Spinocerebellar Ataxia Type 27B: Disability Progression and 4-Aminopyridine Response

VIDEO TRANSCRIPT:

Spinocerebellar ataxia type 27B, or SCA27B, is a rare neurological condition that mainly affects balance, gait, and eye movements.

I conducted a systematic review and meta-analysis to answer two questions:

How does functional disability, as measured by the use of a walking aid, progress over time?

What evidence exists on the effects of 4-aminopyridine, a repurposed medication?

I used a logistic, mixed-effects model to estimate the probability of needing different types of mobility aid by age. SCA27B progresses slowly– for example, about 60% of patients can still walk unaided by age 70, which is more than the general population, but still less than many other ataxias.

As for treatment, more than 90% of patients who tolerated 4-AP had a positive response, but sample sizes were small and evidence was observational.

Overall, my project can help SCA27B patients better understand their prognosis and highlights the need for larger studies to confirm the effectiveness of 4-AP to ultimately improve access to the medication.

Inspiration

My grandfather’s balance and walking has been progressively worsening for many years, but it was only recently that we found out he had Spinocerebellar Ataxia Type 27B (SCA27B). My project was inspired by him and his condition.

Background Information

Spinocerebellar ataxias are rare autosomal dominant, neurodegenerative disorders that affect balance, eye movement, and speech [1]. A GAA repeat expansion in the FGF14 gene was identified in 2023 as causing SCA27B, a late-onset, slowly progressive ataxia associated with oculomotor and episodic symptoms [2,3]. SCA27B is emerging as a common cause of late-onset cerebellar ataxia, with reported prevalence ranging from 9% [7] to 61% [2] across ethnic cohorts.

Despite the disease’s recent identification, 4-Aminopyridine (4-AP), a potassium channel blocker that was developed to improve walking in patients with multiple sclerosis, has shown promise treating SCA27B symptoms in preliminary open-label studies [10-12].

Objectives

To characterize functional outcomes in individuals with SCA27B by modeling disability progression over time, as measured by the use of a mobility aid or ordinal clinical rating scales [1, 2]

To review the direction and scope of preliminary evidence on the potential symptomatic benefit of 4-AP.

Importance

Ultimately, my project can help SCA27B patients understand their prognosis following a genetic diagnosis, providing an patient-interpretable prediction of functional limitation, and reveals key considerations for future studies on 4-AP in SCA27B, highlighting the need for FDA approval given the life-changing impact that the medication might have on patients.

The literature review was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13].

Study Identification & Screening

Studies reporting individual participant data available for patients with genetically diagnosed SCA27B (GAA>=250) were included [14-17]. Patients with comorbid acquired ataxias, other genetic ataxias, or MSA were excluded. Case-control studies, cohort studies, non-randomized control trials, and randomized control trials were included. Abstracts and posters were excluded. Records with no English or French version available were excluded.

Studies were identified through a systematic search of 4 databases (Cochrane, Embase, Pubmed, and Web of Science) and 2 registries (clinicaltrials.gov and International Clinical Trials Registry Platform) searched from 2023 to present using keywords relating to SCA27B.

Both title and abstract screening and full-text screening were undertaken by a single reviewer. Study investigators were messaged when details of whether the study met inclusion criteria were unclear or to request individual participant data when it was not available in the article or supplementary files.

Data Extraction

Data was extracted and recorded in Excel from individual participant observations. Extracted variables included outcomes of interest (disease duration, age at onset, age at examination, functional stage as measured by use of a walking aid or scores on ataxia rating scales, 4-aminopyridine response) and potential moderators (study details, GAA repeat length, ataxia severity, comorbid conditions, and sex). Data on the use of a mobility aid was extrapolated from ordinal rating scales when not directly available [8,9]. Data analysis was performed in R.

Study Quality Assessments

Study quality was assessed according to a modified version of the Newcastle-Ottawa Scale for Assessing the Quality of Studies in Systematic Reviews [23-25]. Separate assessments were conducted for studies evaluating both disability progression and 4-aminopyridine response given the differences in exposures and outcomes.

Study Selection

Figure 1 presents the results of the literature search and screening. Out of 270 unique records identified, 10 studies met the inclusion criteria [2,4,7,11,12,18-22]. A total of n = 268 individual participant observations were available from those studies, with n = 226 observations for disability progression and n = 42 observations for 4-AP response.

