Brain creatine depletion: Guanidinoacetate methyltransferase deficiency (improving with creatine supplementation)

To increase our understanding of imprinting and epigenetic gene regulation, we undertook a search for new imprinted genes. We identified Gatm, a gene that encodes L-arginine:glycine amidinotransferase, which catalyzes the rate-limiting step in the synthesis of creatine. In mouse, Gatm is expressed during development and is imprinted in the placenta and yolk sac, but not in embryonic tissues. The Gatm gene maps to mouse chromosome 2 in a region not previously shown to contain imprinted genes. To determine whether Gatm is located in a cluster of imprinted genes, we investigated the expression pattern of genes located near Gatm: Duox1-2, Slc28a2, Slc30a4 and a transcript corresponding to LOC214616. We found no evidence that any of these genes is imprinted in placenta. We show that a CpG island associated with Gatm is unmethylated, as is a large CpG island associated with a neighboring gene. This genomic screen for novel imprinted genes has elucidated a new connection between imprinting and creatine metabolism during embryonic development in mammals.

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“…include mutations in the GATM gene itself (27), as well as other genes required for synthesis or transport of creatine (28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta

Sandell

Guan

Ingram

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Only 14 patients having this disease have been published so far [Stöckler et al, 1994;Ganesan et al, 1997;Schulze et al, 1997Schulze et al, , 2003Ensenauer et al, 2000;Leuzzi et al, 2000;Van der Knaap et al, 2000;Korall et al, 2002;Stöckler-Ipsiroglu and Jakobs, 2002]. In this study we report on the clinical outcome and laboratory findings of five (four proven and one presumed) patients with GAMT deficiency who were initially investigated based on a high urine uric acid/creatinine ratio [Caldeira Araú jo et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation

Araújo

Smit

Verhoeven

et al. 2005

American J of Med Genetics Pt A

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Our study describes the adult clinical and biochemical spectrum of guanidinoacetate methyltransferase (GAMT) deficiency, a recently discovered inborn error of metabolism. The majority of the previous reports dealt with pediatric patients, in contrast to the present study. A total of 180 institutionalized patients with a severe mental handicap were investigated for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of guanidinoacetate (GAA). Four patients (three related and one from an unrelated family) were identified with GAMT-deficiency. A fifth patient had died before a biochemical diagnosis could be made. They all had shown a normal psychomotor development for the first year of life, after which they developed a profound mental retardation. Three out of four had convulsions and all four totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired and two novel mutations were identified: the 59 G > C and 506 G > A missense mutations. Urinary GAA was increased, but highly variable 347-1,624 mmol/mol creat (Controls <150 mmol/mol creat). In plasma and CSF the GAA levels were fairly constant at 17.3-27.0 mumol/L (Controls 1.33-3.33) and 11.0-12.4 mumol/L, respectively (Controls 0.068-0.114). GAMT deficiency in adults is associated with severe mental retardation and absence or limited speech development. Convulsions may be prominent. The nonspecific nature of the clinical findings as well as the limited availability of GAA assays and/or in vivo magnetic resonance spectroscopy of the brain may mean that many more patients remain undiagnosed in institutions for persons with mental handicaps.

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“…18 ± 21 In animal models of several neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) 22 and Huntington's disease, 23 creatine has proven to be a remarkably potent neuroprotective agent. Orally supplemented creatine is transported by a speci®c creatine transporter into muscle and neural tissues 24 as measured non-invasively by 31 P-NMP spectroscopy, giving rise to a signi®cantly increased PCr/ATP ratio in the rat brain 25 or by 1H-NMR spectroscopy in either creatine-de®cient patients 26 or healthy subjects, 27 showing that total creatine concentration is elevated in the brain after creatine supplementation. In a recent study with several animal species the elevation by creatine supplementation of total creatine into various organs including the brain has been con®rmed by chemical analysis.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of oral creatine supplementation on spinal cord injury in rats

et al. 2002

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Study design: To evaluate a potential protective e ect of increased creatine levels in spinal cord injury (SCI) in an animal model. Objectives: Acute SCI initiates a series of cellular and molecular events in the injured tissue leading to further damage in the surrounding area. This secondary damage is partly due to ischemia and a fatal intracellular loss of energy. Phospho-creatine in conjunction with the creatine kinase isoenzyme system acts as a potent intracellular energy bu er. Oral creatine supplementation has been shown to elevate the phospho-creatine content in brain and muscle tissue, leading to neuroprotective e ects and increased muscle performance. Setting: Zurich, Switzerland. Methods: Twenty adult rats were fed for 4 weeks with or without creatine supplemented nutrition before undergoing a moderate spinal cord contusion. Results: Following an initial complete hindlimb paralysis, rats of both groups substantially recovered within 1 week. However, creatine fed animals scored 2.8 points better than the controls in the BBB open ®eld locomotor score (11.9 and 9.1 points respectively after 1 week; P=0.035, and 13 points compared to 11.4 after 2 weeks). The histological examination 2 weeks after SCI revealed that in all rats a cavity had developed which was comparable in size between the groups. In creatine fed rats, however, a signi®cantly smaller amount of scar tissue surrounding the cavity was found. Conclusions: Thus creatine treatment seems to reduce the spread of secondary injury. Our results favour a pretreatment of patients with creatine for neuroprotection in cases of elective intramedullary spinal surgery. Further studies are needed to evaluate the bene®t of immediate creatine administration in case of acute spinal cord or brain injury.

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Brain creatine depletion: Guanidinoacetate methyltransferase deficiency (improving with creatine supplementation)

Cited by 90 publications

References 9 publications

Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta

Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta

Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation

Protective effects of oral creatine supplementation on spinal cord injury in rats

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