Alternative titles; symbols
SNOMEDCT: 719249005; ORPHA: 98759; DO: 0050967;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q27 | Spinocerebellar ataxia 17 | 607136 | Autosomal dominant | 3 | TBP | 600075 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-17 (SCA17) can be caused by heterozygous expansion of a trinucleotide repeat encoding glutamine (CAG or CAA) in the TATA box-binding protein (TBP; 600075) on chromosome 6q27.
SCA17 is a neurologic disorder characterized by cerebellar ataxia, pyramidal and extrapyramidal signs, cognitive impairment, psychosis, and seizures. Most patients have onset of symptoms after age 30, although earlier onset has been reported. The clinical phenotype and inheritance pattern are similar to Huntington disease (HD; 143100) (Gao et al., 2008).
SCA17 shows a complex pattern of inheritance, including autosomal dominant, autosomal dominant with incomplete penetrance, and digenic (see MOLECULAR GENETICS) depending on the size of the TBP repeat expansion. Unaffected individuals have between 25 and 41 CAG/CAA repeats in the TBP gene. Alleles with 47 or more CAG/CAA repeats are fully penetrant for SCA17. Alleles with 'intermediate expansions' between 41 and 46 repeats show incomplete penetrance. However, patients with intermediate TBP expanded alleles in combination with heterozygous mutations in the STUB1 gene (607207) demonstrate full penetrance of the disease, suggesting that intermediate SCA17 is actually a digenic disease and may represent the same entity as SCA48 (618093), which has a similar phenotype (Magri et al., 2022). Rarely, SCA17 has been found to be caused by homozygous or compound heterozygous TBP repeat expansions, consistent with autosomal recessive inheritance.
For a general discussion of autosomal dominant of spinocerebellar ataxia, see SCA1 (164400).
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.
Magri et al. (2022) reported 30 patients with SCA17 due to intermediate TBP expansions (41-46) in combination with a STUB1 (607207) variant, referred to as SCA17-DI (digenic). The patients had adult onset of the disorder (19-62 years), with 65% of subjects manifesting the disease within the fifth decade. The first reported symptoms were cerebellar ataxia (85%), cognitive decline (23%), behavioral abnormalities (20%), and chorea (12%). Cognitive decline was present in 90% of patients. Brain MRI showed typical features of SCA17, including atrophy of the cerebellum, basal ganglia, and cortex. Linear regression analysis of SCA17-DI patients did not show an association between age at onset and repeat size. However, there was a significant negative correlation observed in SCA17 patients with TBP repeats equal to or greater than 47 and no STUB1 variant.
Minnerop et al. (2005) performed positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging on 2 unrelated male patients with genetically confirmed SCA17. Both patients had significantly reduced glucose metabolism in the putamen and reduced dopamine transporter activity in the basal ganglia and pronounced reduction in the putamen. In addition, 1 patient showed reduced glucose metabolism in the cerebellum and caudate. The findings indicated prominent involvement of the dopaminergic system in SCA17. Minnerop et al. (2005) noted that the severe reduction of glucose metabolism in the putamen of SCA17 patients resembled that seen in patients with Huntington disease.
Lasek et al. (2006) observed 2 patterns of brain degeneration in 12 patients with SCA17 using MRI voxel-based morphometry. Clinical features included ataxia (in 11), spasticity (9), extrapyramidal signs (11), dementia (6), and a psychiatric disorder (11); 1 mutation carrier was clinically unaffected. Compared to controls, SCA17 patients had gray matter atrophy in the cerebellum and basal ganglia, as well as in the frontal and temporal lobes. Regression analysis showed correlations between ataxia and cerebellar atrophy, spasticity/extrapyramidal signs and basal ganglia atrophy, and neuropsychologic scores and atrophy of the nucleus accumbens. Personality changes were correlated with atrophy in the frontal cortex and limbic areas.
Manganelli et al. (2006) reported electrophysiologic studies of 9 patients with SCA17 from 4 families. Two of the families had been previously reported (Bruni et al., 2004; Maltecca et al., 2003). All patients had abnormal brainstem auditory evoked potentials (BAEPs), suggesting brainstem involvement. Three patients tested showed prolonged lower limb motor nerve conduction times, suggesting length-dependent involvement of the pyramidal tract. EMG and nerve conduction studies and visual evoked potentials were normal, indicating lack of peripheral nerve or visual system involvement, respectively. Somatosensory evoked potentials were abnormal in most patients, consistent with involvement of a pathway along the caudal part of the brainstem.
