- Spinocerebellar ataxias (SCAs) are a diverse group of hereditary, progressive neurodegenerative disorders primarily affecting the cerebellum and its connections, leading to problems with coordination, balance, and speech.
- They are genetically heterogeneous, with more than 40 subtypes identified to date, each caused by mutations in different genes.
- Despite this diversity, the clinical hallmark across SCAs is ataxia, a loss of voluntary coordination of muscle movements. Other neurological features may include dysarthria (slurred speech), oculomotor abnormalities, spasticity, neuropathy, parkinsonism, or cognitive decline, depending on the subtype. The disorders typically manifest in adulthood, though onset can range from childhood to late adulthood, and progression varies from relatively slow to rapidly disabling.
- A significant proportion of SCAs belong to the group of trinucleotide repeat expansion disorders, in which abnormal CAG expansions within coding regions of specific genes lead to proteins with elongated polyglutamine (polyQ) tracts. These polyQ-expanded proteins misfold, aggregate, and disrupt neuronal function, contributing to degeneration of cerebellar neurons and related pathways. Classic polyQ SCAs include SCA1, SCA2, SCA3 (Machado–Joseph disease), SCA6, SCA7, and SCA17. Other SCAs arise from different mutational mechanisms, such as repeat expansions in noncoding regions (e.g., SCA10 with ATTCT repeats, SCA31 with TGGAA repeats), conventional point mutations, or deletions. This genetic heterogeneity explains the wide spectrum of clinical phenotypes.
- Clinically, SCAs are distinguished by subtle differences in presentation. For instance, SCA1 is marked by progressive gait and limb ataxia with dysarthria and ophthalmoplegia; SCA2 often presents with slow saccadic eye movements and peripheral neuropathy; SCA3 (Machado–Joseph disease), the most common worldwide, features ataxia alongside spasticity, dystonia, and neuropathy; SCA6 tends to have a later onset with relatively pure cerebellar ataxia; and SCA7 is notable for progressive vision loss due to retinal degeneration. The overlapping but distinct features often guide clinical suspicion toward specific subtypes.
- A key phenomenon in many trinucleotide repeat–related SCAs is anticipation, in which repeat length increases across generations, leading to earlier onset and more severe disease in descendants. This is particularly notable in SCA7, where large expansions correlate with childhood-onset ataxia and blindness. However, in non-repeat expansion SCAs, anticipation is generally absent.
- Diagnosis of SCAs relies on a combination of neurological examination, family history, neuroimaging, and genetic testing. MRI typically reveals cerebellar and sometimes brainstem atrophy. Definitive diagnosis requires identification of the underlying genetic mutation, which is crucial for distinguishing among the many subtypes. With advances in sequencing technology, next-generation sequencing panels now allow more comprehensive screening for known SCA genes.
- Currently, there is no cure for SCAs, and management is primarily supportive. Physical therapy, occupational therapy, and speech therapy help maintain function and independence. Pharmacologic treatment is limited to managing specific symptoms such as spasticity, tremor, or parkinsonism. Genetic counseling is essential for affected families due to the autosomal dominant inheritance pattern of most SCAs.
- Research is increasingly focused on understanding disease mechanisms and developing targeted therapies. In polyQ SCAs, strategies are being investigated to reduce mutant protein expression, prevent aggregation, or enhance cellular clearance. Approaches under study include antisense oligonucleotides, RNA interference, and gene-editing technologies such as CRISPR/Cas9. Neuroprotective and symptomatic therapies are also in development, with the hope of slowing progression and improving quality of life.
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