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Urea Cycle Disorder

Citrullinemia

Urea cycle disorder is a general term referring to a variety of hereditary diseases provoking partial or complete deficiencies of enzymes required for the breakdown of nitrogen compounds and detoxification of ammonia. Hyperammonemia is the clinical hallmark of urea cycle disorders.

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Presentation

The hallmark of UCD is hyperammonemia. In severe UCD, accumulation of neurotoxic ammonia provokes symptoms of hyperammonemic encephalopathy within hours or few days after birth; patients suffering from milder UCD may not experience any symptoms until adulthood, though. Also, residual activity of enzymes may delay the onset of symptoms and attenuate their severity.

Severe neonatal hyperammonemia is commonly observed in the deficiency of NAGS, CPSI, OTC, ASS, and ASL. Parents may claim feeding difficulties, may note their infants to become somnolent or lethargic. Vomiting and respiratory distress are frequently observed. Tremor and seizures may indicate cerebral edema and eventually, affected children may fall into a hyperammonemic coma. Late-onset UCD manifests in form of loss of appetite, vomiting, tremor and ataxia. Patients may experience stroke-like episodes and show psychiatric symptoms [7]. Rising levels of ammonia may provoke cerebral edema and coma in elder UCD patients, too.

Of note, patients diagnosed with and under therapy for UCD may sustain hyperammonemic crises at any time during their lives. Here, a thorough anamnesis may reveal triggers of such an episode: fasting or protein overload, infectious diseases, pregnancy or recent childbirth, surgery, and other forms of physical stress.

