Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans

Item, Chike B.; Stöckler‐Ipsiroglu, Sylvia; Stromberger, Carmen; Mühl, Adolf; Alessandrı̀, Maria Grazia; Bianchi, Maria Cristina; Tosetti, Michela; Fornai, Francesco; Cioni, Giovanni

doi:10.1086/323765

Cited by 232 publications

(151 citation statements)

References 26 publications

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“…Treatment of inborn errors of creatine metabolism (arginine:glycine amidinotransferase and S-adenosyl-l-methionine:Nguanidinoacetate methyltransferase deficiency) showed striking improvement after CS, 14,15 but steady-state concentrations for brain creatine content were reached only after several months of treatment. 16 For ethical reasons, we could only start supple- http://www.pediatrics.org/cgi/content/full/113/4/e303 e305 menting our patients postnatally and after the onset of AOP (median age: 9 days), where CS in the abovementioned animal studies 6 started during fetal life.…”

Section: Discussionmentioning

confidence: 99%

“…In arginine:glycine amidinotransferase and S-adenosyl-l-methionine:N-guanidinoacetate methyltransferase deficiency, neurologic symptoms occur only several months after birth, 14,15 which suggests that these patients may have been fully provided with maternal creatine in utero and that it took some time after birth to become depleted of the maternal creatine pool. Thus, it is conceivable that a lack of PCr in the brain is less relevant to the occurrence of hypoxic ventilatory depression in preterm infants than thought originally.…”

Section: Discussionmentioning

confidence: 99%

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Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

et al. 2004

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ABSTRACT. Background. Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP.Methods. Infants were eligible for this double-blind, controlled trial if gestational age was <32 weeks and AOP was severe enough to require treatment with caffeine. If they had >1 desaturation (pulse oximeter saturation [SpO 2 ] < 80%) or bradycardia (heart rate < two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO 2 ) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (>10 seconds), baseline heart and respiratory rate, and SpO 2 .Results. Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25-30) vs 27 (25-30) weeks, and at study 29 (26 -36) vs 29 (27-33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18 -102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427-11807). CS, however, had no effect on the combined rate of bradycardia and desaturation W ith decreasing use of mechanical ventilation in extremely low birth weight infants, apnea of prematurity (AOP) has become one of the most common problems in neonatal intensive care. AOP is defined as the recurrence of a variable combination of apnea, bradycardia, and desaturation, with the latter 2 components posing a potential risk to neurodevelopment. 1 Current therapy including methylxanthines, nasal continuous positive airway pressure (CPAP), and doxapram often fails to eradicate symptoms. 2 The pathophysiology of AOP is incompletely understood. One factor potentially involved is the socalled hypoxic ventilatory depression, the fetal response to hypoxia that persists until ϳ36 weeks' gestation. 3 The exact pathophysiology mediating this fetal response is unknown, but 1 substance likely involved is creatine, which is a substrate in the regeneration of adenosine diphosphate to adenosine triphosphate via the creatine kinase reaction (phosphocreatine [PCr] ϩ adenosine 5Ј-diphosphate ϩ H ϩ 7 creatine ϩ adenosine 5Ј-triphosphate) during nonoxidative phosphorylation. 4,5 Neonatal mice whose dams were fed creatine (2 g/kg per day for 20 days) before delivery showed significant increases in amplitude and duration of hypoglossal bursts and in synaptic drive currents of single respiratory neurons during anoxia 6 and a reduced decrease in minute ventilation during exposure to Fio 2 o...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

et al. 2004

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“…In addition, the CNS is the main affected target in infants with a creatine deficiency syndrome attributable to guanidinoacetate methyltransferase, arginine:glycine amidinotransferase, or Cr transporter deficiencies. Such patients exhibit delayed psychomotor development or bilateral myelination delay (Stöckler et al, 1994;Schulze et al, 1997;Item et al, 2001;Salomons et al, 2001). We and others have also shown that the synthesis of arginine, the main precursor of creatine, is altered by hyperammonemia (Rao et al, 1995;Braissant et al, 1999b).…”

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confidence: 99%

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Braissant¹,

Henry²,

Villard³

et al. 2002

J. Neurosci.

100

137

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Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH 4 Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.

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“…41 AGAT deficiency appears to be much rarer, with fewer than 20 patients reported to date. 3,30,[42][43][44][45][46] Modes of inheritance CDS due to AGAT or GAMT deficiencies are inherited as autosomal recessive traits, while deficiency of CRTR is inherited as an X-linked trait.…”

Section: Prevalencementioning

confidence: 99%

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

Sharer

Bodamer

Longo

et al. 2017

Genetics in Medicine

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Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

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Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans

Cited by 232 publications

References 26 publications

Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

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