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Spinocerebellar Ataxia Type 1

Synonym: SCA1

, MD and , MD.

Author Information
, MD
Chief, Neuromuscular Division
Associate Chair and Professor, Department of Neurology
University of Florida
Gainesville, Florida
, MD
Executive Director, McKnight Brain Institute
Professor and Chair, Department of Neurology
University of Florida
Gainesville, Florida

Initial Posting: ; Last Update: July 3, 2014.

Summary

Disease characteristics. Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late adult onset have been reported. Those with onset over age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy.

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

Management. Treatment of manifestations: Canes and walkers to help prevent falls; modification of the home with grab bars, raised toilet seats, and ramps for motorized chairs; speech therapy and communication devices for dysarthria; weighted eating utensils and dressing hooks to help maintain independence. Intensive rehabilitation (coordinative physiotherapy) may be beneficial. Medications may help symptomatic secondary problems such as spasticity, bladder urgency, depression, and pain.

Agents/circumstances to avoid: Alcohol, medications (e.g., isoniazid) known to cause nerve damage. Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should be avoided.

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

Diagnosis

Clinical Diagnosis

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

The diagnosis is suspected in individuals who have the following findings:

  • Progressive cerebellar ataxia
  • Dysarthria
  • Eventual deterioration of bulbar functions
  • Family history of similarly affected individuals

Note: In individuals who have symptoms consistent with SCA1 and in whom a first- or second- degree relative has been found to have SCA1 based on the results of molecular genetic testing, the diagnosis is strongly suspected; however, molecular genetic testing of the symptomatic individual for confirmation of the diagnosis is still recommended.

Molecular Genetic Testing

Gene. ATXN1 is the only gene in which trinucleotide repeat mutations are known to cause SCA1.

Expansion of the number of CAG trinucleotide repeats in ATXN1 is the mutational mechanism in all families with SCA1 examined to date [Matilla et al 1993, Orr et al 1993, Jodice et al 1994, Orr & Zoghbi 2001]. Note: Alleles with certain numbers of CAG repeats will require reflex testing for the presence of CAT trinucleotide repeats that interrupt the tract of CAG repeats to determine pathogenicity. This is a normal testing component for ATXN1 and typically does not require additional tests.

The European Molecular Genetics Quality Network (EMQN) has published best practice guidelines for the genetic testing of the spinocerebellar ataxias including SCA1 [Sequeiros et al 2010a, Sequeiros et al 2010b]. See Image guidelines.jpg; updated information is available online.

Allele sizes

  • Normal alleles. 6-44 CAG repeats [Quan et al 1995, Servadio et al 1995, Goldfarb et al 1996]. Alleles with <35 CAG repeats are normal alleles and have not been associated with the SCA1 phenotype. These normal alleles have been found to have CAT trinucleotide repeat interruption(s) and are considered non-mutable. Pathogenicity of alleles in the 36 to 44 range depends on the presence or absence of CAT trinucleotide repeats that interrupt the CAG repeats. Alleles in the 36 to 44 CAG repeat range are considered normal if they have CAT interruptions; if they do not, they may be in the mutable normal (36-38 CAG repeats) or full penetrance (>39 CAG repeats) range.
  • Mutable normal (intermediate) alleles. 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms, but can expand into the abnormal range on transmission to offspring.
  • Reduced penetrance alleles. A woman with 44 CAG repeats with CAT repeat interruptions had an affected father but was herself asymptomatic at age 66 years [Goldfarb et al 1996]; thus, she may be an example of reduced penetrance.
  • Full penetrance alleles. Alleles with more than 39 CAG repeats [Orr et al 1993, Quan et al 1995, Goldfarb et al 1996, Sequeiros et al 2010b]. An allele with 39 CAG repeats without the CAT repeat interruptions has the lowest number of repeats to be associated with symptoms [Zuhlke et al 2002]. However, 39-44 CAG repeat alleles have to be uninterrupted by CAT repeats to be considered abnormal and likely to be associated with symptoms. There is an inverse correlation between the size of the expansion and the age at onset. Complex alleles may occur; one individual has been reported with symptomatic SCA1 with a 58 CAG-repeat sequence interrupted by two CAT repeats [Matsuyama et al 1999]; however, this person had an uninterrupted 45 CAT repeat stretch. More recently additional pathogenic alleles carrying 46 to 70 uninterrupted CAG repeats but with CAT interruptions have been reported [Menon et al 2013]. In the case of such interrupted alleles, correlation with age at onset may be more appropriate if the uninterrupted CAG stretch alone is considered.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in SCA1

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
ATXN1Targeted mutation analysis 2, 3, 4~100%

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Typically, the number of CAG repeats is determined by standard PCR and fragment length analysis.