Anorexia
  • Many newborns with a severe enzyme deficiency initially appear well but rapidly develop hyperammonemia and lethargy, anorexia, abnormal respiratory patterns, hypothermia, seizures, abnormal posturing, and deterioration into coma.[clinicalgate.com]
  • […] supplementation Argininemia (107830) Arginase I ARG1 (6q23)* Biochemical profile: Elevated plasma arginine , diaminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria), orotic aciduria, pyrimidinuria Clinical features: Growth and developmental delay, anorexia[msdmanuals.com]
  • Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma.[themedicalbiochemistrypage.org]
  • […] supplementation Argininemia (107830) Arginase I ARG1 (6q23)* Biochemical profile: Elevated plasma arginine, diaminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria), orotic aciduria, pyrimidinuria Clinical features: Growth and developmental delay, anorexia[merckmanuals.com]
Poor Feeding
  • High ammonia levels in the blood and brain cause irritability, poor feeding, vomiting, drowsiness and, in severe cases, coma.[cafamily.org.uk]
  • Affected infants typically appear normal at birth, but as ammonia builds up in the body they experience a progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness.[mooneyequalsmc2.com]
  • Such babies seem normal right after birth and nurse well, but over time the following symptoms emerge: Irritablity Lethargy Poor feeding Vomiting.[news-medical.net]
  • Clinical features are the result of the development of hyperammonemic encephalopathy and include poor feeding, lethargy leading to coma, hyperventilation, muscle tone abnormalities and, in the late stages, seizures and ultimately death.[idph.state.il.us]
  • While all of these symptoms may not be present, usually the baby will become very sleepy and irritable and will have feeding problems, including poor feeding and vomiting. Seizures, trouble breathing and coma may appear later.[cincinnatichildrens.org]
Hypothermia
  • Approaches to neuroprotection during episodes of hyperammonemia are discussed, including the use of controlled hypothermia (brain cooling), as well as proposed, but as yet untested, pharmacologic therapies.[dovepress.com]
  • Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma.[themedicalbiochemistrypage.org]
  • Many newborns with a severe enzyme deficiency initially appear well but rapidly develop hyperammonemia and lethargy, anorexia, abnormal respiratory patterns, hypothermia, seizures, abnormal posturing, and deterioration into coma.[clinicalgate.com]
  • ASL , ASS1, CPS1, OTC or the cofactor producer encoded by NAGS are typically normal at birth but develop severe symptoms in the first few days of life, including cerebral edema, lethargy, irritability, anorexia, vomiting, hyper- or hypoventilation, hypothermia[invitae.com]
Epilepsy
  • The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: Relationship to blood carnitine status. Epilepsy Res . 2009 May 13. [Medline] . Hauser ER, Finkelstein JE, Valle D, Brusilow SW.[emedicine.medscape.com]
  • Treatment of deficiencies with levomefolic acid (5-MTHF) can decrease many symptoms, including epilepsy, developmental delays, autistic features and even symptoms involved in chronic fatigue syndrome and other myalgias.[sharecare.com]
Feeding Difficulties
  • Parents may claim feeding difficulties, may note their infants to become somnolent or lethargic. Vomiting and respiratory distress are frequently observed.[symptoma.com]
  • .  Common features seen are – severity varies  Feeding difficulties , Lethargy , irritability , protein induced vomiting and poor intellectual development – MR ,cerebral edema, seizures  leads to COMA and death Dr. N. Sivaranjani 24 25.[slideshare.net]
Hypoventilation
  • Infants with a complete enzyme deficiency typically appear normal at birth, but present in the neonatal period as ammonia levels rise with lethargy, seizures, hyper- or hypoventilation, and ultimately coma or death.[mayomedicallaboratories.com]
  • Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma.[themedicalbiochemistrypage.org]
  • Hypoventilation and respiratory arrest can occur as pressure on the brainstem increases.[clinicalgate.com]
Respiratory Distress
  • distress * Retarded growth * Seizures * Vomiting Prevention - Inborn urea cycle disorder Not supplied.[checkorphan.org]
  • Soon after, seizures, hypotonia (poor muscle tone, floppiness), respiratory distress (respiratory alkalosis), and coma may occur. These symptoms are caused by rising ammonia levels in the blood. Sepsis and Reye’s syndrome are common misdiagnoses.[nucdf.org]
  • Vomiting and respiratory distress are frequently observed. Tremor and seizures may indicate cerebral edema and eventually, affected children may fall into a hyperammonemic coma.[symptoma.com]
  • She required intubation because of respiratory distress, and anticonvulsant therapy was started with the onset of clonic arm jerking.[ajnr.org]
  • Vomiting may be an early symptom, along with instability in temperature, respiratory distress, and rapid breathing. 1,3 A less severe deficiency may produce symptoms such as poor appetite (fussy eater) and unconscious avoidance of protein, which may at[acertx.com]
Severe Clinical Course
  • However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome.[ncbi.nlm.nih.gov]
Vomiting
  • Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine , markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability[msdmanuals.com]
  • Location) Comments Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting[merckmanuals.com]
  • : upper abdomen (stomach) pain rash nausea vomiting diarrhea decreased appetite headache The most common side effects of RAVICTI in children 2 months to less than 2 years of age include: low white blood cell count (neutropenia) vomiting diarrhea fever[ravicti.com]
  • The most common side effects of RAVICTI in adults include diarrhea, gas, headache, nausea, vomiting, tiredness, decreased appetite, and dizziness.[ravicti.com]
  • […] disorder The list of signs and symptoms mentioned in various sources for Inborn urea cycle disorder includes the 30 symptoms listed below: * Urea cycle enzyme deficiency * Mental retardation * Brain damage * Coma * Irritability * Feeding problems * Vomiting[checkorphan.org]
Failure to Thrive
  • Encephalopathy * Acidosis * Movement disorders * Low blood sugar Causes - Inborn urea cycle disorder * Acidosis * Agitation * Brain damage * Coma * Delirium * Encephalopathy * Failure to thrive * Feeding problems * Irritability * Lethargy * Low blood[checkorphan.org]
  • Symptoms of mild to moderate urea cycle disorder can show up in childhood, according to the NUCDF, and can initially include refusal to eat high-protein foods, failure to thrive and inconsolable crying.[livescience.com]
  • Earliest symptoms may include failure to thrive, inconsolable crying, agitation or hyperactive behavior, sometimes accompanied by screaming, self-injurious behavior, and refusal to eat meat or other high-protein foods.[nucdf.org]
  • Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD).[themedicalbiochemistrypage.org]
