Yannay Khaikin1, Sarah Sidky2, Jose Abdenur3, Arnaud Anastasi4, Diana Ballhausen5, Sabrina Buoni6, Alicia Chan7, David Cheillan8, Nathalie Dorison9, Alice Goldenberg10, Jennifer Goldstein11, Floris C Hofstede12, Marie-Line Jacquemont13, Dwight D Koeberl11, Laurence Lion-Francois14, Allan Meldgaard Lund15, Karine Mention16, Helen Mundy17, Declan O'Rourke18, Gaele Pitelet19, Miquel Raspall-Chaure20, Maria Tassini21, Thierry Billette de Villemeur22, Monique Williams23, Gajja S Salomons24, Saadet Mercimek-Andrews25. 1. Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. 2. Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada. 3. Division of Metabolic Disorders, CHOC Children's, Hospital Orange, CA, USA. 4. Department of Medicine, Centre Hospitalier Le Vinatier, Bron, France. 5. Center of Molecular Diseases, University Children's Hospital Lausanne, Lausanne, Switzerland. 6. Department of Molecular and Developmental Medicine, Section of Child Neurology and Psychiatry, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy. 7. Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada. 8. Service Maladies Héréditaires du Métabolisme, Groupement Hospitalier Est, Hospices Civils de Lyon - INSERM1060, Université de Lyon, Lyon France. 9. AP-HP Service de Neuropediatrie, Pathologie du Developpement, Hopital Trousseau, Paris, France. 10. Service de Génétique Médicale, CHU Rouen, Rouen, France. 11. Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA. 12. Wilhelmina Children's Hospital, Utrecht, The Netherlands. 13. Unité de Génétique médicale, CHU La Réunion, Saint Pierre, France. 14. Service de Neuropédiatrie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. 15. Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen, Denmark. 16. Centre de référence des Maladies Héréditaires du métabolisme, Hopital Jeanne De Flandre, CHRU Lille, France. 17. Evelina Centre for Inherited Metabolic Disease, Goys and St Thomas NHS Foundation Trust, Evelina Children's Hospital, London, UK. 18. Temple Street Children's University Hospital, Temple Street, Dublin, Ireland. 19. Department of Pediatrics, Chulenval, Nice, France. 20. Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 21. The NMR Center University of Siena, Siena, Italy. 22. Sorbonne University UPMC GRC ConCer-LD and AP-HP, Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris, France. 23. Department of Pediatrics, Sophia Childrens Hospital, Erasmus Medical Center, The Netherlands; Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center & Neuroscience Campus, Amsterdam, The Netherlands. 24. Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center & Neuroscience Campus, Amsterdam, The Netherlands. 25. Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: saadet.andrews@sickkids.ca.
Abstract
PURPOSE: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. METHODS: Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. RESULTS: There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. CONCLUSION: In our small patient cohort, there seems to be no phenotype-genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype. Crown
PURPOSE:Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. METHODS: Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. RESULTS: There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. CONCLUSION: In our small patient cohort, there seems to be no phenotype-genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype. Crown
Authors: Elsa Ghirardini; Francesco Calugi; Giulia Sagona; Federica Di Vetta; Martina Palma; Roberta Battini; Giovanni Cioni; Tommaso Pizzorusso; Laura Baroncelli Journal: Genes (Basel) Date: 2021-07-24 Impact factor: 4.096
Authors: Eva M M Hoytema van Konijnenburg; Saskia B Wortmann; Marina J Koelewijn; Laura A Tseng; Roderick Houben; Sylvia Stöckler-Ipsiroglu; Carlos R Ferreira; Clara D M van Karnebeek Journal: Orphanet J Rare Dis Date: 2021-04-12 Impact factor: 4.123