Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency
- PMID: 40775643
- PMCID: PMC12333098
- DOI: 10.1186/s13023-025-03900-3
Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency
Abstract
Background: Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients with either condition commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to conduct clinical trials on potential treatments for these disorders are made more difficult by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consistent use of outcomes in studies. The current effort included patient and caregiver perspectives into the outcome selection of a COS for CTD and GAMT.
Results: We partnered with caregivers and health professionals to establish the first COS for CTD and GAMT. The COS developed includes seven outcomes ("Adaptive Functioning", "Cognitive Functioning", "Emotional Dysregulation", "MRS Brain Creatine", "Seizure/Convulsions", "Expressive Communication", and "Fine Motor Functions") for both CTD and GAMT, and an additional outcome for GAMT ("Serum/Plasma Guanidinoacetate") that are important to stakeholders and consequently should be considered for measurement in every clinical trial. Caregivers were valued partners throughout the COS development process, which increased community engagement and facilitated caregiver empowerment.
Conclusions: Development of this COS illustrates a patient-centered approach for clinical trial readiness for CTD and GAMT that if utilized will make clinical trial results comparable, minimize bias in clinical trial outcome selection, and promote efficient use of resources.
Keywords: Core outcome set (COS); Creatine transporter deficiency; Guanidinoacetate methyltransferase deficiency; Patient focused drug development; Patient-centered research; Rare disease.
© 2025. The Author(s).
Conflict of interest statement
Declarations. Ethics approval and consent to participate: All focus groups and Delphi surveys received institutional review board (IRB) approval from the North Star Review Board (protocols NB200065, NB300094; https://learningirb.org/ ). Informed consent was obtained from all focus group and Delphi survey participants prior to participation. Consent for publication: Not applicable. Competing interests: ZNM reports a stipend and travel support from ACD for this project. BKP reports a grant from INFORM RARE which receives industry matching research funds from Takeda, Biomarin, Ultragenyx, and Perkin Elmer. NL reports the following: clinical trial support for Amgen/Horizon, Amicus Therapeutics, Audentes/Astellas, BioMarin, Chiesi/Protalix, Genzyme/Sanofi, Jnana, Moderna, PTC Therapeutics, Takeda, and Ultragenyx; serves on advisory boards for Amgen/Horizon, Amicus Therapeutics, Audentes/Astellas, BioMarin, Chiesi/Protalix, Genzyme/Sanofi, Ipsen, Jaguar Gene Therapy, Jnana, Leadiant Biosciences, Moderna, Nestle Pharma, PTC Therapeutics, Reneo, and Ultragenyx Data Safety; serves on monitoring boards for Applied Therapeutics, iEcure, and Regeneron. GSL reports grant and travel support funding from ACD. JSM reports a consulting agreement with Ultragenyx and Johnson & Johnson, and has done legal consultation for a variety of cases. AS reports receiving consultation fees from Ceres Brain. EKR, AT, MS, CG, BHT, SAB, DAB, RB, JB, RC, DPC, TJDG, VH, SM-A, MP, GSS, CPW, KFW, SPY, JL, SB, TS, SS-I, and HW declare they have no conflicts of interest.
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Update of
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Establishing a Core Outcome Set for Creatine Transporter Deficiency and Guanidinoacetate Methyltransferase Deficiency.medRxiv [Preprint]. 2024 Sep 10:2024.09.06.24313213. doi: 10.1101/2024.09.06.24313213. medRxiv. 2024. Update in: Orphanet J Rare Dis. 2025 Aug 7;20(1):408. doi: 10.1186/s13023-025-03900-3. PMID: 39371127 Free PMC article. Updated. Preprint.
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