Thirteen New Patients with Guanidinoacetate Methyltransferase Deficiency and Functional Characterization of Nineteen Novel Missense Variants in the GAMT Gene
Corresponding Author
Saadet Mercimek-Mahmutoglu
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
These authors share first authorship.
Correspondence to: Saadet Mercimek-Mahmutoglu, FCCMG, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada. E-mail: [email protected]; Gajja S. Salomons, Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]Search for more papers by this authorJoseph Ndika
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
These authors share first authorship.
Search for more papers by this authorWarsha Kanhai
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorThierry Billette de Villemeur
AP-HP Service de Neuropédiatrie, Pathologie du Développement, Hôpital Trousseau, Paris, France
Search for more papers by this authorDavid Cheillan
Service Maladies Héréditaires du Métabolisme, Groupement Hospitalier Est, Hospices Civils de Lyon, France
Search for more papers by this authorErnst Christensen
Department of Clinical Genetics, Juliane Marie Center, Copenhagen, Denmark
Search for more papers by this authorNathalie Dorison
AP-HP Service de Neuropédiatrie, Pathologie du Développement, Hôpital Trousseau, Paris, France
Search for more papers by this authorVickie Hannig
Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
Search for more papers by this authorYvonne Hendriks
Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorFloris C. Hofstede
Wilhelmina Children's Hospital, Utrecht, The Netherlands
Search for more papers by this authorLaurence Lion-Francois
Service de Neuropédiatrie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Search for more papers by this authorAllan M. Lund
Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen, Denmark
Search for more papers by this authorHelen Mundy
Evelina Centre for Inherited Metabolic Disease, Goys and St Thomas NHS Foundation Trust, Evelina Children's Hospital, London, England
Search for more papers by this authorGaele Pitelet
Department of Pediatrics, Chulenval, Nice, France
Search for more papers by this authorMiquel Raspall-Chaure
Department of Paediatric Neurology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Search for more papers by this authorJessica A. Scott-Schwoerer
Department of Pediatrics, Division of Genetics and Metobolism, University of Wisconsin, Madison, Wisconsin
Search for more papers by this authorKatalin Szakszon
Institute Pediatrics, Clinical Genetics Center, University of Debrecen, Hungary
Search for more papers by this authorVassili Valayannopoulos
Reference Center for Inherited Metabolic Disease, Paris, France
Search for more papers by this authorMonique Williams
Department of Pediatrics, Sophia Childrens Hospital, Erasmus Medical Center, The Netherlands
Search for more papers by this authorCorresponding Author
Gajja S. Salomons
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Correspondence to: Saadet Mercimek-Mahmutoglu, FCCMG, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada. E-mail: [email protected]; Gajja S. Salomons, Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Saadet Mercimek-Mahmutoglu
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
These authors share first authorship.
Correspondence to: Saadet Mercimek-Mahmutoglu, FCCMG, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada. E-mail: [email protected]; Gajja S. Salomons, Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]Search for more papers by this authorJoseph Ndika
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
These authors share first authorship.
Search for more papers by this authorWarsha Kanhai
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorThierry Billette de Villemeur
AP-HP Service de Neuropédiatrie, Pathologie du Développement, Hôpital Trousseau, Paris, France
Search for more papers by this authorDavid Cheillan
Service Maladies Héréditaires du Métabolisme, Groupement Hospitalier Est, Hospices Civils de Lyon, France
Search for more papers by this authorErnst Christensen
Department of Clinical Genetics, Juliane Marie Center, Copenhagen, Denmark
Search for more papers by this authorNathalie Dorison
AP-HP Service de Neuropédiatrie, Pathologie du Développement, Hôpital Trousseau, Paris, France
Search for more papers by this authorVickie Hannig
Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
Search for more papers by this authorYvonne Hendriks
Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorFloris C. Hofstede
Wilhelmina Children's Hospital, Utrecht, The Netherlands
Search for more papers by this authorLaurence Lion-Francois
Service de Neuropédiatrie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Search for more papers by this authorAllan M. Lund
Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen, Denmark
Search for more papers by this authorHelen Mundy
Evelina Centre for Inherited Metabolic Disease, Goys and St Thomas NHS Foundation Trust, Evelina Children's Hospital, London, England
Search for more papers by this authorGaele Pitelet
Department of Pediatrics, Chulenval, Nice, France
Search for more papers by this authorMiquel Raspall-Chaure
Department of Paediatric Neurology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Search for more papers by this authorJessica A. Scott-Schwoerer
Department of Pediatrics, Division of Genetics and Metobolism, University of Wisconsin, Madison, Wisconsin
Search for more papers by this authorKatalin Szakszon
Institute Pediatrics, Clinical Genetics Center, University of Debrecen, Hungary
Search for more papers by this authorVassili Valayannopoulos
Reference Center for Inherited Metabolic Disease, Paris, France
Search for more papers by this authorMonique Williams
Department of Pediatrics, Sophia Childrens Hospital, Erasmus Medical Center, The Netherlands
Search for more papers by this authorCorresponding Author
Gajja S. Salomons
Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Correspondence to: Saadet Mercimek-Mahmutoglu, FCCMG, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada. E-mail: [email protected]; Gajja S. Salomons, Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]Search for more papers by this authorCommunicated by María-Jesús Sobrido
ABSTRACT
Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.
