Buenos Aires 02 de Noviembre del 2020





           Clinical features and diagnosis of urea cycle disorders


                                                                                                       Brendan Lee, Helen V. Firth

                                                 Up Dated to:  Abril 2009


OVER VIEW — The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body. Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). The urea cycle disorders are  * Carbamyl phosphate synthetase I (CPSI) deficiency (OMIM #237300)

            * Ornithine transcarbamylase (OTC) deficiency (OMIM #311250)

            * Argininosuccinate synthetase (ASS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1, OMIM #215700)

            * Argininosuccinate lyase deficiency (ASL, also known as argininosuccinic aciduria, OMIM #207900)

            * N-acetyl glutamate synthetase (NAGS) deficiency (OMIM#237310)

            * Arginase deficiency (OMIM #207800)

UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening metabolic decompensations in infancy. Survivors of the metabolic decompensation frequently have severe neurologic injury. Prompt recognition and treatment are needed to improve outcome.

EPIDEMIOLOGY — UCDs occur in approximately 1 in 8200 live births [1].

PATHOPHYSIOLOGY — The urea cycle converts nitrogen from peripheral (muscle) and enteral sources (protein ingestion) into urea that is water soluble and can be excreted. Two moles of nitrogen, one from ammonia and one from aspartate, are converted to urea in each cycle. Ammonia nitrogen derives from circulating amino acids, mostly glutamine and alanine. Aspartate is a substrate for argininosuccinic acid synthesis.
Deficiencies in the first four enzymes of the cycle (CPSI, OTC, ASS, or ASL) or in NAGS, the enzyme for co-factor in N-acetylglutamate production, result in accumulations of ammonia and the precursor metabolites. Because one CPS isoform (CPSI), NAGS, and OTC are located in mitochondria, primary mitochondrial disease secondarily may affect urea cycle activity.

GENETICS — The inheritance pattern of all the UCDs except OTC deficiency (which is X-linked) is autosomal recessive. Thus, the recurrence risk for parents of an affected child (except OTC deficiency) is 25 percent.
Because inheritance of OTC is X-linked, all female offspring of a male OTC-deficient parent will carry an OTC mutation, and 50 percent of all offspring (male and female) from a female OTC-deficient parent will carry the mutation. Hemizygous males usually are more severely affected than are heterozygous females. Approximately 10 percent of female carriers of OTC become symptomatic. The clinical severity in affected females depends upon the pattern of X-inactivation in the liver (also known as lyonization) and ranges from asymptomatic to almost as severe as in that of an affected male [

CLINICAL FEATURES — Most affected patients present as newborns, although those with a partial enzyme deficiency may become symptomatic later in childhood or as adults.
In a large cohort of UCD patients from multiple centers (n = 260), 34 percent presented as newborns (<30 days of age); the median age at presentation was two years (range 1 day to 53 years) [
5]. The most common presenting symptoms were neurologic (decreased level of consciousness, altered mental status, abnormal motor function, seizures) and gastrointestinal (vomiting, poor feeding, diarrhea, nausea, constipation).

Typical presentation — UCDs typically present in term newborns who appear well for the first 24 to 48 hours after birth. The infant becomes symptomatic after feeding has started because human milk or infant formula provides a protein load. Initial signs include somnolence and poor feeding, usually followed by vomiting, lethargy, and coma [6,7], a presentation that is identical to that of an infant with sepsis. However, the absence of risk factors for sepsis and a nondiagnostic sepsis evaluation should prompt consideration of a metabolic disorder [8].
A common early sign in newborns with hyperammonemia is central hyperventilation leading to respiratory alkalosis. Hyperventilation is thought to result from cerebral edema caused by the accumulation of ammonia and other metabolites [
9]. Increasing cerebral edema also may result in abnormal posturing and progressive encephalopathy with hypoventilation and respiratory arrest. Approximately 50 percent of infants with severe hyperammonemia have seizures [1].
Affected patients have a lifelong risk of metabolic decompensation with intercurrent hyperammonemia. Metabolic decompensation usually occurs during episodes of increased catabolism, such as intercurrent infections (eg, gastroenteritis, otitis media), fasting, surgery, or trauma.

Atypical presentation — Patients who have partial enzyme deficiencies, such as female carriers of OTC deficiency, may have atypical presentations after the newborn period [2,3]. This delayed presentation is most common with partial OTC deficiency, although it also occurs with partial activity of all urea cycle enzymes.
Some patients with partial urea cycle enzyme deficiency present with chronic vomiting, developmental delay, seizure disorder, or psychiatric illness [
10]. Others may develop symptoms (eg, headache, vomiting, lethargy, ataxia) following increased protein intake or during periods of catabolic stress (eg, viral illness, pregnancy) [2,3]. These patients tend to prefer vegetarian diets because dietary protein intake often is associated with headache. Still others present with laboratory abnormalities. There is emerging clinical evidence that UCDs may be complicated by hepatic dysfunction characterized by elevation of liver enzymes, coagulopathy, and histologic evidence of glycogenoses [11,12]. The cause of this and other anecdotally reported morbidities may relate to deficiency of downstream intermediates, such as arginine, and dysregulation of nitric oxide synthesis or other arginine-derived intermediates.
In patients with partial urea cycle enzyme deficiency, hyperammonemia may be chronic or recur only during metabolic decompensations associated with catabolic stress [
13,14]. It is important to consider a UCD in patients who have recurrent metabolic decompensations and to measure plasma ammonia concentration at the time of decompensation since ammonia may be normal during healthy periods [14]. (See 'Laboratory evaluation' below.)