Risk of Bias of Included Studies

Studies assessing disability progression showed overall moderate risk of bias. Reasons included recruitment from a specialized referral center, small sample sizes, and limited assessment of confounders. Studies evaluating 4-aminopyridine showed overall high risk of bias. None of the studies met criteria for sample representativeness, since all studies focused on selected groups of patients, nor for sample size. Limited assessment of confounders was also a common source of risk of bias.

Results & Analysis - Disability Progression

Use of a mobility aid (stick, walker, or wheelchair) use was modeled using mixed-effects logistic regression in R with age and disease duration as fixed effects and study as a random intercept to account for baseline differences between cohorts. All potential moderators for which data was extracted were evaluated, and model selection was guided by the Akaike Information Criterion (AIC), which balances fit and complexity. GAA repeat length and sex were not significant predictors of mobility aid use.

Figure 2 presents probabilities of mobility aid use by age as predicted by the logistic model. Odds of being able to walk unaided remain around 80% by age 60, but go down to 40% by age 70 and continue to rapidly decrease as age progresses. Use of a wheelchair remained rare even in late disease stages.

Results & Analysis - 4-Aminopyridine Response

Five studies reported data on 42 patients that used 4-AP [2,7,12,19,22]. As seen in Table 1, of 35 participants who tolerated the medication, 32 (91.4%) had a positive response. However, criteria for a positive response with 4-aminopyridine differed across studies and most improvement metrics were subjective. For studies with objective improvement data available, all patients tolerating the medication experienced improvement [7,19,22]. Of value to note, Coulette et al. report a statistically significant decrease in median ataxia severity as measured by the Scale for Assessment and Rating of Ataxia (SARA) scale [11]. The decrease likely corresponds to “modest but meaningful improvement in functional stability” in magnitude [11].  Iruzubieta et al. report one patient who walked with a stick that was removed after treatment with 4-aminopyridine [19]. However, the medication did not influence ataxia progression [12] and, for one patient, drug withdrawal resulted in return of symptoms [19].

Disability Progression

Overall, these results support slow disability progression in SCA27B. Around 40% of patients are predicted to use a walking aid by age 70 compared to 18% of individuals aged 70-74 in the general American population which lies outside the 95% confidence interval for SCA27B patients [26]. Thus, while some disability progression may be attributed to normal aging, especially in higher age ranges, use of a mobility aid in this cohort was still significant compared to the general population. Moreover, because other comorbid conditions causing ataxia were excluded, mobility aid use likely reflects SCA27B-related disability. Odds of being able to walk unaided in later ages remained high compared with other ataxias.

Differences between studies may reflect variation in age at onset definition, variability in scales used, and cultural factors influencing use of a walking aid. Given that only cross-sectional data was available in most studies, the model can only be used to draw conclusions about average progression in the SCA27B population; furthermore, the predicted probabilities fail to account for within-participant variability. Furthermore, risk of bias, in particular sample representativeness, limits the generalizability of the evidence.

4-Aminopyridine response

4-AP is a promising treatment option with high response rates and the potential capacity to produce meaningful change; however, high risk of bias across studies limits the generalizability of the evidence. Placebo-controlled trials are necessary to comprehensively evaluate the drug’s effectiveness. The study also demonstrates the need for standardized outcome measures to facilitate future synthesis and interpretation.

In this study, further moderator or subgroup analyses could be helpful in identifying correlations between factors such as age at onset and ataxia severity. Future studies should include longitudinal, prospective multi-center cohort studies to decrease risk of bias and account for within-patient variability.

Given its promising results in preliminary observational trials, placebo-controlled trials on 4-AP in SCA27B patients should be conducted to provide rigorous evidence on the medication’s effect, since FDA approval of the medication would facilitate access for many patients.

Studies should consider the relevance of the various outcome measures evaluating SCA27B progression or patient-reported outcome measures.

To the Marianopolis College science fair coordinators, Prof. Meghan Marshall and Prof. Simon Sabik, thank you for the thoughtful workshops and for helping me refine my presentation! Thank you also to McGill librarian Martin Morris for showing me how to navigate databases and conduct a literature search.

To the researchers I reached out to over the course of my project, thank you all for being so kind as to share your papers with me and for all the work you've put in to this field!

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