Spinocerebellar Ataxia Type 17 via the TBP CAG/CAA Repeat Expansion

Spinocerebellar ataxia type 17 (SCA17) is a progressive neurodegenerative disorder characterized by variable atrophy of the cerebellum, cerebrum and brain stem. Clinically, patients typically present with ataxia, parkinsonism, cognitive impairment and/or psychiatric symptoms. As the disease progresses, additional symptoms may be observed, including involuntary movements, facial dyskinesia, limb chorea, dystonia, parkinsonism, dementia, and pyramidal signs (Maltecca et al. 2003. PubMed ID: 14638975; Toyoshima et al. 2012. PubMed ID: 20301611). The mean age of onset for SCA17 is approximately 35 years, but has been reported to range from 3 to 75 years (Toyoshima et al. 2012. PubMed ID: 20301611). Clinically, features can resemble those in other types of hereditary ataxias, as well as Huntington disease. For this reason, SCA17 is sometimes referred to as Huntington disease-like type 4 (HDL4) (Toyoshima et al. 2012. PubMed ID: 20301611). There is currently no known cure for SCA17, and medical management focuses on treatment of clinical manifestations of the disease (Toyoshima et al. 2012. PubMed ID: 20301611). Life expectancy is approximately 20 years after the onset of symptoms (Yang et al. 2016. PubMed ID: 28032013).

SCA17 is an autosomal dominant disorder. The exact prevalence of SCA17 is unknown; however, it is apparently quite rare as fewer than 100 individuals have been reported worldwide (Toyoshima et al. 2012. PubMed ID: 20301611). SCA17 is caused by expansion of a CAG/CAA repeat within the third exon of the TBP gene, which encodes a polyglutamine tract beginning at amino acid residue 58. The structure of the repeat is as follows, with both CAA and CAG encoding the amino acid glutamine:

(CAG)₃ (CAA)₃ (CAG)_x CAA CAG CAA (CAG)_y CAA CAG.

A normal repeat allele is considered to be between 25 to 40 total glutamine repeats, while 49 or more repeats is considered a fully penetrant pathogenic allele. The largest pathogenic repeat reported to date is 66 repeats (Maltecca et al. 2003. PubMed ID: 14638975). Patients with a fully penetrant pathogenic allele are expected to develop symptoms by the age of 50 (Toyoshima et al. 2012. PubMed ID: 20301611). There is some disagreement regarding the effect of mid-range repeat sizes (41 through 48 repeats), although the current consensus is that 41 to 48 repeats may be causative, but exhibit reduced penetrance. Penetrance is estimated at ~50% for 41 through 44 repeats, and greater than 80% for 45 through 48 repeats (Tremolizzo et al. 2011. PubMed ID: 21710129; Toyoshima et al. 2012. PubMed ID: 20301611; Shin et al. 2015. PubMed ID: 26267067; Choubtum et al. 2015. PubMed ID: 26374734). A general genotype-phenotype correlation has been observed between the size of the polyglutamine repeat and the age of onset and severity of disease, with larger repeats associated with earlier onset and more severe presentation (Maltecca et al. 2003. PubMed ID: 14638975; Toyoshima et al. 2012. PubMed ID: 20301611). In homozygous individuals, the age of onset is similar to that observed in heterozygotes, but the disease course has been reported to be more severe and rapidly progressive (Toyoshima et al. 2012. PubMed ID: 20301611).

In most patients reported to date, the CAA CAG CAA interruption is present within the repeat region. The occurrence of this interruption is associated with stable inheritance of the repeat size between generations (Toyoshima et al. 2012. PubMed ID: 20301611). However, in some patients the CAA CAG CAA interruption is absent. In those patients, genetic anticipation has been observed, with a progressively larger repeat size observed in each generation (Maltecca et al. 2003. PubMed ID: 14638975). Please note that with our test methodology, we are not able to determine whether or not the CAA CAG CAA interruption is present.

The TBP gene (6q27) contains 7 coding exons and encodes the ubiquitously expressed TATA box-Binding Protein. TBP is a general transcription factor which is involved in transcription by nuclear RNA polymerases (Toyoshima et al. 2012. PubMed ID: 20301611; Yang et al. 2016. PubMed ID: 28032013).

The sensitivity of this test is expected to be ~100% for individuals with known spinocerebellar ataxia type 17, as the disorder is caused solely by expansion of the CAG/CAA repeat within exon 3 of the TBP gene (Toyoshima et al. 2012. PubMed ID: 20301611).

Clinical sensitivity in patients with a diagnosis of spinocerebellar ataxia (SCA) of an unknown genetic etiology is expected to be lower and to vary depending upon the ethnicity of the patient. For example, in a cohort of 225 ataxic individuals from Italy, only ~1% (2 of 225 patients) were found to have pathogenic expansions in TBP (Brusco et al. 2004. PubMed ID: 15148151). However, ~10% of ataxic patients (8 of 82 patients) in a Thai cohort were found to have pathogenic expansions in TBP (Choubtum et al. 2015. PubMed ID: 26374734).

A combination of amplicon-length analysis and repeat-primed PCR is used as a screening method for the presence or absence of a pathogenic CAG trinucleotide repeat expansion located in the third exon of TBP (Warner et al. 1996. PubMed ID: 9004136; Toyoshima et al. 2012. PubMed ID: 20301611). Two repeat-primed PCR assays, for the 3’ and 5’ ends of the repeat region, as well as amplicon-length analysis, are all used as described for different disorders (DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Jama et al. 2013. PubMed ID: 23414820; Cleary et al. 2016. PubMed ID: 27288208). Test controls include DNA samples from individuals known to have a repeat expansion in TBP in either the pathogenic or intermediate size range, as well as healthy individuals.

This test is designed to only detect pathogenic expansions within the CAG/CAA repeat in exon 3 of the TBP gene. With our test methodology, we are unable to determine if the CAA CAG CAA interruption (see Genetics section for additional details) is present.