Ornithine transcarbamylase deficiency (OTCD) is considered to be the most common disorder of the urea cycle [1] [2] [3] [4]. Having in mind the X-linked pattern of inheritance, this condition is principally diagnosed in males, although female cases have been described in the literature [5] [6]. Signs and symptoms stem from the inability of the body to form urea from ammonia and other compounds due to deficiency of ornithine transcarbamylase (OTC), a key enzyme in the urea cycle [5] [6]. As a result, hyperammonemia of variable severity is the principal pathological feature of OTCD [4] [7]. Depending on the type of mutation, OTCD manifests in two age groups, although signs and symptoms may manifest at any point during life [1]. The worst affected patients are hemizygous males, in whom a neonatal onset of hyperammonemia is manifested by poor feeding, vomiting, lethargy, tachypnea, and irritability [3] [6]. In infants and younger children, intellectual and behavioral deficits are frequent [4] [8]. A neonatal onset almost always implies that more severe manifestations will appear and a poorer prognosis is expected, as hemizygous males and individuals harboring null alleles (suggesting a complete absence of enzyme activity) develop seizures, respiratory failure, encephalopathy and coma, which is life-threatening [3] [5] [6] [7]. Conversely, a much milder clinical presentation is seen in heterozygote females and males with incomplete OTCD, since only partial enzyme deficiency occurs [5]. High protein meals, fasting, severe infections, pregnancy, high-dose corticosteroids, use of sodium valproate, various invasive medical procedures or chemotherapy can induce hyperammonemia [3] [4] [6]. Additional reports suggest that a voluntary adoption of a vegetarian diet could be an important clue as well [5].

• Weakness

  Trade deficit has ballooned to USD 88 billion between April and October, up 60 per cent from the comparable period a year ago due to weak exports and a sharp rise in imports, says a report. [economictimes.indiatimes.com]

  She was unable to stand owing to pain and weakness. [jamanetwork.com]

  LONDON, Jan 31- Unilever reported lower-than-expected fourth-quarter sales on Thursday, hurt by troubles in Latin America and weak growth in developed markets as new Chief Executive Alan Jope took over. [cnbc.com]

  Meat exports rebounded strongly after two weak months, and there was a strong lift in log exports. Dairy exports were little changed.” “Seasonally adjusted imports rose by 7% in October, topping $5bn for the first time. [fxstreet.com]

  Weak exports and costlier imports also dampened the overall BOP. The Philippines is the world's biggest buyer of rice this year and imports nearly all of its crude oil needs. [news.abs-cbn.com]

• Vomiting

  As a baby she was in ICU for Four days with Vomiting after being born, she vomited a lot and was taken into hospital a few times, the parents were sent home and told to just syringe her water, consultants said she just had a dairy intolerance and to use [otcdeficiency.com]

  Symptomatic females presented with vomiting,seizure, and altered mentality at age 3.5±3.5 years (range, 0.2–12.8 years; n=24). [ncbi.nlm.nih.gov]

  Clinically, patients present vomiting, refusal to eat, progressive lethargy, and coma. Ornithine Transcarbamylase Deficiency. [accessanesthesiology.mhmedical.com]

  These patients appeared normal at birth, but irritability, vomiting, and lethargy, which were often episodic, later developed. The age at presentation ranged from 2 months to 44 years. [scholars.duke.edu]

• Nausea

  Symptoms are mostly due to hyperammonemia and include nausea, vomiting, lethargia and even convulsions and coma. [ncbi.nlm.nih.gov]

  In children and adults, environmental stressors (i.e. fasting, high protein diet, pregnancy and the postpartum period, intercurrent illness, surgery) can trigger episodes of hyperammonemic encephalopathy along with nausea, vomiting, headaches, erratic [orpha.net]

  Past history revealed that, at age 7 years, the patient had an episode of acute encephalopathy following a 2-month history of intermittent nausea, vomiting and frontal headache. [mja.com.au]