LABORATORY EVALUATION — The laboratory hallmark of a UCD is an elevated plasma ammonia concentration. Additional testing is used to identify the specific enzyme deficiency.

Ammonia — The plasma ammonia concentration can be measured in an arterial or venous blood sample. Measurement from a capillary blood sample is not reliable. Blood should be collected in chilled tubes with ammonia-free sodium heparin (green top) or EDTA (purple top), placed on ice, and delivered rapidly to the laboratory. Ammonia levels can be elevated falsely by hemolysis, delayed processing, and exposure to room temperature.
Normal values for ammonia concentration are often higher in newborns than in older children or adults. In newborns, levels are affected by gestational and postnatal age. In one study, the mean plasma ammonia concentration of healthy term infants at birth was 45 ± 9 micromol/L; the upper limit of normal was 80 to 90 micromol/L [
15]. Initial values in preterm infants less than 32 weeks' gestation were higher (mean 71 ± 26 micromol/L), but declined to term levels by seven days. Normal values in children older than one month and adults are less than 50 and 30 micromol/L, respectively.
If the plasma ammonia concentration is greater than 100 to 150 micromol/L, further testing is performed to establish a diagnosis. Initial tests include arterial pH and carbon dioxide tension, serum lactate, serum glucose, serum electrolytes to calculate the anion gap, plasma amino acids, and urine organic acids and urine orotic acid. An elevated plasma ammonia concentration combined with normal blood glucose and anion gap strongly suggests a UCD.
Additional plasma and urine should be frozen for future diagnostic tests. These samples may be useful to identify metabolic disorders in patients who have mild hyperammonemia and biochemical abnormalities during an acute illness and normal values when they appear well.

Diagnostic studies — Quantitative plasma amino acid analysis is helpful to differentiate among UCDs [7]. Citrulline concentration is increased in ASS and ASL deficiencies; argininosuccinic acid is absent in the former and elevated in the latter.
Citrulline is absent or low in CPSI, OTC, or NAGS deficiencies; arginine also is low, and
glutamine is increased, in these disorders. If citrulline is absent, urine orotic acid measurement may differentiate OTC and CPS deficiencies [6]. Orotic acid can be increased to more than 1000 micromol/mol creatinine (normal, 1 to 11 micromol/mol creatinine) in the former and is low in the latter.

Enzyme analysis — The diagnosis of a specific UCD is confirmed by enzyme analysis of tissue samples, as follows:

        * Liver biopsy: CPSI, OTC, and NAGS deficiencies

        * Fibroblasts from skin biopsy: ASS and ASL deficiencies

        * Red blood cells: arginase deficiency

Enzyme activity must be interpreted carefully. Measured enzyme activity does not always correlate with residual in vivo activity or with phenotypic severity because most in vitro assays are performed with excess substrate. In addition, in the X-linked disorder OTC deficiency, the level of OTC activity measured in a liver biopsy may be normal in an affected female, depending upon the pattern of X-inactivation in the liver.

Specialized testing — Special techniques available in a research setting may be useful to detect abnormalities in patients with UCDs, especially those with partial enzyme deficiencies who have normal laboratory values during asymptomatic periods.
The measurement of urinary excretion of orotic acid after administration of
allopurinol is one such technique that was used to detect women who were carriers of a mutant OTC allele [16,17]. However, mild cases may have minimal elevations, and increased excretion may occur in mitochondrial disease, limiting the specificity of this test [18-20]. With the wide availability of DNA testing, provocative testing (eg, with oral protein loads) should be avoided.
The use of isotopes in vivo is another specialized technique that can be employed to assess altered urea cycle activity [
20,21]. In one report, stable isotopes were used to measure rates of total body urea synthesis and nitrogen flux (which assesses urea cycle activity); these studies detected patients with complete and partial enzyme deficiencies and asymptomatic carriers, and results correlated with clinical severity [21].

DNA mutation analysis — DNA sequencing-based mutation testing is available for all genes of the urea cycle. Because OTC deficiency is the most common UCD, DNA testing for OTC deficiency should be considered, especially if the plasma amino acid pattern is not diagnostic. More than 150 mutations, most of which are single-base substitutions, have been reported [22]. However, microdeletion of part or all of the OTC gene may lead to false negative results on DNA sequencing. Hence, array comparative genomic hybridization or chromosome microarray analysis to detect microdeletions of the gene is indicated when initial DNA sequencing is negative [23]. Detection of a pathogenic mutation in an asymptomatic patient may preclude the need for a liver biopsy to confirm the diagnosis. Failure to detect a pathogenic mutation does not exclude the diagnosis.

