Spinal cerebellar ataxia (SCA) is a group of slowly progressive hereditary neurodegenerative disorders. It refers to autosomal dominant cerebellar ataxia (ADCA) caused by degeneration of the cerebellum or its related pathways.
The prevalence is 1 to 5 per 100,000 people. SCAs are numbered from SCA1 to SCA40, with specific types continuing to increase. SCA3 (Machado-Joseph disease) is the most common worldwide, followed by SCA1, SCA2, SCA6, SCA7, and SCA8, each accounting for at least 2% of all SCAs.
In European populations, approximately 15–30% of late-onset cerebellar ataxia (LOCA) is estimated to be SCA27B. In a German cohort, SCA27B accounted for 16% of genetically confirmed ataxia patients, making it the second most common after SCA3 (19%)6).
Age of onset is typically 30–50 years, but cases have been reported from childhood to the 70s. In SCA27B, the mean age is 57.46 years (range 6–80 years), which is slightly later6).
The overview of ophthalmological signs is as follows. Various findings such as ophthalmoplegia, optic atrophy, retinitis pigmentosa, nystagmus, and saccadic abnormalities are observed, and they differ depending on the type of SCA.
SCA types are numbered from SCA1 to SCA40, and more than 40 types have been identified. The most common worldwide is SCA3 (Machado-Joseph disease), while in Japan, SCA6 and SCA31 are also common.
Initially, gait and balance disorders appear, and as the disease progresses, ophthalmological symptoms are added.
Representative cerebellar oculomotor disorders include fixation abnormalities (nystagmus, saccadic intrusions), saccadic dysmetria, pursuit abnormalities, and vestibulo-ocular reflex (VOR) gain impairment. Oscillopsia, downbeat nystagmus, square-wave jerks (SWJs), and staircase pursuit are also observed. Among hereditary spinocerebellar degenerations (SCD) common in Japan, SCA6 and SCA31 present only cerebellar symptoms, while SCA3 also involves external ophthalmoplegia and parkinsonism.
The main ophthalmological findings by SCA type are shown below.
SCA1 and SCA2
SCA1: Predominantly hypermetric saccades. May be accompanied by optic atrophy (approximately 33%), central scotoma, and color vision abnormalities.
SCA2: Marked slowing of saccades from early stages of the disease. Gaze-evoked nystagmus and saccadic abnormalities are less common, which helps differentiate it from other SCAs.
SCA3, SCA6, SCA7
SCA3: Characteristic findings include eyelid retraction with ophthalmoplegia (“eyelid protrusion”), gaze-evoked nystagmus, and divergence insufficiency esotropia.
SCA6: Downbeat nystagmus is a representative finding.
SCA7: Retinal degeneration, retinitis pigmentosa, and early blue-yellow color vision deficiency. Visual prognosis may be poor.
SCA7 is a representative type that causes retinal degeneration and retinitis pigmentosa, with blue-yellow color vision abnormalities occurring early. Retinitis pigmentosa has also been reported in SCA3. When retinal lesions are present, visual prognosis may be particularly poor.
Most SCAs are autosomal dominant and often caused by expansion of CAG nucleotide repeats.
The correspondence between SCA types and the main causative genes/repeat types is as follows.
| SCA type | Causative gene/mutation | Type of repeat/mutation |
|---|---|---|
| SCA1/2/3/6/7/12/17 | Type-specific genes | Trinucleotide (CAG, etc.) repeat expansion |
| SCA10/31 | Type-specific genes | Pentanucleotide repeat expansion |
| SCA27B | FGF14 | Hexanucleotide (GAA) repeat expansion |
| SCA5/11/13/14/21/28, etc. | Gene specific to each type | Conventional mutations (point mutations, etc.) |
Details of each type are shown below.
In SCAs caused by repeat expansions, the number of repeats tends to increase across generations. This is called anticipation. As the repeat number increases, onset becomes earlier and symptoms become more severe. Even if a parent has mild symptoms, the child may have severe symptoms.
All SCA types show progressive motor impairment, and there is no single definitive sign. The following approaches are important for differential diagnosis.
Recording with electrooculography (EOG) is recommended. Two-dimensional recording in horizontal and vertical directions, and three-dimensional recording including torsion, are desirable. The parameters to be evaluated are as follows.
Essential for definitive diagnosis. Commercial test panels cover major types such as SCA1–8, 12, 17, 27B. Definitive diagnosis is obtained by detecting family history and genetic mutations.
Cerebellar atrophy is commonly observed in many SCA types on brain MRI. In SCA27B, 70.28% have cerebellar atrophy, which progresses from the vermis to the hemispheres 6). In SCA12, cerebellar atrophy 34.7%, cerebral atrophy 16.3%, both combined 34.7%, and normal 6.1% have been reported 1).
It is important to exclude treatable non-hereditary ataxias.
There is no curative treatment; symptomatic therapy is the mainstay.
The following medications are used for SCA12. Usage rates (multiple responses) were: amantadine (100–300 mg/day) 53%, propranolol (20–60 mg/day) 53%, benzodiazepines 42.8%, primidone (250–500 mg/day) 28.5%, L-Dopa (400–600 mg/day) 10.2%, trihexyphenidyl (6–12 mg/day) 6.1%, and baclofen (20–40 mg/day) 4%1).
Physical therapy includes the use of assistive devices such as canes, walkers, and wheelchairs.
GABAB agonists may be highly effective for vertical nystagmus and periodic alternating nystagmus. Baclofen is useful for periodic alternating nystagmus, while gabapentin is considered effective for improving gaze-evoked nystagmus. The efficacy of medications varies depending on the type of SCA and the type of nystagmus.
When the CAG repeat exceeds a threshold of 35–40 units, the polyglutamine chain undergoes abnormal conformation and aggregation, interfering with other neuronal proteins. Neuronal inclusions are a pathological hallmark of polyglutamine diseases, and although the pathogenic protein is widely expressed throughout the nervous system, only specific subsets of neurons show vulnerability.
Regarding the pathological intersection of MS and SCA, ataxin-1 has been shown to have immunomodulatory effects, and the mutant form increases the severity of experimental autoimmune encephalomyelitis (EAE) 4). It has been suggested that SCA-related alleles may increase susceptibility to MS.
It is a drug identified as a candidate for SCA through computational drug repositioning.
Miura et al. (2023) conducted a pilot study (50 mg/day, 24 weeks) in 6 patients3). Four patients completed the study, and 3 of them (75%) showed improvement in ICARS scores (Case 1: SCA6 from 46 to 45; Case 3: SCA36 from 53 to 44). The mechanism is presumed to be voltage-gated sodium channel blockade. However, caution is needed as worsening of ataxia has been reported with 50 mg/day administration in SCA17.
Therapeutic effects are being investigated for SCA27B. In two small cohorts, 86% (6/7 cases) and 75% (21/28 cases) showed positive responses6).
Lamotrigine has been reported to be effective in reducing ataxic gait in SCA3. Similar to topiramate, it is thought to suppress glutamate release3). Dalfampridine is an MS treatment drug (a voltage-gated potassium channel blocker) and is being investigated for experimental use in hereditary ataxia4).
In one case of SCA12, improvement in tremor scores has been reported with bilateral zona incerta DBS 1). However, there is a problem that ataxia worsens with the stimulation parameters required for tremor control.
This is expected to be the most ideal treatment for SCA, but sufficient clinical evidence has not yet been established. The concept of allele-specific silencing has been proposed 5).
