DiagnosisClinical DiagnosisThe phenotypic manifestations of spinocerebellar ataxia type 1 (SCA1) are not specific; thus, the diagnosis of SCA1 rests on molecular genetic testing. Molecular Genetic TestingGene. ATXN1 is the only gene in which mutations are known to cause SCA1. Expansion of the CAG repeat 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]. The European Molecular Genetics Quality Network (EMQN) has recently published best practice guidelines for the genetic testing of the spinocerebellar ataxias including SCA1 [Sequeiros et al 2010a, Sequeiros et al 2010b]. See ; updated information is available at www.scabase.eu.Allele sizes Normal alleles. 6-44 CAG repeats [Quan et al 1995, Servadio et al 1995, Goldfarb et al 1996]. Pathogenicity of alleles in the 36 to 44 range depends on the presence or absence of CAT trinucleotide repeats that interrupt the CAG repeats (see following Note). 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 pathogenic (39-44 CAG repeats) range.
Note: (1) Alleles of fewer than 21 CAG repeats are not associated with the SCA1 phenotype. (2) Alleles with 21-35 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. However, if these are uninterrupted alleles, the stability will need to be determined [Chung et al 1993]. (3) Distinguishing normal interrupted alleles from mutable normal uninterrupted alleles in the 36-38 CAG repeat range as well as from pathogenic uninterrupted alleles in the 39-44 CAG repeat range requires additional evaluation by SfaNI restriction analysis [Chung et al 1993]. A modified method (‘‘dual-fluorescence labeled PCR-restriction fragment length analysis’’) for directly detecting the uninterrupted CAG repeat stretch has been reported [Lin et al 2008].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.
Note: Distinguishing normal CAT-interrupted alleles from mutable normal uninterrupted alleles in the 36-38 CAG repeat range and pathogenic alleles in the 39-44 CAG repeat range requires additional evaluation by SfaNI restriction analysis [Chung et al 1993] or sequencing. 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.
Note: Distinguishing normal CAT-interrupted alleles from pathogenic uninterrupted alleles in the 39-44 repeat range requires additional evaluation by SfaNI restriction analysis [Chung et al 1993] or sequencing.Clinical testing Targeted mutation analysis by direct amplification of the ATXN1 CAG repeat region identifies more than 99% of individuals with a disease-causing ATXN1 mutation.
In some cases of infantile-onset SCA, 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.Table 1. Summary of Molecular Genetic Testing Used in SCA1View in own windowGeneTest MethodMutation DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityATXN1Targeted mutation analysis (PCR)≤ ~100 CAG repeats >99%Clinical Targeted mutation analysis (Southern blot, long-range PCR, CAG-primed PCR)> ~100 CAG repeats <1% ^{21. The ability of the test method used to detect a mutation that is present in the indicated gene2. Typically observed in individuals with infantile or childhood onset in families with SCA1Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband requires molecular genetic testing to identify the ATXN1 CAG repeat expansion. Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family by molecular genetic testing. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be caused by mutations in ATXN1.}

Natural HistorySpinocerebellar 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]. 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.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 [Abele et al 1997, Kubis et al 1999, Pareyson et al 1999]. Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1 [Abele et al 1997]. 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]. 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.

Genotype-Phenotype CorrelationsProbands. 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]. 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.

Differential DiagnosisThe 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 [Durr 2010, Soong & Paulson 2007]. 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Adult-onset SCA1Early-onset SCA1

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 1 (SCA1), the following evaluations are recommended:Medical historyNeurologic examination Molecular genetic testing Medical genetics consultationTreatment of ManifestationsManagement 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. Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals 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. 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 ManifestationsSee Therapies Under Investigation.Prevention of Secondary ComplicationsVitamin supplements are recommended, particularly if caloric intake is reduced. SurveillanceNeurologic evaluation every three to six months is appropriate Agents/Circumstances to AvoidAffected 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).Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationLithium [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 these have been done to date. Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of patients including persons with SCA1; however, further investigation is needed [Ristori et al 2010].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.OtherTremor-controlling drugs do not work well for cerebellar tremors.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATXN16p22​.3Ataxin-1ATXN1 homepage - Mendelian genesATXN1Data 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) View in own window 164400SPINOCEREBELLAR ATAXIA 1; SCA1 601556ATAXIN 1; ATXN1Normal allelic variants. 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. Normal alleles may contain six to 44 CAG repeats and are interrupted with one to three CAT trinucleotides. Pathologic allelic variants. 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 the CAT interruption 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]. 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: Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [Cummings et al 1999]. Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [Fernandez-Funez et al 2000, Cummings et al 2001]. Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [Park et al 2005]. 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]. 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].