3rd Amino Acid Workshop
`
`Clinical Manifestations of Inborn Errors of the Urea Cycle and Related
`Metabolic Disorders during Childhood1
`
`Fumio Endo,2 Toshinobu Matsuura, Kaede Yanagita, and Ichiro Matsuda
`
`Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University,
`Kumamoto 860, Japan
`
`ABSTRACT Various disorders cause hyperammonemia during childhood. Among them are those caused by
`inherited defects in urea synthesis and related metabolic pathways. These disorders can be grouped into two types:
`disorders of the enzymes that comprise the urea cycle, and disorders of the transporters or metabolites of the amino
`acids related to the urea cycle. Principal clinical features of these disorders are caused by elevated levels of blood
`ammonium. Additional disease-specific symptoms are related to the particular metabolic defect. These specific
`clinical manifestations are often due to an excess or lack of specific amino acids. Treatment of urea cycle disorders
`and related metabolic diseases consists of nutritional restriction of proteins, administration of specific amino acids,
`and use of alternative pathways for discarding excess nitrogen. Although combinations of these treatments are
`extensively employed, the prognosis of severe cases remains unsatisfactory. Liver transplantation is one alternative
`for which a better prognosis is reported.
`J. Nutr. 134: 1605S–1609S, 2004.
`KEY WORDS:  urea cycle disorders  hyperammonemia  carbamyl phosphate synthetase
` ornithine transcarbamylase
`
`Basic pathogenesis of defects in the urea cycle and
`related metabolism
`
`In the urea cycle or in urea cycle–related disorders, clinical
`symptoms are mainly caused by two different mechanisms
`(Table 1). First, symptoms caused by hyperammonemia occur
`regardless of the specific metabolic defect. Elevated blood
`ammonium levels cause the chief pathology, because toxicity of
`ammonium is dominant in most of these disorders. Second,
`specific conditions caused by an individual metabolic defect can
`give rise to unique clinical manifestations. The differences seen
`in patients with different disorders arise from excesses or
`deficiencies of amino acids and/or related metabolites. Actual
`clinical manifestations depend on the severity of the metabolic
`defect and the condition of the patient and include factors such
`as age, nutritional status, and associated diseases such as
`infections. As can be seen from the metabolic map (Fig. 1),
`ornithine, citrulline, argininosuccinate, and arginine make up
`the urea cycle. Citrulline is synthesized by ornithine and
`carbamyl phosphate. One of the nitrogen atoms of urea is
`transferred from carbamyl phosphate and another is from
`aspartic acid. Urea synthesis begins with the synthesis of
`
`1 Presented at the conference ‘‘The Third Workshop on the Assessment of
`Adequate Intake of Dietary Amino Acids’’ held October 23–24, 2003 in Nice,
`France. The conference was sponsored by the International Council on Amino
`Acid Science. The Workshop Organizing Committee included Vernon R. Young,
`Yuzo Hayashi, Luc Cynober, and Motoni Kadowaki. Conference proceedings were
`published as a supplement to The Journal of Nutrition. Guest editors for the
`supplement publication were Vernon R. Young, Dennis M. Bier, Luc Cynober,
`Yuzo Hayashi, and Motoni Kadowaki.
`2 To whom correspondence should be addressed. E-mail: fendo@kumamoto-
`u.ac.jp.
`
`0022-3166/04 $8.00 Ó 2004 American Society for Nutritional Sciences.
`
`carbamyl phosphate catalyzed by carbamyl phosphate synthe-
`tase (CPS)3 I. The other known CPS is the enzyme CPS II,
`which catalyzes the reaction of carbamyl phosphate synthesis
`from glutamine. Carbamyl phosphate produced with CPS I
`then reacts with ornithine to make citrulline. Citrulline in turn
`reacts with aspartic acid to produce argininosuccinate. Up to
`this point, the excess nitrogen is bonded to amino acids.