  • Symptoms and Signs Clinical manifestations range from mild (eg, failure to thrive, intellectual disability, episodic hyperammonemia) to severe (eg, altered mental status, coma, death).[merckmanuals.com]
Loss of Appetite
  • Affected individuals thus present with a variety of neurological deficits, ranging from loss of appetite and vomiting to tremor, seizures, and coma.[symptoma.com]
  • Other symptoms include loss of appetite, low core body temperature, vomiting, delusions, hallucinations, and psychosis.[healthstoriesproject.com]
  • Although the clinical signs and symptoms of the specific urea cycle disorders vary to a degree, a typical hyperammonemic episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities.[clinicalgate.com]
  • The signs and symptoms can be the same as the newborn period but may also include poor growth, loss of appetite, delirium, tremors, inconsolable crying, hyperactive behavior, and irritability.[wellness.com]
  • Treatment is to perform dialysis or a renal transplant. [3] Signs and symptoms [ edit ] Classical signs of uremia are: progressive weakness and easy fatigue, loss of appetite due to nausea and vomiting, muscle atrophy, tremors, abnormal mental function[en.wikipedia.org]
Delusion
  • Citrin SCL25A13 (7q21.3)* Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 mo With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions[msdmanuals.com]
  • Other symptoms include loss of appetite, low core body temperature, vomiting, delusions, hallucinations, and psychosis.[healthstoriesproject.com]
  • Manifestations of CTLN2 are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive[themedicalbiochemistrypage.org]
Psychiatric Symptoms
  • Some undiagnosed adults may suffer from psychiatric symptoms like schizophrenia or bipolar disorder. What is the incidence of these disorders? Urea cycle disorders are included in the category of inborn errors of metabolism.[nucdf.org]
  • Some undiagnosed adults may suffer from psychiatric symptoms like schizophrenia or bipolar disorder.”[huffingtonpost.co.uk]
  • Many may be seen by neurologists or psychiatrists because of psychiatric symptoms, including schizophrenia and bipolar disorder. Without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death.[nucdf.org]
  • Patients may experience stroke-like episodes and show psychiatric symptoms. Rising levels of ammonia may provoke cerebral edema and coma in elder UCD patients, too.[symptoma.com]
Abnormal Behavior
  • Development of OTC deficiency in these cases can happen without a family history or other risk factors for the disease. diagnosis General : A urea cycle disorder should be suspected in any patient with unexplained abnormal behavior that may include tremor[wellness.com]
Seizure
  • Ornithine transcarbamylase deficiency is the most common of the urea cycle disorders and frequently presents with coma or seizures during hyperammonemia. However, seizures can also occur without metabolic decompensation.[ncbi.nlm.nih.gov]
  • Acute management may include the technological interventions of exchange transfusion, peritoneal dialysis or hemodialysis, prevention and treatment of seizures, prevention and/or treatment of increased intracranial pressure, and complex nutritional support[ncbi.nlm.nih.gov]
  • Administration of certain medications, high protein diet, excessive exercise, surgical procedures, or trauma can precipitate symptoms of mental confusion, seizure-like activity, and ataxia.[ncbi.nlm.nih.gov]
  • Elevated ornithine and glutamine, decreased citrulline and arginine , markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures[msdmanuals.com]
  • Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures[merckmanuals.com]
Lethargy
  • […] signs and symptoms mentioned in various sources for Inborn urea cycle disorder includes the 30 symptoms listed below: * Urea cycle enzyme deficiency * Mental retardation * Brain damage * Coma * Irritability * Feeding problems * Vomiting * Progressive lethargy[checkorphan.org]
  • Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine , markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy[msdmanuals.com]
  • Such babies seem normal right after birth and nurse well, but over time the following symptoms emerge: Irritablity Lethargy Poor feeding Vomiting.[news-medical.net]
  • Symptoms include episodes of disorientation, confusion, slurred speech, unusual and extreme combativeness or agitation, stroke-like symptoms, lethargy and delirium.[nucdf.org]
  • […] arginine Citrullinemia type I (215700) Argininosuccinic acid synthetase ASS (9q34)* Biochemical profile: High plasma citrulline and glutamine, citrullinuria, orotic aciduria Clinical features: Episodic hyperammonemia, growth failure, protein aversion, lethargy[merckmanuals.com]
Encephalopathy
  • The authors report a 3-year 8-month-old girl presenting with episodic hyperammonemic encephalopathy probably due to a proximal urea cycle disorder.[ncbi.nlm.nih.gov]
  • We describe the clinical course of a liver transplant recipient presenting with acute hyperammonemia and encephalopathy after receiving a liver graft form a donor with unrecognized OTCD.[ncbi.nlm.nih.gov]
  • Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged.[ncbi.nlm.nih.gov]
  • Hyperammonemic encephalopathy is an emergency and requires immediate symptomatic treatment to avoid permanent brain damage.[symptoma.com]
  • […] glutamine in OTCD patients with hyperammonemic encephalopathy.[ajnr.org]
Irritability
  • Symptoms - Inborn urea cycle disorder The list of signs and symptoms mentioned in various sources for Inborn urea cycle disorder includes the 30 symptoms listed below: * Urea cycle enzyme deficiency * Mental retardation * Brain damage * Coma * Irritability[checkorphan.org]
  • Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine , markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability[msdmanuals.com]
  • Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.[wellness.com]
  • Comments Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability[merckmanuals.com]
  • High ammonia levels in the blood and brain cause irritability, poor feeding, vomiting, drowsiness and, in severe cases, coma.[cafamily.org.uk]
Hyperactivity
  • After 1 year of treatment, the autistic-like findings and hyperactivity were no longer apparent.[ncbi.nlm.nih.gov]
  • […] followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity[ncbi.nlm.nih.gov]
  • […] choroid and retina, mild proximal hypotonia, myopathy Treatment: Pyridoxine, low- arginine diet, lysine and α -aminoisobutyrate to increase renal loss of ornithine; proline or creatine supplementation Hyperinsulinism-hyperammonemia syndrome (606762) Hyperactivity[msdmanuals.com]
  • AG symptoms are usually progressive and include growth failure, spastic tetraplegia (lower limbs more severely affected than upper limbs), seizures, psychomotor retardation and hyperactivity.[nucdf.org]
  • […] damage * Coma * Irritability * Feeding problems * Vomiting * Progressive lethargy * Seizures * Reduced muscle tone * Respiratory distress * Respiratory alkalosis * Increased blood ammonia level * Failure to thrive * Constant infant crying * Agitation * Hyperactive[checkorphan.org]

