Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis

Maestri, Nancy E.; Clissold, David B.; Brusilow, Saul W.

doi:10.1016/s0022-3476(99)70448-8

Cited by 120 publications

(81 citation statements)

References 7 publications

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“…1) has two main functions: the detoxification of waste nitrogen into excretable urea and the de novo biosynthesis of arginine [Brusilow and Horwich, 2001]. Deficiencies of all of the enzymes of the urea cycle have been identified, and although each specific disorder results in accumulation of different metabolites, they (except for hyperargininemia) usually present in the newborn period or in early infancy with hyperammonemic encephalopathy and hyperglutaminemia [Batshaw et al, 1980;Maestri et al, 1999;Msall et al, 1984]. Most of these disorders (N-acetyl glutamate synthase deficiency, carbamoyl phosphate synthetase I deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase I deficiency or hyperargininemia) are inherited in an autosomal recessive fashion, whereas ornithine transcarbamylase deficiency is X-linked [Maestri et al, 1998].…”

Section: Introductionmentioning

confidence: 99%

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Scaglia

Lee²

2006

American J of Med Genetics Pt C

103

160

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The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia and hyperglutaminemia. Deficiencies of all of the enzymes of the cycle have been described and although each specific disorder results in the accumulation of different precursors, hyperammonemia and hyperglutaminemia are common biochemical hallmarks of these disorders. Arginase is the enzyme involved in the last step of the urea cycle. It catalyzes the conversion of arginine to urea and ornithine. The latter reenters the mitochondrion to continue the cycle. Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. Unlike other urea cycle disorders, this condition is not generally associated with a hyperammonemic encephalopathy in the neonatal period. It typically presents later in childhood between 2 and 4 years of age with predominantly neurological features. If untreated, it progresses with gradual developmental regression. A favorable outcome can be achieved if dietary treatment and alternative pathway therapy are instituted early in the disease course. With this approach, further neurological deterioration is prevented and partial recovery of skills ensues. Early diagnosis of this disorder through newborn screening programs may lead to a better outcome. This review article summarizes the clinical characterization of this disorder; as well as its biochemical, enzymatic, and molecular features. Treatment, prenatal diagnosis and diagnosis through newborn screening are also discussed.

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Section: Introductionmentioning

confidence: 99%

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Scaglia

Lee²

2006

American J of Med Genetics Pt C

103

160

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“…Chronic HAE is associated with developmental delay, mental retardation, attention deficit/hyperactivity disorder, and impaired executive function in children with UCDs (Batshaw et al, 1980(Batshaw et al, , 1986Gyato et al, 2004;Maestri et al, 1999;Msall et al, 1984Msall et al, , 1988. Chronic hepatic encephalopathy causes neuropsychiatric disturbances in patients with chronic liver dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc spf mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otc spf /GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/ Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport.Since, ions can permeate water and K + -channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.

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“…The only X-linked disorder is ornithine transcarbamylase deficiency (OTCD), which has an estimated incidence of 1 in 14 000 (6). More than 240 mutations have been identified in the ornithine carbamoyltransferase gene, OTC (7). Up to 60% of hemizygous males have a mutation involving the enzyme-active site that manifests with hyperammonemic (HA) coma in the newborn (8,9).…”

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confidence: 99%

Ornithine Transcarbamylase Deficiency with Persistent Abnormality in Cerebral Glutamate Metabolism in Adults

et al. 2009

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Purpose:To determine cerebral glutamate turnover rate in partialornithine transcarbamylase deficiency (OTCD) patients by using carbon 13 ( 13 C) magnetic resonance (MR) spectroscopy. Materials and Methods:The study was performed with approval of the institutional review board, in compliance with HIPAA regulations, and with written informed consent of the subjects. MR imaging, hydrogen 1 ( 1 H) MR spectroscopy, and 13 C MR spectroscopy were performed at 1.5 T in 10 subjects, six patients with OTCD and four healthy control subjects, who were in stable condition. Each received intravenous 13 Cglucose (0.2 g/kg), C1 or C2 position, as a 15-minute bolus. Cerebral metabolites were determined with proton decoupling in a parieto-occipital region (n ϭ 9) and without proton decoupling in a frontal region (n ϭ 1) during 60 -120 minutes. Results:Uptake and removal of cerebral glucose ([1-13 C]-glucose or [2-13 C]-glucose) were comparable in healthy control subjects and subjects with OTCD (P ϭ .1). Glucose C1 was metabolized to glutamate C4 and glucose C2 was metabolized to glutamate C5 at comparable rates, both of which were significantly reduced in OTCD (combined, P ϭ .04). No significant differences in glutamine formation were found in subjects with OTCD (P ϭ .1). [2-13 C]-glucose and its metabolic products were observed in anterior cingulate gyrus without proton decoupling in one subject with OTCD. Conclusion:Treatments that improve cerebral glucose metabolism and glutamate neurotransmission may improve neurologic outcome in patients with OTCD, in whom prevention and treatment of hyperammonemic episodes appear to be insufficient.

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Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis

Cited by 120 publications

References 7 publications

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Ornithine Transcarbamylase Deficiency with Persistent Abnormality in Cerebral Glutamate Metabolism in Adults

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