`Argininosuccinate is cleaved into arginine and fumarate. From
`arginine, urea and ornithine are produced, which completes the
`cycle. Abnormalities of the enzymes involved in these reactions
`or an abnormal N-acetylglutamate leads to congenital hyper-
`ammonemia.
`It is noteworthy that CPS I and ornithine
`transcarbamylase (OTC) exist in the mitochondrial matrix,
`whereas the other enzymes of the urea cycle reside in the
`cytosol. So for this cycle to function smoothly, ornithine must
`be
`transported
`across
`the mitochondrial membrane.
`Abnormalities of this ornithine-transporting protein also cause
`hyperammonemia. Failure to absorb arginine and ornithine in
`the digestive tract is another cause of hyperammonemia.
`
`Toxicity of ammonium
`
`is observed when blood
`The main manifestation that
`ammonium levels increase is central nervous system dysfunc-
`tion including stupor, convulsions, and coma. Blood ammo-
`nium concentrations are strictly maintained in normal humans
`at 15–60 mg/dL. The clinical symptoms caused by elevated
`levels of blood ammonium directly correspond to its levels.
`
`3 Abbreviations used: ASS, arginine succinate synthetase; CPS, carbamyl
`phosphate synthetase; OTC, ornithine transcarbamylase; UCD, urea cycle disorders.
`
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`TABLE 1
`
`Urea cycle and related disorders
`
`Abnormalities of metabolism
`
`Excess metabolites
`
`Reduced metabolites
`
`Specific clinical features
`
`CPSI deficiency
`OTC deficiency
`Citrullinemia (classical)
`Argininosuccinic aciduria
`
`Argininemia
`Gyrate atrophy of retina (OAT deficiency)
`Adult onset citrullinemia type II
`(citrin deficiency)
`Hyperammonemia-hyperornithinemia-
`homocitrullinemia syndrome
`(mutations in ORT1)
`Lysinuric protein intolerance (mutations
`in SLC25A13)
`
`Ammonium, glutamate
`Ammonium, glutamate
`Ammonium, citrulline
`Ammonium, argininosuccinic
`acid, citrulline
`—
`Ammonium (transient), ornithine
`Ammonium, citrulline
`
`Ammonium, ornithine,
`homocitrulline
`
`Arginine
`
`—
`—
`
`—
`
`Ammonium
`
`Lysine, arginine
`
`Citrulline, arginine
`Citrulline, arginine
`Arginine
`Arginine
`
`—
`—
`—
`Hepatomegaly, twisted hair
`
`Spastic paraplegia
`Retinal degeneration
`Liver damage
`
`—
`
`Hepatosplenomegaly,
`osteoporosis
`
`When blood ammonium levels exceed 100 mg/dL, appetite loss,
`nausea, insomnia, agitation, and personality changes emerge.
`With levels ;150–200 mg/dL, seizures and severe loss of
`consciousness occur. Sudden elevations of ammonium from
`normal levels cause a unique flapping tremor of the hands. When
`levels exceed 200–400 mg/dL, severe coma and respiratory
`failure lead to life-threatening conditions. However, tolerance to
`elevated ammonium levels has occurred in patients who have
`undergone treatment for some time, and some patients are
`asymptomatic even with levels of ;200 mg /dL. Damage to the
`central nervous system caused by elevated blood ammonium
`concentrations appears reversible when levels do not exceed
`200–400 mg/dL; however, the damage accumulates and often
`results in irreversible impairment.
`
`Principles of treatment
`
`Basic procedures for therapy have been established (1,2)
`that include protein restriction, arginine administration, use
`of alternative pathways, and mechanical nitrogen excretion.
`Dietary protein restriction is
`almost
`always
`required.
`Administration of citrulline and arginine is effective in most
`cases except for argininemia. In patients with citrullinemia and
`argininosuccinic aciduria, arginine is essential for treatment.
`
`Benzoic acid is conjugated with glycine in the liver and is
`excreted as a glycine-conjugated form. Accordingly,
`this
`process
`results
`in excretion of one molecule of glycine.