3. Distinguishing normal, mutable normal, and pathogenic alleles with 39-44 CAG repeats requires additional evaluation for the presence of CAT trinucleotides that interrupt the CAG repeat tract. Methods may vary (e.g., SfaNI restriction analysis [Chung et al 1993], dual-fluorescence labeled PCR-restriction fragment length analysis [Lin et al 2008], or sequencing the PCR product of the CAG repeat region).

4. In some individuals with infantile or childhood onset of SCA1, direct amplification of the ATXN1 CAG repeat may not detect large repeat lengths in the hundreds. Southern blot analysis, long-range PCR, or CAG-triplet repeat primed PCR analysis can be used to quantitate the CAG repeat number when infantile-onset SCA1 is suspected.

Testing Strategy

To confirm/establish the diagnosis in a proband requires molecular genetic testing to identify the ATXN1 CAG repeat expansion.

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having SCA1 is targeted mutation analysis of ATXN1.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having SCA1 is a multi-gene targeted mutation analysis panel that includes genes known to cause cerebellar ataxia. See Differential Diagnosis.

Clinical Description

Natural History

Spinocerebellar ataxia type 1 (SCA1) is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions [Klockgether et al 1998, Filla et al 2000]. Onset is typically in the third or fourth decade, although early onset in childhood has been documented [Currier et al 1972, Zoghbi et al 1988, Schöls et al 1997]. In adult-onset SCA1, the duration of illness from onset to death ranges from ten to 30 years; individuals with juvenile-onset disease (whose symptoms appear before age 13 years) show more rapid progression and more severe disease, and die before age 16 years [Zoghbi et al 1988].

In the last few years, large-scale natural history studies of some of the common SCAs (including SCA1) using validated neurologic rating scales and timed measures of motor function have been in progress in many countries. The annual increase in the scale for assessment and rating of ataxia (SARA) score for SCA1, SCA2, SCA3, and SCA6 combined in a one-year follow-up study was 1.38 ± 0.37; the SARA score quantifies various aspects of appendicular and limb ataxia; a score of 40 indicates maximum dysfunction [Schmitz-Hübsch et al 2010]. SCA1 appears to have a faster progression (2.18±0.17 points per year, based on SARA) than SCA2 and SCA3 (1.40±0.11 and 1.61±0.12 respectively), an observation that has been reproduced by studies in the US [Jacobi et al 2011, Ashizawa et al 2013].

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

Affected individuals may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus in the early stages of disease [Genis et al 1995]. Mild dysphagia, indicated by choking on food and drink, may also occur early in the disease.

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

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

Optic nerve atrophy and variable degrees of ophthalmoparesis may be detected in some individuals. Recently occult or clinically significant maculopathy has been noted in some individuals with SCA1 [Lebranchu et al 2013, Vaclavik et al 2013].

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

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

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

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

Juvenile-onset SCA1 is characterized by severe brain stem dysfunction in addition to the cerebellar symptoms. The brain stem dysfunction occurs rapidly, leading to death within four to eight years of symptom onset.

Electrophysiologic studies. A sensory-predominant polyneuropathy can be documented in a significant number of persons with SCA1 by nerve conduction studies [Schols et al 2008].

Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1. Oculomotor recordings reveal abnormalities of eye movements in a quantitative fashion.

Neuroimaging. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain reveal pontocerebellar atrophy [Döhlinger et al 2008]. More sophisticated quantitative techniques such as voxel-based morphometry show volume loss in cerebellum and brain stem involving both gray and white matter [Guerrini et al 2004, Ginestroni et al 2008, Goel et al 2011]. Spinal cord atrophy may also be seen [Pedroso & Barsottini 2013]. Measurements of metabolites such as N-acetylaspartate and myoinositol reveal evidence of neuronal loss in the cerebellum, pons and even the supratenotorial structures [Oz et al 2010].

Minor motor dysfunction and loss of cerebellar and brain stem grey matter by quantitative imaging studies have been recently documented in pre-symptomatic persons known to have an ATXN1 trinucleotide repeat expansion [Jacobi et al 2013].

