N-Acetyl-DL-Leucine Improves Ataxia in Patients with CACNA1A-Related Disorders

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Background/Purpose: CACNA1A-related disorders are rare, progressive, and prematurely fatal. They can manifest with a variety of symptoms, such as ataxia, epilepsy, central hypotonia, developmental delay or intellectual disability. To date, there is no approved specific treatment. N -acetyl-DL-leucine (NAL) is an orally administered racemic mixture approved in France for vertigo. Clinical trials with the active L-enantiomer have demonstrated a broad potential applicability for a range of neurodegenerative disorders, which feature hallmark symptoms of ataxia, cognitive impairment, and epilepsy. Most recently, N -acetyl-L-leucine was demonstrated to be effective for the treatment of Niemann–Pick disease type C in a double-blind placebo-controlled trial. Thus, we hypothesized that NAL may be an effective therapy for patients with CACNA1A-related disorders. Methods: Four patients (1 boy, age 15 years, 3 girls, age 5, 9, and 14 years, respectively) were treated with NAL on the basis of an individualized clinical trial in Germany and Greece. Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA score), the Spinocerebellar Ataxia Functional Index (SCAFI), and the Clinical Global Impression of Improvement Scale for Investigators (CGI-I). Results: In all four children, NAL resulted in a rapid improvement of ataxia, including gait, balance, fine motor skills and speech (mean SARA score improvement at first follow-up: 3.25 points). The improvement was sustained up to 3 years (mean long-term SARA score improvement: 5.13 points). SCAFI and CGI-I showed similar improvements. NAL was well-tolerated with no serious adverse reactions. Conclusion: This case series provides evidence of N -acetyl-Leucine as a novel potential treatment for the so far untreatable spectrum of CACNA1A-related disorders. The sustained benefit is reflective of a neuroprotective effect seen in other populations. Larger studies are warranted to assess the generalizability of the results. Publication History Article published online: 08 October 2024 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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