`Similarly, phenylacetate is conjugated with glutamine before
`excretion; two molecules of nitrogen are excreted when one
`molecule of phenylacetate is administered. Thus, administra-
`tion of sodium benzoate and sodium phenylacetate results in
`excretion of excess nitrogen. These drugs, which use alterna-
`tive pathways to excrete excess nitrogen, are being used in
`combination with administration of arginine and/or citrulline.
`Amino acids combined with these two compounds have been
`used for treatment of urea cycle disorders (UCDs), especially
`for patients with OTC and CPS deficiencies (Fig. 2).
`Liver transplantation has been used to treat UCD patients
`(3,4). In some cases, auxiliary liver transplantation has been
`successfully performed (5). Considering that the long-term
`prognosis of patients with UCDs is generally poor,
`liver
`transplantation becomes an important treatment (as discussed
`below).
`
`FIGURE 1 The urea cycle. ASL, argininosuccinate lyase; ARG,
`arginase; NAGS, N-acetylglutamate synthetase.
`
`FIGURE 2 A representative clinical course of a hyperammonemia
`attack in children. Continuous hemodialysis with filtration (CHDF) and
`intravenous infusion of sodium benzoate and arginine effectively reduced
`blood ammonium levels in this 4-y-old male patient with OTC deficiency.
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`Disease-specific pathogenesis
`
`CPS deficiency. CPS deficiency is caused by mutation of
`the CPS gene and is inherited in an autosomal recessive
`manner (6,7). The clinical presentation of patients with CPS
`deficiency is indistinguishable from those with OTC deficiency.
`With severe enzyme deficiency, patients show neonatal onset of
`the disease. Adult-onset cases with mild mutations have also
`been reported. The approach for treatment of CPS deficiency is
`similar to that for OTC deficiency, and nutritional restriction of
`protein and administration of arginine/citrulline and sodium
`benzoate/sodium phenylacetate are employed. Gene analysis of
`family members has been used for prenatal diagnosis of the
`disease (8)
`OTC deficiency. This is an X-linked inherited disorder of
`a mutation in the OTC gene (9,10). Male patients usually show
`clinically severe symptoms at younger ages
`than female
`patients. Accordingly, neonatal-onset patients are mostly male
`with rare exceptions. The most severely affected individuals
`show increases in ammonium within 1–2 d after birth. The
`typical clinical features include loss of consciousness, respir-
`atory failure, and seizures, which resemble neonatal sepsis.
`Patients with less-severe effects manifest their first symptoms
`later in life, mostly after 1 mo of age, and are referred to as late-
`onset patients. Symptoms are typically nausea, vomiting, loss of
`consciousness, and seizures. A specific mutation is reported to
`cause adult-onset OTC deficiency with high mortality, which
`suggests that clinical features are influenced by gene mutations
`(11). Frequent elevation of blood ammonium level is a typical
`feature in patients who survive the initial attack, although
`sudden death sometimes occurs among male adult-onset
`patients. Most female patients show initial symptoms after 1
`mo of age; however, levels of ammonium occasionally elevate
`suddenly to life-threatening levels. Under these conditions,
`patients should receive intensive treatment
`including in-
`travenous infusion of effective amino acids and/or drugs to
`employ alternative pathways to discard excess nitrogen (see
`below for details). This condition, called acute illness or acute
`attack, is one of the typical features of patients with UCDs.
`Acute illness is usually seen in the more severe cases.
`Treatment of this disorder depends on the severity of the
`disease. In mild cases, nutritional restriction of protein intake
`improves clinical symptoms and prognosis. Many patients
`should receive oral administration of citrulline and arginine to
`cope with decreased synthesis of arginine in the urea cycle.