References
- Akiyama T, Osaka H, Shimbo H, Nakajiri T, Kobayashi K, Oka M, Endoh F, Yoshinaga H. 2014. A Japanese adult case of guanidinoacetate methyltransferase deficiency. JIMD Rep 12: 65–69.
10.1007/8904_2013_245 Google Scholar
- Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN. 2006a. Exocytotic release of creatine in rat brain. Synapse 60: 118–123.
- Almeida LS, Rosenberg EH, Martinez-Muñoz C, Verhoeven NM, Vilarinho L, Jakobs C, Salomons GS. 2006b. Overexpression of GAMT restores GAMT activity in primary GAMT-deficient fibroblasts. Mol Genet Metab 89: 392–394.
- Caldeira Araújo H, Smit W, Verhoeven NM, Salomons GS, Silva S, Vasconcelos R, Tomás H, Tavares de Almeida I, Jakobs C, Duran M. 2005. Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation. Am J Med Genet A 133A: 122–127.
- Cheillan D, Joncquel-Chevalier Curt M, Briand G, Salomons GS, Mention-Mulliez K, Dobbelaere D, Cuisset JM, Lion-François L, Portes VD, Chabli A, Valayannopoulos V, Benoist JF, et al. 2012. Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms. Orphanet J Rare Dis 7: 96.
- Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud D, Sun Q, Wong LJ. 2013. Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes. Mol Genet Metab 109: 260–268.
- Dhar SU, Scaglia F, Li FY, Smith L, Barshop BA, Eng CM, Haas RH, Hunter JV, Lotze T, Maranda B, Willis M, Abdenur JE, et al. 2009. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 96: 38–43.
- El-Gharbawy AH, Goldstein JL, Millington DS, Vaisnins AE, Schlune A, Barshop BA, Schulze A, Koeberl DD, Young SP. 2013. Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency. Mol Genet Metab 109: 215–217.
- Engelke UF, Tassini M, Hayek J, de Vries M, Bilos A, Vivi A, Valensin G, Buoni S, Zannolli R, Brussel W, Kremer B, Salomons GS, et al. 2009. Guanidinoacetate methyltransferase (GAMT) deficiency diagnosed by proton NMR spectroscopy of body fluids. NMR Biomed 22: 538–544.
- Fujioka M, Konishi K, Takata Y. 1988. Recombinant rat liver guanidinoacetate methyltransferase: reactivity and function of sulfhydryl groups. Biochemistry 27: 7658–7664.
- Fujioka M, Takata Y, Gomi T. 1991. Recombinant rat guanidinoacetate methyltransferase: structure and function of the NH2-terminal region as deduced by limited proteolysis. Arch Biochem Biophys 285: 181–186.
- Kabsch W, Sander C. 1983. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22: 2577–2637.
- Komoto J, Huang Y, Takata Y, Yamada T, Konishi K, Ogawa H, Gomi T, Fujioka M, Takusagawa F. 2002. Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase. J Mol Biol 320: 223–35.
- Komoto J, Yamada T, Takata Y, Konishi K, Ogawa H, Gomi T, Fujioka M, Takusagawa F. 2004. Catalytic mechanism of guanidinoacetate methyltransferase: crystal structures of guanidinoacetate methyltransferase ternary complexes. Biochemistry 43: 14385–14394.
