DiagnosisClinical DiagnosisThe clinical features of spinocerebellar ataxia type 2 (SCA2) do not allow diagnosis with certainty; thus, diagnosis depends on molecular genetic testing.Molecular Genetic TestingGene. ATXN2 is the only gene in which mutation is known to cause SCA2. One hundred percent of individuals affected with SCA2 have an ATXN2 CAG trinucleotide repeat expansion. Allele sizesNormal alleles. 31 or fewer CAG repeats Pathologic alleles. 32 or more pure CAG repeats or repeats interrupted by a CAA repeat [Pulst et al 1996, Charles et al 2007]:Alleles of 32 and 33 CAG repeats are considered "late onset" (after age 50 years).The most common disease-causing alleles have 37 to 39 repeats. Extreme CAG repeat expansion (>200) has been reported [Babovic-Vuksanovic et al 1998] (see Anticipation). Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because CAA codes for glutamine as well [Costanzi-Porrini et al 2000]; however, the interruption may enhance the meiotic stability of the repeat [Choudhry et al 2001]. Conversely, the lack of CAA interruption in some expanded alleles may increase the instability of the expansion and therefore increase the risk of transmission of a larger expansion to offspring, who may become symptomatic.Clinical testingTargeted mutation analysisTesting is typically performed by PCR amplification of the ATXN2 trinucleotide repeat region followed by gel or capillary electrophoresis.Highly expanded alleles (generally >100 repeats) may not be detectable by the PCR-based assay; additional testing (e.g., Southern blot analysis) is needed to detect a highly expanded allele in individuals with a single allele size detected by PCR [Mao et al 2002]. Such testing may be indicated in symptomatic infants and children.Table 1. Summary of Molecular Genetic Testing Used in SCA2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityATXN2Targeted mutation analysis: PCR amplificationCAG trinucleotide repeat expansions up to ~100 repeats~100%ClinicalTargeted mutation analysis: Southern blot analysisHighly expanded CAG trinucleotide repeat expansions (>100 repeats)1. The ability of the test method used to detect a mutation that is present in the indicated geneTesting StrategyTo confirm/establish the diagnosis in a proband. The presence of one abnormally expanded ATXN2 allele is diagnostic.Note: Testing individuals with a positive family history of ataxia has a much higher yield than testing individuals with ataxia without an obvious family history. Only two of 842 affected individuals without a family history of ataxia in the series of Riess et al [1997] had an ATXN2 expansion in the abnormal range (41 and 49 repeats). Only two of 90 individuals with olivopontocerebellar atrophy without a known family history in the series reported by Cancel et al [1997] had an ATXN2 expansion in the abnormal range (37 and 39 repeats).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) DisordersIn addition to ataxia, L-dopa-responsive parkinsonism with or without ataxia has been reported in individuals and families.}

Natural HistorySpinocerebellar ataxia type 2 (SCA2) is characterized by slowly progressive ataxia and dysarthria associated with the ocular findings of nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis. Tendon reflexes are brisk during the first years of life, but absent later. Mean age of onset is typically in the fourth decade with a ten- to 15-year disease duration. The disease is more rapidly progressive when onset occurs before age 20 years.In the original study from Cuba, the earliest symptoms included gait ataxia often accompanied by leg cramps [Orozco Diaz et al 1990]. More than 50% of affected individuals developed a kinetic or postural tremor, decreased muscle tone, decreased tendon reflexes, and abnormal eye movements with slowed saccades progressing to supranuclear ophthalmoplegia. Detailed analyses of the eye movement abnormalities have been reported [Engel et al 2004, Velazquez-Perez et al 2004].In one family, Belal et al [1994] described fasciculations, dystonia, and/or chorea in 9%-38% of affected individuals and dementia in approximately 33%. Durr et al [1995] identified dementia in 29% of affected individuals. The above studies, conducted before identification of ATXN2, relied on linkage analysis to define the genotype. In individuals with molecularly confirmed ATXN2, Geschwind et al [1997b] found almost universal presence of cerebellar ataxia and slow saccadic eye movements in affected individuals, as well as a relatively high incidence of dystonia or chorea (38%) and dementia (37%). Mild, primarily cerebellar symptoms appeared to segregate in some families, whereas others had an early onset with dementia and chorea.Similar findings were also reported by Cancel et al [1997] in a series of 111 individuals from 32 families of diverse origins. Slow eye movements were seen in 56%, fasciculations in 25%, and dystonia in 9%. The authors also correlated these findings with disease duration and increasing CAG repeat length.An SCA2 phenotype that includes L-dopa-responsive parkinsonism has been reported [Furtado et al 2002, Payami et al 2003, Infante et al 2004, Lu et al 2004, Charles et al 2007].Neuropathology. Seven post-mortem examinations have been reported in the Holguin population of Cuba [Orozco et al 1989]. A marked