Prenatal testing — Prenatal testing can be performed for OTC deficiency by DNA analysis if the mutation is known; if an extended sibship is available, linkage analysis can be used. DNA linkage testing also can be used to detect CPSI deficiency.
For other disorders, prenatal diagnosis may be available by biochemical testing. ASS and ASL enzyme activity can be measured directly in amniocytes and chorionic villus cells. Elevated citrulline and argininosuccinic acid can be measured in amniotic fluid. CPSI and OTC can be measured in fetal liver.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal hyperammonemia includes a limited number of disorders, discussed below [6]. Distinguishing features of UCDs include very high ammonia levels, which can be greater than 1000 micromol/L, in contrast to other etiologies in which ammonia rarely is higher than 200 to 300 micromol/L [8]. Other findings that suggest a UCD are normal blood glucose, normal anion gap, and respiratory alkalosis.
Primary genetic causes of hyperammonemia include organic acidemias, fatty acid oxidation defects, and disorders of pyruvate metabolism [

 * Hyperammonemia in organic acidemias results from inhibition of one of the urea cycle enzymes, most likely CPSI [24]. Patients with these disorders typically have metabolic acidosis and/or ketotic hypoglycemia.

* Fatty oxidation defects can cause hyperammonemia, but affected children typically have nonketotic hypoglycemia and present later in infancy.

 * In disorders of pyruvate metabolism, lactic acidemia usually accompanies the elevated ammonia concentration.

Hyperornithinemia, hyperammonemia, homocitrullinemia (HHH syndrome, OMIM #238970) is a rare cause of hyperammonemia. It is caused by impaired transport of ornithine, a basic amino acid, across the inner mitochondrial membrane [25,26], which leads to functional impairment of the urea cycle and elevated plasma concentrations of ornithine, ammonia, and citrulline (algorithm 1). Affected newborns typically present with lethargy, muscular hypotonia, and seizures. If untreated, death occurs within the first few days. The majority of survivors have pyramidal tract signs, with spastic paraparesis [25,27]. Most have myoclonic seizures, ataxia, and mental retardation. A milder form of the disorder has been reported in adults, who become symptomatic following protein-rich meals [25,26].
Transient hyperammonemia of the newborn (THAN) is an unusual cause of hyperammonemia. This condition may be distinguished from UCDs by its clinical features. In one report, patients with THAN had lower birth weight and gestational age, earlier presentation of hyperammonemia, and more respiratory distress than did those with UCDs [
Causes of hyperammonemia that are not genetic include severe dehydration and liver failure. However, the plasma ammonia level typically is less than 100 to 200 micromol/L in dehydration and returns to normal with volume replacement. Hyperammonemia usually is seen late in the course of severe hepatocellular damage. Severe elevated hyperammonemia can also present with hepatic failure due to neonatal or perinatal herpes simplex virus infection, though the presentation is usually later in the first week of life or beyond [


*  The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (algorithm 1). Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). Prompt recognition and treatment are needed to improve outcome.

*  Ornithine transcarbamylase deficiency is X-linked. The other UCDs are autosomal recessive. (See 'Genetics' above.)

*   Most patients with complete enzyme deficiency present as newborns. Patients with partial enzyme deficiency may develop symptoms later in life.

*   In newborns, UCDs typically present at 24 to 48 hours of age. Clinical features include somnolence and poor feeding followed by lethargy, vomiting, and coma. Other features include central hyperventilation, hyperammonemia, and seizures.

*   Patients with partial enzyme deficiency may present with chronic vomiting, developmental delay, seizure disorder, or psychiatric illness. Symptoms (eg, headache, vomiting, lethargy, ataxia) may be precipitated by increased protein intake or catabolic stress (eg, illness, pregnancy).

*  The initial laboratory evaluation for suspected UCD should include arterial pH and carbon dioxide; serum ammonia, lactate, glucose, electrolytes, and amino acids; and urine organic acids and orotic acid. Elevated plasma ammonia concentration combined with normal blood glucose and normal anion gap strongly suggests a UCD. Additional testing is necessary to establish the diagnosis and identify the specific enzyme deficiency.

*   The differential diagnosis of neonatal hyperammonemia includes organic acidemias; fatty acid oxidation defects; disorders of pyruvate metabolism; hyperornithinemia, hyperammonemia, homocitrullinemia; transient hyperammonemia of the newborn; severe dehydration; and liver failure.

*   Distinguishing features of UCD include the degree of elevation of plasma ammonia (typically >1000 micromol/L compared with 200 to 300 micromol/L), normal blood glucose, normal anion gap, and respiratory alkalosis. 



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