Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring

Sylvia Stockler-Ipsiroglu; Clara van Karnebeek; Nicola Longo; G Christoph Korenke; Saadet Mercimek-Mahmutoglu; Iris Marquart; Bruce Barshop; Christiane Grolik; Andrea Schlune; Brad Angle; Helena Caldeira Araújo; Turgay Coskun; Luisa Diogo; Michael Geraghty; Goknur Haliloglu; Vassiliki Konstantopoulou; Vincenzo Leuzzi; Alina Levtova; Jennifer Mackenzie; Bruno Maranda; Aizeddin A Mhanni; Grant Mitchell; Andrew Morris; Theresa Newlove; Deborah Renaud; Fernando Scaglia; Vassili Valayannopoulos; Francjan J van Spronsen; Krijn T Verbruggen; Nataliya Yuskiv; William Nyhan; Andreas Schulze

doi:10.1016/j.ymgme.2013.10.018

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.

Authors

Sylvia Stockler-Ipsiroglu¹, Clara van Karnebeek², Nicola Longo³, G Christoph Korenke⁴, Saadet Mercimek-Mahmutoglu⁵, Iris Marquart⁴, Bruce Barshop⁶, Christiane Grolik⁷, Andrea Schlune⁸, Brad Angle⁹, Helena Caldeira Araújo¹⁰, Turgay Coskun¹¹, Luisa Diogo¹², Michael Geraghty¹³, Goknur Haliloglu¹¹, Vassiliki Konstantopoulou¹⁴, Vincenzo Leuzzi¹⁵, Alina Levtova¹⁶, Jennifer Mackenzie¹⁷, Bruno Maranda¹⁸, Aizeddin A Mhanni¹⁹, Grant Mitchell²⁰, Andrew Morris²¹, Theresa Newlove²², Deborah Renaud²³, Fernando Scaglia²⁴, Vassili Valayannopoulos²⁵, Francjan J van Spronsen²⁶, Krijn T Verbruggen²⁶, Nataliya Yuskiv²², William Nyhan⁶, Andreas Schulze²⁷

Affiliations

¹ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. Electronic address: sstockler@cw.bc.ca.
² Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
³ Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
⁴ Department of Pediatric Neurology, Children's Hospital Oldenburg, Germany.
⁵ Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada.
⁶ Department of Pediatrics, University of California, San Diego, CA, USA.
⁷ Department of Pediatric Neurology, Children's Hospital Cologne, Germany.
⁸ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
⁹ Division of Birth Defects and Metabolism, Children's Memorial Hospital, Chicago, IL, USA.
¹⁰ Unit of Medical Sciences, University of Madeira, Funchal, Madeira, Portugal.
¹¹ Department of Pediatrics, Hacettepe University, Ankara, Turkey.
¹² Pediatric Hospital CHUC-EPE, Coimbra, Portugal.
¹³ Department of Pediatrics, CHEO, University of Ottawa, Ottawa, ON, Canada.
¹⁴ Department of Pediatrics, Medical University Vienna, Vienna, Austria.
¹⁵ Department of Pediatrics, Child Neurology and Psychiatry, La Sapienza University of Rome, Rome, Italy.
¹⁶ Department of Pediatrics, Sainte Justine University Hospital Centre, Montreal, QC, Canada.
¹⁷ Department of Pediatrics, Queen's University, Kingston, ON, Canada.
¹⁸ Division of Genetics, University of Sherbrooke, Sherbrooke, QC, Canada.
¹⁹ Department of Pediatrics and Child Health, University of Mannitoba, Winnipeg, MB, Canada.
²⁰ Department of Pediatrics, Sainte Justine University Hospital Centre, Montreal, QC, Canada; Sainte Justine University Research Center, Montreal, QC, Canada.
²¹ Department of Genetic Medicine, Manchester Academic Health Sciences Centre, Manchester, UK.
²² Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
²³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁵ Reference Center for Inborn Errors of Metabolism, Hopital Necker Enfants Malades, Paris, France.
²⁶ Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, The Netherlands.
²⁷ Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada; Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.

PMID: 24268530
DOI: 10.1016/j.ymgme.2013.10.018

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.

Keywords: Autism; Creatine deficiency; Magnetic resonance spectroscopy; Neurodevelopmental outcome; Speech delay; Treatment evidence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Arginine / metabolism*
Arginine / therapeutic use*
Brain / metabolism
Child
Child, Preschool
Combined Modality Therapy
Creatine / metabolism*
Creatine / therapeutic use*
Female
Glycine / analogs & derivatives*
Glycine / blood
Glycine / cerebrospinal fluid
Guanidinoacetate N-Methyltransferase / deficiency*
Guanidinoacetate N-Methyltransferase / metabolism
Humans
Infant
Infant, Newborn
Intellectual Disability / metabolism
Intellectual Disability / therapy*
Language Development Disorders / diagnosis
Language Development Disorders / metabolism
Language Development Disorders / therapy*
Male
Middle Aged
Movement Disorders / congenital*
Movement Disorders / diagnosis
Movement Disorders / metabolism
Movement Disorders / therapy
Ornithine / therapeutic use*
Practice Guidelines as Topic
Sodium Benzoate / therapeutic use*
Treatment Outcome
Young Adult

Substances

Arginine
Ornithine
Guanidinoacetate N-Methyltransferase
glycocyamine
Creatine
Sodium Benzoate
Glycine

Supplementary concepts

Guanidinoacetate methyltransferase deficiency