Neuropathology. Neuropathologic studies reveal atrophy of cerebellum and brain stem [Schut & Haymaker 1951, Robitaille et al 1997]. In the cerebellum, the Purkinje cells are severely depleted and the vermis may be maximally affected; the flocculonodular lobe is relatively spared [Robitaille et al 1997]. There is some loss of dentate neurons, some of which may show “grumose” degeneration [Yamada et al 2008]. Granule cells are moderately lost and torpedos may be seen [Genis et al 1995]. Calbindin immuncytochemistry reveals reduced dendritic arbors [Genis et al 1995]. Brain stem shows loss of basis pontis neurons and olivary neurons. There is loss of afferent fibers in middle and inferior cerebellar peduncles leading to loss of myelin stain reactivity, as well as neuronal loss in the oculomotor nuclei and the ninth and tenth cranial nerve nuclei. The spinal cord shows loss of anterior horn cells and neurons from the Clarke’s column, and there is loss of fibers in the posterior column.

Recent systematic studies have shown that SCA1 neuropathology can involve components of the cerebello-thalamocortical loop, the basal ganglia-thalamocortical loop, the visual system, the nuclei of the auditory system, the somatosensory system at many levels, the vestibular nuclei, both infranuclear and supranuclear oculomotor neurons, several brain stem nuclei, the midbrain dopaminergic system, and the basal forebrain and midbrain cholinergic systems [Rub et al 2013].

Genotype-Phenotype Correlations

Probands. A strong correlation exists between the number of CAG repeats and severity of disease: the larger the CAG repeat, the earlier the onset and more severe the disease. However, the correlation is broad; only 50% to 70% of age-at-onset variance can be explained by CAG repeat size [Orr et al 1993, Schöls et al 1997, Stevanin et al 2000]. Routine testing does not determine the presence of interruptions if the expansion is longer than 44 repeats; however, the presence of interruptions in such alleles delays the age at onset beyond that predicted by the total repeat size [Menon et al 2013].

The largest expansions of the CAG repeat tract are found in individuals with infantile- or juvenile-onset SCA1, who typically experience more rapid disease progression and are most commonly the offspring of affected males.

Some clinical signs (facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis) are more common with larger repeat size, independent of disease duration.

Affected individuals with more than 52 CAG repeats tend to become significantly disabled five years after the onset of disease.

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

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

Penetrance

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

Anticipation

Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1 [Schut 1950, Zoghbi et al 1988]. The tendency of the ATXN1 CAG repeat to expand as it is transmitted provides a biologic explanation for the earlier age of onset in subsequent generations. Expansions are more likely to occur when the mutated ATXN1 allele is paternally transmitted, and contractions are more typical of maternal transmissions [Chung et al 1993, Matilla et al 1993, Jodice et al 1994].

Nomenclature

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

Prevalence

Approximately one to two individuals in 100,000 develop SCA1.

Worldwide SCA1 represents approximately 6% of individuals with autosomal dominant cerebellar ataxia, although this figure varies considerably based on geographic location and ethnic background [Schöls et al 2004]. For example, SCA1 represented 6% of autosomal dominant ataxia in a North American study [Moseley et al 1998], 34% in Serbia [Dragasevic et al 2006], 22% in India [Mittal et al 2005], and no cases in a Korean study [Jin et al 1999]. (See also Ataxia Overview.)

Differential Diagnosis

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

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

SCA17 and dentatorubral pallidoluysian atrophy (DRPLA) are other inherited ataxias caused by expanded CAG repeats; these disorders often exhibit a more florid phenotype with added extrapyramidal signs, cognitive decline, and myoclonus (DRPLA only).

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

If an affected individual has visual loss related to a maculopathy, the most likely diagnosis is SCA7, which can be tested for first. Note that not all individuals with SCA7 have visual loss related to a maculopathy; however, history of visual loss in other affected family members may suggest a diagnosis of SCA7.

Other more recently defined SCAs are related to point mutations or other types of repeat expansions. Overall, they are rarer, often having been described in a limited number of families. Recent reviews can be consulted for their differential diagnostic features [Soong & Paulson 2007, Durr 2010].