  Watch for signs of ammonia build-up (hyperammonemia) including: nausea, vomiting, sleepiness, or unusual problems with your mood or thinking. If you have any of these, get medical care right away. [newenglandconsortium.org]

• Failure to Thrive

  Entry H00187 Disease Name Ornithine transcarbamylase deficiency Supergrp Primary hyperammonemic disorders (Urea cycle disorders) [DS:H01398] Description Ornithine transcarbamylase deficiency, the most common urea cycle defect, results in failure to thrive [genome.jp]

  Late-Onset Presentation: Long history of chronic hepatogastric symptoms such as recurrent episodes of vomiting, failure to thrive, and hepatomegaly. [accessanesthesiology.mhmedical.com]

  Order test Add-on Hereditary Orotic Aciduria Gene (1 gene) Hereditary orotic aciduria is a disorder characterized by massive excretions of orotic acid in the urine, megaloblastic anemia, failure to thrive, growth retardation and psychomotor disability [invitae.com]

  Historical note and terminology Ornithine transcarbamylase deficiency (OTCD) was first reported in 1962 in 2 girls, aged 20 months and 6 years, who were found to have hyperammonemia associated with episodic vomiting, delirium, stupor, failure to thrive [medlink.com]

• Recurrent Vomiting

  Both heterozygous females and partially deficient males may present with late onset of symptoms, even into adulthood, with recurrent vomiting, history of protein avoidance, Reye-like syndrome, or with major neurologic impairment, neurobehavioral changes [genedx.com]

  A pre-existing history of recurrent vomiting (3/3) and developmental delay (2/3) was retrospectively noted. [ojrd.biomedcentral.com]

  In patients with late onset, gastrointestinal symptoms are second in number and are represented by loss of appetite and recurrent vomiting, a clinical picture reminiscent of Reye’s syndrome. (Glasgow and Middleton, 2001). [itjem.org]

• Hypotension

  […] stroke, hypothermia Central nervous system pathology Subdural hematoma, epidural hematoma, subarachnoid hemorrhage, hydrocephalus, seizure, stroke, tumor, demyelinating lesion, transient ischemic attack Hypoxia or cardiopulmonary condition Hypoxemia, hypotension [hindawi.com]

  Perisulcal infarcts: lesions caused by hypotension during increased intracranial pressure. Ann Neurol 1979 ; 6 : 399 –404 ↵ Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. [ajnr.org]

  & Syncope, Vasodepressor Syncope (Common Faint) A Case of Spontaneous Intracranial Hypotension ... [catsclem.nl]

  Since arginine is the precursor of NO, it is advisable to reduce the dose if the patient presents hypotension and vasodilation. [itjem.org]

• Asterixis

  Hyperammonemia in asterixis induced by carbamazepine: two case reports. Acta Neurol Scand. 1984; 69:186-9 Rivelli M, El-Mallakh RS, Nelson WH. Carbamazepine-associated asterixis and hyperammonemia. Am J Psychiatry. 1988; 145:269-70 EN. [itjem.org]

  Signs and symptoms Hyperammonemia from OTC deficiency can be manifested clinically by some or all of the following: Anorexia Irritability Heavy or rapid breathing Lethargy Vomiting Disorientation Somnolence Asterixis (rare) Combativeness Obtundation Coma [emedicine.medscape.com]

• Delusion

  They include: Avoiding foods high in protein or a dislike of meat Loss of appetite Nausea or vomiting Behavior problems, including hyperactivity Mental problems (confusion, delusions, hallucinations, psychosis ) Diagnosis Most newborns in the U.S. are [webmd.com]

• Lethargy

  Signs and symptoms include seizures, delayed growth, behavioral changes, ataxia, lethargy, and coma. [icd10data.com]

  Ornithine transcarbamylase deficiency causes vomiting, lethargy, hyperventilation, and even death, mainly in the neonatal period. [ncbi.nlm.nih.gov]

  During a hyperammonemic episode, affected children may experience vomiting, lethargy, and irritability. [rarediseases.org]

