DiagnosisClinical DiagnosisAlthough formal diagnostic criteria have not been established, the diagnosis of spinocerebellar ataxia type 7 (SCA7) can be established in adults who have the following findings: Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia Cone-rod retinal dystrophy with the following: Abnormalities of rod and cone function on electroretinogram testing A tritan-axis (blue/yellow) defect on detailed color vision testing Macular changes on fundoscopic examination (late in the disease course) Family history consistent with autosomal dominant inheritance In children, the disease progression is often more rapid and aggressive than in adults. In infants, clinical diagnosis may be difficult because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings [Benton et al 1998]. Molecular Genetic TestingGene. ATXN7 is the only gene in which mutations are known to cause spinocerebellar ataxia type 7 (SCA7). Allele sizes Normal alleles. Approximately 75% of normal alleles have ten CAG repeats [Michalik et al 2004]. To date, no normal allele with greater than 19 CAG repeats has been reported. Thus, no data regarding the significance of alleles between 19 and 27 CAG repeats are available. Alleles of questionable significance. Whether alleles with 28-36 repeats are mutable normal alleles or alleles with reduced penetrance awaits long-term clinical follow up of individuals with this number of repeats [Stevanin et al 1998]. Mutable normal alleles. 28 to 33 CAG repeats [Lebre et al 2003]. Previously called "intermediate alleles," mutable normal alleles are meiotically unstable and not convincingly associated with an abnormal phenotype. Because of the instability of alleles in the mutable normal range, an asymptomatic individual with a mutable normal allele may be predisposed to having a child with an expanded allele [Mittal et al 2005].Reduced-penetrance alleles. 34-36 CAG repeats may be provisionally defined as alleles with reduced penetrance (i.e., variably associated with disease manifestations). When they occur, symptoms are more likely to be later in onset and milder than average. A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [Nardacchione et al 1999]. Koob et al [1998] described a symptomatic individual with 35 CAG repeats, in contrast to the 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]. Full-penetrance alleles. Alleles of greater than 36 CAG repeats [Nardacchione et al 1999, Michalik et al 2004] to extreme expansions, e.g., 460 CAG repeats [van de Warrenburg et al 2001] are considered fully penetrant.Note: The distinction between the allele size for reduced-penetrance alleles and for full-penetrance alleles is likely to remain unclear until more families are reported; nonetheless, regardless of the "descriptor" used for these alleles, they should be considered unstable and pathologic.Clinical testing Targeted mutation analysis PCR analysis may be used to detect trinucleotide repeat expansions in the first exon of ATXN7 that are up to approximately 100 repeats [Fu et al 1991]. PCR analysis may show either two heterozygous normal-sized alleles or a single normal-sized allele. In the latter case, it may be necessary to perform Southern analysis to determine if the two alleles are the same size and within normal range or if one of the alleles is expanded and therefore not detectable by the PCR analysis. Southern analysis may be necessary to detect repeat expansions of more than approximately 100 CAG repeats. Table 1. Summary of Molecular Genetic Testing Used in the Diagnosis of SCA7View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test Availability ATXN7Targeted mutation analysis: PCR amplificationCAG trinucleotide repeat expansions of up to ~100 repeats ~100%ClinicalTargeted mutation analysis: Southern 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 geneInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information 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 proband1.Use targeted mutation analysis to determine the number of CAG trinucleotide repeats.2.If a single normal-sized allele is identified, determine if there is a family history of SCA7 and/or autosomal dominant cerebellar ataxia with retinal degeneration. Based on the family history and the age of onset in the proband, determine if Southern blot analysis to detect very large ATXN7 CAG repeat expansions is appropriate for the proband or another family member. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.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 phenotypes other than those described in this GeneReview chapter have been associated with mutations in ATXN7.}