- Leuzzi V, Carducci C, Carducci C, Matricardi M, Bianchi MC, Di Sabato ML, Artiola C, Antonozzi I. 2006. A mutation on exon 6 of guanidinoacetate methyltransferase (GAMT) gene supports a different function for isoform a and b of GAMT enzyme. Mol Genet Metab 87: 88–90.
- Lion-François L, Cheillan D, Pitelet G, Acquaviva-Bourdain C, Bussy G, Cotton F, Guibaud L, Gérard D, Rivier C, Vianey-Saban C, Jakobs C, Salomons GS, et al. 2006. High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 67: 1713–1714.
- Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, Appleton R, Araújo HC, Duran M, Ensenauer R, Fernandez-Alvarez E, Garcia P, Grolik C, Item CB, Leuzzi V, et al. 2006. GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 67: 480–484.
- Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Salomons GS. 2009. In: RA Pagon, MP Adam, TD Bird, CR Dolan, CT Fong, K Stephens, editors. Creatine deficiency syndromes. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle. p 1993–2013 [updated 2011 Aug 18].
- Mercimek-Mahmutoglu S, Dunbar M, Friesen A, Garret S, Hartnett C, Huh L, Sinclair G, Stockler S, Wellington S, Pouwels PJ, Salomons GS, Jakobs C. 2012a. Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency. Mol Genet Metab 105: 155–158.
- Mercimek-Mahmutoglu S, Sinclair G, van Dooren SJ, Kanhai W, Ashcraft P, Michel OJ, Nelson J, Betsalel OT, Sweetman L, Jakobs C, Salomons GS. 2012b. Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease. Mol Genet Metab 107: 433–437.
- Nasrallah F, Kraoua I, Joncquel-Chevalier Curt M, Bout MA, Taieb SH, Feki M, Khouja N, Briand G, Kaabachi N. 2012. Guanidinoacetate methyltransferase (GAMT) deficiency in two Tunisian siblings: clinical and biochemical features. Clin Lab 58: 427–432.
- O'Rourke DJ, Ryan S, Salomons G, Jakobs C, Monavari A, King MD. 2009. Guanidinoacetate methyltransferase (GAMT) deficiency: late onset of movement disorder and preserved expressive language. Dev Med Child Neurol 51: 404–407.
- Pauling L, Corey RB, Branson HR. 1951. The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. Proc Natl Acad Sci USA 37: 205–211.
- Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B, Knopp MV, De Deyn PP, Bremer HJ, Rating D. 1997. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 131: 626–631.
- Schulze A, Bachert P, Schlemmer H, Harting I, Polster T, Salomons GS, Verhoeven NM, Jakobs C, Fowler B, Hoffmann GF, Mayatepek E. 2003. Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol 53: 248–251.
- Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E. 2006. Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67: 719–721.
- Scot-Scwoerer JA, Obernolte L, Zabrowski A, Rice GM. 2011. Clinical improvement on treatment in a patient with guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 34(suppl 3): S126.
- Sempere A, Fons C, Arias A, Rodríguez-Pombo P, Merinero B, Alcaide P, Capdevila A, Ribes A, Duque R, Eirís J, Poo P, Fernández-Alvarez E, et al. 2009. Cerebral creatine deficiency: first Spanish patients harbouring mutations in GAMT gene. Med Clin (Barc) 133: 745–749.
- Stöckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K. 1996. Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 58: 914–922.
- Verbruggen KT, Sijens PE, Schulze A, Lunsing RJ, Jakobs C, Salomons GS, van Spronsen FJ. 2007. Successful treatment of a guanidinoacetate methyltransferase deficient patient: findings with relevance to treatment strategy and pathophysiology. Mol Genet Metab 91: 294–296.
- Verhoeven NM, Roos B, Struys EA, Salomons GS, van der Knaap MS, Jakobs C. 2004. Enzyme assay for diagnosis of guanidinoacetate methyltransferase deficiency. Clin Chem 50: 441–443.
- Viau KS, Ernst SL, Pasquali M, Botto LD, Hedlund G, Longo N. 2013. Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 110: 255–262.
- Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. 1992. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the Fphosphocreatine circuit for cellular energy homeostasis. Biochem J 281: 21–40.
- Wyss M, Kaddurah-Daouk R. 2000. Creatine and creatinine metabolism. Physiol Rev 80: 1107–1213.
