Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate.
BACKGROUND
Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome.


METHODS
This is a 6-year-old girl who was diagnosed with guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months.


RESULTS
Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma guanidinoacetate levels, which questions the relevance of this therapy.


CONCLUSIONS
Treatment did not improve moderate intellectual disability or normalize guanidinoacetate accumulation in the central nervous system.
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: saadet.mahmutoglu@sickkids.ca.
Saadet
S
Mercimek-Mahmutoglu
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.
Gajja S
GS
Salomons
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Alicia
A
Chan
D000596:Amino Acids / Q000097:blood; D002648:Child; D003401:Creatine / Q000008:administration & dosage; D019587:Dietary Supplements; D005260:Female; D005520:Food Preservatives / Q000009:adverse effects*; D050937:Guanidinoacetate N-Methyltransferase / Q000134:cerebrospinal fluid / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007805:Language Development Disorders / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D009069:Movement Disorders / Q000134:cerebrospinal fluid / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009952:Ornithine / Q000008:administration & dosage; D011522:Protons; D011581:Psychological Tests; D020160:Sodium Benzoate / Q000009:adverse effects*; D017211:Treatment Failure; D016896:Treatment Outcome
D000596:Amino Acids; D005520:Food Preservatives; D011522:Protons; D009952:Ornithine; D050937:Guanidinoacetate N-Methyltransferase; D003401:Creatine; D020160:Sodium Benzoate
GAMT deficiency; arginine-restricted diet; creatine therapy; global developmental delay; seizure; sodium benzoate