Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.
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PMID:Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. 1155 93

Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.
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PMID:Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? 1204 43

Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the proband's AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The proband's parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patient's lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.
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PMID:Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. 1246 79

Creatine metabolism disorders have so far been described at the level of two synthetic steps, guanidinoacetate N-methyltransferase and arginine:glycine amidinotransferase, and at the level of the creatine transporter 1. Guanidinoacetate N-methyltransferase and arginine:glycine amidinotransferase deficiency respond positively to substitutive treatment with creatine monohydrate. Guanidinoacetate N-methyltransferase deficiency results in a severe neurologic disease (age of onset 3 months to 2 years) characterized by developmental arrest, neurologic deterioration, movement disorders, mental retardation, autistic-like behavior, and epilepsy. Severe early-onset epilepsy with pleomorphic seizures is a key symptom of this disorder. Data suggest that in patients with guanidinoacetate N-methyltransferase deficiency, epilepsy and associated electroencephalographic abnormalities are more responsive to creatine supplementation than to conventional antiepilepsy drugs. Arginine:glycine amidinotransferase and creatine transporter 1 mainly present with mental retardation and severe language disorder. All cases of creatine disorders reported to date have been detected by brain proton magnetic resonance spectroscopy, an expensive technique not routinely used in pediatric neurology. A potential diagnostic strategy to select patients for evaluation using proton magnetic resonance spectroscopy is proposed in this review.
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PMID:Inborn errors of creatine metabolism and epilepsy: clinical features, diagnosis, and treatment. 1259 58

Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes--the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment. The study of creatine deficiency syndromes and their comparative consideration contributes to the better understanding of the pathophysiological role of creatine and other guanidino compounds in man.
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PMID:Creatine deficiency syndromes. 1270 24

Creatine deficiency syndromes are a newly described group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoaceteate methyltransferase (GAMT) deficiency) and creatine transport (creatine transporter (CRTR) deficiency). The common clinical denominator of creatine deficiency syndromes is mental retardation and epilepsy, suggesting the main involvement of cerebral grey matter (grey matter disease). Patients with GAMT deficiency exhibit a more complex clinical phenotype with dystonic hyperkinetic movement disorder and epilepsy that in some cases is unresponsive to pharmacological treatment. The common biochemical denominator of creatine deficiency syndromes is cerebral creatine deficiency which is demonstrated by in vivo proton magnetic resonance spectroscopy. Measurement of guanidinoacetate in body fluids may discriminate GAMT (high concentration), AGAT (low concentration) and CRTR (normal concentration). Further biochemical characteristics include changes in creatine and creatinine concentrations in body fluids. GAMT and AGAT deficiency are treatable by oral creatine supplementation, while patients with CRTR deficiency do not respond to this type of treatment. Further recognition of patients will be of major importance for the estimation of the frequency, for the understanding of phenotypic variations and for treatment strategies.
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PMID:Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. 1288 68

Creatine deficiency syndromes are a newly described group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency) and of creatine transport (creatine transporter (CRTR) deficiency). The common clinical feature of creatine deficiency syndromes is mental retardation and epilepsy suggesting main involvement of cerebral gray matter. The typical biochemical abnormality of creatine deficiency syndromes is cerebral creatine deficiency, which is demonstrated by in vivo proton magnetic resonance spectroscopy. Measurement of guanidinoacetate in body fluids may discriminate between the GAMT (high concentration), AGAT (low concentration) and CRTR (normal concentration) deficiencies. Further biochemical characteristics include changes in creatine and creatinine concentrations in body fluids. GAMT and AGAT deficiency are treatable by oral creatine supplementation, while patients with CRTR deficiency do not respond to this type of treatment. The creatine deficiency syndromes are underdiagnosed, so their possibility should be considered in all children affected by unexplained mental retardation, seizures and speech delay.
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PMID:Biochemical and clinical characteristics of creatine deficiency syndromes. 1562 59

In recent years, three inherited defects in the biosynthesis and transport of creatine have been described. The biosynthetic defects include deficiencies of L-arginine:glycine amidinotransferase and guanidinoacetate methyltransferase. The third defect is a functional defect in the creatine transporter (SLC6A8). Clinical symptoms of the three defects vary in severity, are aspecific and include mental retardation with severe speech delay, autistiform behaviour, and epilepsy. Some patients with GAMT deficiency exhibit a more complex clinical phenotype with extrapyramidal movement disorder. All three defects can be diagnosed by in vivo proton magnetic resonance spectroscopy of the brain, which shows a severe reduction or absence of creatine. Laboratory investigations for the diagnosis start with the analysis of guanidinoacetate, creatine and creatinine in body fluids (plasma and urine). Based on these findings, enzyme assays for AGAT or GAMT, or a creatine uptake assay for the transporter defect can be performed. DNA mutation analysis of the genes involved can prove the defects at the molecular level. To diagnose female patients with SLC6A8 deficiency, mutation analysis may be the only choice.
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PMID:Laboratory diagnosis of defects of creatine biosynthesis and transport. 1616 44

Arginine:glycine amidinotransferase deficiency is a treatable inborn error of creatine synthesis, characterized by mental retardation, language impairment, and behavioral disorders. We describe a patient in whom arginine:glycine amidinotransferase was diagnosed at birth and treated at 4 months with creatine supplementation. In contrast with his 2 older sisters, he had normal psychomotor development at 18 months.
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PMID:Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. 1676 97

Inherited defects in creatine biosynthesis and cellular uptake are neurometabolic disorders characterized by seizures, developmental delay, mental retardation, autistic-like behavior, and creatine deficiency in the brain. Metabolic screening of these disorders is possible using analytical techniques that quantify creatine and its precursor guanidinoacetate in urine, plasma, or cerebrospinal fluid (CSF). Elevated creatine in urine is suggestive of a deficiency of the X-linked creatine transporter, SLC6A8. Decreased or elevated levels of guanidinoacetate in urine, plasma, or CSF suggest deficiencies of the creatine biosynthetic enzymes, arginine:glycine amidinotransferase (AGAT) or guanidinoacetate methyltransferase (GAMT), respectively. This unit describes three stable isotope dilution-mass spectrometric methods for analyzing creatine and guanidinoacetate. Gas chromatography/mass spectrometry with negative-ion chemical ionization is a highly sensitive technique, suitable for detection of low analyte levels resulting from AGAT deficiency and in CSF. The two liquid chromatography-tandem mass spectrometric approaches are amenable to high-throughput screening and have simple sample preparation requirements.
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PMID:Quantification of creatine and guanidinoacetate using GC-MS and LC-MS/MS for the detection of cerebral creatine deficiency syndromes. 1842 9


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