Natural HistoryThe onset of spinocerebellar ataxia type 7 (SCA7) ranges from infancy (with an accelerated course and early death) to the fifth or occasionally sixth decade (with slowly progressive retinal degeneration and cerebellar ataxia) [Giunti et al 1999]. In infancy or early childhood, ataxia may not be obvious but muscle wasting, weakness, and hypotonia are common [Enevoldson et al 1994]. Two infants with severe disease and expansions of more than 200 and 306 CAG repeats had neonatal hypotonia, developmental delay, poor feeding, dysphagia, congestive heart failure, cerebral and cerebellar atrophy, and retinal disease [Babovic-Vuksanovic et al 1998, Benton et al 1998]. Ansorge et al [2004] reported a child with 180 CAG repeats dying in infancy.In those with infantile-onset disease, the cerebellar and brain stem degeneration is so rapid that retinal degeneration and related vision loss may not be evident. When initial symptoms occur at or before adolescence, blindness from retinal degeneration can occur within a few years. Individuals showing symptoms in their teens may be blind within a decade or less. In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) may precede, but usually follows, the onset of visual symptoms. While the rate of progression varies, the eventual result is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.Brisk tendon reflexes and spasticity become evident as the disease progresses. Ocular saccades may become markedly slowed.Cognitive decline and psychosis have been reported [Benton et al 1998]. Neuropsychiatric testing of some individuals with SCA7 has revealed selective deficits in social cognition [Sokolovsky et al 2010].The retinal degeneration is a progressive, cone-rod dystrophy that results in total blindness [To et al 1993, Aleman et al 2002, Ahn et al 2005, Hugosson et al 2009]. The onset of retinal degeneration is often characterized in the late teens or early 20s by hemeralopia (inability to see clearly in bright light), photophobia (extreme sensitivity to light), and abnormalities in color vision and central visual acuity [Miller et al 2009]. During the earliest stages of retinal degeneration, young adults may have no symptoms, but may have subtle granular changes in the macula and make errors in the tritan (blue-yellow) axis on detailed color vision testing using the Farnsworth dichromatous (D15) test. Electroretinogram 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]. As cone function decreases over time, central visual acuity decreases to the 20/200 (legally blind) range, more prominent macular changes appear (see Figure 1), all color discrimination is lost, and eventually all vision. FigureFigure 1. Funduscopic photo shows extreme macular degeneration of late-stage SCA7. It is important to note that in adult-onset disease visual loss from retinal degeneration may precede, accompany, or follow the onset of ataxia [Miller et al 2009] and that profound visual loss can be accompanied by minimal ophthalmoscopic findings and minimal ataxia [Thurtell et al 2009]. Pathology. Neuronal loss, loss of myelinated fibers, and gliosis are observed in the cerebellum (especially Purkinje cells); inferior olivary, dentate, and pontine nuclei; and to a lesser extent in cerebral cortex, basal ganglia, thalamus and midbrain [Rüb et al 2008, Seidel et al 2012]. In a detailed pathoanatomical study, Rüb et al [2008] correlated the widespread pattern of brain neuronal degeneration with the variable clinical phenotype, comparing degeneration in 18 different regions with various clinical manifestations such as ataxia, pyramidal signs, visual loss, diplopia, and impaired hearing. Nuclear inclusion aggregates, containing mutant ataxin-7 in neurons from both degenerating and spared areas, are largely absent from Purkinje cells [Michalik & Van Broeckhoven 2003]. In a severely affected infant, Ansorge et al [2004] identified ataxin-7 nuclear inclusions in the hippocampus and many non-nervous system tissues including the intestine, pancreas, and cardiovascular system. Abnormal mitochondria have also been observed in biopsies from skeletal muscle and liver [Han et al 2010a].Degeneration is evident in the posterior columns and spinocerebellar tracks of the spinal cord [Martin et al 1994, Lebre et al 2003, Koeppen 2005]. Degeneration of photoreceptors and bipolar and granular cells is evident in the retina, especially in the foveal and parafoveal regions [Martin et al 1994].

Genotype-Phenotype CorrelationsA correlation between CAG repeat length and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease. Despite observations correlating CAG repeat length with age of onset, disease severity, and course, current consensus is that ATXN7 allele size cannot provide sufficient predictive value for clinical prognosis [Andrew et al 1997].

