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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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

Creatine transporter deficiency is an X-linked disorder characterized by mental retardation and language delay. The authors report a patient affected by creatine transport deficiency caused by a novel mutation in the SLC6A8 gene. Impairment in social interaction represents a consistent clinical finding in the few cases described to date and may be a diagnostic clue for creatine transporter deficiency in males affected by mental retardation, seizures, and language impairment.
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PMID:X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation. 1608 85

We report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3' end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.
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PMID:X-linked creatine transporter defect: a report on two unrelated boys with a severe clinical phenotype. 1660 97

Disorders of creatine synthesis or its transporter resulting in neurological impairment with mental retardation and epilepsy have only been recognized in recent years. To date, the epileptic disorder observed in creatine transporter deficiency (CRTR-D) has been described as a mild phenotype with infrequent seizures and favorable response to common antiepileptic drugs. We report on a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. After extensive investigations, metabolite analysis and brain 1H-MRS suggested CRTR-D, which was confirmed by the detection of a known pathogenic mutation in the SLC6A8 gene (c.1631C>T; p.Pro544Leu).
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PMID:Severe epilepsy in X-linked creatine transporter defect (CRTR-D). 1755 21

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

Creatine (Cr) is required to maintain ATP levels in the brain. The transport of Cr across the blood-brain barrier and into neurones requires a specific creatine transporter (CRT). Mutations in the CRT gene (SLC6A8) result in a novel form of X-linked mental retardation, characterised by developmental delays, seizures and a complete absence of Cr from the brain. To identify cell types and regions that depend on Cr for energy metabolism we have determined the regional and cellular localisation of CRT protein in the rat brain using immunohistochemical techniques with a highly specific, affinity-purified, CRT antibody. The results show high levels of CRT localisation is associated with specific brain regions and certain cell types. The CRT is predominantly found in neurones. CRT immunoreactivity is particularly abundant in the olfactory bulb, granule cells of the dentate gyrus of the hippocampus, pyramidal neurones of the cerebral cortex, Purkinje cells of the cerebellum, motor and sensory cranial nerve nuclei in the brainstem and the dorsal and ventral horns of the spinal cord. Low levels of CRT were seen in the basal ganglia and white matter. Overall, CRT was found to show high intensities of labelling in the major motor and sensory regions of the forebrain, brainstem and spinal cord and forebrain regions associated with learning, memory and limbic functions. It is hypothesised that regions with high CRT expression are likely to have high metabolic ATP requirements and that areas with low CRT levels are those regions which are particularly vulnerable in neurodegenerative diseases.
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PMID:Immunohistochemical localisation of the creatine transporter in the rat brain. 1958 Aug 54

Creatine deficiency syndromes, which have only recently been described, represent a group of inborn errors of creatine synthesis (L-arginine-glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency) and transport (creatine transporter deficiency). Patients with creatine deficiency syndromes present with mental retardation expressive speech and language delay, and epilepsy. Patients with guanidinoacetate methyltransferase deficiency or creatine transporter deficiency may exhibit autistic behavior. The common denominator of these disorders is the depletion of the brain creatine pool, as demonstrated by in vivo proton magnetic resonance spectroscopy. For diagnosis, laboratory investigations start with analysis of guanidinoacetate, creatine, and creatinine in plasma and urine. Based on these findings, enzyme assays or DNA mutation analysis may be performed. The creatine deficiency syndromes are underdiagnosed, so the possibility should be considered in all children affected by unexplained mental retardation, seizures, and speech delay. Guanidinoacetate methyltransferase deficiency and arginine-glycine amidinotransferase deficiency are treatable by oral creatine supplementation, but patients with creatine transporter deficiency do not respond to this type of treatment.
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PMID:Creatine and creatine deficiency syndromes: biochemical and clinical aspects. 2015 24

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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PMID:Creatine transporter deficiency in two half-brothers. 2060 86


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