Spinocerebellar Ataxia Type 17

Clinical characteristics.

Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. 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. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course.

Diagnosis/testing.

The diagnosis of SCA17 is established in a proband by identification of an abnormal CAG/CAA repeat expansion in TBP. Affected individuals usually have more than 41 repeats. The CAA and CAG codons both encode glutamine residues resulting in a pathogenic polyglutamine expansion.

Management.

Treatment of manifestations: Psychotropic medications for psychiatric problems, antiepileptic drugs for seizures (AEDs); botulinum toxin injections for dystonia; adaptation of the environment to accommodate dementia.

Prevention of secondary complications: Side effects of psychotropic medications and AEDs may require total or intermittent discontinuation of the treatment or reduction in dose.

Surveillance: Annual or semiannual evaluation by a neurologist or more frequently if symptoms are progressing rapidly.

Agents/circumstances to avoid: Sedative/hypnotic agents, such as ethanol or certain medications, may exacerbate incoordination.

Genetic counseling.

SCA17 is inherited in an autosomal dominant manner. Offspring of affected individuals are at a 50% risk of inheriting the expanded TBP allele. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the diagnosis has been established in an affected family member by molecular genetic testing.

Suggestive Findings

Spinocerebellar ataxia type 17 (SCA17) should be suspected in individuals with the following:

• Ataxia
• Dementia
• Involuntary movements – e.g., chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia)
• Psychiatric symptoms

Establishing the Diagnosis

The diagnosis of SCA17 is established in a proband by identification of a heterozygous pathogenic variant of CAG (and sometimes CAA) repeats in TBP by molecular genetic testing (see Table 1). Because both codons CAA and CAG encode glutamine residues, the resulting proteins will have variable tracts of glutamine residues.

Allele sizes. The structure of the repeat sequence in a normal, stably transmitted allele is variable but typically consists of series of CAG repeats interrupted by CAA repeats – e.g., (CAG)₃ (CAA)₃ (CAG)₉ CAA CAG CAA (CAG)₁₆ CAA CAG. Allele size (sometimes expressed as length or number of repeats) is determined by counting all triplet repeats; the total number of CAG/CAA repeats in the example above would be 36, which would translate to 36 contiguous 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 have been reported [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 disorders caused by repeat expansions [Maltecca et al 2003, Zühlke et al 2003b, Zühlke et al 2005].

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Targeted analysis for a heterozygous CAG/CAA repeat number in TBP should be performed first.
• A multigene panel that includes TBP CAG/CAA repeat analysis and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [Cellini et al 2004, Toyoshima et al 2004]. 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 & Takahashi 2018; 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].

Figure 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 2004]. 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.

Genotype-Phenotype Correlations

Heterozygotes

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 2 unreported) (Table 2, Figure 2). As the information reported in the literature was incomplete, the frequencies listed for symptom occurrence 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 symptoms and chorea.

2. . The clinical features in SCA17 depend on the length of CAG/CAA repeats.">

Figure 2.

The clinical features in SCA17 depend on the length of CAG/CAA repeats. The clinical features reported in affected individuals are denoted by letter. For example, A-E denotes affected individuals who have ataxia with parkinsonism. A = ataxia

• CAG/CAA repeat size from 41 to 50. More than 75% of individuals have intellectual deterioration; in some individuals, intellectual problems and involuntary movements are the only signs. Psychiatric symptoms 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 2004].
• CAG/CAA repeat size from 43 to 47. Individuals with an allele of 43-47 repeats tend to have a parkinsonian phenotype [Kim et al 2009, Chen et al 2010].
• CAG/CAA repeat size from 50 to 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 one 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 Spinocerebellar Ataxia Type 17 Correlated with TBP Repeat Size

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CAG/CAA Repeat Size of Allele	Ataxia	Dementia / Psychiatric Symptoms	Increased DTRs	Dystonia	Parkinsonism	Chorea
41-49	85%	85%	50%	6%	32%	35%
≥50	96%	88%	56%	56%	48%	16%

Toyoshima & Takahashi [2018]

DTRs = deep tendon reflexes

Penetrance

The penetrance of alleles of 41-44 repeats is estimated at 50% and the penetrance of alleles of 45-48 repeats is estimated at greater than 80% [Toyoshima et al 2004].

