Spinocerebellar Ataxia Type 1

Clinical characteristics.

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy.

Diagnosis/testing.

The diagnosis of SCA1 rests on the result of molecular genetic testing to detect an abnormal CAG trinucleotide expansion in ATXN1. Affected individuals have alleles with 39 or more CAG trinucleotide repeats. Such testing detects 100% of cases.

Management.

Treatment of manifestations: Canes and walkers to help prevent falls; modification of the home with grab bars, raised toilet seats, and ramps for motorized chairs; speech therapy and communication devices for dysarthria; weighted eating utensils and dressing hooks to help maintain independence. Intensive rehabilitation (coordinative physiotherapy) may be beneficial. Weight control is important because obesity can exacerbate difficulties with ambulation and mobility. Video esophagram can help to identify the consistency of food least likely to trigger aspiration and feeding devices may be indicated when dysphagia becomes troublesome.

Prevention of secondary complications: Medications may help symptomatic secondary problems such as spasticity, bladder urgency, depression, and pain; vitamin supplements are recommended if caloric intake is reduced.

Surveillance: Neurologic evaluation every three to six months.

Agents/circumstances to avoid: Alcohol, medications known to cause nerve damage (e.g., isoniazid). Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should be avoided.

Genetic counseling.

SCA1 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the expanded allele. Prenatal diagnosis for at-risk pregnancies is possible if the diagnosis has been confirmed by molecular genetic testing in an affected relative; however, requests for prenatal testing of typically adult-onset diseases are not common.

Suggestive Findings

Spinocerebellar ataxia type 1 (SCA1) should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Progressive cerebellar ataxia
• Dysarthria
• Eventual deterioration of bulbar functions

Family history of similarly affected individuals

• In individuals who have (a) symptoms consistent with SCA1 and (b) a first- or second-degree relative with molecularly proven SCA1, the diagnosis is strongly suspected; however, molecular genetic testing of the symptomatic individual for confirmation of the diagnosis is still recommended.
• Absence of a family history of similarly affected individuals does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SCA1 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide expansion in ATXN1 by molecular genetic testing (see Table 1).

Allele sizes

• Normal alleles
  • 6-35 CAG repeats [Quan et al 1995, Servadio et al 1995, Goldfarb et al 1996]. These normal alleles have been found to have CAT trinucleotide repeat interruption(s) and are considered non-mutable.
  • 36-44 CAG repeats. Pathogenicity of alleles in the 36 to 44 range depends on the presence or absence of CAT trinucleotide repeats that interrupt the CAG repeats. Alleles in the 36 to 44 CAG repeat range are considered normal if they have CAT interruptions; if they do not, they may be in the mutable normal (36-38 CAG repeats) or full-penetrance (>39 CAG repeats) range.
• Mutable normal (intermediate) alleles. 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms, but can expand into the abnormal range on transmission to offspring.
• Reduced-penetrance alleles. A woman with 44 CAG repeats with CAT repeat interruptions had an affected father but was herself asymptomatic at age 66 years [Goldfarb et al 1996]; thus, she may be an example of reduced penetrance.
• Full-penetrance alleles
  • 39-44 CAG-repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and likely to be associated with symptoms [Orr et al 1993, Quan et al 1995, Goldfarb et al 1996, Zühlke et al 2002, Sequeiros et al 2010b]. However, there is an inverse correlation between the size of the expansion and the age at onset.
  • 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62 CAG-repeat allele with 51 uninterrupted CAGs) have been reported [Menon et al 2013].
  • Complex alleles may occur; one individual with symptomatic SCA1 with a 58 CAG-repeat sequence interrupted by two CAT repeats has been reported [Matsuyama et al 1999]; however, this person had an uninterrupted 45 CAT-repeat stretch. More recently additional pathogenic interrupted alleles have been described [Menon et al 2013]. In the case of such interrupted alleles, correlation with age at onset may be more appropriate if the uninterrupted CAG stretch alone is considered. While interrupted alleles that included a stretch of ≥45 uninterrupted CAGs may have caused the disease, further studies are needed to determine the precise minimum number of uninterrupted CAGs associated with pathogenicity.

