Acetyl-DL-leucine (Tanganil™) in three patients with advanced multiple system atrophy.

Background: Multiple system atrophy (MSA) is a rare, rapidly progressive alpha-synucleinopathy characterized by autonomic dysfunction, parkinsonism and marked cerebellar ataxia, with very limited treatment options. N-acetyl-DL-leucine (ADLL) (Tanganil™), a racemic derivative of leucine is usually well tolerated and has shown promise in improving cerebellar symptoms and reducing REM sleep behavior disorder (RBD), a common non-motor dream-sleep disorder feature of alpha-synucleinopathy. Given this dual potential, we treated three patients with advanced-stage MSA under compassionate use rules.

Case presentations: Three patients with advanced-stage MSA and severe cerebellar symptoms-two of whom also had moderate RBD-were treated with ADLL (Tanganil^TM), titrated to 5g/day over 10 days. While both patients with RBD reported self-assessed decrease of RBD symptoms within 2-3 weeks on the full dosage (approximately four weeks after treatment initiation), all three patients had major worsening of gait and balance during the same period, leading to sudden falls and overall health decline. These adverse events prompted early discontinuation of therapy. Gait improved within two weeks after discontinuation of therapy in two patients. In parallel, the RBD phenotype reoccurred. In the third, who had very advanced MSA and concurrent infections, gait only slowly improved over time and it remains unclear whether his worsening of truncal ataxia was attributable to ADLL (Tanganil^TM), or whether it was related to his concurrent infections with slow recovery.

Conclusions: While ADLL improved RBD, it was poorly tolerated in these three patients with advanced-stage MSA of predominantly cerebellar type. Further studies are needed to evaluate its safety and efficacy in different, preferably early, stages of MSA.