Long-term disease progression in spinocerebellar ataxia quantified

By Lucy Piper, Senior medwireNews Reporter

Researchers have quantified the progression of the most common spinocerebellar ataxias (SCAs) over a follow-up period of up to 8 years in steps to improve sample size calculations for future interventional trials.

They found that scores on the Scale for the Assessment and Rating of Ataxia (SARA) progressed in a linear fashion over a median 49 months of observation for all of the SCA genotypes studied – SCA1, SCA2, SCA3 and SCA6.

Progression was fastest for patients with SCA1, with an annual score increase of 2.11, followed by SCA2 and SCA3, with annual increases of 1.49 and 1.56, respectively, while patients with SCA6 had the slowest rate of progression at an increase of 0.80 per year.

This linearity suggests that “the neurodegeneration underlying the development of ataxia in SCA1, SCA2, SCA3, and SCA6 is a steady process continued over an extended time period”, note Thomas Klockgether (University Hospital Bonn, Germany) and co-researchers in The Lancet Neurology.

The benefits of knowing the magnitude of SARA score progression are highlighted in a related comment by Luis Velázquez-Pérez (Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba) who says it will be of value in improving the main clinical manifestations of the condition and even achieving stabilisation of cerebellar features.

The main determinants of SARA score progression among the 107 patients with SCA1 were having fewer than 3 years of follow-up, longer CAG repeat expansions and older age at study inclusion. Follow-up duration was also a significant factor among the 146 patients with SCA2, along with younger age at disease onset and lower SARA score at baseline.

Only lower SARA score at baseline significantly predicted faster score progression among the 87 patients with SCA6 and there were no significant factors associated with progression among the 122 SCA3 patients.

While ataxia symptoms progressed steadily over time, non-ataxia symptoms, measured using the Inventory of Non-Ataxia Signs (INAS), reached a plateau among the patients with SCA1, SCA2 and SCA3 over the observation period.

The researchers note that the frequency of these symptoms differed among these SCA genotypes; for instance, in patients with SCA1, the frequency of paresis, muscular atrophy and sensory symptoms increased whereas in patients with SCA2 areflexia, spasticity and resting tremor became more common.

The team recognises, however, that the INAS is not a suitable measure for quantifying an increase in the severity of these symptoms, something Velázquez-Pérez believes should be done with other methods and “associated with the SARA as the standard clinical measure of disease progression.”

For patients with SCA6, there was a paucity of extracerebellar degeneration. These patients had fewer non-ataxia symptoms than the other groups and the number increased linearly and more slowly.

Based on their data, the researchers calculate that for interventional trials, 142 to 202 patients with SCA1, SCA2 or SCA3 would be needed to detect a 50% reduction in SARA score progression over a year. This number could be reduced by extending the trial to 2 or 3 years, but they note that the risk of dropout increases substantially beyond 3 years.

Because progression is slower in SCA6 patients, the researchers say that interventional trials aimed at slowing disease progression in these patients would be “very challenging” and require much larger sample sizes.

Velázquez-Pérez says the “study increases understanding of the large clinical, genetic and pathological heterogeneity of spinocerebellar ataxias and marks an important step forward in the clinical research of these disorders.”

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