The European Molecular Genetics Quality Network (EMQN) has published best practice guidelines for the genetic testing of the spinocerebellar ataxias including SCA1 [Sequeiros et al 2010a, Sequeiros et al 2010b]. See full text. The guidelines improve the accuracy of genetic testing, although the exact number of repeat units may still vary [Ramos et al 2016].

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

• Single-gene testing. Targeted analysis for the heterozygous CAG repeat number in ATXN1 should be performed first.
• A multigene panel that includes ATXN1 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 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

Spinocerebellar ataxia type 1 (SCA1) is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions [Orr & Zoghbi 2007, Matilla-Dueñas et al 2008, Donato et al 2012]. Onset is typically in the third or fourth decade, although early onset in childhood has been documented [Currier et al 1972, Zoghbi et al 1988, Schöls et al 1997]. In adult-onset SCA1, the duration of illness from onset to death ranges from ten to 30 years; individuals with juvenile-onset disease (whose symptoms appear before age 13 years) show more rapid progression and more severe disease, and die before age 16 years [Zoghbi et al 1988].

Large-scale natural history studies of some of the common SCAs (including SCA1) using validated neurologic rating scales and timed measures of motor function have been in progress in many countries. The annual increase in the scale for assessment and rating of ataxia (SARA) score for SCA1, SCA2, SCA3, and SCA6 combined in a one-year follow-up study was 1.38±0.37; the SARA score quantifies various aspects of appendicular and limb ataxia; a score of 40 indicates maximum dysfunction [Schmitz-Hübsch et al 2010]. SCA1 appears to have a faster progression (2.18±0.17 points per year, based on SARA) than SCA2 and SCA3 (1.40±0.11 and 1.61±0.12 respectively), an observation that has been reproduced by studies in the US [Jacobi et al 2011, Ashizawa et al 2013, Jacobi et al 2015].

The majority of affected individuals initially present with difficulties in gait; slurred speech is also common. They may first notice problems of balance in going down stairs or making sudden turns; athletic individuals may notice difficulties at an earlier stage of disease in the course of activities that require a high degree of control, such as skiing or dancing.

Affected individuals may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus in the early stages of disease [Matilla-Dueñas et al 2008, Donato et al 2012]. Mild dysphagia, indicated by choking on food and drink, may also occur early in the disease.

As the disease progresses the saccadic velocity slows and an up-gaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities.

As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.

Optic nerve atrophy and variable degrees of ophthalmoparesis may be detected in some individuals. Occult or clinically significant maculopathy has been noted in some individuals with SCA1 [Lebranchu et al 2013, Vaclavik et al 2013].

Muscle atrophy, decreased or absent deep tendon reflexes, and loss of proprioception or vibration sense may occur in the middle or late stages of the disease [van de Warrenburg et al 2004]. Sensorimotor, mixed (i.e., axonal and demyelinating) polyneuropathy occurs in 82% of individuals with SCA1 [Linnemann et al 2016].

Non-ataxia signs measured by the Inventory of Non-Ataxia Signs (INAS) increased in number with time and correlated with the CAG repeat size until the increase reached a plateau [Schmitz-Hübsch et al 2008, Schmitz-Hübsch et al 2010, Jacobi et al 2011, Jacobi et al 2015]. Extrapyramidal signs were found in 37.5% of persons with SCA1 (less common than in those with SCA2 and SCA3), and included staring look (53.3%), dystonia and bradykinesia (33.3% for each), and postural tremor (26.7%) [Jhunjhunwala et al 2014].

Individuals with SCA1 experience impaired executive function, speed, attention, and theory of mind. The cognitive spectrum is broader and cognitive decline more rapid in individuals with SCA1 than in those with SCA2, SCA3, or SCA6 [Klinke et al 2010, Fancellu et al 2013, Ma et al 2014, Moriarty et al 2016].