Hubner et al. (2007) observed eye movement abnormalities in 15 patients with SCA17 from 4 families. Four mutation carriers were clinically unaffected. Specific oculomotor examinations using a video-based system showed strong impairment of smooth pursuit initiation and maintenance, whereas latency, velocity, and position error of the first catch-up saccade were normal. Gaze-evoked nystagmus was found in one-third of patients, and there was a pathologic increase in error rates of antisaccades (52%) and memory-guided saccades (42%). Oculomotor disorders were not correlated with repeat length but increased with disease duration. Hubner et al. (2007) concluded that some of the oculomotor disturbances were compatible with cerebellar degeneration, whereas increased error rates in anti- and memory-guided saccades were consistent with deficient frontal cortical inhibition of reflexive movements.
SCA17 is most commonly inherited as an autosomal dominant disorder (Zuhlke et al., 2001).
Anticipation in SCA17 is uncommon due to the interrupted configuration of the repeat alleles, which results in stabilization during intergenerational transmission. Rasmussen et al. (2007) reported 3 multigenerational Mexican SCA17 families with expansion of uninterrupted TBP repeat alleles. There was clear clinical evidence of anticipation, with earlier age at onset and increased disease severity in subsequent generations. Genetic analysis showed that the uninterrupted expanded alleles were prone to further expansion during transmission. Larger expansions were observed with paternal transmissions and age. Small gains in polyglutamine tract length resulted in high levels of genetic anticipation. More than one-third of the patients in these families showed disease onset in childhood, which is uncommon in SCA17.
Gao et al. (2008) used small pool PCR to compared somatic instability of expanded CAG repeats in 1 Mexican, 4 Japanese, and 2 German SCA17 families. CAG repeats had 2 distinct configurations: complex or group I consisting of (CAG)3 (CAA)3 (CAG)n1 CAA-CAG-CAA (CAG)n2 CAA-CAG ('n1' from 7 to 11 and 'n2' from 9 to 21) and simple or group II consisting of (CAG)3 (CAA)3 (CAG)n1 CAA-CAG ('n1' from 42 to 47). Both CAG and CAA in these repeat tracts code for glutamine. Group I mutations were prone to contraction, whereas group II mutations were prone to continuing expansion. Analysis of individual alleles showed a correlation between mutation frequency and the number of CAG/CAA repeats (0.76), but the difference between the 2 groups was no significant. However, there was a strong correlation between the configuration of the CAG/CAA repeat and instability: those with more CAA interruptions showed more stability, whereas those with less or no CAA interruptions showed more instability. These changes also correlated with intergenerational instability and anticipation in regard to age at onset. Of note, the pure CAG repeats showed both expansion and contraction, while the interrupted repeats exhibited mostly contraction at a significantly lower frequency. Gao et al. (2008) suggested that repeat configuration is a critical determinant for instability, and that CAA interruptions (i.e., CAA-CAG-CAA or domain 3) might serve as a limiting element for further expansion of CAG repeats at the SCA17 locus.
Autosomal Recessive Inheritance
Hire et al. (2011) reported a consanguineous Indian family in which several individuals had SCA17. The proband, born of related parents, was found to be homozygous for 47/47 CAG/CAA repeats in the TBP gene. He had onset at age 36 years and died at age 54 from a Huntington disease-like disorder. There were several other affected family members, but genetic analysis was only available for a 21-year-old nephew of the proband who had a heterozygous 37/48 repeat genotype and onset of ataxia at age 19. In a second family, an Indian man born of related parents was found to be homozygous for a 48/48 CAG/CAA repeat expansion. He had onset at age 41 years of a Huntington-like disorder followed by death at age 47. There was no family history of a similar disorder and both of his unaffected parents lived to a late age. The phenotype of these homozygous patients did not differ in severity or age at onset compared to symptomatic heterozygotes with similar repeat lengths. The normal repeat range in Indian controls was 21 to 42, with 91% of the alleles between 33 and 39 repeats.
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.
