Pharmacological Treatment of Cerebellar Ataxia in Pediatric Ataxia-Telangiectasia: A Systematic Review

Ataxia-telangiectasia (AT) is characterized by progressive cerebellar ataxia, oculomotor apraxia, immunodeficiency, and increased cancer susceptibility. No disease-modifying treatment is available. This systematic review aimed to evaluate the efficacy and safety of pharmacological interventions for ataxia in pediatric AT.

A systematic search was conducted across MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov through December 2025. Eligible studies included randomized controlled trials (RCTs) and single-arm interventional studies evaluating pharmacological treatments for cerebellar ataxia in patients aged ≤ 18 years with genetically confirmed AT.

Thirteen studies (3 RCTs, 10 single-arm trials) involving 314 participants (mean age 10.87 years) were included. Interventions included betamethasone, erythrocyte-encapsulated dexamethasone (eDSP), nicotinamide riboside (NR), leucine derivatives, and amantadine. Betamethasone demonstrated transient improvements in the Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) scores, with dose-dependent systemic toxicity. eDSP showed favorable tolerability but was ineffective in phase 3 trials, although subgroup analyses suggested a potential benefit in children aged 6-9 years. NR supplementation improved SARA and AT Neurological Examination Scale Toolkit (AT-NEST) scores in open-label studies. Leucine derivatives showed mixed results. Amantadine showed benefits in patients with extrapyramidal symptoms.

The recurrent pattern of promising open-label findings followed by negative phase 3 results highlights a translational gap attributable to methodological limitations, including small sample sizes, heterogeneous populations, and variable outcome measures. The non-linear disease progression and age-dependent treatment response further complicate trial design. Current evidence remains insufficient to guide clinical practice.

PROSPERO number: CRD420251184721.