Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins’ diet

Ben‐Ari, Ziv; Dalal, Adam; Morry, Ady; Pitlik, Silvio; Zinger, P; Cohen, Jonathan; Fattal, Ittai; Galili-Mosberg, Ronit; Tessler, Debora; Baruch, Ruth Gershoni; Nuoffer, Jean-Marc; Largiadèr, Carlo R.; Mandel, Hanna

doi:10.1016/j.jhep.2009.11.014

Cited by 44 publications

(40 citation statements)

References 16 publications

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“…Individuals with sequence variants that allow residual OTC activity can present with hyperammonemia at any point in life, while others remain asymptomatic. In patients with late onset OTCD, acute hyperammonemia can be triggered by a high protein meals (Ben-Ari et al, 2010; Thurlow et al, 2010; Cavicchi et al, 2014), fasting (Marcus et al, 2008), infections (McGuire et al, 2013), invasive medical procedures (Chiong et al, 2007; Hu et al, 2007; Bezinover et al, 2010), chemotherapy (Lipskind et al, 2011; Cavicchi et al, 2014), or other environmental insults that result in increased protein catabolism and ammonia production (Seminara et al, 2010). Missense mutations that cause partial OTCD reduce OTC enzymatic activity or stability while mutations in the vicinity of consensus splice sites can potentially affect mRNA processing and result in decreased abundance of the OTC enzyme.…”

Section: Clinical Diagnostic and Biological Relevancementioning

confidence: 99%

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Caldovic

Abdikarim

Narain

et al. 2015

Journal of Genetics and Genomics

125

137

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Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publically available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations.

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Section: Clinical Diagnostic and Biological Relevancementioning

confidence: 99%

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Caldovic

Abdikarim

Narain

et al. 2015

Journal of Genetics and Genomics

125

137

View full text Add to dashboard Cite

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“…Pathogenesis of UCD was exemplarily assumed as a linear decrease of the enzyme activity of ornithine transcarbamylase (OTC), leading to complete impairment of the enzyme (Figure 4 A) [56]. Simultaneously, the glutamine and alanine production rates are increased fourfold above the nominal glutamine and alanine production rates [57].…”

Section: Resultsmentioning

confidence: 99%

Integrating Cellular Metabolism into a Multiscale Whole-Body Model

et al. 2012

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Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.

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“…Thyroid function tests on day 20 Molecular testing revealed a mutation in codon 159 of exon 5 of the OTC gene, which has been previously reported as causative for late-onset OTC. 4 Our patient' s brother, mother, maternal grandfather, and maternal uncle were also screened, and his grandfather had the same mutation.…”

Section: Remainder Of Hospital Coursementioning

confidence: 98%

“…[1][2][3] Although commonly diagnosed in neonates, patients can present at any age with hyperammonemic crisis owing to environmental stressors. [3][4][5][6][7] Preceding symptoms are often nonspecific among late-onset cases and include vomiting, altered mental status, hyperammonemia, and cerebral edema in severe cases. 3 As a consequence, the initial presentation may be associated with lifethreatening complications owing to unrecognized hyperammonemia.…”

mentioning

confidence: 99%

Late-Onset Ornithine Transcarbamylase Deficiency: Treatment and Outcome of Hyperammonemic Crisis

Bergmann¹,

McCabe²,

Smith³

et al. 2014

Pediatrics

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Hyperammonemic crises in ornithine transcarbamylase deficiency (OTC) can be associated with devastating cerebral edema resulting in severe long-term neurologic impairment and death. We present an 8-year-old boy who had late-onset OTC deficiency in which early and aggressive management of hyperammonemia and associated cerebral edema, including therapeutic hypothermia and barbiturateinduced coma, resulted in favorable neurologic outcome. Our patient presented with vomiting and altered mental status, and was found to have a significantly elevated serum ammonia level of 1561 mmol/L. Hyperammonemia was managed with hemodialysis, 10% sodium phenylacetate, 10% sodium benzoate, L-arginine, intravenous 10% dextrose, intralipids, and protein restriction. He developed significant cerebral edema with intracranial pressures .20 mm Hg, requiring treatment with 3% saline and mannitol. Despite this treatment our patient continued to have elevated intracranial pressures, which were treated aggressively with non-conventional modalities including therapeutic hypothermia, barbiturate-induced coma, and external ventricular drainage. This therapy resulted in stabilization of hyperammonemia and resolution of cerebral edema. Molecular testing later revealed a hemizygous mutation within the OTC gene. Neuropsychological testing 1 year after discharge showed normal intelligence with no visualmotor deficits, minor deficits in working memory and processing speed, and slightly below average processing speed and executive functioning. Pediatrics 2014;133:e1072-e1076 Dr Bergmann conceptualized the case report, drafted the initial manuscript, and critically reviewed and revised the manuscript; Dr McCabe coordinated data collection and critically reviewed and revised the manuscript; Dr Smith critically reviewed and revised the manuscript; Dr Guillaume provided expertise in neurosurgical management and critically reviewed and revised aspects of the manuscript pertaining to neurosurgical intervention; Dr Sarafoglou provided expertise in endocrine and metabolic management and critically reviewed and revised aspects of the manuscript pertaining to endocrine and metabolic intervention; Dr Gupta conceptualized the case report and critically reviewed and revised the manuscript with emphasis on aspects pertaining to critical care medicine; and all authors approved the final manuscript as submitted.www.pediatrics.org/cgi

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Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins’ diet

Cited by 44 publications

References 16 publications

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

Integrating Cellular Metabolism into a Multiscale Whole-Body Model

Late-Onset Ornithine Transcarbamylase Deficiency: Treatment and Outcome of Hyperammonemic Crisis

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