Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency.
BACKGROUND
Guanidinoacetate methyltransferase (GAMT) deficiency causes cerebral creatine deficiency. Patients can have autistic behavior, seizures, intellectual disability, and severe speech delay. The goal of therapy is to increase creatine while reducing potentially neurotoxic guanidinoacetate concentrations. Here we evaluate how different therapies affect plasma guanidinoacetate levels in patients with GAMT deficiency.


METHODS
Retrospective analysis of data from five new patients with GAMT deficiency (four with delays and seizures, one diagnosed at birth).


RESULTS
The four symptomatic patients had decreased brain creatine by magnetic resonance spectroscopy and three also had abnormal globi pallidi by MRI. GAMT sequencing identified four previously reported mutations and one novel missense mutation (c.233T>A/p.V78E). Treatment with creatine (250-1000 mg/kg/day), ornithine (100-800 mg/kg/day), and sodium benzoate (50-135 mg/kg/day) supplements along with dietary protein restriction (0.8-1.5 g/kg/day) improved seizures and development with all patients becoming verbal. The patient treated at birth remains developmentally normal. Reduction in glycine and increase in ornithine levels significantly decreased plasma guanidinoacetate, with glycine levels being the best predictor of guanidinoacetate levels. In contrast, arginine levels were not significantly correlated with plasma guanidinoacetate.


CONCLUSIONS
Our results show that supplements of creatine, sodium benzoate (to reduce glycine) and ornithine reduce guanidinoacetate levels in patients with GAMT deficiency (dietary therapy was not evaluated in our study). Normal development with early therapy renders GAMT deficiency an ideal candidate for inclusion in newborn screening panels.
Department of Pediatrics, Division of Medical Genetics, University of Utah, 50 North Mario Capecchi Drive, 2C412 SOM, Salt Lake City, UT 84132, USA. Electronic address: krista.viau@hsc.utah.edu.
Krista S
KS
Viau
Sharon L
SL
Ernst
Marzia
M
Pasquali
Lorenzo D
LD
Botto
Gary
G
Hedlund
Nicola
N
Longo
D003401:Creatine / Q000008:administration & dosage; D018753:Diet, Protein-Restricted; D005260:Female; D005838:Genotype; D050937:Guanidinoacetate N-Methyltransferase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007805:Language Development Disorders / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009069:Movement Disorders / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009154:Mutation; D009952:Ornithine / Q000008:administration & dosage; D016896:Treatment Outcome
D009952:Ornithine; D050937:Guanidinoacetate N-Methyltransferase; D003401:Creatine
Creatine; GAMT deficiency; Guanidinoacetate; Intellectual disability; Magnetic resonance spectroscopy