SCA17 is an autosomal dominant neurologic disorder characterized by ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures. Its clinical phenotype and inheritance pattern are similar to Huntington disease (HD; 143100). Individuals with normal TBP alleles have ... SCA17 is an autosomal dominant neurologic disorder characterized by ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures. Its clinical phenotype and inheritance pattern are similar to Huntington disease (HD; 143100). Individuals with normal TBP alleles have between 25 and 44 repeats, whereas SCA17 patients have between 47 and 63 repeats. Reduced penetrance is seen with 45 to 46 repeats (summary by Gao et al. (2008)).
Koide et al. (1999) described a sporadic case of a complex neurologic disorder with cerebellar ataxia, pyramidal signs, and severe intellectual impairment.
Zuhlke et al. (2001) described 2 German families with an autosomal dominant degenerative multisystem ... Koide et al. (1999) described a sporadic case of a complex neurologic disorder with cerebellar ataxia, pyramidal signs, and severe intellectual impairment. Zuhlke et al. (2001) described 2 German families with an autosomal dominant degenerative multisystem disorder with predominant ataxia and intellectual impairment but also involvement of the pyramidal, extrapyramidal, and possibly autonomic system. Nakamura et al. (2001) identified a form of spinocerebellar ataxia (SCA17) in 4 Japanese pedigrees. Age at onset ranged from 19 to 48 years, and symptoms included ataxia, bradykinesia, and dementia. Postmortem brain tissue from 1 patient exhibited shrinkage and moderate loss of small neurons with gliosis predominantly in the caudate nucleus and putamen, with similar but moderate changes in the thalamus, frontal cortex, and temporal cortex. Moderate Purkinje cell loss and an increase of Bergmann glia were seen in the cerebellum. Immunocytochemical analysis performed with anti-ubiquitin (191339) and anti-TBP antibodies showed neuronal intranuclear inclusion bodies, and most neuronal nuclei were diffusely stained with 1C2 antibody, which recognizes expanded polyglutamine tracts. Among 1,318 Caucasian patients with SCA, Rolfs et al. (2003) identified 15 patients from 4 families with repeat expansions in the TBP gene, indicating SCA17. One of the families had been reported by Koeppen et al. (1981). The repeats ranged from 45 to 54 repeats. Median age at onset was 23 years, and by age 43 years, all patients with an expanded allele showed neurologic or psychiatric dysfunction. There was only a weak correlation between length of the repeat and age at onset. Clinical features were somewhat variable, but all patients except 1 showed 1 or more features of ataxia, dysarthria, and dysphagia, and most showed psychiatric symptoms, including depression, disorientation, aggression, paranoia, and dementia. Dystonia and extrapyramidal movements were occasionally present. In at least 8 patients, psychiatric symptoms were 1 of the presenting signs. Neuropathologic examination of 3 sisters from 1 family showed overall reduction in brain weight, loss of Purkinje cells in the cerebellum, and numerous neuronal inclusion bodies with immunoreactivity to anti-TBP and anti-1C2 widely distributed throughout the brain gray matter. Rolfs et al. (2003) emphasized the psychiatric manifestations of SCA17. Maltecca et al. (2003) reported an Italian family in which 9 members in 4 generations were affected with autosomal dominant SCA17. The 1 affected member in the last generation had very early disease onset at age 3 years. She presented at that time with ataxic gait with foot intrarotation and dysarthria. By age 13 years, she had developed loss of sphincter control, seizures, spasticity, tremor, hyperreflexia, extensor plantar responses, and mental retardation. Other affected members had disease onset in the third to seventh decade characterized by ataxia, dementia, psychiatric symptoms, extrapyramidal features, and cerebellar atrophy. Genetic analysis showed that affected members in the third generation had a 53 CAG/CAA repeat allele in the TBP gene, whereas the affected member in the fourth generation had a 66-repeat expansion. Maltecca et al. (2003) noted that this was the largest reported expansion in the TBP gene, and emphasized the extremely severe phenotype and early onset in this patient. In 2 of 60 patients with a Huntington disease-like phenotype, but no mutation in the huntingtin gene, Stevanin et al. (2003) identified expanded trinucleotide repeats in the TBP gene. The patients, who were both from France, presented at ages 23 and 29 years, respectively, with behavioral changes, which later progressed to dementia. Other features included chorea, cerebellar gait, lower limb hyperreflexia, and pontocerebellar atrophy. One of the patients showed rigidity. There was no family history in either case, but one patient's unaffected father had the same TBP repeat expansion, indicating reduced penetrance of the disorder. Bauer et al. (2004) reported 9 patients with repeat