• Headache

  Of the 24 non-hyperammonemic carriers, 10 often developed headaches. Their daily NOx and arginine levels were significantly lower than those in headache-free carriers (p < 0.05). [ncbi.nlm.nih.gov]

  [Guideline] Pearlman E, National Headache Foundation. Special treatment situations: pediatric migraine. Standards of care for headache diagnosis and treatment. 2004. 98-107. [Full Text]. [emedicine.medscape.com]

  Vegetarian diets are preferred because dietary protein intake often is associated with migraine-like headache. • Hemodialysis is used to achieve rapid reduction of extremely high blood ammonia levels (in some cases exceeding 2000 mg/dL) in comatose individuals [secure.ssa.gov]

  Symptoms of this form may include episodes of delirium, erratic behavior, a reduced level of consciousness, headaches, vomiting, and seizures.[1] OTC is caused by mutations in the OTCgene and inheritance is X-linked .[1] Treatment involves removing protein [rarediseases.info.nih.gov]

• Irritability

  Others present a neurologic picture of chronic encephalopathy; behavioral disorders such as agitation, delirium, and irritability; or Reye-like syndrome following sodium valproate therapy for seizures. [accessanesthesiology.mhmedical.com]

  A 3-day-old infant presented with anorexia, irritability, hypotonia, and seizures. Blood ammonia was 2115 micromol/L and amino and organic acid analyses were consistent with ornithine transcarbamylase deficiency. [ncbi.nlm.nih.gov]

  These patients appeared normal at birth, but irritability, vomiting, and lethargy, which were often episodic, later developed. The age at presentation ranged from 2 months to 44 years. [scholars.duke.edu]

  The worst affected patients are hemizygous males, in whom a neonatal onset of hyperammonemia is manifested by poor feeding, vomiting, lethargy, tachypnea, and irritability. [symptoma.com]

• Confusion

  Hyperammonaemic encephalopathy should be considered in patients of any age who experience fluctuating confusion. [ncbi.nlm.nih.gov]

• Somnolence

  A 22-year-old woman with a negative urine drug screen and somnolence rapidly reversed by intravenous flumazenil was found to have elevated ammonia levels and punctate calcifications of the subcortical frontal white matter. [ncbi.nlm.nih.gov]

  Clinical description Males with the severe, neonatal-onset type are normal at birth but develop poor sucking, hypotonia and lethargy after a few days, rapidly progressing into somnolence and coma. Seizures and hyperventilation may also be present. [orpha.net]

  Six months after bariatric surgery, she again became intermittently encephalopathic with symptoms of somnolence, perseveration, echolalia, and difficulties with short-term memory. [jamanetwork.com]

The workup of neonates or adults in whom OTCD, or any UCD in general, is suspected, should start with a meticulous patient history that will determine similar manifestations or neonatal deaths in the family, voluntary avoidance of protein intake in diet, and either neurological or psychiatric disorders in close family members that cold be attributed to OTCD [2]. A thorough physical examination must follow, comprised of a full body inspection and a complete neurological exam that will assess various CNS abnormalities and the state of consciousness. Apart from serum measurement of ammonia levels, which is the first important marker when a disorder of the urea cycle is suspected, an extensive laboratory workup should be carried out soon after, comprised of liver and kidney function tests, arterial blood gas analysis (ABG), a complete blood count (CBC) and a full electrolyte panel. OTCD-specific studies include detection of plasma citrulline and arginine, and most importantly, evaluation of orotic acid in urine [2] [3]. The urinary increase of orotic acid, together with low plasma citrulline and arginine, is a diagnostic hallmark of hyperammonemia due to OTCD [2], in which case genetic studies are employed for confirmation. Mutational analysis is performed to detect mutations responsible for OTCD, located on the p21.1 segment of chromosome X [1] [5] [6]. If UCDs are confirmed in parents or close family members, a prenatal diagnosis can be achieved through chorionic villus sampling (CVS) [5].

