood, middle age, or old age.

When onset is at or before adolescence, initial manifestations are typically impaired vision, ultimately progressing to blindness from retinal degeneration. Individuals with manifestations in their teens may be blind within a decade or less.

In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) usually precedes the onset of visual manifestations. The age of onset inversely correlates with rate of progression and extent of symptomatology, as onset in or after the fifth decade of life gives a predominant cerebellar ataxia without progression to significant visual impairment, whereas onset prior to middle age often features progression to vision loss.

Progression to severe disability resulting in death varies based on age of onset, ranging from months in infants to fewer than ten years in older children to two to three decades in adolescents and adults. While the rate of progression varies, the eventual result for almost all affected individuals is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.

To date, more than 1,000 individuals with SCA7 have been identified worldwide. Frequency of select features in adolescent- or adult-onset disease are summarized in Table 2.

Adolescent- or Adult-Onset SCA7

Table 2.

Select Features of Adolescent- or Adult-Onset SCA7

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Feature	% of Persons w/Feature	Comment
Cerebellar ataxia	100%	Unsteady gait; finger-to-nose dysmetria
Dysarthria	100%	Garbled or slurred speech
Dysphagia	40%	Difficulty swallowing
Oculomotor abnormalities	80%	Slowed ocular saccades Ophthalmoplegia
Motor neuron degeneration	100%	Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia. Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Sensory loss	40%	↓ sensation to light touch, pinprick, &/or joint position
Restless leg syndrome	35%	Discomfort in legs resulting in uncontrollable urge to move one’s legs, typically worse in evening or nighttime
Cognitive decline	20%	Impaired executive function
Behavior disorder/ Psychosis	10%	Altered mentation Impaired reality testing
Cone-rod dystrophy	70%	Loss of central vision & color vision Abnormal fundoscopic exam

Neurologic findings. In adult-onset disease (age >30 years), cerebellar ataxia (manifesting as difficulty with walking, manual dexterity, and speech) is the most common clinical feature and is often the first reported manifestation (see Genotype-Phenotype Correlations). Affected individuals often then develop more extensive neurologic deficits, dysarthria, dysphagia, hypoacusis (hearing loss), and eye movement abnormalities (slow ocular saccades, staring). Slowing of ocular saccades may progress to frank ophthalmoplegia.

Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses.

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

Retinal degeneration. The retinal degeneration is a progressive cone-rod dystrophy that may result in total blindness [To et al 1993, Aleman et al 2002, Ahn et al 2005, Hugosson et al 2009].

In adolescent- or young adult-onset disease (age <30 years), profound visual loss can be accompanied by minimal ophthalmoscopic findings and minimal ataxia [Thurtell et al 2009] (see Genotype-Phenotype Correlations). The onset of cone-rod dystrophy is often characterized by hemeralopia (inability to see clearly in bright light), photophobia (extreme sensitivity to light), decreased central visual acuity, and abnormalities in the tritan (blue-yellow) axis on detailed color vision testing [Miller et al 2009]. As cone function decreases over time, central visual acuity decreases to 20/200 (legally blind) and central scotomas develop; more prominent macular changes appear (see Figure 1), and all color discrimination is lost. Eventually all vision is lost.

Figure 1.

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

Early signs of cone-rod dystrophy are subtle granular changes in the macula. 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].

In classic adult-onset disease (age >40 years), vision loss from retinal degeneration typically follows the onset of ataxia (sometimes many years to decades later) and gradually declines, seldom progressing to total blindness [Miller et al 2009].

Genotype-Phenotype Correlations

A correlation between CAG repeat sizes and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease.

• Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the ATXN7CAG repeat region that often underestimate the repeat expansion size may report a CAG repeat size of fewer than 150.
• Childhood onset is usually associated with CAG repeat sizes greater than 100.
• Juvenile onset is often associated with CAG repeat sizes 60-100.

A correlation between CAG repeat size and initial clinical manifestation exists [Johansson et al 1998]:

• CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
• CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.

Despite observations correlating CAG repeat length with age of onset, disease severity, and course, CAG repeat size cannot provide sufficient predictive value for clinical prognosis within the classic adult-onset CAG repeat size range of 38 to 50 repeats [Andrew et al 1997].

Reports of pathogenic (age-related reduced-penetrance) repeats include the following:

• A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [Nardacchione et al 1999].
• An individual with 35 CAG repeats was symptomatic [Koob et al 1998], in contrast to asymptomatic adults with 35 CAG repeats described 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].

Penetrance

See Genotype-Phenotype Correlations for CAG repeat sizes associated with age-related reduced penetrance.

Anticipation

In families with a pathogenic (full-penetrance) CAG repeat expansion, the repeat size 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 all CAG repeat disorders.

Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004].

Repeat contraction has not been reported.

Nomenclature

Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and ADCA type II.

