Abstract
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.
Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E. Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology. 2006 Aug 22;67(4):719-21. doi: 10.1212/01.wnl.0000230152.25203.01. PMID: 16924036.
Abstract
Prospective observation in a neonate with guanidinoacetate methyltransferase deficiency (GAMT-D), a severe neurometabolic disorder, revealed increased guanidinoacetate levels at birth. After 14-month treatment with creatine, high-dose ornithine, benzoate, and an arginine-restricted diet, the patient's development is normal and she does not present any symptoms of GAMT-D. The authors' observation indicates that early detection of GAMT-D is possible in the neonatal period, and presymptomatic treatment may prevent its manifestation.
Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araújo HC, Coskun T, Diogo L, Geraghty M, Haliloglu G, Konstantopoulou V, Leuzzi V, Levtova A, Mackenzie J, Maranda B, Mhanni AA, Mitchell G, Morris A, Newlove T, Renaud D, Scaglia F, Valayannopoulos V, van Spronsen FJ, Verbruggen KT, Yuskiv N, Nyhan W, Schulze A. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2014 Jan;111(1):16-25. doi: 10.1016/j.ymgme.2013.10.018. Epub 2013 Nov 7. PMID: 24268530.
Abstract
We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.
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