reduction in the number of cerebellar Purkinje cells was observed. In silver preparations, Purkinje cell dendrites had poor arborization and torpedo-like formation of their axons as they passed through the granular layer. Parallel fibers were scanty. Granule cells were decreased in number, whereas Golgi and basket cells were well preserved, as were neurons in the dentate and other cerebellar nuclei. In the brain stem, marked neuronal loss in the inferior olive and pontocerebellar nuclei was observed. Six of seven brains also had marked loss in the substantia nigra. In five spinal cords that were available for analysis, marked demyelination was present in the posterior columns and to a lesser degree in the spinocerebellar tracts. Motor neurons and neurons in Clarke's column were reduced in size and number. In the lumbar and sacral segments, anterior and posterior roots were partially demyelinated. Degeneration in the thalamus and reticulotegmental nucleus of the pons has also been reported [Rub et al 2003, Rub et al 2004, Rub et al 2005].In addition, Orozco et al [1989] noted severe gyral atrophy, most prominent in the frontotemporal lobes. The cerebral cortex was thinned, but without neuronal rarefaction. The cerebral white matter was atrophic and gliotic. Degeneration in the nigro-luyso-pallidal system mainly involved the substantia nigra. One brain showed patchy loss in parts of the third nerve nuclei. Adams et al [1997] reported similar findings in one individual.A case with white matter pathology has been described [Armstrong et al 2005].Nerve biopsy has shown moderate loss of large myelinated fibers [Filla et al 1995].

Genotype-Phenotype CorrelationsProbands. In general, a clear inverse correlation exists between age of onset and CAG repeat length. However, repeat length cannot predict age of onset or severity in an individual.The widest range of age of onset is observed in individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset past age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [Pulst et al 1996].For larger repeat sizes, the variability in age of onset is less; repeat sizes greater than 45 are almost always associated with disease onset before age 20 years [Imbert et al 1996, Pulst et al 1996, Sanpei et al 1996, Cancel et al 1997, Geschwind et al 1997b, Riess et al 1997, Moretti et al 2004].Age of onset is also determined by other genetic modifiers, such as normal allelic variations in the RAI1 and CACNA1A genes [Hayes et al 2000, Pulst et al 2005], and by non-shared environmental factors [Pulst et al 2005].The size of the CAG repeat is significantly larger in individuals with dystonia, myoclonus, and myokymia, whereas both CAG length and duration of disease influence the frequency of muscle atrophy, fasciculations, decreased tendon reflexes and vibration sense in the lower extremities, and slow eye movements.Homozygosity for an expanded ATXN2 allele does not appear to influence age of onset [Sanpei et al 1996].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 by molecular genetic (DNA) testing.

Differential DiagnosisIt is difficult and often impossible to distinguish spinocerebellar ataxia type 2 (SCA2) from the other hereditary ataxias (see Ataxia Overview). The differential diagnosis should also include Parkinson disease and acquired causes of cerebellar ataxia.In six families detected with SCA2 out of 64 families with autosomal dominant cerebellar ataxia (ADCA) of German ancestry, Schols et al [1997b] determined that no specific single feature was sufficient to distinguish SCA2 from the other SCAs; however, slowed saccades, postural and action tremors, myoclonus, and hyporeflexia were more common in individuals with SCA2 than in those with SCA1 and SCA3.Two studies reported quantitative eye movement recordings in individuals with SCA2 and compared them with other ADCAs:Burk et al [1996] compared several individuals with SCA2 defined by linkage analysis with individuals who had SCA1 or SCA3. Individuals with SCA2 had significantly slower saccadic speed (138°/sec) than individuals with SCA1 (244°/sec) or SCA3 (347°/sec). All eight individuals with SCA2 had saccadic velocities two standard deviations below the mean of a control group. Buttner et al [1998] compared saccades in individuals with SCA1, SCA2, SCA3, and SCA6 identified by molecular genetic testing. Individuals with SCA2 had the slowest peak saccadic velocity, ranging from 80 to 295°/sec (normal: >400°/sec). Saccades were also slowed in individuals with SCA1, but individuals with SCA3 and SCA6 had normal saccades.SCA2 should be in the differential diagnosis of adult-onset sporadic progressive ataxia, multiple system atrophy (MSA; Shy-Drager syndrome), L-dopa-responsive parkinsonism, and atypical Friedreich ataxia [Abele et al 2002].Table 2. Proportion of Individuals with SCA2 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA6View in own windowPhenotypic FeatureSCA2SCA1SCA3SCA6Cerebellar dysfunction100%100%100%100%Reduced saccadic velocity71%-92%50%10%0%-6%Myoclonus0%-40%0%4%0%Dystonia or chorea0%-38%20%8%0%-25%Pyramidal involvement29%-31%70%70%33%-44%Peripheral neuropathy44%-94%100%80%16%-44%Intellectual impairment31%-37%20%5%0%Percentages were modified from Schols et al [1997a], Schols et al [1997b], Geschwind et al [1997a], Geschwind et al [1997b].