Bulbar dysfunction (atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia leading to frequent aspiration) become prominent in the final stages of the disease [Shiojiri et al 1999]. Affected individuals eventually develop respiratory failure, which is the main cause of death.

Individuals with SCA1 who have gait ataxia as the initial manifestation (comprising 2/3 of affected individuals [Globas et al 2008]) typically have slower disease progression than those whose initial manifestations did not include gait ataxia [Luo et al 2017].

Juvenile-onset SCA1 is characterized by severe brain stem dysfunction in addition to cerebellar symptoms. The brain stem dysfunction occurs rapidly, leading to death within four to eight years of symptom onset.

Electrophysiologic studies. Persons with SCA1 often show abnormal nerve conduction [Schöls et al 2008] in addition to abnormal visual evoked potentials (41%), median somatosensory evoked potentials (41%), and brain stem auditory evoked response (73%) [Chandran et al 2014].

Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1. Oculomotor recordings reveal eye movement abnormalities in a quantitative fashion.

Neuroimaging. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain reveal pontocerebellar atrophy [Döhlinger et al 2008]. Although MRI can provide better imaging of the posterior fossa than CT and quantitative MRI studies have documented minor motor dysfunction and loss of cerebellar and brain stem gray matter in presymptomatic persons with SCA1 [Jacobi et al 2013], conventional MRI has limited sensitivity at the presymptomatic stage [Mascalchi et al 1998, Ragno et al 2005].

Voxel-based morphometry show volume loss in cerebellum and brain stem involving both gray and white matter [Guerrini et al 2004, Ginestroni et al 2008, Goel et al 2011]. Spinal cord atrophy may also be seen [Pedroso & Barsottini 2013].

Regional damage to white matter in individuals with SCA1 has been repeatedly demonstrated by diffusion tensor imaging [Mandelli et al 2007, Della Nave et al 2008, Prakash et al 2009, Guimarães et al 2013].

While positron emission tomography studies have demonstrated hypometabolism in presymptomatic individuals with an ATXN1 trinucleotide expansion, measurements of metabolites such as N-acetylaspartate and myoinositol by MR spectroscopy revealed evidence of neuronal loss in the cerebellum, pons, and even the supratenotorial structures [Oz et al 2010, Emir et al 2013].

Minor motor dysfunction and loss of cerebellar and brain stem gray matter by quantitative imaging studies have been documented in presymptomatic persons known to have an ATXN1 trinucleotide expansion [Jacobi et al 2013].

Neuropathology. Neuropathologic studies reveal cerebellum and brain stem atrophy [Schut & Haymaker 1951, Robitaille et al 1997]. In the cerebellum, the Purkinje cells are severely depleted and the vermis may be maximally affected; the flocculonodular lobe is relatively spared [Robitaille et al 1997]. There is some loss of dentate neurons, some of which may show "grumose" degeneration [Yamada et al 2008]. Granule cells are moderately lost and torpedos may be seen [Genis et al 1995]. Calbindin immuncytochemistry reveals reduced dendritic arbors [Genis et al 1995]. Brain stem shows loss of basis pontis neurons and olivary neurons. There is loss of afferent fibers in middle and inferior cerebellar peduncles leading to loss of myelin stain reactivity, as well as neuronal loss in the oculomotor nuclei and the ninth and tenth cranial nerve nuclei. The spinal cord shows loss of anterior horn cells and neurons from the Clarke's column, and there is loss of fibers in the posterior column.

Systematic studies have shown that SCA1 neuropathology can involve components of the cerebello-thalamocortical loop, the basal ganglia-thalamocortical loop, the visual system, the nuclei of the auditory system, the somatosensory system at many levels, the vestibular nuclei, both infranuclear and supranuclear oculomotor neurons, several brain stem nuclei, the midbrain dopaminergic system, and the basal forebrain and midbrain cholinergic systems [Rüb et al 2013].

