Spinocerebellar Ataxia Type 8

Clinical characteristics.

SCA8 is a slowly progressive ataxia with disease onset typically occurring in adulthood. Onset ranges from age one to 73 years. The progression is typically over decades regardless of the age of onset. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability; life span is typically not shortened. Some individuals present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperreflexity and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened.

Diagnosis/testing.

The SCA8 phenotype is caused by an expansion involving two overlapping genes, ATXN8OS and ATXN8.

The diagnosis of SCA8 is confirmed by the presence of a (CTG)_n trinucleotide repeat expansion in ATXN8OS (formerly known as SCA8). The pathogenic (CTG)_n repeat is adjacent to a non-pathogenic but highly polymorphic, stably transmitted (CTA)_n repeat, which makes it technically difficult to determine the precise number of pathogenic (CTG)_n repeats. Therefore, the current reference ranges are based on the total number of both the (CTA)_n and (CTG)_n repeats. Normal alleles have 15 to 50 repeats. The repeat lengths most often associated with ataxia range from 80 to 250; however, repeat lengths ranging from 71 to more than 1300 have been found in some individuals with ataxia. Although reduced penetrance is observed for alleles of all repeat lengths, it is most often observed with alleles of fewer than 100 repeats.

The pathogenesis of SCA8 also involves a (CAG)_n repeat in ATXN8.

Management.

Treatment of manifestations: Canes and walkers to help prevent falls; modification of the home (e.g., grab bars, raised toilet seats, ramps for motorized chairs) as needed; speech therapy and communication devices for those with dysarthria; weighted eating utensils and dressing hooks to maintain some independence; feeding evaluations to reduce risk of aspiration from dysphagia; physical activity to maintain muscular and cardiopulmonary conditioning.

Prevention of secondary complications: Vitamin supplements if caloric intake is reduced.

Surveillance: Routine follow up with a neurologist.

Agents/circumstances to avoid: Alcohol can exacerbate incoordination.

Other: Tremor-controlling drugs do not work well.

Genetic counseling.

The ATXN8OS (CTA)_n(CTG)_n composite repeat expansion is transmitted in an autosomal dominant manner with reduced penetrance. To date, all affected individuals whose parents have been evaluated with molecular genetic testing have one parent with an ATXN8OS (CTA)_n(CTG)_n expanded allele; de novo expansion has not been reported. The (CTG)_n component of the (CTA)_n(CTG)_n composite repeat is highly unstable and almost always expands on maternal transmission. When paternally transmitted, the (CTG)_n repeat tract almost always contracts in length, usually to a length below 100 combined (CTA)_n(CTG)_n repeats. Each child of an individual with an ATXN8OS expanded allele has a 50% chance of inheriting the expanded allele. Although individuals with expansions of >50 combined repeats are at risk of developing ataxia sometime during their life span, the reduced penetrance of the disease means that the presence of an SCA8-related expansion cannot be used to predict whether offspring will ever develop symptoms of SCA8. Prenatal testing for pregnancies at 50% risk for SCA8 is possible.

Clinical Diagnosis

SCA8 is suspected [Day et al 2000] in individuals with the following:

• Principally cerebellar ataxia
• Slowly progressing ataxia
• Scanning dysarthria characterized by a drawn-out slowness of speech
• Marked truncal instability
• Hyperactive tendon reflexes
• Family history of ataxia consistent with single occurrence in the family or either an autosomal recessive or autosomal dominant pattern of inheritance.
  Note: Because of the reduced penetrance, a single occurrence in a family is the most common presentation of the disease.

The spinocerebellar ataxias share many clinical symptoms in common and the diagnosis of SCA8 must be confirmed by molecular genetic testing.

Molecular Genetic Testing

Gene. The expansion associated with the SCA8 phenotype involves two overlapping genes, ATXN8OS and ATXN8 [Moseley et al 2006]:

• In the CTG direction, ATXN8OS (formerly known as SCA8) expresses transcripts containing the CUG expansion.
• In the CAG direction, ATXN8 expresses the transcripts that encode a nearly pure polyglutamine expansion protein plus a polyalanine expansion protein expressed by repeat-associated non-ATG (RAN) translation [Zu et al 2011].

