Caspi Liora, Hayeems Robin, Schulze Andreas
Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Child Health Evaluative Sciences Program, Hospital for Sick Children, Toronto, Ontario, Canada.
Neurol Genet. 2025 May 30;11(3):e200262. doi: 10.1212/NXG.0000000000200262. eCollection 2025 Jun.
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.
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.
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.
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.
胍乙酸甲基转移酶缺乏症（GAMT-D）是一种罕见的肌酸代谢先天性缺陷疾病，由于脑肌酸耗竭和胍乙酸蓄积的共同作用，它是一种致残性神经发育障碍。现有治疗方法能有效改善这两种生化异常情况。本研究的目的是为治疗开始时的年龄对受影响个体临床结局的关键作用提供证据。
在一项基于访谈和问卷的混合方法队列研究中，招募了4对患有GAMT-D的兄弟姐妹（病例组）和8对年龄匹配的健康兄弟姐妹（对照组）。在病例组中，每个年幼的兄弟姐妹比其年长的兄弟姐妹更早被诊断和治疗。对病例组的父母进行访谈，以确定兄弟姐妹之间主要的可感知差异，并构建一份问卷，由两组中每个孩子的父母填写。
在病例组中，与年长的兄弟姐妹相比，所有年幼且更早接受治疗的兄弟姐妹在所有确定的领域都有明显更好的结局，包括发育、认知、学校水平、运动技能、协调能力、适应功能、行为、需求或支持措施以及癫痫发作。值得注意的是，在病例组中，2名新生儿期接受治疗的儿童的结局与健康对照组无异；另外2名婴儿期开始治疗的儿童的结局比2岁后开始治疗的儿童更好。
对于尚未实施GAMT-D新生儿筛查的项目而言，在症状前期或婴儿早期开始治疗的GAMT-D患者所观察到的良好结局应成为一个有说服力的论据。
