scholarly journals Urea Cycle Defects: Early-Onset Disease Associated with A208T Mutation in OTC Gene—Expanding the Clinical Phenotype

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Ana Isabel Sánchez ◽  
Alejandra Rincón ◽  
Mary García ◽  
Fernando Suárez-Obando
Keyword(s):  
Urea Cycle ◽  
Late Onset ◽  
Clinical Phenotype ◽  
High Plasma ◽  
Ammonium Concentration ◽  
Adult Males ◽  
Expanded Newborn Screening ◽  
History Of ◽  
Otc Deficiency ◽  
Cycle Disorders

Ornithine transcarbamylase deficiency (OMIM: 311250) is the most common disorder of urea cycle disorders, accounting for nearly 50% of all cases. We report a case of a two-month- old male patient, who attends our medical genetics consultation because of low citrulline levels and elevated glutamine to citrulline ratio detected by expanded newborn screening with tandem mass spectrometry. He is an asymptomatic male with a normal physical examination and appropriate neurodevelopmental milestones. The patient has a family history of one older brother who died at 18 months old from severe and sudden hyperammonemia and a maternal aunt who suddenly died at two years old. He had high plasma ammonium concentration and a confirmed OTC mutation (p.A208T). Usually, this mutation causes OTC deficiency of late onset in adult males. However, this report raises awareness about mutations previously described as a late-onset causing disease, which can cause severe hyperammonemia and high risk of dying at an early age.

Valproate-induced fatal acute hyperammonaemia-related encephalopathy in late-onset ornithine transcarbamylase deficiency

2021 ◽  
Vol 14 (5) ◽  
pp. e241429
Author(s):  
Daniel Kazmierski ◽  
Nishant Sharma ◽  
Kelly O'Leary ◽  
Pius Ochieng
Keyword(s):  
Cerebral Oedema ◽  
Urea Cycle ◽  
Late Onset ◽  
Genetic Disorder ◽  
Management Strategies ◽  
Ornithine Transcarbamylase ◽  
Ornithine Transcarbamylase Deficiency ◽  
History Of ◽  
Otc Deficiency ◽  
Psychiatric Conditions

Ornithine transcarbamylase (OTC) deficiency is a genetic disorder of the urea cycle characterised by deficiency in the enzyme OTC, resulting in an accumulation of ammonia. Valproic acid (VPA), a commonly used medication in the treatment of neurologic and psychiatric conditions, has been known to cause episodes of acute hyperammonaemia in patients with OTC deficiency. We present the case of a 29-year-old man with a long history of non-specific psychiatric disorders, who suffered from a hyperammonaemic crisis following the administration of VPA, leading to the diagnosis of OTC deficiency. The patient’s hospital course was complicated by progressive cerebral oedema, which resulted in worsening encephalopathy, seizures and death. We discuss the pathophysiology of hyperammonaemia in OTC deficiency, and various management strategies, including lactulose, levocarnitine, scavenger therapy and haemodialysis.

scholarly journals Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Ruby Upadhyay ◽  
Thomas P. Bleck ◽  
Katharina M. Busl
Keyword(s):  
Case Report ◽  
English Language ◽  
Clinical Presentation ◽  
Urea Cycle ◽  
Late Onset ◽  
Unique Case ◽  
Hyperammonemic Encephalopathy ◽  
Search Terms ◽  
Otc Deficiency ◽  
Cycle Disorders

Purpose. A 66-year-old man who presented with coma was found to have isolated severe hyperammonemia and diagnosed with a late-onset urea-cycle disorder. He was treated successfully and had full recovery.Methods. We report a novel case of noncirrhotic hyperammonemia and review the literature on this topic. Selected literature for review included English-language articles concerning hyperammonemia using the search terms “hyperammonemic encephalopathy”, “non-cirrhotic encephalopathy”, “hepatic encephalopathy”, “urea-cycle disorders”, “ornithine transcarbamylase (OTC) deficiency”, and “fulminant hepatic failure”.Results. A unique case of isolated hyperammonemia diagnosed as late-onset OTC deficiency is presented. Existing evidence about hyperammonemia is organized to address pathophysiology, clinical presentation, diagnosis, and treatment. The case report is discussed in context of the reviewed literature.Conclusion. Late-onset OTC deficiency presenting with severe hyperammonemic encephalopathy and extensive imaging correlate can be fully reversible if recognized promptly and treated aggressively.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

2015 ◽  
Vol 38 (6) ◽  
pp. 1059-1074 ◽  
Author(s):  
Stefan Kölker ◽  
Vassili Valayannopoulos ◽  
Alberto B. Burlina ◽  
Jolanta Sykut-Cegielska ◽  
Frits A. Wijburg ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Clinical Phenotype ◽  
Urea Cycle Disorders ◽  
Organic Acidurias ◽  
Phenotypic Spectrum ◽  
Cycle Disorders

scholarly journals Late-Onset Ornithine Carbamoyltransferase Deficiency Accompanying Acute Pancreatitis and Hyperammonemia