The expansion associated with the SCA8 phenotype is located in both the 3' untranslated region of ATXN8OS and a short polyglutamine ORF in the more recently identified overlapping gene ATXN8 [Moseley et al 2006]. The CTG·CAG repeat is adjacent to a CTA·TAG repeat that is highly polymorphic but stable when transmitted from one generation to the next [Koob et al 1999, Moseley et al 2000c].

The reduced penetrance of CTG·CAG and the presence of the polymorphic CTA·TAG repeat have made it difficult to determine the pathogenic size range of the CTG·CAG repeat.

Allele sizes

• Normal alleles: 15 to 50 combined (CTA·TAG)_n(CTG·CAG)_n repeats
• Alleles of questionable significance: It is not yet clear whether repeat sizes ranging from 50 to 70 repeats can be pathogenic.
• Reduced penetrance allele size: Reduced penetrance is found for (CTA·TAG)_n(CTG·CAG)_n repeats of all sizes [Ranum et al 1999].
• Higher penetrance allele size: 80 to 250 (CTA·TAG)_n(CTG·CAG)_n repeats are most often seen in individuals with ataxia; however, repeat sizes ranging from 71 to more than 1300 repeats have been found both in individuals who develop ataxia and in those who do not.

Clinical testing

• Targeted analysis for pathogenic variants. Although it is the (CTG·CAG)_n portion of the repeat tract that expands in affected individuals, the current method of detection measures (and the reference range is based on) the combined (CTA·TAG)_n(CTG·CAG)_n repeat total. For smaller allele sizes (expansions <200 repeats), the pathogenic variant can be detected by PCR. For larger expansions (>200 combined (CTA·TAG)_n(CTG·CAG)_n CAG repeats), Southern analysis is needed to reliably detect expansions.

Testing Strategy To Confirm/Establish the Diagnosis in a Proband

Single-gene testing. One strategy for molecular diagnosis of a proband suspected of having SCA8 is analysis of ATXN8OS/ATXN8:

• PCR can be used as a first screen for an ATXN8OS/ATXN8 pathogenic variant. If a person has two normal alleles of different sizes, SCA8 can be ruled out. PCR can also detect small (<250-repeat) expansions.
• If PCR analysis fails to detect an expansion, and the PCR results indicate that the individual apparently has two alleles of the same size, Southern analysis should be performed to determine if an expansion that failed to be amplified by PCR is present.

Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having SCA8 is use of a multigene panel that includes analysis of the other genes associated with disorders of similar phenotype (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (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

SCA8 is a slowly progressive ataxia with disease onset typically in adulthood. Onset has been reported from age one to 73 years [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000, Silveira et al 2000, Felling & Barron 2005, Maschke et al 2005]. The progression is typically over decades regardless of the age of onset. Common initial symptoms reported are dysarthria and gait instability; life span is typically not shortened [Day et al 2000, Juvonen et al 2000].

Clinical symptoms observed in most individuals with the SCA8 form of ataxia are dysarthria and clumsiness of gait and limb movements [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000, Cellini et al 2001, Brusco et al 2002, Tazón et al 2002, Topisirovic et al 2002, Mosemiller et al 2003, Schöls et al 2003, Zeman et al 2004, Lilja et al 2005]. One distinguishing feature of SCA8 is scanning dysarthria with a characteristic drawn-out slowness of speech. At an early stage, speech can be disproportionately affected relative to other cerebellar signs. Ataxic symptoms of the lower extremities appear to be more pronounced than those of upper extremities. Severe truncal titubation that advances with disease progression is characteristic. Some individuals with SCA8 present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperactivity and extensor plantar responses are present in some severely affected individuals [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000].

Cognitive impairment, found in 40% of affected individuals of Finnish heritage, has not been observed in other populations [Juvonen et al 2000, Stone et al 2001, Zeman et al 2004, Baba et al 2005, Lilja et al 2005].

Atypical clinical features identified in individuals heterozygous for an ATXN8OS/ATXN8 expansion include parkinsonism, multiple-system atrophy, severe childhood onset, oramandibular dystonia, dysphagia, respiratory muscle weakness, seizure-like episodes [Baba et al 2005, Factor et al 2005, Felling & Barron 2005, Munhoz et al 2006, Gupta & Jankovic 2009, Ushe & Perlmutter 2012, Kim et al 2013]. The causative relationship between the ATXN8OS/ATXN8 expansion and these other conditions remains unknown, given the relatively high frequency of the ATXN8OS/ATXN8 expansion in the general population and the reduced penetrance of the disease.

