Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans.
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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. (+info)
Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program.
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BACKGROUND: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. METHODS: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in approximately 1.9 min. Cutoffs for each marker were set at 6-13 SD above the population mean. RESULTS: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. CONCLUSIONS: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns. (+info)
Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I.
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Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of amino acid metabolism resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients accumulate glutaric acid (GA) and 3-OH glutaric acid (3-OHGA) in their blood, urine and CSF. Clinically, GA-I is characterized by macrocephaly, progressive dystonia and dyskinesia. Degeneration of the caudate and putamen of the basal ganglia, widening of the Sylvian fissures, fronto-temporal atrophy and severe spongiform change in the white matter are also commonly observed. In this report we describe the phenotype of a mouse model of GA-I generated via targeted deletion of the Gcdh gene in embryonic stem cells. The Gcdh-/- mice have a biochemical phenotype very similar to human GA-I patients, including elevations of GA and 3-OHGA at levels similar to those seen in GA-I patients. The affected mice have a mild motor deficit but do not develop the progressive dystonia seen in human patients. Pathologically, the Gcdh-/- mice have a diffuse spongiform myelinopathy similar to that seen in GA-I patients. However, unlike in human patients, there is no evidence of neuron loss or astrogliosis in the striatum. Subjecting the Gcdh-/- mice to a metabolic stress, which often precipitates an encephalopathic crisis and the development of dystonia in GA-I patients, failed to have any neurologic effect on the mice. We hypothesize that the lack of similarity in regards to the neurologic phenotype and striatal pathology of GA-I patients, as compared with the Gcdh-/- mice, is due to intrinsic differences between the striata of mice and men. (+info)
Isolated sulfite oxidase deficiency is a rare autosomal inherited disorder of the normal degradation of sulfur-containing amino acids. Premature death in infancy secondary to severe neurologic deterioration is the usual outcome. This article provides an analysis, in temporal form, of brain imaging findings in this disorder. (+info)
Crystals in corneal epithelial lesions of tyrosine-fed rats.
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Tyrosine-fed rats develop corneal disease which mimics that found in the human metabolic disorder, tyrosinosis. By electron and polarizing microscopy needle-shaped birefringent crystals are demonstrable in early corneal epithelial lesions of tyronsine-fed rats. The crystals appear as negative images by electron microscopy, their content apparently extracted by fixation and/or embedding fluids. Crystals may be arranged in sheaves or bundles and pass from one cell to another disrupting the continuity of membranes of both cells and nuclei. They are present in desquamating epithelial cells along corneal ulcers. Polarizing microscopy of whole mounts of diseased tissue shows that the crystals are limited to epithelial lesion areas. We hypothesize that the crystals are tyrosine and that crystal growth in cells initiates lesion and subsequent ulcer formation. (+info)
Urinary phenolic acid and alcohol excretion in the newborn.
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Mean urinary excretion values of some phenolic acids and alcohols have been measured by gas chromatography in 44 neonates (36 males, 6 females) during the first 2 days and days 3-7 of life, and the effect of prematurity and jaundice assessed. 4-Hydroxy-3-methoxymandelic acid (VMA) output rises immediately after birth in term but not in preterm infants. A similar increase in homovanillic acid (HVA) output was restricted to nonjaundiced term babies; in nonjaundiced preterm babies there was a steady rise during the first week. The ratio of HVA to VMA output was higher in these infants than in adults, suggesting a more rapid turnover of dopamine than adrenaline and noradrenaline. Unlike adult values, both HVA and VMA excretion values were directly related to urine volume, an observation perhaps related to renal immaturity. An unexplained reduction in HVA output in jaundiced as opposed to nonjaundiced infants was observed in the first 2 days of life. The ratio of 4-hydroxy-3-methoxyphenylglycol to VMA was about the same as in the adult. p-Hydroxyphenyl-lactic acid (p-HPLA), because of its superior stability, was measured in preference to p-hydroxyphenylpyruvic acid as an index of tyrosyluria. An output of 1 mg p-HPLA/24 h is proposed as the upper limit of normal. Prematurity was associated with a significant rise in p-HPLA output. A dramatic increase in excretion of this acid was noted in jaundiced, compared with nonjaundiced infants, presumably a manifestation of general enzyme immaturity. (+info)
Asymptomatic type II hyperprolinaemia associated with hyperglycinaemia in three sibs.
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Three clinically normal sibs were discovered to have type II hyperprolinaemia in a routine serum amino acid screening programme in Sicily. In addition to the basic biochemical features of type II hyperprolinaemia, all 3 children had marked hyperglycinaemia, whereas their parents had both normal blood proline and glycine concentrations. Clinical normality in individuals with hyperprolinaemia may suggest that these two metabolic disorders (types I and II) are benign entities. Furthermore, the absence of clinical abnormality in these sibs, despite the presence of marked hyperprolinaemia and hyperglycinaemia, may suggest that neither of these findings alone causes brain damage. The hyperglycinaemia in these sibs is unexplained and is an unusual if not unique finding in association with hyperprolinaemia. (+info)
Hyperhomocyst(e)inemia induces accelerated transplant vascular sclerosis in syngeneic and allogeneic rat cardiac transplants.
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Chronic rejection (CR) and transplant vascular sclerosis (TVS) cause the majority of graft failures in cardiac transplantation. Hyperhomocyst(e)inemia [hH(e)] is associated with human TVS without a proven causal relationship. This study investigated the effect of hH(e) on graft survival and TVS in allogeneic and syngeneic rat cardiac transplants. Lewis recipients of heterotopic F344 heart allografts, received normal or hH(e)-inducing (folate, methionine) diets [controls: syngeneic transplanted [+/- hH(e), + CsA] and nontransplanted rats [+/- hH(e), +/- CsA]]. Serial plasma homocyst(e)ine [H(e)] levels were measured. TVS was assessed in clinically rejected grafts and a subset of pre-rejection normal diet allografts (day 64) (neointimal index, NI). The hH(e) diet elevated plasma H(e) levels. When compared with normal diet controls (n = 9), hH(e) diet allografts (n = 9) had decreased time to onset of CR (40 +/- 9 vs. 72 +/- 10d, p = 0.02), and graft failure (64 +/- 10 vs. 107 +/- 12d, p = 0.009). hH(e) diet allografts at rejection (n = 9, 64d) had more severe TVS (NI = 68 +/- 2) than both time-matched normal diet allografts (NI = 49 +/- 6, n = 8, 64d, p <0.001) and normal diet allografts at rejection (NI = 58 +/- 5, n = 9, 107d, p = 0.007). hH(e) induced TVS in syngeneic grafts (NI=50 +/- 3, n = 10 vs. NI = 5 +/- 3, n = 10, 130d, p <0.001). hH(e) accelerated rejection and increased the severity of TVS in allogeneic cardiac transplants, and induced TVS in syngeneic cardiac transplants. (+info)