expansions in the TBP gene who had a disease phenotype indistinguishable from Huntington disease. In addition to cerebellar ataxia, patients exhibited psychiatric disturbances, dementia, and chorea. The authors suggested that mutation in the TBP gene may be the underlying genotype in patients with cerebellar ataxia, HD-like symptoms, a positive family history (dominant segregation), and in whom the huntingtin gene mutation has been excluded. Toyoshima et al. (2004) reported neuropathologic findings in a patient with a Huntington disease-like phenotype who was homozygous for 48 trinucleotide repeats in the TBP gene. There was mild neuronal loss with compaction of the neuropil in the cerebral cortex, mild loss of neurons in the striatum, and moderate loss of Purkinje cells in the cerebellum. Many 1C2-positive neuronal nuclei were present in the deep layers of the cerebral cortex, as well as in the putamen and cerebellum. The authors also found diffuse intranuclear polyglutamine aggregate accumulation in a wide range of CNS regions beyond those affected by neuronal loss. Filla et al. (2002) reported a family from Southern Italy with early-onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy. There were 14 affected individuals spanning 5 generations. Age at onset ranged from 22 to 53 years, and 75% of patients presented with psychiatric features, including depression, personality changes, negligence of personal care, delusions, hallucinations, and alcoholism. The disease was slowly progressive, and all patients eventually developed dementia, ataxia, axial rigidity, and dysarthria. Most patients had generalized seizures and mild dystonia. In the latest stages of disease, patients were bedridden, anarthric, dysphagic, and incontinent. MRI showed cortical and cerebellar atrophy. Bruni et al. (2004) reported neuropathologic findings of a patient from the family reported by Filla et al. (2002). She had onset of behavioral and frontal lobe impairment at age 17 years and followed a progressive course until death at age 48 years. The brain showed diffuse atrophy in all brain regions, with the cerebellum most affected. There was severe neuronal loss and gliosis in the striatum, the dorsomedial thalamic nucleus, and inferior olive. Neuronal intranuclear inclusions stained with anti-TBP and 1C2. Hagenah et al. (2004) reported a German family in which a mother and 2 of her daughters had SCA17. All presented with focal dystonia as the presenting sign, including foot dystonia, hand dystonia, and torticollis, respectively. Dystonia was followed by progressive cerebellar ataxia. The 48-year-old mother developed dementia, mutism, dysphagia, and marked spasticity later in the disease course. Her daughters, age 27 and 23 years at the time of the report, had not yet developed additional symptoms. Hagenah et al. (2004) emphasized that focal dystonia may be a presenting sign of SCA17.
The case reported by Koide et al. (1999) was associated with expansion of the CAG repeat in exon 3 of the TBP gene (600075.0001). The gene encoded 63 glutamines, far exceeding the range in normal individuals (25 to ... The case reported by Koide et al. (1999) was associated with expansion of the CAG repeat in exon 3 of the TBP gene (600075.0001). The gene encoded 63 glutamines, far exceeding the range in normal individuals (25 to 42 in Caucasians; 31 to 42 in Japanese). In the families reported by Zuhlke et al. (2001), expanded (CAG)n alleles of the TBP gene ranged between 50 and 55 residues in affected individuals. In 1 family, 2 affected sisters differed by 1 trinucleotide repeat, and upon transmission from one of the sisters to her daughter the repeat was elongated by 2 units. This expansion may have contributed to the earlier age at onset in the daughter. In the other family, the (CAG)n element was combined with CAA interruptions, which had not been described for CAG expansions in other genes. In the Japanese pedigrees reported by Nakamura et al. (2001), there was abnormal (CAG)n expansion in TBP to a range of 47 to 55 repeats. Silveira et al. (2002) reported a patient with onset of gait ataxia at age 52, with progressive mental deterioration and dementia. Sequence analysis of the TBP gene showed an interrupted repeat configuration of (CAG)n and (CAA)n, encoding 43 glutamines. Silveira et al. (2002) suggested that the late onset of disease and milder clinical symptoms in this patient correlated with the small size of the expanded allele. In patients with a Huntington disease-like phenotype, Stevanin et al. (2003) and Bauer et al. (2004) identified repeat expansions in the TBP gene. In the family reported by Filla et al. (2002), Bruni et al. (2004) identified a 52 CAG repeat expansion in the TBP gene, establishing the diagnosis of SCA17. In a patient who was originally thought to have variant Creutzfeldt-Jakob disease (see 123400), Shatunov et al. (2004) found no mutation in the PRNP gene (176640) and identified an expanded allele with 55 CAG/CAA repeats in the TBP gene, establishing the diagnosis of SCA17.