2013 ◽  
Vol 2013 ◽  
pp. 1-3 ◽  
Author(s):  
Marcel Cerqueira Cesar Machado ◽  
Gilton Marques Fonseca ◽  
José Jukemura
Keyword(s):  
Urea Cycle ◽  
Late Onset ◽  
Neuronal Damage ◽  
Clinical Care ◽  
Subsequent Treatment ◽  
Neurological Symptoms ◽  
Urea Cycle Disorders ◽  
Cycle Disorders ◽  
Serum Ammonia ◽  
Timely Treatment

Hyperammonemia related to urea cycle disorders is a rare cause of potentially fatal encephalopathy that is encountered in intensive care units (ICUs). Left undiagnosed, this condition may manifest irreversible neuronal damage. However, timely diagnosis and treatment initiation can be facilitated simply by increased awareness of the ICU staff. Here, we describe a patient with acute severe pancreatitis who developed hyperammonemia and encephalopathy without liver disease. Urea cycle disorder was suspected and hemodialysis was initiated. Following reduction of ammonia levels, subsequent treatment included protein restriction and administration of arginine and sodium benzoate. The patient was discharged to home after 47 days with plasma ammonia within normal range and without neurological symptoms. In clinical care settings, patients with neurological symptoms unexplained by the present illness should be assessed for serum ammonia levels to disclose any urea cycle disorders to initiate timely treatment and improve outcome.

scholarly journals Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

2015 ◽  
Vol 38 (6) ◽  
pp. 1157-1158 ◽  
Author(s):  
Stefan Kölker ◽  
Vassili Valayannopoulos ◽  
Alberto B. Burlina ◽  
Jolanta Sykut-Cegielska ◽  
Frits A. Wijburg ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Clinical Phenotype ◽  
Urea Cycle Disorders ◽  
Organic Acidurias ◽  
Phenotypic Spectrum ◽  
Cycle Disorders

Carrier Detection of Urea Cycle Disorders

PEDIATRICS ◽  
1981 ◽  
Vol 68 (3) ◽  
pp. 448-452
Author(s):  
W. G. Ng ◽  
J. Oizumi ◽  
R. Koch ◽  
K. N. F. Shaw ◽  
J. McLaren ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Screening Program ◽  
Cost Benefit ◽  
Carrier Detection ◽  
Urea Cycle Disorders ◽  
Frequency Of Occurrence ◽  
Cycle Enzyme ◽  
Carrier Identification ◽  
Otc Deficiency ◽  
Cycle Disorders

Published reports100,102,108 indicate that the degree of success attained in the treatment of infants with urea cycle disorders has not been completely satisfactory. Some new approaches in dietary management, using a combination of arginine, benzoate, and phenylacetate may be useful,67,72,76 but more studies are required. In many instances, clinical problems reflect delays in biochemical diagnosis. Families at risk need to be identified and the genotype of the fetus should be established as soon as feasible after conception, so that appropriate management can be provided during pregnancy and after delivery. Availability of effective methods for carrier detection is a critical component of this process. With any metabolic disorder, a number of factors should be considered for carrier detection. These include: (1) frequency of occurrence of affected patients in the available population, (2) mode of inheritance, (3) cost-benefit ratio, (4) soundness of the methodology used, and (5) feasibility of prenatal diagnosis. Interestingly, the Tay-Sachs prevention program with the major objective of carrier identification is the only accepted program that has been widely discussed and evaluated.109 The frequency of occurrence of each of the five urea cycle enzyme disorders is uncertain, but ornithine transcarbamylase (OTC) deficiency, the only sex-linked disorder, is considered to be the most common. Not only the hemizygotes, but also many of the heterozygotes of OTC deficiency are clinically affected. The frequency of argininosuccinic aciduria has been estimated to be 1 in 60,000, based on results of a newborn screening program carried out in Massachusetts.110 Carrier identification of urea cycle disorders in the general population is not practical because of cost considerations, but it should be applied to members of affected families.

scholarly journals Whole exome sequencing make a definitive diagnosis of a Vietnamese patient with a late onset urea cycle disorder

2020 ◽  
Vol 18 (2) ◽  
pp. 209-221
Author(s):  
Ngoc-Lan Nguyen ◽  
Ngoc Khanh Nguyen ◽  
Chi Dung Vu ◽  
Nguyen Thi Thu Huong ◽  
Nguyen Huy Hoang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Urea Cycle ◽  
De Novo ◽  
Late Onset ◽  
Stop Codon ◽  
Definitive Diagnosis ◽  
De Novo Mutation ◽  
Whole Exome ◽  
Otc Deficiency