Prevalence

The prevalence is fewer than 1:300,000. In several studies, SCA7 represented 2% of all SCAs [Filla et al 2000, Storey et al 2000].

SCA7 occurs predominantly in two racial population groups: northern Europeans and Africans. Indeed, SCA7 is the only repeat expansion disease, with the exception of Huntington disease-like 2 (HDL2), with a large number of affected individuals of African racial ancestry. For this reason, a substantial fraction of individuals with SCA7 in the United States are of African racial ancestry. Worldwide, SCA7 is seen in North America, Europe, Eurasia, Australia, South Africa, and South America.

As a result of a founder effect in Mexico dating back to the colonial era, a very large concentration of individuals with SCA7 have been ascertained in the state of Veracruz in Mexico, with well over 150 documented affected individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7) of adolescent or adult onset, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

Surveillance

Agents/Circumstances to Avoid

Avoid drinking alcoholic beverages, as alcohol intake can further impair cerebellar function, especially if excessive.

Avoid foods identified by a registered dietician as potentially causing dizziness or disorientation.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Ongoing clinical trials for SCA7 include a study of:

• Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov: NCT03701399);
• Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov: NCT03660917).

Ionis Pharmaceuticals™ is developing an antisense oligonucleotide for dosage reduction of ataxin-7 in the retina and brain, as a preclinical trial of this strategy was found to be an effective treatment for retinal degeneration in an SCA7 mouse model [Niu et al 2018].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 with SCA7 have an affected parent. Note: Anticipation in a family may be so dramatic that a child may be diagnosed with SCA7 years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004].
• A proband with SCA7 may have the disorder as the result of expansion of a pathogenic reduced-penetrance CAG repeat (34-36 CAG repeats) or a mutable normal CAG repeat (28-33 CAG repeats) inherited from an unaffected parent.
• If neither of the parents of the proband is known to have SCA7, recommendations for the evaluation of parents include physical examination and consideration of ATXN7 molecular genetic testing.
• The family history of some individuals diagnosed with SCA7 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the parents:

• If a parent of the proband is affected and/or is known to have an abnormal CAG repeat, the risk to each sib of inheriting the CAG repeat expansion is 50%. Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see Anticipation).
• Clinical presentation in sibs who inherit an abnormal CAG repeat usually correlates with their CAG repeat size: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease (see Genotype-Phenotype Correlations).
• If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA7 because of the possibility of late onset of SCA7 in a heterozygous parent.

Offspring of a proband

• Each child of an affected individual has a 50% chance of inheriting the CAG repeat expansion.
• Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see Anticipation).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the CAG repeat expansion, the parent's family members are at risk.

Related Genetic Counseling Issues

Note: If neither parent of a proband with SCA7 has a CAG repeat expansion, nonmedical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

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

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a CAG repeat expansion in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see 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.

In a family with an established diagnosis of SCA7, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. (Note: While the prenatal finding of a CAG repeat expansion cannot be used to accurately predict onset, severity, specific manifestation, or rate of progression of SCA7, disease-causing alleles longer than 59 CAG repeats usually result in onset before age 30 years.)

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ATXN7 encodes ataxin-7, a predominantly nuclear protein that shuttles between the nucleus and cytoplasm. Ataxin-7 is 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].

Mechanism of disease causation. Gain of function as a result of a CAG expansion in ATXN7

Methods to characterize ATXN7 CAG repeats. Because of the technical challenges of detecting and sizing ATXN7 CAG repeat expansions (see Table 7), multiple methods may be needed to rule out or detect an expanded allele (see Table 8). Repeats up to about 100 CAG may be detected by traditional PCR. However, detection of apparent homozygosity for a normal CAG repeat does not rule out the presence of an expanded CAG repeat; thus, testing by triplet-primed PCR (TP-PCR) or Southern blotting is required.

In addition, somatic and germline instability of expanded repeats must be considered.

Published Guidelines / Consensus Statements

• 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 6-10-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-10-22.

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Author History

Thomas D Bird, MD; University of Washington (2007-2012)
Gwenn Garden, MD, PhD; University of Washington (2012-2020)
Launce G-C Gouw, MD, PhD; University of Utah School of Medicine (1998-2007)
Albert R La Spada, MD, PhD (2007-2012; 2020-present)
Roberta A Pagon, MD; University of Washington (2007-2012)
Louis J Ptacek, MD; University of California, San Francisco (1998-2007)

Revision History

• 23 July 2020 (bp) Comprehensive update posted live
• 20 December 2012 (me) Comprehensive update posted live
• 6 September 2007 (tb) Revision: Natural History (Clinical Description)
• 9 February 2007 (me) Comprehensive update posted live
• 11 December 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 27 August 1998 (pb) Review posted live
• 1 June 1998 (lg) Original submission