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Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report.
Alessandrì, MG, Strigini, F, Cioni, G, Battini, R
BMC pregnancy and childbirth. 2020;(1):506
Abstract
BACKGROUND Creatine (Cr), an amino acid derivative, is one of the most important sources of energy acting as both a spatial and temporal energy buffer through its phosphorylated analogue phosphocreatine (PCr) and creatine kinase (CK). Maternal Cr biosynthesis and metabolism seem to play an important role in pregnancy, as shown in preclinical and in healthy human pregnancy studies. Patients with Arginine:Glycine Amidino-Transferase deficiency (AGAT-d), due to the deficit of the first enzyme involved in Cr synthesis, are at a disadvantage due to their failure to synthesize Cr and their dependence on external intake, in contrast to normal subjects, where changes in Cr biosynthesis supply their needs. We report the outcomes of a pregnancy in an AGAT-d woman, and the challenge we faced in managing her treatment with oral Cr to ensure optimal conditions for her fetus. CASE PRESENTATION A 22-year-old AGAT-d woman referred to our Institute for the management of her first conception at 11 weeks of fetal gestational age. Sonographic monitoring at 20 w GA indicated a reduction of fetal growth, in particular of the head circumference that was below the 3rd centile. Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations, in particular in the urine sample, requiring prompt correction of the Cr dose. At 35 weeks of gestation the patient delivered a male infant, heterozygous for GATM mutation, with normal brain Cr levels; at one year the baby achieved typical developmental milestones. CONCLUSIONS This rare pregnancy demonstrates that Cr levels in the blood and urine of the mother with AGAT-d decreased since the first months of gestation. The increase of the Cr daily dose administered to the mother seems to have produced beneficial effects also on the fetus.
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2.
Creatine transporter deficiency in two half-brothers.
Ardon, O, Amat di San Filippo, C, Salomons, GS, Longo, N
American journal of medical genetics. Part A. 2010;(8):1979-83
Abstract
X-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter encoded by the SLC6A8 gene. Here, we report two half-brothers with this condition and characterize creatine transport in human fibroblasts. The propositus presented at 6 months of age with delays in development and slow progress since then with no regression. Seizures started at 3.5 years of age and responded well to treatment with anticonvulsants. He had failure to thrive with all growth parameters (including head size) at or below the fifth centile. Brain MRI indicated hemispheric white matter abnormalities, while MR spectroscopy indicated markedly reduced creatine peak. Biochemical testing indicated increased urine creatine/creatinine ratio, with normal plasma creatine and guanidinoacetate. To confirm the diagnosis, we measured ([14])C-creatine transport in fibroblasts. ([14])C-Creatine transport in normal human fibroblasts was linear for up to 2 hr at 37 degrees C. Kinetic studies indicated the presence of a single saturable creatine transporter with a K(m) of 34.7 +/- 2.5 microM. Fibroblasts from the propositus lacked creatine transport. DNA testing indicated hemizygosity for a novel deletion producing a frameshift (c.974_975delCA, p.Thr325SerfsX139) in the creatine transporter gene. His 12-year-old half-brother had similar biochemical and clinical abnormalities except for the presence of macrocephaly and the absence of seizures. The mother had history of seizures in childhood, but had normal development. These results show that human fibroblasts have a single major creatine transporter and that measurement of its specific activity can confirm creatine transporter deficiency.
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3.
1H MR spectroscopy as a diagnostic tool for cerebral creatine deficiency.
Dezortova, M, Jiru, F, Petrasek, J, Malinova, V, Zeman, J, Jirsa, M, Hajek, M
Magma (New York, N.Y.). 2008;(5):327-32
Abstract
OBJECTIVE Total creatine (tCr) constitutes one of the most prominent signals in human brain MR spectra. A significant decrease in the tCr signal indicates a severe disorder of creatine metabolism. We describe the potential of 1H MR spectroscopy in differential diagnosis of creatine transporter (SLC6A8) deficiency syndrome. MATERIALS AND METHODS Two siblings, a 7-year-old female presenting with mild psychomotor delay, and a 5-year-old male with severe psychomotor retardation, epilepsy and autistic spectrum of problems including speech delay, underwent MR examination because of suspected creatine deficiency. After the MRI examination, 1H MR spectroscopy using the CSI technique was performed. RESULTS Metabolic images of N-acetylaspartate, tCr and choline concentrations showed a very low tCr signal in the male, which was approximately three times lower than in his sister (male/female/controls: tCr=1.6/4.6/7.5 mM). Despite creatine supplementation, no improvement in clinical status and tCr concentration in the MR spectra of the male was observed and diagnosis of SLC6A8 deficiency was proposed. Sequence analysis of the SLC6A8 gene revealed a novel pathogenic frameshift mutation c.219delC; p.Asn74ThrfsX23, hemizygous in the male and heterozygous in the female. CONCLUSIONS The diagnosis of X-linked mental retardation caused by the SLC6A8 deficiency can be independently established by 1H MR spectroscopy.
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4.
Lithium-induced nephropathies.
Raedler, TJ, Wiedemann, K
Psychopharmacology bulletin. 2007;(2):134-49
Abstract
Lithium, an alkali metal, remains the gold-standard of the pharmacological treatment of bipolar disorder. Over the past decades, the potential of lithium to cause renal damage has been an issue of debate. Polyuria, polydipsia, and, to a lesser degree, nephrogenic diabetes insipidus are frequently observed under treatment with lithium. The glomerular filtration rate (GFR) decreases progressively in a smaller proportion of subjects after several years of treatment with lithium. An even smaller number of patients continue to develop renal insufficiency, ultimately leading to hemodialysis in a small minority of subjects exposed to lithium. So far, no tests exist to identify subjects at risk of lithium-induced nephropathy at an early stage. Therefore, regular monitoring of creatinine and creatinine clearance are recommended in all subjects taking lithium.
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5.
Creatine deficiency syndromes.
Schulze, A
Molecular and cellular biochemistry. 2003;(1-2):143-50
Abstract
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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6.
[Magnetic resonance imaging and spectroscopic metabolites assessment in brain cryptococcosis].
Wiercińska-Drapało, A, Tarasow, E
Wiadomosci parazytologiczne. 2001;(3):535-41
Abstract
Cryptococcus neoformans is the causative agent of cryptococcosis and cryptococcal meningitis, which are serious pathological conditions affecting up to 10% of patients with AIDS. In this paper we present results magnetic resonance imaging and spectroscopic metabolites (1H MR) in brain cryptococcosis. In 1 HMR spectroscopy we find decreased metabolic ratios to nonsaturated water (H2O) signal N-acetylaspartate (NA/H2O, creatine (Cr/H20), choline (Cho/H2O). We show increased mioinositol to H2O ratio. Spectroscopy results suggest about massive neuronal injury and accompanying gliosis in brain cryptococcosis.