• Individuals with 41 CAA/CAG repeats developed ataxia and mild dementia [Nanda et al 2007, Doherty et al 2014]. Two individuals who had 41 repeats developed parkinsonism and chorea [Herrema et al 2014, Park et al 2016]. One individual with 41 repeats developed late-onset chorea and psychiatric symptoms [Alibardi et al 2014].
• Four individuals with 42 CAG/CAA repeats developed a relatively benign phenotype consisting of mild gait ataxia, dysarthria, and dysdiadochokinesia [Nolte et al 2010].
• An individual with 43 CAG/CAA repeats developed ataxia with dementia at age 52 years [Silveira et al 2002]; six individuals diagnosed with parkinsonism were found to have 43 CAG/CAA repeats [Kim et al 2009]. An individual with 43 repeats developed severe dementia [Nielsen et al 2012].
• An individual with 46 CAG/CAA repeats developed symptoms at age 75 years, the latest onset observed to date [Wu et al 2005].
• Asymptomatic elderly individuals with 43-49 CAG/CAA repeats have also been reported [Nakamura et al 2001, Zühlke et al 2003a, Oda et al 2004, Zühlke et al 2005, Mariotti et al 2007].

Age of onset. The correlation between the size of the CAG/CAA repeat and the age of onset in SCA17 (Figure 3) is not as strong as in other disorders (SCA1, SCA2, SCA3, SCA6, SCA7, Huntington disease, DRPLA, SBMA]) caused by expansion of a polyglutamine tract [Rolfs et al 2003, Toyoshima et al 2004,Toyoshima & Takahashi 2018].

Figure 3.

Correlation between age at onset and length of CAG/CAA repeat in individuals with SCA17 For references, see Penetrance, Age of onset.

Nomenclature

Bauer et al [2004] reported nine individuals with TBP alleles larger than 45 CAG/CAA repeats among 1,712 individuals with Huntington disease-like 2, and observed that CAG/CAA repeat expansions in TBP represented a more common monogenic cause for a Huntington disease-like phenotype than Huntington disease-like 1 [Xiang et al 1998] or Huntington disease-like 2 [Margolis et al 2001]. Therefore, SCA17 is also referred to as Huntington disease-like 4 [Stevanin et al 2003, Schneider et al 2007, Harbo et al 2009].

Anticipation

Instability of the TBP CAG repeat in germline transmission is not clear in SCA17 [Fujigasaki et al 2001, Nakamura et al 2001, Shatunov et al 2004]. CAG repeats in TBP have two distinct configurations, which are differentiated by the absence or presence of CAA trinucleotide repeat interruptions. The basic structure of the allele is (CAG)₃ (CAA)₃ (CAG)_x CAA CAG CAA (CAG)_y CAA CAG. If the basic structure is broken (i.e., CAA repeat interruptions are absent), repeat stability may be reduced. In German and Italian families, an absence of CAA interruptions resulting in longer pure tracts of CAG repeats was detected. It is of note that intergenerational instability and anticipation were documented in these families [Zühlke et al 2001, Maltecca et al 2003]. It has been proposed that CAA interruptions may serve as a limiting element for further expansion of CAG repeats in TBP [Gao et al 2008].

The phenomenon termed anticipation, a trend toward an earlier age at onset and more severe disease manifestations in offspring of an affected individual, is infrequently documented in families with SCA17. In addition, because of low penetrance of the intermediate alleles (41-48 repeats), the age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by family history or size of expansion.

Prevalence

Fewer than 100 families with SCA17 have been reported.

The prevalence of SCA17 in the Japanese population is estimated at 0.47:1,000,000. SCA17 accounts for approximately 0.3% of autosomal dominant SCA [Maruyama et al 2002].

The minimum prevalence of SCA17 in northeast England is 0.16:100,000 [Craig et al 2005].

In a study of the Yugoslav population, none of the 115 individuals with autosomal dominant cerebellar ataxia or simplex cases of adult-onset ataxia had SCA17 [Alendar et al 2004].

The prevalence of SCA17 may be underestimated because some individuals with SCA17 have a phenotype similar to that of Huntington disease.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
• Brain MRI to evaluate areas and degree of atrophy
• Neurology consultation, if not completed prior to initial diagnosis
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Secondary Complications

The side effects of psychotropic medications and AEDs (e.g., depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia) 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.

Surveillance

Affected 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 2004].

Agents/Circumstances to Avoid

Agents with sedative/hypnotic properties, such as ethanol or certain medications, may markedly increase incoordination.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.