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

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 needs in an individual who has molecularly confirmed spinocerebellar ataxia type 1 (SCA1), the following evaluations are recommended:

  • Medical history
  • Neurologic examination
  • Medical genetics consultation

Treatment of Manifestations

Management of individuals with SCA1 remains supportive as no known therapy to delay or halt the progression of the disease exists. Affected persons should be followed by a neurologist with consultation from physiatrists, physical and occupational therapists, and other specialists as needed. Certain manifestations directly or indirectly related to the disease such as spasticity, depression, and pain may require appropriate pharmacotherapy.

Studies have shown that intensive rehabilitation (or coordinative physiotherapy) improves motor function in a heterogeneous group of individuals with various types of cerebellar degeneration [Ilg et al 2009, Ilg et al 2010, Miyai et al 2012]. Although these studies did not include individuals with SCA1, intensive coordinative training may be recommended for persons with SCA1 because of symptomatic improvement with limited adverse events. However, further studies which include individuals with SCA1 will need to be performed to determine the efficacy of such training.

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

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

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

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

When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration. Repeated aspiration or significant weight loss may also point to the need for a feeding device in some.

Prevention of Primary Manifestations

See Therapies Under Investigation.

Prevention of Secondary Complications

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

Surveillance

Neurologic evaluation every three to six months is appropriate

Agents/Circumstances to Avoid

Affected individuals should avoid alcohol as well as medications known to be neurotoxic such as those that cause neuropathy (e.g., isoniazid, large-dose vitamin B6) or those associated with central nervous system toxicity (e.g., diphenylhydantoin). Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should be avoided.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Lithium [Watase et al 2007] and insulin-like growth factor 1 [Vig et al 2006] have improved neurologic function in a mouse model of SCA1; no human trials with insulin-like growth factor 1 have been done to date. Metabolomics data using the mouse model of SCA1 showed that lithium restores purine metabolism in the cerebellum [Perroud et al 2013]. A human phase I trial of oral lithium has been completed as an intramural NIH study; results have not been published (NCT00683943).

Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of individuals including persons with SCA1; however, further investigation is needed [Ristori et al 2010].

Chronic treatment with 3,4-diaminopyridine had beneficial effects in a mouse model of spinocerebellar ataxia type 1 (SCA1) [Hourez et al 2011]. Therefore, Giordano et al [2013] treated 16 individuals with chronic cerebellar ataxia, including three with SCA1, with 4-aminopyridine (4-AP). This open-label case series suggested modest short-term improvements of ataxia. Similarly, an open-label case series of 13 persons with cerebellar ataxia, including one with SCA1, who were treated with acetyl-DL-leucine (5 g/day) for one week suggested modest improvement of ataxia without side effects [Strupp et al 2013]. However, randomized placebo-controlled studies will be needed to assess the efficacy of such treatment.

Cvetanovic et al [2011] reported that mutant Atxn1 repressed transcription of vascular endothelial growth factor A (Vegfa) in Sca1 mice, which show a decrease in cerebellar microvessel density and length. Overexpression or pharmacologic infusion of Vegfa ameliorated the phenotype of Sca1 mice and improved cerebellar pathology.

Intrathecal injection of 3,000 mesenchymal stem cells in SCA1 transgenic mice mitigated the cerebellar neuronal disorganization, atrophy of dendrites and motor function [Matsuura et al 2014]. Investigators at the General Hospital of Chinese Armed Police Forces is recruiting study subjects with hereditary cerebellar ataxia for clinical trials using umbilical stem cell therapy (NCT01489267).

SCA1 mice (Atxn1 with 154Gln residues) showed no improvements in motor function on the accelerating rotor-rod test after acute doses of riluzole, amantadine, zolpidem, and buspirone over two days [Nag et al 2013].

Downregulation of several molecules of the RAS-MAPK-MSK1 pathway decreases ataxin1 levels and suppresses neurodegeneration in Drosophila and murine models of SCA1. Pharmacologic inhibitors of this pathway also decrease ataxin1 levels, suggesting that these components represent therapeutic targets in SCA1 [Park et al 2013].

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

Other

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

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

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with SCA1 have an affected parent.
  • A proband with SCA1 who appears to have SCA1 as the result of de novo mutation may in fact have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-38 CAG repeats that are not interrupted by CAT sequences is not likely to display any symptoms of SCA1, but does have a "mutable normal" (intermediate) allele that can expand on transmission to any offspring (see Molecular Genetic Testing).
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include mutation analysis of ATXN1.