Workup

It is of utmost importance to recognize UCD and to initiate treatment before irreversible brain damage occurs. Thus, serum ammonia levels should be determined in all patients presenting with symptoms consistent with hyperammonemic encephalopathy. In the case of hyperammonemia, it should be evaluated whether a patient suffers from metabolic acidosis, which is not characteristic of primary UCD but may indicate organic acidemia. Further analyses of blood samples should be realized to assess the following parameters:

  • Glucose
  • Amino acids
  • Acylcarnitines
  • Aspartate transaminase, alanine transaminase
  • Alkaline phosphatase
  • BUN, creatinine

Urine samples should be obtained and examined with regards to their contents of orotic acid and organic acids.

Findings may be interpreted as follows:

  • Serum concentrations of glutamine and alanine are increased in the case of NAGS, CPSI and OTC deficiency, with CPSI and OTC deficiency being additionally characterized by low citrulline levels.
  • Urinary excretion of orotic acid is unaltered in patients suffering from NAGS or CPSI deficiency but is enhanced in OTC-deficient individuals.
  • Also, urine contents of orotic acid are elevated in ASS, ASL, and ARG-deficient patients.
  • Serum citrulline levels are increased in the case of ASS, ASL, and ARG deficiency, i.e., in the case of distal UCD, with highest values registered in ASS-deficient patients.
  • Serum levels of arginine are decreased in case of ASS or ASL deficiency but are elevated in ARG-deficient people.
  • Urinary excretion of argininosuccinic acid is enhanced in patients suffering from ARG deficiency.

Genetic screens may confirm the diagnosis of a particular UCD, may allow for the determination of the mutation underlying the disease, and this information may be valuable as a prognostic factor.

Neuroimaging is usually not required for the diagnosis of UCD, but may reveal brain lesions consistent with hyperammonemia.

Treatment

Although there is no causative treatment for either gene defect, long-term administration of certain drugs may compensate for enzyme deficiencies:

  • Patients diagnosed with NAGS deficiency benefit from administration of N-carbamoyl glutamate, a compound that fulfills the role of N-acetyl-glutamate and activates CPSI
  • This same compound may be used in patients suffering from partial CPSI deficiency

Otherwise, general recommendations include the reduction of dietary protein intake to diminish protein catabolism. Patients should consume less than 2 g of protein per kg and day [11], but development and growth are to be monitored to prevent nutrient deficiencies. Essential amino acids are often required to this end.

Hyperammonemic encephalopathy is an emergency and requires immediate symptomatic treatment to avoid permanent brain damage. Treatment protocols depend on serum ammonia levels and may comprise the following [4]:

  • Prohibition of protein intake for up to 48 hours
  • Administration of dextrose, possibly plus insulin, or intra-lipids to reverse catabolism
  • Provision of L-arginine and L-citrulline
  • Administration of ammonia scavengers, e.g., sodium benzoate, sodium phenylacetate, sodium phenylbutyrate
  • Hemodialysis or hemofiltration

Finally, patients may be considered for liver transplantation.