`Because one amino group is incorporated into citrulline by the
`reaction of argininosuccinate synthetase, use of this amino acid
`is essential
`for severe cases. Alternatively, arginine is an
`essential amino acid in patients with UCDs except for arginase
`deficiency. In addition, drugs for alternative pathways such as
`sodium benzoate and sodium phenylacetate are given for severe
`cases (12). Liver transplantation is one of the most important
`treatments in OTC deficiency for both male and female
`patients. Transplantation from live relative donors including
`heterozygotes for OTC deficiency has been effective (13).
`OTC deficiency is initially suspected based upon high blood
`ammonium levels and amino acid analysis. Low levels of
`citrulline and arginine with high levels of glutamate/glutamine
`are typical features. Elevation of ornithine may be seen but is
`not essential.
`Citrullinemia. Citrullinemia is caused by deficiency of
`argininosuccinate synthetase and is inherited as an autosomal
`recessive trait with a mutation in the argininosuccinate
`synthetase gene (14). Blood levels of citrulline are very high
`in these patients; however, the clinical symptoms of these
`patients are apparently due to hyperammonemia. Accordingly,
`
`In severe cases, clinical
`seems harmless.
`citrulline itself
`symptoms due to elevated blood ammonium levels develop in
`the neonatal period, although this progresses slower than in
`those with severe OTC or CPS deficiency. Amino acid analysis
`reveals very low levels of arginine in addition to extremely high
`levels of citrulline, and diagnosis of this disorder can be made
`based on these findings. Citrin is a mitochondrial aspartate
`transporter, and its deficiency is one important disease to be
`distinguished from citrullinemia in the neonatal period (15)
`(see below).
`Treatment of citrullinemia consists of nutritional restriction
`of protein intake and administration of arginine. Because
`biosynthesis of arginine is severely affected in these patients,
`administration of arginine is effective and is an essential part
`of treatment. The prognosis for patients with this disorder is
`generally better than for those with OTC or CPS deficiency.
`However, some degree of mental retardation is seen in most
`cases.
`Argininosuccinic aciduria. This autosomal recessive dis-
`order is due to a loss of argininosuccinate lyase, which produces
`arginine and fumarate from argininosuccinate (16,17). There
`is an increase of argininosuccinate in the blood and urine.
`In addition, severe arginine deficiency is observed, which
`resembles citrullinemia. Clinical features of this disorder are
`characterized by hepatomegaly and in some cases abnormally
`kinky hair as well as hyperammonemia. Elevation of ammonium
`is mostly due to arginine deficiency, and restriction of arginine
`and protein is effective. Clinical symptoms are milder compared
`with those observed with OTC or CPS deficiency; however,
`severe cases present clinical symptoms during the neonatal
`period. Mental retardation is observed in almost all patients
`even when control of blood ammonium has been well achieved.
`Accumulation of argininosuccinate in body fluids, including the
`cerebrospinal fluid, might relate to mental retardation in these
`patients. This leads us to believe that argininosuccinate is not
`harmless.
`Argininemia. Argininemia is caused by deficiency of
`arginase I, which is present in soluble fractions of hepatocytes
`(18,19) (arginase II exists in the mitochondria of the liver and
`kidney). Clinical features of this disorder are characterized by
`spastic paraplegia as well as intractable mental retardation
`(20,21). These features are not associated with other types of
`UCDs and are probably related to the accumulation of arginine
`in body fluids. Protein restriction is the only measure for
`prevention or delay of progression of
`these neurological
`symptoms. Long-term investigations on patients with arginase
`deficiency reveal that blood arginine levels are well correlated
`with the severity of the neurological damage (21). Diagnosis of
`this disorder is made by amino acid analysis of plasma.
`N-acetylglutamate synthetase deficiency. This disorder is
`caused by mutations in the N-acetylglutamate synthetase
`gene (22,23). N-acetylglutamate is required for activation
`of carbamoyl phosphate synthetase. When synthesis of
`N-acetylglutamate synthetase is limited, asecondary deficiency of
`CPS is produced. Hence, clinical symptoms of N-acetyl-
`glutamate synthetase deficiency resemble CPS deficiency. It
`is one of the most rare disorders of the UCDs. Treatments for
`this disorder include restriction of protein intake and adminis-
`tration of arginine. Administration of carbamylglutamate, an
`analog of N-acetylglutamate, is also reported to be effective (24).