• Multifocal Independent Spikes

  An electroencephalogram (EEG) revealed multifocal independent spike-and-sharp-wave discharges. After initial stabilization he was placed on a low-protein diet with citrulline and phenylbutyrate. [ncbi.nlm.nih.gov]

Standard Therapies Treatment Treatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. [rarediseases.org]

There is currently one approved treatment for ornithine transcarbamylase deficiency. [raredr.com]

• Intravenous administration of sodium benzoate, arginine, and sodium phenylacetate in a large medical facility setting with close laboratory monitoring is a treatment form. [secure.ssa.gov]

No neurological damage was apparent at 18 months after treatment. [ncbi.nlm.nih.gov]

This protocol is only a guideline and should not be used for definitive treatment without metabolic consultation. [newenglandconsortium.org]

The aim of this study was to determine the prognostic factors that affect the prognosis of life, to explore a basis for therapeutic strategy. [ncbi.nlm.nih.gov]

Prognosis Prognosis depends on disease severity but is considered bleak in patients with early neonatal disease. Without early diagnosis and treatment of hyperammonemic episodes, the neurological outcome is poor. [orpha.net]

Liver mitochondria are the primary site of the urea cycle.[1] The urea cycle converts ammonia into urea, which is water soluble and readily excreted in the urine.[2] Etiology The underlying cause of OTC deficiency is a gene mutation on the X chromosome [statpearls.com]

In our patient, the results of plasma and urine amino acid analyses were compatible with OTCD, allowing us to explain the etiology of her hyperammonemia and neurocognitive deficits. [karger.com]

Etiology OTCD is due to mutations in the OTC gene (Xp21.1) which encodes OTC, responsible for catalyzing the synthesis of citrulline (in liver and small intestine) from carbamoyl phosphate and ornithine. [orpha.net]

Epidemiology It is considered the most common inborn error of metabolism of the urea cycle, with an incidence of one case per 14,000 live births. [radiopaedia.org]

Genatlas disease for OTC Gene neonatal distress and hyperammonemia,including late-onset hyperammonemic coma Relevant External Links for OTC Genetic Association Database (GAD) OTC Human Genome Epidemiology (HuGE) Navigator OTC Atlas of Genetics and Cytogenetics [genecards.org]

Summary Epidemiology Ornithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Worldwide prevalence estimates range between 1/56,500 to 1/113,000 live births. [orpha.net]

We report the pathophysiologic characteristics, clinical features, clinical course, and differential diagnosis of OTCD and discuss the therapeutic options, including continuous venovenous hemodiafiltration and pharmacologic therapy for reduction of plasma [ncbi.nlm.nih.gov]

Conclusion: This case suggests that the pathophysiology of metabolic stroke is complicated. [deepblue.lib.umich.edu]

Gene therapy has the potential to prevent hyperammonemic episodes while awaiting liver transplantation, and possibly also to avert the need for transplantation altogether. [ncbi.nlm.nih.gov]

Deterrence and Patient Education Prevention and immediate treatment prevent mortality and reduce morbidity from OTC deficiency. [statpearls.com]

Rapid control of the hyperammonemia is crucial in preventing or lessening the degree of mental retardation. [newenglandconsortium.org]

1. Batshaw ML, Tuchman M, Summar M, Seminara J, the Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Molecular genetics and metabolism. 2014;113(0):127-130.
2. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.
3. Pinner JR, Freckmann M-L, Kirk EP, Yoshino M. Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature. Journal of Medical Case Reports. 2010;4:361.
4. Ben-Ari Z, Dalal A, Morry A, et al. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet. J Hepatol. 2010;52(2):292-295.
5. Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol. 2003;7(3):115-121.
6. Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015;42(5):181-194.
7. Venkateswaran L, Scaglia F, McLin V, et al. Ornithine Transcarbamylase Deficiency: A Possible Risk Factor for Thrombosis. Pediatr Blood Cancer. 2009;53(1):100-102.
8. Krivitzky L, Babikian T, Lee H, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, Adaptive, and Behavioral Functioning in Children with Urea Cycle Disorders. Pediatr Res. 2009;66(1):96-101.