Prognosis

Despite considerable improvements in survival rates of UCD patients, the neurological outcome generally remains poor [9] [1]. Cognitive and motor development may be severely affected by hyperammonemia and brain damage due to UCD. There is a negative correlation between the severity of hyperammonemia, the duration of hyperammonemic coma and the neurological outcome [6]. Therefore, any diagnostic delay that leads to the postponement of therapy is likely to exacerbate the outcome.

Recently, heterozygosity for OTC mutations has been shown to affect neurocognitive and psychological functions in women [10]. According to that study, the severity of neurological deficits correlates with the amount of residual urea synthetic capacity and the mutation type, and may indeed be predicted based on these parameters. It is tempting to speculate that this also applies to other UCD.

Etiology

UCD comprise of five deficiencies of catalytic enzymes (CPS-I, OTC, ASS, ASL, and ARG), one deficiency of an enzyme providing an allosteric activator of a catalytic enzyme (NAGS), and two dysfunctional transporters (OTL, CIT) [3]. All these diseases are caused by sequence anomalies affecting those genes encoding for the respective proteins. With the exception of OTC, UCD is inherited as an autosomal recessive trait. The gene encoding for OTC is located on the X-chromosome. There is considerable heterogeneity regarding the precise mutations underlying a specific UCD. While frameshift and nonsense mutations typically provoke complete deficiencies, missense mutations may be associated with a residual activity of the respective protein. It has been proposed that such residual activity accounts for the delay of symptom onset observed in some cases [4].

Epidemiology

In the United States, the overall incidence of UCD has been calculated to be about 1 per 35,000 inhabitants [5], while international studies yielded estimates of up to 1 per 8,000 live births [4]. Summar et al. provided detailed estimates of incidence rates of individual UCD [5]:

NAGS deficiency <1:2,000,000
CPSI deficiency 1:1,300,000
OTC deficiency 1:56,500
ASS deficiency 1:250,000
ASL deficiency 1:218,750
ARG deficiency 1:950,000
OTL deficiency <1:2,000,000
CIT deficiency <1:2,000,000

Considerable gender predilection has to be noted for OTC deficiency. Since the gene encoding for OTC is located on the X-chromosome, men are affected significantly more often. Women may compensate for a defective allele, but about 15% of carriers still develop hyperammonemia at some point in their lives [3].

Sex distribution
Age distribution

Pathophysiology

The urea cycle plays a crucial role in the catabolic metabolism of nitrogen compounds since it allows for the breakdown of such molecules without an accumulation of ammonia as a by-product. Ammonia mainly arises during the conversion of glutamate to α-ketoglutarate in the liver, a reaction mediated by glutamate dehydrogenase, and deamination of adenosine monophosphate in skeletal muscles [6]; other reactions comprising oxidative deamination contribute to ammonia synthesis to a lesser extent. Detoxification of ammonia is initiated by the irreversible conversion of ammonia and bicarbonate to carbamoyl phosphate, and this reaction is catalyzed by CSPI. CSPI is dependent on the presence of N-acetyl-glutamate, which serves as an allosteric activator and is provided by NAGS. In a subsequent reaction, OTC mediates the production of citrulline from carbamoyl phosphate and ornithine. Accordingly, CSPI deficiency directly provokes the accumulation of neurotoxic ammonia. NAGS deficiency causes a reduced activity of CSPI and similarly leads to hyperammonemia. Conversion of carbamoyl phosphate and ornithine to citrulline and phosphate is impaired in OTC-deficient patients.

All reactions described so far take place in mitochondria, but at this point, citrulline needs to be transported into the cytoplasm. This transport is mediated by an antiporter, namely by OTL, which allows for the transport of citrulline into the cytoplasm and for the import of ornithine into mitochondria. Under physiological conditions, ASS catalyzes the conversion of citrulline and aspartate to argininosuccinate. Thus, besides citrulline, aspartate is required for this reaction to take place. Aspartate is transported into the cytoplasm via an aspartate-glutamate transporter termed citrin, and this protein is defective in patients suffering from CIT. Consequently, substrates needed for argininosuccinate synthetase activity are not supplied adequately in case of OTL or CIT deficiency, and the urea cycle is interrupted at this point. An inherent deficiency of ASS has similar consequences. Both ASL and ARG are required for the breakdown of argininosuccinate and recovery of ornithine. In patients suffering from ASL or ARG deficiency, the regeneration of ornithine and the synthesis of urea are impaired. Therefore, OTC activity is reduced due to lack of substrates.