Neuroimaging. MRI and CT have consistently shown cerebellar atrophy, specifically in the cerebellar hemisphere and vermis in individuals with SCA8 [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000, Cellini et al 2001, Brusco et al 2002, Tazón et al 2002, Topisirovic et al 2002, Schöls et al 2003, Zeman et al 2004, Lilja et al 2005]. In one individual in whom serial MRI scans were performed nine years apart, little progression was seen in the cerebellar atrophy [Day et al 2000]. Mild cerebellar atrophy was observed in an asymptomatic male age 71 years with an ATXN8OS/ATXN8 expansion [Ikeda et al 2000b].

Genotype-Phenotype Correlations

Although there is a correlation between repeat number and penetrance in some families [Koob et al 1999, Day et al 2000], longer alleles in the size range from 50 to 250 CTA/CTG repeats are more often found in affected individuals than in unaffected relatives (p<0.001).

No correlation between the size of the expansion and age of onset or disease severity was observed [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000].

The clinical presentation in the two individuals from the MN-A family homozygous for the ATXN8OS/ATXN8 expansion did not differ in severity from the clinical presentation in sibs heterozygous for the ATXN8OS/ATXN8 expansion [Day et al 2000].

Individuals homozygous for the ATXN8OS/ATXN8 expansion have been reported more frequently than for other forms of spinocerebellar ataxia caused by similar expansions [Koob et al 1999, Day et al 2000, Stevanin et al 2000, Tazón et al 2002, Izumi et al 2003, Schöls et al 2003, Brusco et al 2004, Corral et al 2005, Juvonen et al 2005]. The ages at onset in most individuals homozygous for an ATXN8OS/ATXN8 expansion were not obviously accelerated compared to the ages of onset of individuals heterozygous for an ATXN8OS/ATXN8 expansion.

Penetrance

In the large family (MN-A) originally reported to have SCA8 (Lod 6.8 at ϴ:0.00), affected individuals have longer CTG·CAG repeat tracts (mean: 117) than the 21 asymptomatic individuals with a CTG·CAG repeat expansion (mean: 92; p<10^-6). These results indicate that repeat length plays a role in disease penetrance [Koob et al 1999, Day et al 2000]. Further analysis of other families showed that the pathogenic range can vary among families and that a positive test for an ATXN8OS/ATXN8 expansion, regardless of the repeat size, cannot be used to predict whether an asymptomatic individual will develop ataxia [Ranum et al 1999, Moseley et al 2000c, Worth et al 2000, Ikeda et al 2004].

The molecular basis for the reduced penetrance is not yet fully understood; however, the following features of SCA8 may play a role in reduced penetrance.

• The polymorphic CTA·TAG repeat. The CTA·TAG repeat, which is adjacent to the CTG·CAG repeat, remains stable during transmission; however, the CTA·TAG repeat varies among families, ranging in size from one to 21 repeats [Koob et al 1999, Moseley et al 2000c, Stevanin et al 2000]. Because the PCR assay measures the length of both repeats, the polymorphic CTA·TAG may account for some of the apparent interfamilial differences in affected allele size ranges and reduced penetrance of the pathogenic variant.
• Interruptions within the CTG·CAG expansion. Interruptions within the CTG·CAG expansion by one or more CCG·CGG, CTA·TAG, CTC·GAG, CCA·TGG, or CTT·AAG trinucleotides have also been observed in full-penetrance alleles [Moseley et al 2000c]. Surprisingly, these interruptions can duplicate when transmitted from one generation to the next. Individuals with the SCA8 form of ataxia have been shown to have both pure CTG·CAG tracts and tracts with interruptions. Most normal-length alleles do not have interrupted CTG·CAG repeat tracts, although one normal allele (23 combined repeats) with an interruption in the CTG·CAG portion of the repeat tract has been reported [Sobrido et al 2001]. The potential influence of the interruptions on the development of ataxia is not yet clear [Moseley et al 2000c, Mosemiller et al 2003].
• Intergenerational size changes. The ATXN8OS/ATXN8 expansion is unstable and almost always changes in size when transmitted from generation to generation. A maternal penetrance bias for disease transmission that occurs in some families appears to be related to the maternal expansion bias of the CTG·CAG repeat tract (-11 to +900) [Koob et al 1999, Ranum et al 1999, Day et al 2000, Corral et al 2005]. In contrast, a bias for contraction (-86 to +7) of the CTG·CAG repeat is observed with paternal transmission [Koob et al 1999, Ranum et al 1999]. In sperm from males with SCA8, nearly all of the expanded alleles contract, resulting in tracts that usually contain fewer than 100 combined repeats [Moseley et al 2000c]. It is likely that these dramatic repeat contractions in sperm play a role in the reduced penetrance of paternal transmissions. In summary, intergenerational changes in repeat size appear to play a role in the reduced penetrance of SCA8, with ataxia more likely to result from the larger maternally transmitted repeat tracts than from smaller paternally transmitted expansions.

