title: Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.
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.
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. Electronic address: sstockler@cw.bc.ca.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: van Karnebeek
authors.affiliation: Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.affiliation: Department of Pediatric Neurology, Children's Hospital Oldenburg, Germany.
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada.
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.affiliation: Department of Pediatric Neurology, Children's Hospital Oldenburg, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Marquart
authors.affiliation: Department of Pediatrics, University of California, San Diego, CA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Barshop
authors.affiliation: Department of Pediatric Neurology, Children's Hospital Cologne, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Grolik
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlune
authors.affiliation: Division of Birth Defects and Metabolism, Children's Memorial Hospital, Chicago, IL, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Angle
authors.affiliation: Unit of Medical Sciences, University of Madeira, Funchal, Madeira, Portugal.
authors.forename: Helena Caldeira
authors.initials: HC
authors.lastname: Araújo
authors.affiliation: Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Turgay
authors.initials: T
authors.lastname: Coskun
authors.affiliation: Pediatric Hospital CHUC-EPE, Coimbra, Portugal.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diogo
authors.affiliation: Department of Pediatrics, CHEO, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Geraghty
authors.affiliation: Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Goknur
authors.initials: G
authors.lastname: Haliloglu
authors.affiliation: Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Konstantopoulou
authors.affiliation: Department of Pediatrics, Child Neurology and Psychiatry, La Sapienza University of Rome, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Department of Pediatrics, Sainte Justine University Hospital Centre, Montreal, QC, Canada.
authors.forename: Alina
authors.initials: A
authors.lastname: Levtova
authors.affiliation: Department of Pediatrics, Queen's University, Kingston, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mackenzie
authors.affiliation: Division of Genetics, University of Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Department of Pediatrics and Child Health, University of Mannitoba, Winnipeg, MB, Canada.
authors.forename: Aizeddin A
authors.initials: AA
authors.lastname: Mhanni
authors.affiliation: Department of Pediatrics, Sainte Justine University Hospital Centre, Montreal, QC, Canada; Sainte Justine University Research Center, Montreal, QC, Canada.
authors.forename: Grant
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Department of Genetic Medicine, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Newlove
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Renaud
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Hopital Necker Enfants Malades, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, The Netherlands.
authors.forename: Francjan J
authors.initials: FJ
authors.lastname: van Spronsen
authors.affiliation: Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, The Netherlands.
authors.forename: Krijn T
authors.initials: KT
authors.lastname: Verbruggen
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Yuskiv
authors.affiliation: Department of Pediatrics, University of California, San Diego, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Nyhan
authors.affiliation: Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada; Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
mesh_terms: D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000378:metabolism* / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003401:Creatine / Q000378:metabolism* / Q000627:therapeutic use*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000378:metabolism / Q000628:therapy*; D007805:Language Development Disorders / Q000175:diagnosis / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000151:congenital* / Q000175:diagnosis / Q000378:metabolism / Q000628:therapy; D009952:Ornithine / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic; D020160:Sodium Benzoate / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001120:Arginine; D009952:Ornithine; D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D003401:Creatine; D020160:Sodium Benzoate; D005998:Glycine
keywords: Autism; Creatine deficiency; Magnetic resonance spectroscopy; Neurodevelopmental outcome; Speech delay; Treatment evidence