The central nervous system is very sensitive to ammonia and therefore, the clinical presentation of patients suffering from UCD-related hyperammonemia is that of hyperammonemic encephalopathy. Ammonia may pass the blood-brain barrier and is subsequently converted to glutamine. This reaction takes place in astrocytes, but because glutamine is osmotically active, astrocytes start to swell [7]. Cytotoxic brain edema develops, and this condition further interferes with glia function [8]. Exacerbation of brain edema leads to increased intracranial pressure, brain herniation, and death. Histopathologically, cortical atrophy, basal ganglia lesions and white matter damage may be observed. Prolonged exposure of the brain to enhanced concentrations of ammonia results in irreversible brain damage and permanent neurological deficits.

Prevention

Affected families may benefit from genetic counseling. Genetic screens are indicated to identify carriers, and this approach allows to deduce the likelihood of a child to be affected by a determined UCD. Furthermore, prenatal tests are available. Chorionic villus or amniotic fluid samples can be examined accordingly, and in the case of a positive result, parents may opt for a premature termination of pregnancy.

Summary

The urea cycle comprises several complex biochemical reactions and aims at the breakdown of proteins, amino acids, and nitrogen compounds while at the same time preventing an accumulation of ammonia. Various enzymes are required for the proper execution of each single step on the way to the production of urea. Mutations may occur in any gene encoding for these enzymes, thus giving rise to an interruption of this catabolic process. Gene defects interfering with the transport of intermediate products may ensue similar clinical features as enzyme deficiencies. In detail, the term urea cycle disorder (UCD) encompasses the following diseases:

NAGS deficiency, CPS-I deficiency, and OTC deficiency are sometimes referred to as the most severe UCD. Indeed, these UCD are all proximal UCD, i.e., enzyme deficiencies impair early steps of the urea cycle. Disturbance of late reactions is typical of distal UCD and may be associated with milder symptoms and late-onset disease. However, no significant differences have been encountered regarding the clinical outcome of proximal and distal UCD [1]. Also, entities like ARG, not usually characterized by neonatal hyperammonemia, may occasionally manifest as severe UCD [2].

Patient Information

Urea cycle disorder (UCD) is a general term referring to a total of eight hereditary diseases, all characterized by disturbances of protein catabolism and ammonia detoxification. These are important metabolic processes that comprise a chain of biochemical reactions which constitute the urea cycle. In simple terms, each reaction provides the substrates needed for the following reaction, with nitrogenous compounds like proteins, amino acids, and ammonia being required for the first step. These molecules are eventually converted into urea. Each reaction is catalyzed by an enzyme, and most UCDs are indeed enzyme deficiencies. Other UCDs are characterized by defective transporters that impair substrate trafficking. In any case, gene defects provoking UCD lead to an interruption of the urea cycle and to the accumulation of ammonia.

Ammonia is neurotoxic, i.e., the brain is most sensitive to enhanced levels of this compound. Affected individuals thus present with a variety of neurological deficits, ranging from loss of appetite and vomiting to tremor, seizures, and coma. Blood levels of ammonia have to be diminished as soon as possible to prevent irreversible brain damage. Unfortunately, long-term prevention of hyperammonemic crises is not always possible and the neurological outcome of UCD is often poor.

References

Article

  1. Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013; 162(2):324-329.
  2. Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol Genet Metab. 2011; 104(1-2):107-111.
  3. Ah Mew N, Lanpher BC, Gropman A, et al. Urea Cycle Disorders Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle.
  4. 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.
  5. Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013; 110(1-2):179-180.
  6. Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012; 27(2):207-222.
  7. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007; 30(6):865-879.
  8. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008; 56(4):365-377.
  9. Enns GM. Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol. 2008; 15(3):132-139.
  10. Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004; 55(1):80-86.
  11. Nakamura K, Kido J, Mitsubuchi H, Endo F. Diagnosis and treatment of urea cycle disorder in Japan. Pediatr Int. 2014; 56(4):506-509.

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Last updated: 2019-07-11 21:19