An n-of-1 gene-directed drug repurposing trial for an ultrarare genetic condition

Gain-of-function (GoF) variants in the KCNC1 potassium channel subunit gene (Kv3.1) cause motor/cognitive delays and hypotonia and have been associated with seizures. Fluoxetine has inhibitory effects on Kv3.1. However, open-label nonrandomized administration is insufficient to guide clinical decision-making in ultrarare conditions. This 40-week randomized, double-blind, n-of-1 trial evaluated the safety and effectiveness of fluoxetine for motor development in a 2-year, 10-month-old female child with a GoF KCNC1 variant.

This study used an ABA phase design (placebo-fluoxetine-placebo), with randomization and blinding of treatment transition moments. The active treatment, fluoxetine powder, was provided at 2.5 mg (low dose) and subsequently 5 mg (target dose) per day. Motor developmental was measured using the parent-reported Early Motor Questionnaire (EMQ), completed weekly. Secondary outcomes included cognitive and adaptive skills and other parent target symptoms (nystagmus, communication, purposeful hand movements).

Treatment with fluoxetine was associated with a 6.61-point gain on the EMQ (95% credible interval [CrI] = -.53 to 14.78), beyond the effects of time (.52 points/week, 95% CrI = .28-.91). Treatment was well tolerated; possible withdrawal irritability emerged during the second placebo phase. A higher dose was associated with a larger treatment effect on the EMQ (2.5 mg = 6.81, 95% CrI = -.43 to 14.56; 5 mg = 8.68, 95% CrI = -4.29 to 21.76). Secondary outcomes showed significant improvements in purposeful hand movements (-.65, 95% CrI = -1.27 to -.003, on a 7-point scale), and there were small increases in adaptive behavior and cognitive skills during the trial. Clinical biomarkers suggested a shift toward increased excitation on electroencephalogram and electroretinogram.

Fluoxetine treatment was possibly associated with increased motor skill development in a young child with KCNC1-related disorder involving a GoF variant. Trials studying developmental endpoints require innovative designs; this study provides a template for treatment assessment in ultrarare genetic neurodevelopmental disorders.