Genotype-Phenotype Correlations

Probands. A strong correlation exists between the number of CAG repeats and severity of disease: the larger the CAG repeat, the earlier the onset and more severe the disease. However, the correlation is broad: only 36% to 70% of age-at-onset variance can be explained by CAG repeat size [Orr et al 1993, Schöls et al 1997, Stevanin et al 2000, Globas et al 2008, Ashizawa et al 2013]. Routine testing does not determine the presence of interruptions if the expansion is longer than 44 repeats; however, the presence of interruptions in such alleles delays the age at onset beyond that predicted by the total repeat size [Menon et al 2013]. In a large European study of 317 individuals with SCA1, the size of both the expanded and normal alleles were significant determinants in the prediction of the age at onset of symptoms [Tezenas du Montcel et al 2014].

The largest expansions of the CAG repeat tract are found in individuals with infantile- or juvenile-onset SCA1, who typically experience more rapid disease progression and are most commonly the offspring of affected males.

Some clinical signs (facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis) are more common with larger repeat size, independent of disease duration.

Affected individuals with more than 52 CAG repeats tend to become significantly disabled five years after the onset of disease.

Individuals who have biallelic pathogenic ATXN1 alleles do not appear to develop disease that is more severe than what can be predicted by the larger of their two alleles.

At-risk individuals. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by family history or results of molecular genetic testing.

Progression rate. Longer repeat expansions were associated with faster progression (0.06 ± 0.02 SARA total score unit per additional repeat unit; p=0.0128) [Jacobi et al 2015].

Penetrance

Penetrance is considered to be greater than 95%, but is age dependent. Onset after age 60 years has occasionally been reported [Sasaki et al 1996, van de Warrenburg et al 2004].

Anticipation

Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1 [Schut 1950, Zoghbi et al 1988]. The tendency of the ATXN1 CAG repeat to expand as it is transmitted provides a biologic explanation for the earlier age of onset in subsequent generations. Expansions are more likely to occur when the pathogenic ATXN1 allele is paternally transmitted, and contractions are more typical of maternal transmissions [Chung et al 1993, Matilla et al 1993, Jodice et al 1994].

Nomenclature

The nomenclature for the autosomal dominant hereditary ataxias has varied over the years. Terms no longer used to refer to SCA1 include Marie's ataxia, atypical Friedreich's ataxia, and olivopontocerebellar atrophy.

Prevalence

Approximately one to two individuals in 100,000 develop SCA1.

Worldwide SCA1 represents approximately 6% of individuals with autosomal dominant cerebellar ataxia; this figure varies considerably based on geographic location and ethnic background [Schöls et al 2004]. For example, SCA1 represented 6% of autosomal dominant ataxia in a North American study [Moseley et al 1998]. In other studies worldwide the prevalence of SCA1 (as a % of AD cerebellar ataxia) was as follows (see also Ataxia Overview):

• Essentially 100% in Eastern Siberia [Platonov et al 2016]
• 68% in Poland [Krysa et al 2016]
• 34% in Serbia [Dragasević et al 2006]
• 25% in Japan [Onodera et al 2000]
• 22% in India [Mittal et al 2005]
• No cases in Korea [Jin et al 1999]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual with molecularly confirmed spinocerebellar ataxia type 1 (SCA1), the following evaluations are recommended if they have not already been completed:

• Neurologic examination
• Video esophagram in those with dysphagia to determine the consistency of food that is least likely to trigger aspiration
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of individuals with SCA1 remains supportive, as no known therapy to delay or halt the progression of the disease exists. Affected persons should be followed by a neurologist with consultation from physiatrists, physical and occupational therapists, and other specialists as needed.

Studies have shown that intensive rehabilitation (or coordinative physiotherapy) improves motor function in a heterogeneous group of individuals with various types of cerebellar degeneration [Ilg et al 2009, Ilg et al 2010, Miyai et al 2012]. Although these studies did not include individuals with SCA1, intensive coordinative training may be recommended for persons with SCA1 because of symptom improvement with limited adverse events. However, further studies that include individuals with SCA1 will need to be performed to determine the efficacy of such training.