Lee et al. (2009) identified expanded repeats in the TBP gene in 2 (0.3%) of 661 Korean patients with ataxia and in 2 (2.0%) of 98 patients with chorea. The patients in each group were the same 2 ... Lee et al. (2009) identified expanded repeats in the TBP gene in 2 (0.3%) of 661 Korean patients with ataxia and in 2 (2.0%) of 98 patients with chorea. The patients in each group were the same 2 patients and had been included in both larger groups because they manifested both symptoms. One patient had onset in his teens, and the other had onset in his late twenties.
Spinocerebellar ataxia type 17 (SCA17) is suspected in individuals with the following:...
DiagnosisClinical DiagnosisSpinocerebellar ataxia type 17 (SCA17) is suspected in individuals with the following:Psychiatric symptoms or dementia Cerebellar ataxia or involuntary movement Molecular Genetic TestingGene. TBP, encoding the TATA-box-binding protein, is the only gene in which mutations are known to cause SCA17. The expansion of an imperfect CAG/CAA repeat is the only mutation observed [Koide et al 1999, Nakamura et al 2001]. Because both codons CAA and CAG encode a glutamine residue, the repeat results in a variable tract of glutamines.Allele sizes. The structure of the repeat sequence is (CAG)3 (CAA)3 (CAG)x CAA CAG CAA (CAG)y CAA CAG. Allele sizes are determined by counting all triplet repeats; for example, if x=9 in (CAG)x and y=16 for (CAG)y, the total number of CAG/CAA repeats in the example above would be 36, translating to 36 glutamine residues in the protein.Normal alleles. 25 to 40 CAG/CAA repeats Mutable normal alleles. Not reported to date Reduced penetrance alleles. 41 to 48 CAG/CAA repeats. An individual with an allele in this range may or may not develop symptoms. The significance of alleles of 41 and 44 repeats is particularly controversial because penetrance is estimated to be 50%, making genotype-phenotype correlations difficult. One symptomatic individual having 41 repeats and four symptomatic persons having 42 repeats were reported recently [Nanda et al 2007, Nolte et al 2010]. Full penetrance alleles. 49 or greater CAG/CAA repeats. The largest repeat size reported to date is 66 [Maltecca et al 2003]. CAA CAG CAA interruption. The CAA CAG CAA interruption between (CAG)x and (CAG)y is present in all expanded alleles that are stably transmitted (i.e., the allele size is unchanged during meiosis). The CAA CAG CAA interruption between (CAG)x and (CAG)y was absent in two families with allele size instability (i.e., change in allele size) during transmission [Zühlke et al 2001, Maltecca et al 2003]. Thus, loss of this interruption may be a prerequisite of instability in SCA17 as in other diseases caused by repeat expansions [Maltecca et al 2003, Zühlke et al 2003b, Zühlke et al 2005].Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 17View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilityTBPTargeted mutation analysisCAG/CAA repeat expansion100%Clinical 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, molecular genetic testing must reveal an expanded CAG/CAA repeat in TBP. Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in an affected family member. Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis in an affected family member. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TBP.
The main symptoms of spinocerebellar ataxia type 17 (SCA17) are ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [Toyoshima et al 2004b]. Psychiatric symptoms, pyramidal signs, and rigidity are common. ...
Natural HistoryThe main symptoms of spinocerebellar ataxia type 17 (SCA17) are ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [Toyoshima et al 2004b]. Psychiatric symptoms, pyramidal signs, and rigidity are common. Onset ranges from age three to 75 years (mean: 34.6 years) [Stevanin & Brice 2008]. All individuals with full penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years [Koide et al 1999; Fujigasaki et al 2001; Nakamura et al 2001; Zühlke et al 2001; Silveira et al 2002; Maltecca et al 2003; Stevanin et al 2003; Zühlke et al 2003b; Bauer et al 2004; Hagenah et al 2004; Oda et al 2004; Toyoshima, personal observation].Although the disease course is variable, ataxia and psychiatric abnormalities are frequently the initial findings followed by involuntary movement, parkinsonism, dementia, and pyramidal signs.Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum (Figure 1). Most people present with cerebellar atrophy. The age of the individual and the length of CAG/CAA repeat influence the degree of atrophy. For example, in older individuals – even those with a small full-penetrance allele – severe atrophy is present on brain MRI. High-intensity T2-weighted images and selective atrophy on caudate nucleus are not observed. Some correlation of region of brain atrophy with clinical characteristics is seen [Lasek et al 2006]. FigureFigure 1. Number of CAG/CAA repeats versus age of individuals with SCA17 Neuropathology. The brain shows atrophy of the striatum (more apparent in the caudate nucleus) and cerebellum. Histologically, neuronal loss is observed in the striatum and Purkinje cell layer. Loss of cerebral cortical neurons is seen in some individuals. Immunohistochemistry for the expanded polyglutamine (polyQ) tracts shows diffuse labeling of the neuronal nucleoplasm. Note: Intranuclear inclusions are a much less common finding than diffuse labeling. No labeling is detectable in the cytoplasm or in the neuropil. Glial cell involvement is occasionally seen. In individuals who are homozygous for an expanded allele in the full-penetrance range, nuclear polyQ pathology involves other CNS regions including the cerebral cortex, thalamus, and brain stem [Toyoshima et al 2004a]. The abundant nuclear accumulation of polyQ in the cerebral cortices and subcortical nuclei (e.g., dorsomedian thalamic nucleus) are possibly associated with the prominent cognitive and behavioral decline in affected individuals.