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 2 (SCA2), the following evaluations are recommended:Neurologic examinationOphthalmologic examinationBaseline assessment of cognitionNeuroimaging Treatment of ManifestationsManagement of 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 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.Improvement of severe tremor with thalamic stimulation has been reported in one individual [Pirker et al 2003]. Another patient showed improvement with stimulation of the subthalamic nucleus [Freund et al 2007].Prevention of Secondary ComplicationsNo 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.SurveillanceAffected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.Agents/Circumstances to AvoidAlcohol and medications known to affect cerebellar function should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATXN212q24​.12Ataxin-2alsod/ATXN2 genetic mutations
ATXN2 homepage - Mendelian genesATXN2Data 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 2 (View All in OMIM) View in own window 183090SPINOCEREBELLAR ATAXIA 2; SCA2 601517ATAXIN 2; ATXN2Normal allelic variants. Normal alleles have 31 or fewer CAG repeats. The normal alleles are not highly polymorphic. The two normal alleles, which account for more than 95% of alleles in most studies, have 22 and 23 CAG repeats [Pulst et al 1996, Sanpei et al 1996, Riess et al 1997]. Rare normal alleles ranging from 15 to 31 repeats have also been identified [Sanpei et al 1996, Imbert et al 1996, Riess et al 1997].Normal alleles typically show one or two CAA interruptions. In contrast to the CAT interruptions coding for histidine that are found in SCA1, the CAA interruptions do not interrupt the glutamine tract at the protein level. The 5' sequence of the ATXN2 cDNA is extremely GC rich and two potential ATG initiation codons can be identified. The most 5' ATG is located 78 bp downstream of an in-frame stop codon. Usage of this translation initiation site predicts a protein of 140.1 kd. The second ATG, which has a better Kozak consensus sequence, is located just 5' to the CAG repeat and would result in a protein with a relative molecular weight of 125 kd.Pathologic allelic variantsDisease alleles have 32 or more CAG repeats without interruption [Pulst et al 2005].Note: Intermediate alleles (i.e., meiotically unstable alleles that expand into an abnormal allele in the subsequent generation) are not reported in SCA2.Table 3. Selected ATXN2 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.496_498CAG(≤31)
(31 or fewer CAG repeats)p.Gln166(≤31)NM_002973​.3
NP_002964​.3Pathologicc.496_498CAG(≥32)
(32 or more CAG repeats)p.Gln166(≥32)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. Pulst et al [1996] predicted 1312 amino acids (22 glutamines) and Sanpei et al [1996] predicted 1313 amino acids (23 glutamines) with the CAG repeat coding for polyglutamine. Proteins observed by western blot analysis and conservation of the 5' ATG in the mouse [Nechiporuk et al 1998] suggest that the 5' ATG is the predominant site of translation initiation. In analogy to gene products encoded by other SCA-related genes, the ATXN2 gene product has been designated ataxin-2.In normal brains and in brains from individuals with SCA2, ataxin-2 has a cytoplasmic localization. It associates with Golgi membranes [Huynh et al 2003]. Using antibodies to ataxin-2, the expression pattern of ataxin-2 was identical in brains of normal individuals and those affected with SCA2 [Huynh et al 2000].Ataxin-2 interacts with ataxin-2 binding protein 1 (NM_001142333.1), a protein containing RNA-recognition motifs [Figueroa & Pulst 2003]. Interaction of ataxin-2 with ataxin-2 binding protein suggests involvement of ataxin-2 in mRNA translation or transport [Shibata et al 2000]. Ataxin-2-deficient mice do not develop marked neurodegeneration but show reduced fertility, obesity, and changes in hippocampal plasticity [Kiehl et al 2006, Huynh et al 2009].Abnormal gene product. The CAG expansion codes for a protein that has an abnormally long stretch of glutamine amino acid residues. The biologic consequence of this abnormal protein is undetermined. A mouse model of SCA2 has been described by Huynh et al [2000]. Atxn2 transgenic mice had accumulation of ataxin-2 in the cytoplasm. Intranuclear aggregates were not observed. In vitro, expression of mutant ataxin-2 causes apoptotic cell death [Huynh et al 2003]. In the Atxn2 transgenic mouse, ataxin-2 interacts with the inositol-triphosphate receptor type 1 causing abnormally increased Ca++ release from intracellular calcium stores. This can be ameliorated by treatment in vivo with dantrolene prior to onset of symptoms [Liu et al 2009].