Note: Although most individuals diagnosed with SCA1 have an affected parent or a parent with an intermediate expansion, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of an affected person depends on the genetic status of the parents.
  • If one parent has an expanded ATXN1 allele, the risk to each sib of inheriting an expanded ATXN1 allele is 50%.
  • A parent with an ATXN1 allele of 36-38 CAG repeats that are not interrupted by CAT trinucleotide repeat sequences is not likely to display any symptoms of SCA1, but does have a "mutable normal" (intermediate) allele that can expand on transmission to any offspring (see Molecular Genetic Testing).

Offspring of a proband

  • Each child of an individual with SCA1 has a 50% chance of inheriting the expanded ATXN1 allele.
  • Expanded CAG repeat tracts are unstable: during transmission to offspring they may contract by a few trinucleotides, though they are more likely to expand. Larger intergenerational expansions tend to occur more frequently on paternal than on maternal transmission.

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

Related Genetic Counseling Issues

When neither parent of a proband with SCA1 has an expanded allele, an intermediate expansion, or clinical evidence of the disorder, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.

Testing of at-risk asymptomatic adults 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 SCA1, an affected family member should be tested first to confirm that the disorder in the family is SCA1.

Testing for the abnormally expanded ATXN1 allele in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA1, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

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

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.

Family planning

  • The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking 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

If the an expanded ATXN1 allele in an affected family member has been identified, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for (typically) adult-onset conditions such as SCA1 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the length of the expanded ATXN1 allele 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 1: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ATXN16p22​.3Ataxin-1ATXN1 homepage - Mendelian genesATXN1

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 1 (View All in OMIM)

164400SPINOCEREBELLAR ATAXIA 1; SCA1
601556ATAXIN 1; ATXN1

Gene structure. ATXN1 spans an estimated 450 kb of DNA and consists of nine exons. The coding region is 2448 bp long. The 5' untranslated region is found in the first seven exons, and the region encoding the ataxin-1 protein is located within the large exons 8 and 9, which are 2079 and 7805 bp, respectively. Both the 5' untranslated and 3' untranslated region of the ATXN1 transcript are extremely long at 935 bp and 7000 bp, respectively. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants

  • Normal ATXN1 variants may contain six to 44 CAG repeats and are interrupted with one to three CAT trinucleotides. However, sequencing cloned alleles have shown that repeat instability can occur even in the presence of interruptions [Menon et al 2013], raising the possibility that rare occurrence of allele size instability of interrupted alleles could be detected in clinical samples.
  • Mutable normal (intermediate) alleles have 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms, but can expand into the abnormal range on transmission to offspring.

Pathogenic allelic variants

  • Reduced penetrance alleles. A woman with 44 CAG repeats with CAT repeat interruptions had an affected father but was herself asymptomatic at age 66 years [Goldfarb et al 1996]; thus, she may be an example of reduced penetrance.
  • Alleles of 39 or more uninterrupted CAG repeats are associated with disease. Somatic and meiotic instability has been observed for the ATXN1 CAG repeats, particularly in tissues that have higher mitotic potential, such as peripheral blood cells and sperm [Chong et al 1995]. The presence of CAT trinucleotide interruptions within the CAG repeat tract has demonstrated a stabilizing effect in somatic tissues. Comparative analysis of a large normal allele (39 repeats with CAT interruptions) with a small expanded allele (40 uninterrupted repeats) revealed that the interrupted allele was somatically stable, whereas the allele with an uninterrupted CAG tract was unstable [Chong et al 1995].

Normal gene product. The CAG repeat encodes a glutamine tract in ataxin-1, a nuclear protein of unknown function. The transcript expressed from ATXN1 is approximately 11 kb and is found in a wide variety of different cell and tissue types [Servadio et al 1995]. Normal ataxin-1 has 792 to 829 amino acids, depending on the number of CAG repeats that encode the polyglutamine tract within the protein. Ataxin-1 has been postulated to have several functions in the nucleus, including transcription regulation and RNA processing. Deletion of ATXN1 leads to mild impairment of spatial learning in mice. But no SCA1-like phenotypes were produced by complete deletion of ATXN1, arguing against a loss-of-function mechanism in SCA1 pathogenesis [Matilla et al 1998]. Translation initiated at an alternative ATG codon has been shown to yield a 21-kDa polypeptide with a completely different amino acid sequence from ATXN1. This polypeptide, alternative ATXN1 (Alt-ATXN1), interacts with poly(A)(+) RNA [Bergeron et al 2013].