Digenic SCA17
In SCA17 families with intermediate-sized TBP repeat alleles (41-49), Magri et al. (2022) observed that about 40% of family members carrying a 41-49 allele were not affected at age 50 years or older, consistent with incomplete penetrance. Next-generation sequencing revealed a role for the STUB1 gene (607207) in the pathogenesis of SCA17 that could explain the missing heritability in those with intermediate TBP alleles. Among 31 affected index cases with SCA17 associated with an intermediate TBP expansion allele (41 to 49 CAG/CAA repeats), 27 (87%) patients also carried heterozygous variants in the STUB1 gene. All patients with STUB1 variants had a TBP expansion ranging from 41 to 46 CAG/CAA repeats. Three patients with the largest TBP expansions (47-49) did not have pathogenic variants in the STUB1 or other genes. One patient with a TBP(42) expansion carried a missense variant (G334V) in the VCP gene (601023). STUB1 mutations were not observed in 9 additional SCA17 index cases carrying fully penetrant TBP alleles (51-54). Segregation studies in families with STUB1 variants showed that individuals with both an intermediate TBP (41-46) allele and a heterozygous STUB1 variant presented with an SCA17 phenotype, whereas individuals heterozygous for either a TBP(41-46) allele or a STUB1 variant (8 patients) were unaffected. Six more families were found to segregate a STUB1 variant with a TBP(40) allele. In 2 families (43 and 49), 3 affected and 1 unaffected individuals had a STUB1 variant and a TBP(39) allele. No STUB1 variants were found in healthy controls carrying TBP(40-45) alleles. Magri et al. (2022) concluded that SCA17 has a complex inheritance pattern: it is monogenic for TBP repeats equal to or greater than 47, whereas it is digenic for TBP repeats between 40 and 46 when combined with a STUB1 mutation. These data indicated that the presence of a STUB1 mutation is necessary for disease manifestation in subjects carrying a TBP(41-46) intermediate allele, whereas TBP repeats of 47 or greater are sufficient to cause the disease. Heterozygous STUB1 mutations have been associated with SCA48 (618093), which has a similar phenotype to SCA17. Magri et al. (2022) concluded that heterozygous STUB1 variants alone do not cause the disease, casting doubt on the existence of SCA48 as a monogenic disease, and suggesting that digenic SCA17 and SCA48 may be the same disease. These authors noted the implications for genetic counseling.
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.
Martianov et al. (2002) inactivated the murine Tbp gene by targeted disruption. Tbp +/- mice were born in the expected mendelian frequency and were of normal size and weight, displayed no obvious abnormalities, and were fertile. Crossing TBP heterozygote mice failed to generate viable newborn homozygous mutant mice. However, at 3.5 days postcoitum (E3.5), an approximately mendelian ratio of Tbp -/- mice could be detected with PCR. When examined by immunofluorescence for expression of the Tbp protein, blastocysts were detected that were totally negative for Tbp labeling. TBP was absent in explanted blastocysts grown for 1 day in vitro. Strongly reduced Tbp levels were also detected at E2.5 in 8 cell-stage embryos, which indicates that the maternal Tbp pool was significantly depleted at this stage and was undetectable by the blastocyst stage. Blastocysts from Tbp heterozygote crosses were explanted at E3.5 and cultivated in vitro. Approximately 25% of the blastocysts rapidly ceased growth and died, whereas the others hatched from the zona pellucida and continued to develop. After 2 days, extensive apoptosis was observed in the growth-arrested Tbp homozygous mutant embryos. Embryos staining negatively for Tbp were also recovered at E4.5. These embryos typically comprised 30 to 40 cells, fewer than normally seen in wildtype E3.5 blastocysts, indicating that growth arrest occurred before E3.5, just as Tbp levels became undetectable.
Shah et al. (2009) characterized cellular and mouse models expressing polyQ-expanded TBP. The rat PC12 cellular model exhibited characteristic features of neuronal dysfunction, including decreased cell viability and defective neurite outgrowth. The high-affinity nerve growth factor receptor, Trka (NTRK1; 191315), was downregulated by mutant TBP in PC12 cells. Downregulation of Trka also occurred in the cerebellum of SCA17 transgenic mice prior to Purkinje cell degeneration. Mutant TBP bound more Sp1 (189906), reduced its occupancy of the Trka promoter and inhibited the activity of the Trka promoter. Shah et al. (2009) suggested that the transcriptional downregulation of TRKA by mutant TBP may contribute to SCA17 pathogenesis.
Kindreds with olivopontocerebellar atrophy V (OPCA5) were reported by Carter and Sukavajana (1956), Konigsmark and Lipton (1971) and Chandler and Bebin (1956). In addition to cerebellar signs, rigidity and mental deterioration were consistent features. Neuronal loss was observed in the basal ganglia in all cases. Cortical changes correlated with dementia. Carter and Sukavajana (1956) described a father and 5 sons and a daughter (out of a sibship of 19) with a familial form of cerebelloolivary degeneration with late development of rigidity and dementia. Postmortem showed profound cerebellar atrophy with degeneration in the olivary nuclei and substantia nigra.
In cerebelloparenchymal disorder II (CPD2), ataxia and dysarthria develop in the fourth or fifth decades of life. Richter (1940) described 3 affected sibs, and Thorpe (1935) described 2 affected sibs. Autopsies showed absent Purkinje cells but only mild loss of granule cells and dentate neurons. The inferior olivary nuclei and the pons were normal.
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