Anticipation

Maternal transmission. The CTG·CAG expansion is more likely to become larger when maternally transmitted. Therefore, individuals who inherit the expansion from their mothers may be at a greater risk of developing ataxia because their allele sizes tend to be larger and, at least in some families, in a more penetrant size range. It should be pointed out, however, that all expansion sizes show reduced penetrance; thus, repeat length cannot be used to predict whether an individual will or will not develop disease.

Paternal transmission. The CTG·CAG expansion is more likely to contract with paternal transmission, usually resulting in smaller alleles that may fall into less penetrant size ranges. Therefore, individuals who inherit the expansion from their fathers, at least in some families, are at a lower risk of developing ataxia. However, all expansion sizes show reduced penetrance; thus, repeat length cannot be used to predict whether an individual will or will not develop disease.

Prevalence

Epidemiologic studies of the frequency of the ATXN8OS/ATXN8 expansion have not been performed, but estimates of the prevalence of ATXN8OS/ATXN8 expansions in various control groups suggest that the prevalence of ATXN8OS/ATXN8 expansions larger than 50 combined repeats ranges from approximately 1:100 to 1:1200 chromosomes in various ethnic populations [Koob et al 1999, Ikeda et al 2000a, Juvonen et al 2000, Vincent et al 2000a, Sułek et al 2004, Zeman et al 2004]. (See Molecular Genetics).

The prevalence of the expansion and the SCA8 form of ataxia may be especially common in Finland [Juvonen et al 2000, Juvonen et al 2005].

The SCA8 form of ataxia is thought to account for 2%-5% of autosomal dominant forms of inherited ataxia. The prevalence of the disease is far lower than the prevalence of abnormal ATXN8OS/ATXN8 expansions because of the reduced penetrance of the expanded allele. Most of the expansions found in control groups are either in repeat ranges that are less penetrant or at the lower end of the expansion range (50-100 combined repeats), or are very large expansions (>500 repeats) [Ikeda et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8), the following evaluations are recommended:

• Neurologic assessment, including neuroimaging (brain MRI or CT)
• Assessment of the family pedigree and the disease course in other affected family members to aid in establishing a clinical prognosis
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Use of canes and walkers helps 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, communication devices such as writing pads, and computer-based devices may benefit those with dysarthria.

Weighted eating utensils and dressing hooks help maintain some degree of independence.

When dysphagia becomes troublesome, a video esophagram can identify the consistency of food least likely to trigger aspiration.

Although neither exercise nor physical therapy has been shown to stem the progression of incoordination, individuals with SCA8 should try to remain active in order to maintain their muscular and cardiopulmonary conditioning.

Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

Prevention of Primary Manifestations

Management of affected individuals remains supportive, as there is no known therapy to delay or halt the progression of the disease.

Prevention of Secondary Complications

No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.

Surveillance

Affected individuals should regularly visit a neurologist familiar with the ataxia syndromes to identify potential complications that develop over time and to manage clinical challenges associated with decreased mobility and exercise or difficulties with speech and swallowing.

Agents/Circumstances to Avoid

Alcohol should be avoided because it can exacerbate problems with incoordination.

Affected individuals should get plenty of rest; symptoms are often aggravated by fatigue.

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 www.ClinicalTrialsRegister.eu in Europe 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.

Other

Tremor-controlling drugs do not work well for cerebellar tremors.