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Published online before print July 19, 2006, doi:10.1212/01.wnl.0000234852.43688.bf)
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Received March 23, 2005
Accepted March 30, 2006

GAMT deficiency. Features, treatment, and outcome in an inborn error of creatine synthesis

S. Mercimek-Mahmutoglu MD, S. Stoeckler-Ipsiroglu MD*, A. Adami MD, R. Appleton MD, H. Caldeira Araújo PhD, M. Duran PhD, R. Ensenauer MD, E. Fernandez-Alvarez MD, P. Garcia MD, C. Grolik MD, C. B. Item PhD, V. Leuzzi MD, I. Marquardt MD, A. Mühl PhD, R. A. Saelke-Kellermann MD, G. S. Salomons PhD, A. Schulze MD, R. Surtees MD, M. S. van der Knaap MD, R. Vasconcelos MD, N. M. Verhoeven PhD, L. Vilarinho PhD, E. Wilichowski MD, and C. Jakobs PhD

From the Division of Biochemical Diseases (S.M.-M., S.S.I.), British Columbia Children’s Hospital, Vancouver, Canada; U.O. di Pediatria Azienda (A.A.), Ospidaliera San Carlo Borromeo, Milan, Italy; Royal Liverpool Children’s Hospital (R.A.), NHS Trust Hospital, Liverpool, England; Unidade de Ciências da Saúde (H.C.A.), Universidade da Madeira, Funchal, Portugal; Laboratory Genetic Metabolic Diseases (M.D.), Academic Medical Centre, Amsterdam, The Netherlands; Pediatric Research enter (R.E.), Dr. von Haunersches Kinderspital, Ludwig-Maximilians-University Munich, Germany; Neuropediatric Department (E.F.A.), Hospital Sant Joan de Déu, Barcelona, Spain; Hospital Pediatrico de Coimbra (P.G.), Portugal; Kinderkrankenhaus Kliniken Stadt Koeln (C.G.), Koeln, Germany; Department of Pediatrics (C.B.I., A.M.), Medical University Vienna, Vienna, Austria; Department of Child Neurology and Psychiatry (V.L.), Universita La Sapienza, Rome, Italy; Zentrum fuer Kinder- und Jungendmedizin (I.M.), Abteilung fuer Neuropaediatrie, Oldenburg, Germany; Swiss Epilepsy Centre (R.A.S.-K.), Zurich, Switzerland; Department of Clinical Chemistry (C.J., G.S.S., N.M.V.), Metabolic Unit and Department of Child Neurology (M.v.d.K.), VU University Medical Center Amsterdam, The Netherlands; AS: Department of Pediatrics I (A.S.), University Children’s Hospital, Heidelberg, Germany; Neurosciences Unit (R.S.), Institute of Child Health, Wolfson Centre, London, UK; Centro Psicopedagógico da Sagrada Família (R.V.), Funchal, Portugal; Unidade de Biologia Clinica (L.V.), Instituto de Genetica Medica Jacinto de Magalhaes, Porto, Portugal; Children’s Hospital (E.W.), Georg-August-University, Goettingen, Germany.


* To whom correspondence should be addressed. E-mail: sstockler{at}cw.bc.ca.

Abstract-- Background: Guanidinoactetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine synthesis. The authors analyzed clinical, biochemical, and molecular findings in 27 patients. Methods: The authors collected data from questionnaires and literature reports. A score including degree of intellectual disability, epileptic seizures, and movement disorder was developed and used to classify clinical phenotype as severe, moderate, or mild. Score and biochemical data were assessed before and during treatment with oral creatine substitution alone or with additional dietary arginine restriction and ornithine supplementation. Results: Intellectual disability, epileptic seizures, guanidinoacetate accumulation in body fluids, and deficiency of brain creatine were common in all 27 patients. Twelve patients had severe, 12 patients had moderate, and three patients had mild clinical phenotype. Twenty-one of 27 (78%) patients had severe intellectual disability (estimated IQ 20 to 34). There was no obvious correlation between severity of the clinical phenotype, guanidinoacetate accumulation in body fluids, and GAMT mutations. Treatment resulted in almost normalized cerebral creatine levels, reduced guanidinoacetate accumulation, and in improvement of epilepsy and movement disorder, whereas the degree of intellectual disability remained unchanged. Conclusion: Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.




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