Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

Stöckler‐Ipsiroglu, Sylvia; Apatean, Delia; Battini, Roberta; DeBrosse, Suzanne D.; Dessoffy, Kimberley; Edvardson, Simon; Eichler, Florian; Johnston, Katherine; Koeller, David M.; Nouioua, Sonia; Tazir, Mériem; Verma, Ashok; Dowling, Monica; Wierenga, Klaas J.; Wierenga, Andrea; Zhang, Victor; Wong, Lee Jun

doi:10.1016/j.ymgme.2015.10.003

Cited by 53 publications

(40 citation statements)

References 19 publications

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“…Further concerns have been raised about a possible GAA neurotoxicity in inborn errors of creatine metabolism, with neurocognitive dysfunction in GAMT deficiency accompanied by GAA accumulation and creatine deficit in the brain (Hanna-ElDaher et al 2015). A more severe phenotype reported in GAMT deficiency, as compared to AGAT deficiency which is characterized by low levels of both GAA and creatine (Stockler-Ipsiroglu et al 2015), suggests specific GAA-induced neuropathological features. The possibility that dietary GAA accumulates in the normal brain to toxic levels (~ 300-fold above normal in the brain of GAMT deficient patients) and contributes to neurotoxicity is highly unlikely due to transport limitations (Braissant 2012) yet no conclusive human studies are available so far.…”

Section: Page 5 Of 10mentioning

confidence: 95%

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men

Ostojić

Drid

2016

Appl. Physiol. Nutr. Metab.

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In this randomized, double-blind, crossover trial, we evaluated whether 4-week supplementation with guanidinoacetic acid (GAA) is superior to creatine in facilitating creatine levels in healthy men (n = 5). GAA (3.0 g/day) resulted in a more powerful rise (up to 16.2%) in tissue creatine levels in vastus medialis muscle, middle-cerebellar peduncle, and paracentral grey matter, as compared with creatine (P < 0.05). These results indicate that GAA as a preferred alternative to creatine for improved bioenergetics in energy-demanding tissues.

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Section: Page 5 Of 10mentioning

confidence: 95%

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men

Ostojić

Drid

2016

Appl. Physiol. Nutr. Metab.

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“…One of the primary concerns in designing treatment protocols should be targeting the critical periods in which Cr is necessary to facilitate cognitive processes. It has been shown that early‐life Cr supplementation provides a greater cognitive improvement than later life treatment in individuals with mutations of the Cr‐synthesis genes Arginine: glycine amidinotransferase ( AGAT ) or guanidinoacetate‐methyltransferase (GAMT) . Mitochondrial dysfunction or CK inhibition reduces the growth and dendritic arborization of cerebellar Purkinje cells in vitro .…”

Section: Introductionmentioning

confidence: 99%

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

Udobi

Delcimmuto

Kokenge

et al. 2019

J of Inher Metab Disea

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Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (ATP). The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X‐linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen‐inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5 to 10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.

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“…As above stated (see Section 1), the body obtains the creatine it needs partly from dietary sources and partly from endogenous synthesis and arginine:glycine amidinotransferase (AGAT) deficiency …”

Section: Creatine Administration In Conditions Where Creatine Is Missmentioning

confidence: 99%

“…Two rare diseases exist where the body cannot synthesize creatine due to genetic lack of the relevant enzymes: guanidinoacetate methyltransferase (GAMT) deficiency and arginine:glycine amidinotransferase (AGAT) deficiency …”

Section: Creatine Administration In Conditions Where Creatine Is Missmentioning

confidence: 99%

Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle

Balestrino

Adriano

2019

Medicinal Research Reviews

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Creatine is pivotal in energy metabolism of muscle and brain cells, both in physiological and in pathological conditions. Additionally, creatine facilitates the differentiation of muscle and neuronal cells. Evidence of effectiveness of creatine supplementation in improving several clinical conditions is now substantial, and we review it in this paper. In hereditary diseases where its synthesis is impaired, creatine has a disease‐modifying capacity, especially when started soon after birth. Strong evidence, including a Cochrane meta‐analysis, shows that it improves muscular strength and general well‐being in muscular dystrophies. Significant evidence exists also of its effectiveness in secondary prevention of statin myopathy and of treatment‐resistant depression in women. Vegetarians and vegans do not consume any dietary creatine and must synthesize all they need, spending most of their methylation capacity. Nevertheless, they have a lower muscular concentration of creatine. Creatine supplementation has proved effective in increasing muscular and neuropsychological performance in vegetarians or vegans and should, therefore, be recommended especially in those of them who are athletes, heavy‐duty laborers or who undergo intense mental effort. Convincing evidence also exists of creatine effectiveness in muscular atrophy and sarcopenia in the elderly, and in brain energy shortage (mental fatigue, sleep deprivation, environmental hypoxia as in mountain climbing, and advanced age). Furthermore, we review more randomized, placebo‐controlled trials showing that creatine supplementation is safe up to 20 g/d, with a possible caveat only in people with kidney disease. We trust that the evidence we review will be translated into clinical practice and will spur more research on these subjects.

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Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

Cited by 53 publications

References 19 publications

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle

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