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.

• Fatigue

  Further, it is related to many more familiar diseases, including autism, Parkinson’s, Alzheimer’s, Lou Gehrig’s disease (ALS), muscular dystrophy and chronic fatigue syndrome. [sharecare.com]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 28, 2019 [patientslikeme.com]

  In children with mild or moderate UCD who do not show symptoms until early childhood, symptoms may include: disliking meat or other foods rich in protein, vomiting, nausea, mental confusion or hyperactive behaviour, fatigue, weakness and drowsiness. [comidamed.com]

  By doing this, users can minimise their acid levels during exercise and reduce overall fatigue to a significant extent. [sarmsstore.co.uk]

• 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]

  Arginine supplementation Argininemia (107830*) Arginase I 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]

• Poor Feeding

  Symptoms may include: irritability, poor feeding, vomiting, drowsiness and, in severe cases, coma. [comidamed.com]

  High ammonia levels in the blood and brain cause irritability, poor feeding, vomiting, drowsiness and, in severe cases, coma. [cafamily.org.uk]

  The major presenting symptoms are vomiting, lethargy, hypothermia, and poor feeding. The estimated incidence of ASL deficiency is 1:70,000 newborns 5. [centogene.com]

  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]

  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]

• 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]

  Affected boys are normal at birth but soon after birth they develop acute neonatal encephalopathy with hyperventilation and hypothermia. [centogene.com]

  […] a urea cycle defect reflect those of hyperammonemic encephalopathy (brain edema, metabolic dysregulation and neurotransmitter disturbance), with the exception of ARG deficiency General: Poor feeding, lethargy, behavioral changes Vital Sign Changes: Hypothermia [pedclerk.bsd.uchicago.edu]

  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]

• Sepsis

  Due to possibility of sepsis, ampiric antibiotherapy was started after taking blood culture. Blood gas and ammonia levels were studied with a preliminary diagnosis of metabolic disease in the cases in which... [go.gale.com]

  Sepsis and Reye’s syndrome are common misdiagnoses. If untreated, these severely affected infants will die. [nucdf.org]

  Urea cycle disorders in infants are commonly misdiagnosed as sepsis or Reye’s syndrome. Infants with severe symptoms will die if not treated in time. [news-medical.net]

  Early on, a urea cycle disorder might be mistaken for sepsis, an overwhelming response that the body makes to some sort of infection. However, in a urea cycle disorder, no such infection is actually present. [verywellhealth.com]

  The most common misdiagnosis is neonatal sepsis. [en.wikipedia.org]

• Respiratory Distress

  distress * Respiratory alkalosis * Increased blood ammonia level * Failure to thrive * Constant infant crying * Agitation * Hyperactive behavior * Self-injury * Screaming * Dislike of eating meat * Dislike of eating high protein foods * Lethargy * Delirium [checkorphan.org]

  Very soon after birth affected infants show signs of seizures, hypotonia, and respiratory distress. [centogene.com]

  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]

  distress Liver failure (often 2/2 to perinatal HSV)- severe liver malfunction and elevated liver enzymes Acute management of Urea Cycle Defect Respiratory management- if respiratory failure is ensuing, mechanical ventilation is indicated to decrease [pedclerk.bsd.uchicago.edu]

  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]

• Tachypnea

  Early symptoms include poor feeding, vomiting, lethargy, irritability, tachypnea, and somnolence.1,5 Other symptoms may include respiratory alkalosis, which can be used as a diagnostic clue, as well as neuromuscular irritability and stridor. [mhc.cpnp.org]

• Vomiting

  Proteins or Enzymes Comments Ornithine-transcarbamoylase (OTC) deficiency (311250*) OTC Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting [msdmanuals.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]

  […] which begin at the age of 9 months and mental retardation  Symptoms included delayed menarche, insomnia, nocturnal sweats, recurrent vomiting, tremors, lethargy, convulsions and hallucination 20 21.  It has 3 type  Type 1 which is duo to the changes [slideshare.net]

  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]

• 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]

  Frequently occurring symptoms are as follows: nausea and vomiting, loss of appetite, acidemia, failure to thrive, hyperammonemia, convulsions, abnormal brain magnetic resonance imaging and/or computed tomography, liver failure, fatty liver, hepatomegaly [onlinelibrary.wiley.com]

  CA5A GLUD1 GLUL SLC7A7 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 [invitae.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]

  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]

• 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]

  *, 603471*) Citrin Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 months With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions [msdmanuals.com]

• Psychiatric Symptoms

  Anytime a person has unexplained neurological or psychiatric symptoms, doctors must consider the possibility of elevated ammonia levels (called hyperammonemia). Infants with such symptoms should be tested for this promptly. [verywellhealth.com]