Canes and walkers help 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 and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.

Weighted eating utensils and dressing hooks help maintain a sense of independence.

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

Repeated aspiration or significant weight loss may point to the need for a feeding device in some.

Prevention of Primary Manifestations

See Therapies Under Investigation.

Prevention of Secondary Complications

Certain manifestations indirectly related to the disease such as spasticity, depression, and pain may require appropriate pharmacotherapy.

Vitamin supplements are recommended, particularly if caloric intake is reduced.

Surveillance

Neurologic evaluation every three to six months is appropriate

Agents/Circumstances to Avoid

Affected individuals should avoid alcohol as well as medications known to be neurotoxic such as those that cause neuropathy (e.g., isoniazid, large-dose vitamin B₆) or those associated with central nervous system toxicity (e.g., diphenylhydantoin). Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should be avoided.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Lithium [Watase et al 2007] and insulin-like growth factor 1 [Vig et al 2006] have improved neurologic function in a mouse model of SCA1; no human trials with insulin-like growth factor 1 have been done to date. Metabolomics data using the mouse model of SCA1 showed that lithium restores purine metabolism in the cerebellum [Perroud et al 2013]. A human Phase I trial of oral lithium has been completed as an intramural NIH study; results have not been published (NCT00683943). A similar trial for SCA2 did not lead to any significant difference in the SARA score, but was well tolerated and did lead to a reduction in the Beckman depression inventory scale (BDI-II).

Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of individuals including persons with SCA1 [Ristori et al 2010, Romano et al 2015]; however, further investigation is needed, particularly longer-term disease-specific trials. An eight-week double-blind randomized placebo control trial of riluzole prodrug BHV4157 is ongoing (NCT02960893).

Chronic treatment with 3,4-diaminopyridine had beneficial effects in a mouse model of SCA1 [Hourez et al 2011]; Giordano et al [2013] subsequently treated 16 individuals with chronic cerebellar ataxia (including 3 with SCA1) with 4-aminopyridine (4-AP). This open-label case series suggested modest short-term improvement in ataxia. Similarly, an open-label case series of 13 persons with cerebellar ataxia, including one with SCA1, who were treated with acetyl-DL-leucine (5 g/day) for one week suggested modest improvement of ataxia without side effects [Strupp et al 2013]. Similar encouraging results have also been observed in a follow-up four-week case series by the same group [Schniepp et al 2016]. However, randomized placebo-controlled studies will be needed to assess the efficacy of such treatment. The protocols for these studies are now being formulated [Feil et al 2017].

Cvetanovic et al [2011] reported that mutated Atxn1 repressed transcription of vascular endothelial growth factor A (Vegfa) in mice with SCA1; the mice showed a decrease in cerebellar microvessel density and length. Overexpression or pharmacologic infusion of Vegfa resulted in phenotypic improvement and decreased cerebellar pathology.

Intrathecal injection of 3,000 mesenchymal stem cells in SCA1 transgenic mice mitigated the cerebellar neuronal disorganization, atrophy of dendrites, and motor function [Matsuura et al 2014, Nakamura et al 2015]. Investigators at the General Hospital of Chinese Armed Police Forces is recruiting study subjects with hereditary cerebellar ataxia for clinical trials using umbilical stem cell therapy (NCT01489267).

SCA1 mice (Atxn1 with 154Gln residues) showed no improvements in motor function on the accelerating rotor-rod test after acute doses of riluzole, amantadine, zolpidem, and buspirone over two days [Nag et al 2013].

Downregulation of several molecules of the RAS-MAPK-MSK1 pathway decreases ataxin1 levels and suppresses neurodegeneration in Drosophila and murine models of SCA1. Pharmacologic inhibitors of this pathway also decrease ataxin1 levels, suggesting that these components represent therapeutic targets in SCA1 [Park et al 2013].

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.

Other

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