Cerebellum. 2026 Oct 31;25(6):165. doi: 10.1007/s12311-026-02108-w.
ABSTRACT
Ataxia-telangiectasia (A-T) causes progressive neurological disability. Following two phase III trials published in 2026, this study is an updated randomized evidence for pharmacological interventions targeting neurological manifestations of A-T. PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Cochrane Library were searched. Eligible studies were RCTs in children or adults with A-T. Risk of bias was assessed using Cochrane RoB 2. N-acetyl-L-leucine/levacetylleucine SARA treatment effects were pooled using a random-effects generic inverse-variance model with restricted maximum likelihood (REML), with common-effect and Hartung-Knapp-Sidik-Jonkman sensitivity analyses. Secondary analyses pooled full-ICARS efficacy and safety outcomes from the two eDSP trials. Six RCTs evaluated oral betamethasone, N-acetyl-L-leucine/levacetylleucine, erythrocyte-encapsulated dexamethasone sodium phosphate (eDSP), and triheptanoin. Two crossover trials contributed to the SARA meta-analysis. The pooled REML effect was not significant (MD -0.90, 95% CI -3.20 to 1.40; p = 0.443; I²=75.8%). Two eDSP trials contributed comparable full-ICARS estimates in children aged 6-9 years; the conventional pooled result favored eDSP (MD -4.03, 95% CI -6.78 to -1.29). Neither eDSP trial met its prespecified primary neurological endpoint. Pooled eDSP risk ratios were 1.05 (0.94 to 1.17) for any treatment-emergent adverse event, 1.45 (0.995 to 2.12) for treatment-related events, and 0.94 (0.40 to 2.22) for serious adverse events. Betamethasone and triheptanoin were each represented by one RCT. Despite FDA approval of levacetylleucine for ataxia in A-T, pooled SARA effects remain inconsistent. The favorable secondary eDSP full-ICARS estimate does not supersede the unsuccessful primary trial analyses. Harmonized, feasible neurological outcome measures are needed.PROSPERO Registration NumberCRD420261474940.
PMID:42965751 | DOI:10.1007/s12311-026-02108-w