Abnormal gene product. In SCA1, as in several other polyglutamine diseases, the mutant protein accumulates in the nucleus into a single aggregate, often referred to as a nuclear inclusion (NI). It is believed that the expanded polyglutamine tract resulting from the CAG expansion results in misfolding of mutant ataxin-1 leading to insoluble aggregates. Because these NIs also accumulate, affecting portions of the cell's protein refolding and degradation machinery (chaperones, ubiquitin, and proteasomal subunits), it is thought that impaired protein clearance underlies the pathogenesis of SCA1 and related diseases. At least three lines of evidence support this hypothesis:

Studies revealed that serine 776 in ataxin-1, which is phosphorylated by Akt kinase, mediates specific protein-protein interactions and is critical for pathogenicity of mutant ataxin-1 [Chen et al 2003, Emamian et al 2003]. Preventing phosphorylation at serine 776 by substituting alanine at this location reduces the toxicity of mutant ataxin-1.

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

A review provides details of the many proteins that have been found to interact with ataxin-1, including many transcriptional co-regulators and proteins involved in RNA binding and metabolism [Matilla-Duenas et al 2008].

One of the functionally important domains of ataxin-1 is the conserved AXH domain that is homologous to a portion of the high mobility group box transcription factor-binding protein 1 (HBP1). Many proteins appear to interact with ataxin-1 via the AXH domain including the ataxin-1 paralog BOAT and several transcriptional regulators such as SMRT, Drosophila SENS, the human homolog of the Drosophila repressor CIC (Capicua), and the ROR α-Tip60 complex [Zoghbi & Orr 2009]. Importance of AXH-CIC interaction as a therapeutic target has been proposed based on further characterization of this interaction [de Chiara et al 2013].

It has been shown that duplication of ATXN1L, a paralog of ATXN1, suppresses SCA1 neuropathology by decreasing incorporation of mutant ataxin-1 into the native complex containing Capicua [Bowman et al 2007]. These studies suggest that SCA1 pathogenesis is mediated at least in part by modulating the normal activity of ataxin-1.

Among ataxin 1-interacting proteins, the pathogenic importance of Tip60 [Gehrking et al 2011] and 14-3-3ε [Jafar-Nejad et al 2011] have been recently demonstrated in transgenic mice. Ataxin-1 also has several residues at which it is SUMOylated, suggesting its role in transcriptional regulation [Riley et al 2005]. Additionally, disrupting the nuclear localizing signal toward the N terminus prevents ataxin-1 entry into the nucleus and abolishes toxicity of mutant ataxin-1 [Klement et al 1998], suggesting that the pathogenic process is mainly localized to the nucleus.

An analysis of the genomic expression profile in SCA1 transgenic mice showed consistently altered levels of mRNA from five genes forming a biologic cohort centered on glutamate signaling pathways in Purkinje cells [Serra et al 2004]. These findings identify this pathway as a target to investigate potential therapies in animal models. In addition, transcriptional dysregulation of calcium homeostasis genes also appears to be an early feature [Lin et al 2000].

References

Published Guidelines/Consensus Statements

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Suggested Reading

  1. 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). Chap 226. New York, NY: McGraw-Hill. Available online. 2014. Accessed 7-1-14.

Chapter Notes

Author History

Tetsuo Ashizawa, MD (2005-present)
Vicki L Brandt; Baylor College of Medicine (1998-2005)
Xi Lin, MD, PhD; University of Texas Medical Branch (2005-2011)
SH Subramony, MD (2011-present)
Huda Y Zoghbi, MD; Baylor College of Medicine (1998-2005)

Revision History

  • 3 July 2014 (me) Comprehensive update posted live
  • 20 October 2011 (me) Comprehensive update posted live
  • 1 November 2007 (me) Comprehensive update posted to live Web site
  • 18 July 2005 (me) Comprehensive update posted to live Web site
  • 18 June 2003 (ca) Comprehensive update posted to live Web site
  • 29 January 2001 (me) Comprehensive update posted to live Web site
  • 1 October 1998 (pb) Review posted to live Web site
  • 26 June 1998 (hz) Original submission
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