Abstract
This observational case series summarizes clinical experiences with 4-aminopyridine (4-AP) and acetyl-DL-leucine (ADLL) in patients with RFC1-related disorders treated under named patient use conditions. Clinical data from 30 patients treated at four university centers in Germany, Switzerland, and France were analyzed. Except for three patients previously enrolled in the ALCAT randomized crossover trial, treatments were initiated as part of routine care and were not standardized for dose or duration. Analyses were based on medical records, including patient-reported outcomes and physician assessments. Four patients from Strasbourg underwent SARA and SDFS assessments before and during treatment; SARA total scores for three ALCAT participants were obtained from the original study dataset. Twelve patients received 4-AP only, seven ADLL only, and eleven both treatments at different time points. Median treatment duration was 29 days for 4-AP and 53 days for ADLL. Subjective improvement was reported in 3/22 patients (13.6%) treated with 4-AP and 3/15 (20.0%) treated with ADLL. Objective gait improvement was observed in 2/13 patients (15.4%) on 4-AP and in 2/10 (20.0%) on ADLL. No effects on downbeat nystagmus were observed. Exploratory analyses revealed no significant differences in SARA total scores between ADLL and placebo or baseline; neither SARA nor SDFS scores improved in Strasbourg patients. Responses to 4-AP and ADLL in RFC1-related disorders were rare and limited, suggesting that neurodegenerative dysfunction of cerebellar circuits in RFC1-disease—in contrast to certain genetic cerebellar disorders such as SCA27B—is unlikely to be improved to clinically relevant thresholds by these agents. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12311-026-01982-8.