Ornithine transcarbamylase deficiency is a rare, but life-threatening X-linked genetic disorder of the urea cycle. Deficiency of a key enzyme in this metabolic process leads to hyperammonemia, which often presents either in the first few weeks of life or in later adulthood. The diagnosis rests on clinical, biochemical and genetic studies.
Ornithine transcarbamylase deficiency (OTCD) is considered to be the most common disorder of the urea cycle    . 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  . 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  . As a result, hyperammonemia of variable severity is the principal pathological feature of OTCD  . Depending on the type of mutation, OTCD manifests in two age groups, although signs and symptoms may manifest at any point during life . The worst affected patients are hemizygous males, in whom a neonatal onset of hyperammonemia is manifested by poor feeding, vomiting, lethargy, tachypnea, and irritability  . In infants and younger children, intellectual and behavioral deficits are frequent  . 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    . Conversely, a much milder clinical presentation is seen in heterozygote females and males with incomplete OTCD, since only partial enzyme deficiency occurs . High protein meals, fasting, severe infections, pregnancy, high-dose corticosteroids, use of sodium valproate, various invasive medical procedures or chemotherapy can induce hyperammonemia   . Additional reports suggest that a voluntary adoption of a vegetarian diet could be an important clue as well .
Entire Body System
She was unable to stand owing to pain and weakness. [jamanetwork.com]
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Common clinical manifestations include stroke-like episodes, encephalopathy with seizures, muscle weakness, recurrent headaches and vomiting, hearing impairment, and short stature. Uncommon clinical presentations like cerebral venous thrombo... [allmedx.com]
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]
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]
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]
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]
- 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]
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]
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]
- 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]
[…] 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]
Liver, Gall & Pancreas
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.com]
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]
Ornithine transcarbamylase deficiency causes vomiting, lethargy, hyperventilation, and even death, mainly in the neonatal period. [ncbi.nlm.nih.gov]
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.com]
Symptoms of this form may include episodes of delirium, erratic behavior, a reduced level of consciousness, headaches, vomiting, and seizures. OTC is caused by mutations in the OTCgene and inheritance is X-linked . Treatment involves removing protein [rarediseases.info.nih.gov]
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]
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]
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]
Male and female infant or childhood presentations have been reported with vomiting, irritability, and failure to thrive, often triggered by illnesses. [cancertherapyadvisor.com]
Hyperammonaemic encephalopathy should be considered in patients of any age who experience fluctuating confusion. [ncbi.nlm.nih.gov]
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]
Initial signs include somnolence and poor feeding, usually followed by vomiting, lethargy, and coma central. [path.upmc.edu]
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 . 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  . The urinary increase of orotic acid, together with low plasma citrulline and arginine, is a diagnostic hallmark of hyperammonemia due to OTCD , 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   . If UCDs are confirmed in parents or close family members, a prenatal diagnosis can be achieved through chorionic villus sampling (CVS) .
No neurological damage was apparent at 18 months after treatment. [ncbi.nlm.nih.gov]
Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. [en.wikipedia.org]
Liver mitochondria are the primary site of the urea cycle. The urea cycle converts ammonia into urea, which is water soluble and readily excreted in the urine. Etiology The underlying cause of OTC deficiency is a gene mutation on the X chromosome [statpearls.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]
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]
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]
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]
Males are more commonly affected as neonates or children, and generally at younger ages than females. Male patients lack the OTC enzyme which leads to more severe disease than seen in females. Epidemiology Ornithine transcarbamylase deficiency is [statpearls.com]
We detail its presentation and management, explore potential underlying pathophysiology, and propose a practice change to optimize care of FL-HCC patients. [ncbi.nlm.nih.gov]
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]
Liver transplantation cannot cure brain damage which has already occurred, but it will prevent future hyperammonemic episodes and prevent further damage. In popular culture Mob Rules (House) References a b c d e f Wraith, J. [en.wikipedia.org]
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- 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.