Clinical features. The length of the CAG/CAA repeat in TBP correlates with the clinical features based on data available from 52 individuals (50 from the literature and two unreported) (Table 2, Figure 2). As the information reported in the literature was incomplete, the percentage of each symptom may be underestimated [Koide et al 1999, Fujigasaki et al 2001, Nakamura et al 2001, Zühlke et al 2001, Silveira et al 2002, Maltecca et al 2003, Rolfs et al 2003, Stevanin et al 2003, Zühlke et al 2003a, Bauer et al 2004, Hagenah et al 2004, Oda et al 2004]. Of note is the high proportion of individuals with psychiatric problems and chorea. ...
Genotype-Phenotype CorrelationsHeterozygotes Clinical features. The length of the CAG/CAA repeat in TBP correlates with the clinical features based on data available from 52 individuals (50 from the literature and two unreported) (Table 2, Figure 2). As the information reported in the literature was incomplete, the percentage of each symptom may be underestimated [Koide et al 1999, Fujigasaki et al 2001, Nakamura et al 2001, Zühlke et al 2001, Silveira et al 2002, Maltecca et al 2003, Rolfs et al 2003, Stevanin et al 2003, Zühlke et al 2003a, Bauer et al 2004, Hagenah et al 2004, Oda et al 2004]. Of note is the high proportion of individuals with psychiatric problems and chorea. FigureFigure 2. The clinical features in SCA17 depend on the length of CAG/CAA repeats. The clinical features of SCA17 in each case are denoted by letter. For example, A-E denotes ataxia with parkinsonism. A = ataxia D = dementia or psychiatric (more...)CAG/CAA repeat size from 43 to 50. More than 75% of individuals have intellectual deterioration; in some individuals intellectual problems and involuntary movements are the only signs. Psychiatric problems or dementia, parkinsonism, and chorea, a clinical constellation resembling Huntington disease, are more frequently observed in individuals with CAG/CAA repeats in this range than in individuals with larger repeats [Stevanin et al 2003, Bauer et al 2004, Toyoshima et al 2004a]. CAG/CAA repeat size from 43-47. Individuals with 43-47 repeat size tend to have a parkisonian phenotype [Kim et al 2009, Chen et al 2010]. CAG/CAA repeat size from 50-60. All individuals have ataxia and 75% have reduced intellectual function. Pyramidal signs (e.g., increased deep tendon reflexes) and dystonia are more common than in those with smaller repeats. CAG/CAA repeat size greater than 60. Two individuals with repeats in this size range have been reported. The largest CAG/CAA repeat is 66 repeats, observed in a familial case [Maltecca et al 2003]. The child developed gait disturbance at age three years followed by spasticity, dementia, and psychiatric symptoms. The other child, who had a de novo CAG repeat expansion of 63 repeats, developed ataxia and intellectual deterioration at age six years followed later by spasticity [Koide et al 1999]. Brain MRI showed severe atrophy in the cerebrum, cerebellum, and brain stem.Table 2. Frequency of Clinical Features in SCA17 Correlated with Repeat SizeView in own windowCAG/CAA Repeat SizeAtaxiaDementia / Psychiatric SymptomsIncreased DTRs 1 DystoniaParkinsonismChorea43-4993%90%45%7%42%39%≥50100%75%55%40%25%10%1. DTR = deep tendon reflexHomozygotesFour homozygous individuals and one compound heterozygous individual have been reported [Zühlke et al 2003b, Oda et al 2004, Toyoshima et al 2004a, Hire et al 2010]. Four individuals who were homozygous for 47 and 48 CAG/CAA repeats had onset in the fourth decade, not unlike the onset age predicted for heterozygotes [Zühlke et al 2003b, Toyoshima et al 2004a]. Their symptoms were severe and rapidly progressive, and in one individual differed from those of his parents, suggesting that the presence of two expanded alleles influences the severity and rate of progression of symptoms.