Differential DiagnosisWhile many of the clinical and pathologic findings of the other spinocerebellar ataxias (SCAs) overlap with SCA7, retinal degeneration is the distinguishing feature of SCA7 (see Ataxia Overview).A few individuals with SCA1 have been reported to have progressive visual loss [Illarioshkin et al 1996, Abe et al 1997].The SCA7 phenotype may be confused with acquired ataxia associated with other forms of visual loss such as diabetic retinopathy, multiple sclerosis, or age-related macular degeneration.Mitochondrial encephalopathies such as Leber hereditary optic neuropathy (LHON) can present with ataxia and, in some cases, concomitant visual degeneration; these mitochondrially based ataxias can be distinguished from SCA7 by molecular genetic testing, by pattern of inheritance (maternal inheritance rather than autosomal dominant inheritance), and by the absence of anticipation, which is normally seen in SCA7 (see Mitochondrial Diseases Overview).Infantile and childhood-onset SCA7 may be confused with lipid storage diseases and the neuronal ceroid-lipofuscinoses. 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).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with spinocerebellar ataxia type 7 (SCA7), the following evaluations are recommended:Medical history Neurologic examination Ophthalmologic examination including assessment of visual acuity, visual fields, and color vision Medical genetics consultationTreatment of ManifestationsManagement of affected individuals remains supportive as no known therapy to delay or halt the progression of the disease exists.Cerebellar ataxia. Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals with spinocerebellar ataxia type 7 (SCA7) should maintain activity. Canes and walkers help prevent falls.Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.Weighted eating utensils and dressing hooks help maintain a sense of independence.When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.Note: Tremor-controlling drugs do not work well for cerebellar tremors.Retinal degeneration. Use of sunglasses and limitation of UV exposure are encouraged in order to limit damage to the retina.Various optical aids have been proposed for individuals with peripheral visual loss and preserved central vision, although all have drawbacks.Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.Wide-field, high-intensity flashlights produce a bright wide beam of light and improve the nighttime mobility of individuals with retinal degeneration. They are inexpensive and allow binocular viewing, but are large, heavy, and conspicuous. 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. SurveillanceRoutine follow up by an ophthalmologist is appropriate to measure visual acuity and visual fields and to help identify appropriate visual aids. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementWalking during pregnancy may be more difficult than usual because of the ataxia.Therapies Under InvestigationScholefield et al [2009] have suggested allele-specific RNA interference as a therapeutic approach for SCA7.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.

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 7: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATXN73p14​.1Ataxin-7ATXN7 homepage - Mendelian genesATXN7Data 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 7 (View All in OMIM) View in own window 164500SPINOCEREBELLAR ATAXIA 7; SCA7 607640ATAXIN 7; ATXN7Molecular Genetic Pathogenesis Normal allelic variants. ATXN7 is 136,094 bp in length encoding an 892-amino acid protein. A polymorphic CAG repeat tract occurs in the first exon; normal alleles have between four and 19 CAG repeats. In unaffected, unrelated reference populations, (CAG)₁₀ was the most common allele and alleles larger than 19 repeats were not observed [Del-Favero et al 1998, Gouw et al 1998]. Splice variants appear to exist, although their significance is unknown. Pathologic allelic variants. The ATXN7 mutation is an abnormal (CAG)_n trinucleotide repeat expansion in the coding region of the protein [David et al 1997]. Disease-causing alleles range from 36 to more than 450 CAG repeats [Michalik et al 2004]. Alleles with 28-36 CAG repeats are of questionable significance (see Molecular Genetic Testing).Normal gene product. Ataxin-7, the gene product of ATXN7, is expected to be about 95 kd. The protein is predominantly nuclear, but shuttles between the nucleus and cytoplasm. One function of ataxin-7 is as 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]. Abnormal gene product. The CAG repeats in ATXN7 code for a run of glutamines. In unaffected individuals, the polyglutamine tract is from four to 19 amino acids long. Abnormal proteins have an expanded polyglutamine tract of 37 or more amino acids. Protein from an affected individual has been detected in the nuclear fraction and appears to run at approximately 130 kd [Trottier et al 1995]. CAG repeat expansions in ATXN7 suppress transcription of an antisense non-coding RNA that promotes repressive chromatin modification of the ataxin-7 promoter [Sopher et al 2011], leading to increased expression of the mutant protein.The precise molecular mechanism by which mutant ataxin-7 causes neurodegeneration is not well defined. In a cell culture model, Ajayi et al [2012] report that mutant ataxin-7 leads to increased production of reactive oxygen species, which contribute to toxicity. Both Mookerjee et al [2009] and Janer et al [2010] noted that post-translational modification of lysine 257 in ataxin-7 is important in pathogenesis. In an SCA7 transgenic mouse model, expanded polyglutamine tracts induce neurodegeneration and transneuronal alterations in cerebellum and retina [Yvert et al 2000]. Deletion of Gcn5, an enzymatic component of the STAGA complex, worsens cerebellar and retinal pathology [Chen et al 2012]. Abnormal Bergmann glia in the cerebellum may cause degeneration by way of impaired glutamate transport resulting in non-cell autonomous degeneration of cerebellar Purkinje cells [Garden et al 2002, Custer et al 2006]. Neurons in the inferior olive that project climbing fibers to the cerebellum also appear to play a role in SCA7 pathogenesis. Deletion of the mutant gene from three cell types – Bergmann glia, inferior olive neurons, and Purkinje cells – doubled the presymptomatic period in transgenic mice [Furrer et al 2011]. Suppression of mutant protein expression by 50% in transgenic mice reverses several aspects of the mouse SCA7 phenotype, suggesting avenues for potential therapy [Furrer et al 2012].