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Clinically meaningful improvements after gene therapy for aromatic L-amino acid decarboxylase deficiency (AADCd) in the Peabody Developmental Motor Scale, Second Edition (PDMS-2) and correlation with Bayley-III scores and motor milestones.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101266602 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1172 (Electronic) Linking ISSN: 17501172 NLM ISO Abbreviation: Orphanet J Rare Dis Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, 2006-
    • Subject Terms:
      Genetic Therapy*/methods; Humans ; Female ; Male ; Amino Acid Metabolism, Inborn Errors/genetics ; Amino Acid Metabolism, Inborn Errors/therapy ; Aromatic-L-Amino-Acid Decarboxylases/deficiency ; Aromatic-L-Amino-Acid Decarboxylases/genetics ; Child, Preschool ; Child ; Infant
    • Abstract:
      Background: Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare genetic disorder characterized by movement disorders, motor and autonomic dysfunction, and developmental delays. The gene therapy eladocagene exuparvovec has become available in some regions; pooled clinical trial results demonstrate continuous long-term improvement in motor development and cognitive function. We sought to characterize clinically meaningful change in motor function, as measured by Total Peabody Developmental Motor Scales-Second Edition (PDMS-2) score, and assess correlations with cognition and language domains of the Bayley-III and motor milestone (MM) achievement.
      Methods: Data from N = 30 patients from three single-arm clinical studies of eladocagene exuparvovec were analyzed. Anchor-based estimation of the meaningful score difference (MSD) of Total PDMS-2 score was conducted using mean-difference and receiver operating characteristic curve (ROC) approaches. MM achievement served as the anchor defining meaningful change.
      Results: An MSD of 40 points for Total PDMS-2 score was selected for analysis as it yielded specificity > 0.95 using the ROC approach, and generally aligned with the mean-difference approach. Cumulative incidence analysis reflected that 50% of patients treated with eladocagene exuparvovec may achieve the MSD of 40-point change in Total PDMS-2 score at 6 months, and 86% at 18 months. Correlations between measures were of large magnitude and improved over time (Month 6: r = 0.599 [p = 0.0032]; Month 18: r = 0.796 [p = 0.0002]; Month 60: r = 0.861 [p = 0.0007]).
      Conclusions: The MSD of 40 points for Total PDMS-2 score enables the interpretation of changes observed in patients with AADCd, and suggests that treatment with eladocagene exuparvovec leads to significant improvements in motor and cognitive function.
      Competing Interests: Declarations. Ethics approval and consent to participate: All three single-arm, open-label clinical trials were approved by the appropriate institutional and/or national research ethics committee and have been performed in accordance with the ethical standards as described in the Declaration of Helsinki. Written informed consent was obtained from trial participants or their parents in the case of children. Consent for publication: Not applicable. Competing interests: RZ, JRS, AW, CW, and IT are/were employees of and may hold stocks in PTC Therapeutics at the time of writing. TO, JJW, and MC are employees of Medicus Economics, which received funding from PTC Therapeutics for this work. W-LH, H-ML, and JDP received consulting fees from PTC Therapeutics.
      (© 2025. The Author(s).)
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    • Grant Information:
      PTC Therapeutics PTC Therapeutics
    • Contributed Indexing:
      Keywords: Aromatic L-amino acid decarboxylase deficiency; Cognitive function; Gene therapy; Motor function
    • Accession Number:
      EC 4.1.1.28 (Aromatic-L-Amino-Acid Decarboxylases)
    • Subject Terms:
      Aromatic amino acid decarboxylase deficiency
    • Publication Date:
      Date Created: 20250207 Date Completed: 20250208 Latest Revision: 20250210
    • Publication Date:
      20250210
    • Accession Number:
      PMC11806574
    • Accession Number:
      10.1186/s13023-025-03584-9
    • Accession Number:
      39920752