The differential diagnosis of spinocerebellar ataxia type 17 (SCA17) includes many of the other hereditary ataxias that are summarized in the Hereditary Ataxia Overview and described in detail for specific ataxias, including SCA1, SCA2, SCA3, and SCA7....
Differential DiagnosisThe differential diagnosis of spinocerebellar ataxia type 17 (SCA17) includes many of the other hereditary ataxias that are summarized in the Hereditary Ataxia Overview and described in detail for specific ataxias, including SCA1, SCA2, SCA3, and SCA7.DRPLA is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. Huntington disease (HD) also needs to be considered [Rolfs et al 2003]. HD is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival is 15 to 18 years after onset. Bauer et al [2004] reported nine individuals with TBP alleles larger than 45 CAG/CAA repeats among 1,712 individuals with Huntington disease-like (HDL), and observed that CAG/CAA repeat expansions in TBP represented a more common monogenic cause for a HD-like phenotype than Huntington disease-like 1 (HDL-1) [Xiang et al 1998] or Huntington disease-like 2 (HDL-2) [Margolis et al 2001]. Therefore SCA17 is also referred to as Huntington disease-like disorder 4 (HDL-4) [Stevanin et al 2003, Schneider et al 2007, Harbo et al 2009].Lin et al [2007] reported an individual with SCA17 whose findings of ataxia, autonomic dysfunction, parkinsonism, supranuclear palsy, and cognitive impairment resembled multiple system atrophy.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).
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations are recommended:Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance Brain MRI to evaluate areas and degree of atrophyNeurology consultation, if not completed prior to initial diagnosis Medical genetics consultationTreatment of ManifestationsThe following are appropriate:Treatment of psychiatric problems with appropriate psychotropic medications Treatment of seizures with antiepileptic drugs (AEDs) Adaptation of environment and care to the level of dementia Treatment of dystonia with local injections of botulinum toxin Prevention of Secondary ComplicationsThe side effects of psychotropic medications and AEDs (e.g., depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dsykinesia) can be major secondary complications in persons with SCA17. For some individuals, the side effects of certain therapeutics may be worse than the symptoms of the disease; such individuals may benefit from total or intermittent discontinuation of the treatment or reduction in dose.SurveillanceAffected individuals should be followed annually or semiannually by a neurologist or more frequently if symptoms are progressing rapidly, as may happen in the advanced stages [Toyoshima et al 2004a].Agents/Circumstances to AvoidAgents with sedative/hypnotic properties, such as ethanol or certain medications, may markedly increase incoordination.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Affected women may be on medications (e.g., antiepileptics) to control the symptoms of SCA17. Because some medications can have adverse effects on the developing fetus, a thorough discussion of the medical benefits vs. risks to the fetus of such medications before pregnancy (or, in the case of an unplanned pregnancy, immediately after pregnancy is determined) is appropriate. 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 17: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTBP6q27TATA-box-binding proteinTBP homepage - Mendelian genesTBPData 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 17 (View All in OMIM) View in own window 600075TATA BOX-BINDING PROTEIN; TBP 607136SPINOCEREBELLAR ATAXIA 17; SCA17Normal allelic variants. TBP has eight exons (NM_003194.4); the CAG/CAA repeat tract is in exon 3. Two transcript variants encoding different protein isoforms were identified (Table A, Gene Symbol TBP). Normal allelic variants have between 25 to 42 CAG/CAA repeats.Pathologic allelic variants. The CAG/CAA repeat length in individuals with TBP ranges from 43 to 66 repeats. Normal gene product. TATA-box-binding protein (TBP) is also called transcription factor IID (TFIID). Human TBP has 339 amino acids (NP_003185.1) and a molecular size of 37.8 kd. TBP is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D, the multi-subunit complex crucial for the expression of most genes. Abnormal gene product. Because TBP is a fundamental transcription factor expressed ubiquitously in all organs including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of SCA17 remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [Toyoshima et al 2004a]. Taking into consideration the ubiquitous presence of TBP, the selective neuronal degeneration suggests no significant loss of protein function in individuals with SCA17.