            Our report describes a female presenting with vomiting, fever, coma and right hemiplegia at 26 months of age. Biochemical tests revealed hyperammonemia, hyperlactatemia, elevated glutamine level, elevated transaminase and disorder of prothrombin time. She was priory diagnosed with urea cycle disorders (UCDs). UCDs are caused by mutations in eight genes that regulate the synthesis of enzymes and cofactors involved in urea metabolism. Singleton whole exome sequencing was applied to screen causative variants in these genes in the patient at 6 years of age. The result showed one heterozygous stop loss mutation c.1065A>G in the OTC gene as a potential disease causing in the patient. The mutation c.1065A>G leads to alternation of stop codon to tryptophan, resulting in elongation of fourteen amino acids in ornithine transcarbamylase (OTC) protein (p.Ter355TrpextTer14). Sanger sequencing in the family revealed the mutation c.1065A>G was not present in healthy parents and brother. Therefore, this mutation is considered as a de novo mutation in the patient. The mutation c.1065A>G was conferred to pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology with 1 strong (PS2), 3 moderate (PM2, PM4 and PM5) and 1 support criteria (PP2). Although OTC deficiency is an X-linked recessive inheritance, approximately 15% of females carrying heterozygous variants showed the late onset OTC deficiency. Therefore, in combination of clinical presentations, laboratory findings and molecular genetic analyses, we made a definitive diagnosis of the patient with late onset OTC deficiency, a disorder of UCDs.

Summarizing Remarks

PEDIATRICS ◽  
1981 ◽  
Vol 68 (3) ◽  
pp. 458-462
Author(s):  
Vivian E. Shih
Keyword(s):  
Urea Cycle ◽  
Urea Cycle Disorders ◽  
Important Message ◽  
Number Of Patients ◽  
Otc Deficiency ◽  
Cycle Disorders ◽  
Overall Functioning ◽  
Urea Cycle Enzymes

The foregoing presentations have been most informative. Snodgrass, who has developed microassays of the urea cycle enzymes and has been instrumental in the study of a number of patients with urea cycle disorders, reviewed the biochemistry of the urea cycle in normal and in diseased states. He, as well as the others, has drawn our attention to acetylglutamate synthetase and its important role in the regulation of the urea cycle. Although the mechanism is not entirely clear, acetylglutamate synthesis seems to be a critical step in governing the entry of ammonia into the urea cycle. Perhaps it may also regulate the overall functioning of the urea cycle. The reason that patients with a defect of this enzyme have not been described is most likely due to our ignorance. Another important message from Snodgrass is that at physiologic conditions, the urea cycle enzymes do not function at maximum rates and the ratio of enzyme activity as obtained by in vitro studies does not exist in vivo. Rather, the enzyme activities are limited in vivo by the availability of substrates that are present at Km levels. Therefore, small changes in concentration cause large changes in velocity. Ornithine transcarbamylase (OTC) deficiency and argininosuccinate lyase deficiency are the two most common of the five urea cycle disorders. Enzyme studies have revealed several variants (or mutants) in each disorder including defects in altered enzyme kinetics and the absence of enzyme proteins. There has been no satisfactory explanation for the cause of hyperammonemia found in all five urea cycle disorders.

scholarly journals Recurrent Altered Mental State Associated with Nonhepatic Hyperammonemia Presented in an Elderly Female Patient: Probable Late-Onset Urea Cycle Disorder

2021 ◽  
Vol 11 (1) ◽  
pp. 96-99
Author(s):  
Jung-Ju Lee ◽  
Soohyun Cho ◽  
Byung Kun Kim ◽  
Ohyun Kwon ◽  
Jong-Moo Park ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Late Onset ◽  
Elevated Serum ◽  
Serum Levels ◽  
Ammonia Level ◽  
Abnormal Behavior ◽  
Altered Mental State ◽  
Neurologic Sequelae ◽  
Cycle Disorders ◽  
Serum Ammonia

Altered mentality associated with hyperammonemia is usually diagnosed in patients with liver disease. Nonhepatic hyperammonemia may be present in critically ill patients or may be caused by high protein diets or certain drugs. Urea cycle disorders (UCDs) rarely present with altered mentality with hyperammonemia in adult patients. An 82-year-old female visited our hospital with complaints of abnormal behavior and confusion. Routine blood tests revealed elevated serum ammonia. Her mentality and serum ammonia level normalized after lactulose enema and she was discharged thereafter. However, she was later re-admitted because of recurrent altered mentality. Amino acid analysis revealed that serum levels of ornithine and glutamine increased significantly, whereas the levels of alanine and glutamic acid increased slightly, and the levels of arginine, lysine, and citrulline were normal, which were probably caused by reduced activity of the mitochondrial ornithine carrier-1. Although our patient was not diagnosed genetically, this case illustrates the under-recognized fact that UCD can occur in a senile age. Clinical suspicion of UCDs in patients with hyperammonemia is critical for early diagnosis and to prevent the significant neurologic sequelae.

Coma, hyperammonemia, metabolic acidosis, and mutation: Lessons learned in the acute management of late onset urea cycle disorders

2011 ◽  
pp. n/a-n/a ◽  
Author(s):  
Hari Iyer ◽  
Mithu Sen ◽  
Chitra Prasad ◽  
C. Anthony Rupar ◽  
Robert M. Lindsay
Keyword(s):  
Metabolic Acidosis ◽  
Urea Cycle ◽  
Late Onset ◽  
Lessons Learned ◽  
Urea Cycle Disorders ◽  
Acute Management ◽  
Cycle Disorders
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