Outcomes in Early-Treated Guanidinoacetate Methyltransferase Deficiency: A Sibling Cohort Study.

Background and Objectives: Guanidinoacetate methyltransferase deficiency (GAMT-D), a rare inborn error of creatine metabolism, is a disabling neurodevelopmental disorder due to the combined effect of cerebral creatine depletion and guanidinoacetate accumulation. Existing therapies efficiently improve both of the biochemical abnormalities. The goal of this study was to provide evidence for the crucial role of age at treatment initiation in clinical outcomes in affected individuals. Methods: In a mixed-method interview-based and questionnaire-based cohort study, 4 sibling pairs with GAMT-D (case group) and 8 healthy, age-matched sibling pairs (control group) were enrolled. In the case group, each younger sibling was diagnosed and treated earlier than their older sibling. Interviews with parents in the case group were performed to ascertain major perceived differences between the siblings and to construct a questionnaire that was completed by the parents for each child in both groups. Results: In the case group, all younger, earlier treated siblings had distinctly better outcomes in all ascertained domains compared with their older siblings, including development, cognition, school level, motor skills, coordination, adaptive functioning, behavior, needs or supportive measures, and seizures. Remarkably, in the case group, the outcomes in 2 children treated as neonates were not different from the healthy controls; the outcomes in 2 other children treated since infancy were better compared with those treated after the age of 2 years. Discussion: The favorable outcome observed in patients with GAMT-D when treatment is initiated in the presymptomatic period or early infancy should serve as a compelling argument for those programs that have not already implemented newborn screening of GAMT-D.