  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]

  Common symptoms amongst both acute and chronic hyperammonemia include lethargy, seizures, and psychiatric symptoms.8 The clinical presentation of urea cycle disorders is dependent on which enzymes of the urea cycle are deficient. [mhc.cpnp.org]

• Psychomotor Retardation

  * Feeding problems * Irritability * Lethargy * Low blood sugar * Mental retardation * Movement disorders * Psychomotor retardation * Reduced muscle tone * Respiratory distress * Retarded growth * Seizures * Vomiting Prevention - Inborn urea cycle disorder [checkorphan.org]

  Serious neurological sequelae, seizures, severe psychomotor retardation are seen in the survivors of hyperammonic decompensation (1-3). [go.gale.com]

  The most well known disorder in the larger group is phenylketonuria (PKU), characterized by an accumulation of the amino acid phenylalanine, which frequently results in mental and psychomotor retardation, if not treated. [tributyrate.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]

  Arginase deficiency symptoms are progressive growth failure with severely affected lower limbs, seizures, and psychomotor retardation. [news-medical.net]

• 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]

  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]

  The patient remained in status epilepticus and phenobarbital was initiated, which controlled the seizures. She was started on dialysis and ammonul, an ammonia binder. [journals.lww.com]

  […] 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 * Seizures [checkorphan.org]

• 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]

  The major presenting symptoms are vomiting, lethargy, hypothermia, and poor feeding. The estimated incidence of ASL deficiency is 1:70,000 newborns 5. [centogene.com]

  Comments Ornithine-transcarbamoylase (OTC) deficiency (311250*) OTC Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy [msdmanuals.com]

  A urea cycle defect is first suspected in an infant with anorexia, alterations in respiratory function and thermoregulation, lethargy, seizures, and deteriorating neurological status or in a child with decreased appetite, vomiting, lethargy, behavioral [clinicalgate.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]

  Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases. Clin Lymphoma Myeloma. 2008 Dec. 8(6):363-9. [Medline]. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. [medscape.com]

  Practice points Urea cycle disorders are a rare but important cause of acute encephalopathy and can present for the first time in adulthood. [pn.bmj.com]

  * 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 sugar * Mental [checkorphan.org]

  Hyperammonemic encephalopathy is an emergency and requires immediate symptomatic treatment to avoid permanent brain damage. [symptoma.com]

• 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]

  Neonatal onset results in clinical features that include irritability, vomiting, lethargy, seizures, NEONATAL HYPOTONIA; RESPIRATORY ALKALOSIS; HYPERAMMONEMIA; coma, and death. [mesh.kib.ki.se]

  […] or Enzymes Comments Ornithine-transcarbamoylase (OTC) deficiency (311250*) OTC 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]

• Ataxia

  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]

  Argininemia may present with paraplegia, tetraplegia and ataxia. Newborn Screening and Definitive Diagnosis In Illinois, newborn screening for urea cycle defects is performed using tandem mass spectrometry. [idph.state.il.us]

  Ammonia is particularly toxic to the nervous system, which helps explain the neurologic symptoms (such as lethargy, seizures, and ataxia) that are often seen in type I citrullinemia. [mooneyequalsmc2.com]

  Other clinical manifestations that might help with diagnosis and management ASA lyase deficiency can also present with hepatomegaly and chronic ataxia as part of the clinical picture. [cancertherapyadvisor.com]

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.

• Hyperuricemia

  Enzyme deficiencies and transport defects on this pathway lead to hyperuricemia-induced urea cycle disorders (UCD). [go.gale.com]

  Incidence of clinical symptoms in urea cycle disorder: 1, nausea and vomiting; 2, loss of appetite; 3, failure to thrive; 4, hypoglycemia; 5, acidemia; 6, hyperammonemia; 7, hyperuricemia; 8, convulsion; 9, mental retardation; 10, visual disturbance; [onlinelibrary.wiley.com]

• Ammonia Increased

  Use of these for treatment is increasing. Treatment of the acute phase In the acute phase, first the blood ammonia should be decreased. [onlinelibrary.wiley.com]

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.

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.

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].

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]:

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].

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.

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.

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:

• N-acetyl-glutamate synthase deficiency / hyperammonemia type 3 (NAGS)
• Carbamoyl phosphate synthase I deficiency / hyperammonemia type 1 (CPSI)
• Ornithine transcarbamylase deficiency / hyperammonemia type 2 (OTC)
• Argininosuccinate synthetase deficiency / citrullinemia (ASS)
• Argininosuccinate lyase deficiency (ASL)
• Arginase deficiency (ARG)
• Ornithine translocase deficiency / hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (OTL)
• Citrin deficiency (CIT)

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].

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.

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.