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].