Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study

Abstract: Purpose: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidi noacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an in ternational 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 pa tients 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 ach ieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. Conclusion: In our small patient cohort, there seems to be no phenotypeegenotype corre lation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype. Supplementations decrease GAA accumulation by competitive inhibition of L-arginine:glycine amidinotransferase Guanidinoacetate methyltransferase (EC#2.1.1.2) (GAMT) deficiency (MIM #612736) is an autosomal recessively inheri ted creatine biosynthesis disorder.1,2 Pathogenic variants in GAMT (MIM #601240) (NM_000156.5) result in brain creatine depletion and guanidinoacetate (GAA) accumulation in body fluids.3 Since its first description in 1994, less than 120 patients have been reported worldwide.4 GAMT deficiency is a neurodegenerative disease and causes global developmental delay (GDD), intellectual disability (ID), hypotonia, epilepsy, movement disorder and behavioral problems.4e8 Elevated GAA levels in urine, plasma or cerebrospinal fluid (CSF) and/or creatine defi ciency in brain proton magnetic resonance spectroscopy (1H-MRS) raise the suspicion of GAMT deficiency. The diagnosis is confirmed by direct sequencing of GAMT.4,5,8,9 The treatment of GAMT deficiency consists of creatine, ornithine, arginine- or protein-restricted diet and sodium benzoate.2,5,8,10e14 Creatine supplementation replenishes cerebral creatine levels. Creatine and ornithine (AGAT) activity, which is the first enzyme in the creatine synthesis. Arginine and glycine are the precursor amino acids in creatine synthesis. Arginine- or protein-restricted diet and sodium benzoate by conjugating glycine decrease GAA production by decreasing precursor amino acids of creatine synthesis.2,5,8,10e14 Limited effects of arginine restricted diet and sodium benzoate therapy in addition to ornithine and creatine have been reported in single cases.12,13 The majority of patients diagnosed at the symptomatic stage of GAMT deficiency cannot achieve normal neurodevelopmental or neurocognitive functions. However, three patients treated in the neonatal period achieved normal neurodevelopmental outcome.7,11,14 Standard recommended treatment protocols are not applied to all patients due to restricted accessibility to ornithine, limited resources of arginine content in foods, compliance problems due to difficulties in adhering to strict protein restricted diet, unpleasant taste of medical food and sodium benzoate and lack of metabolic dieticians to monitor diet therapy.

Link to article: https://doi.org/10.1016/j.ejpn.2018.02.007

PubMed:  https://pubmed.ncbi.nlm.nih.gov/29506905/

Authors: Yannay Khaikin, Sarah Sidky, Jose Abdenur, Arnaud Anastasi, Diana Ballhausen, Sabrina Buoni, Alicia Chan, David Cheillan, Nathalie Dorison, Alice Goldenberg, Jennifer Goldstein, Floris C. Hofstede, Marie-Line Jacquemont, Dwight D. Koeberl, Laurence Lion-Francois, Allan Meldgaard Lund, Karine Mention, Helen Mundy, Declan O’Rourke, Gaele Pitelet, Miquel Raspall-Chaure, Maria Tassini, Thierry Billette de Villemeur, Monique Williams, Gajja S. Salomons, Saadet Mercimek-Andrews

Key Terms: GAMT, Clinical Study, Supplements, Mutation Study, Diagnostic, MRS, Pediatric Patient, Male + Female Patients