Spinocerebellar Ataxias (SCAs)

The spinocerebellar ataxias (SCAs) are a group of autosomal dominant disorders characterized by progressive ataxia due to degeneration of the cerebellum and its afferent and efferent pathways.

Diagnosis

The most common SCAs are repeat-expansion diseases. A first step in establishing a diagnosis of a specific SCA is to screen for these repeat expansions, particularly for the most common subtypes - SCA1, SCA2, SCA3, SCA6, and SCA7. Detection and sizing of repeat-expansion mutations are currently accomplished by conventional PCR, repeat-primed PCR, or Southern blot analyses, depending on the size of the repeat. Internal repeat sequence irregularities are found in some SCAs, which can alter the characteristics of repeat length stability. The expansion size and, in some SCAs, repeat-interrupting motifs can substantially alter disease penetrance, age at onset, or even clinical manifestations.

For SCAs caused by point mutations, whole-genome sequencing (WGS) and whole-exome sequencing (WES) are useful for the detection of mutations in known SCA genes and the identification of new genetic causes of SCA.

Biomarkers

Biomarkers are crucial for new drug discovery and development and are often used to stratify patient populations to reduce the variability of the clinical outcome. Although reliable molecular biomarkers in body fluids are yet to be discovered for the SCAs, MRI-based biomarkers have shown promising results.

• Imaging Biomarkers

Validated imaging biomarkers also enable enrolment of mutation carriers at the premanifest stage of SCA by providing evidence of early pathological changes in the brain. MRI-based modalities have been used in multisite settings and have been more widely validated in SCAs than PET. In addition, conventional structural MRI has been the standard of care to monitor the characteristic cerebellar and brainstem atrophy in patients with SCAs. Among the many MRI modalities, morphometric MRI, diffusion MRI and magnetic resonance spectroscopy (MRS) have been evaluated as biomarkers in SCAs by several groups worldwide.

• Biofluids and Other Biomarkers

In the past few years, SCA consortia have initiated the search for body fluid biomarkers via transcriptomics, proteomics, and investigations of molecules of particular interest in CSF, plasma, serum, exosomes, and peripheral cells. Among these markers, the CSF level of ataxin 1 (ATXN1), ATXN2, ATXN3, ATXN7, and other SCA disease proteins that possess toxic gain-of-function properties is a promising biomarker for monitoring the response to nucleotide-based gene-silencing therapeutic approaches such as ASOs or RNAi.

Fig.1 Biomarkers for SCAs. (Ashizawa, 2018)

Electrophysiological Evaluations

Electrophysiological evaluations include nerve conduction studies (NCS), electromyography (EMG), visual evoked potential (VEP), brainstem acoustic-evoked potential (BAEP), somatosensory-evoked potential (SSEP), motor-evoked potential (MEP), electro-oculography, electroencephalography (EEG), and polysomnography, all of which are helpful in the study of SCAs. NCS and EMG findings may provide essential information for the diagnosis of neuromuscular disease. Electrophysiological examination of SCA1, SCA2, and SCA3 usually shows sensorimotor and pure sensory neuropathy, while pure motor neuropathy is rarer, being seen only in SCA2.

Genetic Testing

Genetic testing for SCA has exploded in the past decade. There are five distinct scenarios in which genetic testing can be used by clinicians: diagnostic testing, predictive testing, prenatal testing, carrier testing, and risk factor assessment. The primary benefit of diagnostic genetic testing is that it may provide a specific and accurate diagnosis. In SCAs, gene testing can specify a diagnosis from a group of clinically similar genetic conditions.

Treatment

• Disease-Modifying Drugs

For dominantly inherited diseases such as the SCAs, the most compelling therapeutic targets lie upstream in the pathogenic cascade, regardless of the type of mutation and pathogenic mechanism.

• PolyQ SCAs

At least seven degenerative ataxias are caused by expanded CAG repeats encoding polyQ tracts: SCAs 1, 2, 3, 6, 7, 17, and dentatorubral-pallidoluysian atrophy, the last of which shares features with the SCAs and another polyQ disease, Huntington disease. The accumulation of aggregated protein in polyQ SCAs suggests that efforts to enhance protein quality-control pathways in the brain offer a route to disease-modifying therapy.

• SCAs Caused by Toxic RNA

Viable strategies that intervene in the upstream portion of the pathogenic pathway might include reduction of the level of toxic RNA by ASO or other RNA interference (RNAi) technology, disruption of the interaction between the toxic RNA and the RBP by decoys or competitors, overexpression of the RBP and modulation of stress granule formation.

• SCAs Caused by Point Mutation

Most of the mutations identified are predicted to lead to a novel toxic function or a dominant negative effect by the mutant protein. Therapeutic strategies for such SCAs might involve gene silencing, skipping of the mutated exon by RNAi or ASO technologies, or intervention in specific downstream pathways.

Fig.2 Therapeutic strategies for the SCAs. (Ashizawa, 2018)

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Reference

1. Ashizawa, T.; et al. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol. 2018 Oct; 14(10): 590-605.