`Defects
`in amino
`acid transporters
`as
`causes
`for
`hyperammonemia. One group of disorders is caused by defects
`in the transport of amino acids related to functions of the urea
`cycle (25,26). Lysinuric protein intolerance is caused by
`mutations in the gene that leads to malabsorption of dibasic
`amino acids including lysine, arginine, and ornithine (25–27).
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`Deficiency of arginine results in mild hyperammonemia. This
`disorder is characterized by hepatosplenomegaly and osteopo-
`rosis. Hyperornithinemia-hyperammonemia-homocitrullinuria
`syndrome is caused by mutations in the ornithine transporter
`gene, the product of which functions at the inner mitochondrial
`membrane for ornithine incorporation. As a result of gene
`mutation, malfunction of the transporter results, which leads to
`ornithine deficiency in the mitochondria and hence hyper-
`ammonemia (28).
`Citrin is a mitochondrial aspartate transporter, and
`mutation in the citrin gene can cause the adult-onset type of
`citrullinemia (15,29). This disorder is characterized by pro-
`gressive liver disease that begins during adolescence and results
`in cirrhosis. During infancy, some individuals who carry
`homozygous mutations present with liver disease with chole-
`stasis, although these symptoms are transient and self-limited in
`most cases (30). Activity of hepatic arginine succinate
`synthetase (ASS) is severely affected, but its activity in other
`parts of the body is not defective, and there is no mutation in
`the ASS gene (30). The precise mechanism for the de-
`velopment of liver disease and ASS deficiency has not been
`elucidated. Because clinical symptoms vary among patients,
`definitive diagnosis was made possible by gene analysis for
`several common mutations. This disorder has a higher in-
`cidence among East-Asian populations and is one of the most
`frequent disorders to cause hyperammonemia in adults.
`Administration of arginine is effective in ameliorating
`hyperammonemia; however, the effect is transient. Specific
`treatment has not been established, and liver transplantation is
`necessary for cases with liver failure (31).
`
`Long-term management and prognosis
`
`After recovery from the initial attack, which is often
`associated with a comatose state, the long-term prognosis for
`patients with UCDs depends on the blood ammonium levels
`during the chronic phase and the frequency and severity of
`acute attacks (32). During an acute attack, sudden elevations
`of ammonium levels and associated symptoms emerge in
`patients whose blood ammonium levels were controlled at
`normal or near-normal
`levels. These conditions are often
`caused by seasonal infections, high fever, hunger, and surgery.
`Treatment should aim to decrease blood ammonium levels and
`includes intravenous administrations of arginine and/or citrul-
`line. In addition, infusion of sodium benzoate and/or sodium
`phenylacetate should be used for severe cases. To eliminate
`ammonium from body fluids in severe cases, dialysis or other
`measures are effective. When ammonium levels decrease and
`feeding becomes possible, administration of essential amino
`acids should be gradually increased. Once blood ammonium
`levels are stabilized, oral administration of natural proteins
`combined with oral administration of essential amino acids
`can begin. The degree of damage depends on the level
`of ammonium and the length of duration (32,33). Despite
`employment of these treatments, mental
`injuries of these
`patients cannot be avoided (33,34). The relative long-term
`prognoses of patients with UCDs (Fig. 3) reveal that the IQs of
`patients decrease in inverse proportion to the degree of
`hyperammonemia and frequency of acute attacks (32).
`Malnutrition and deficiencies of essential amino acids as well
`as other essential nutrients are problems associated with
`treatment for UCDs. Symptoms caused by essential amino acid
`deficiency such as eruptions, intractable diaper rash, redness,
`and skin exfoliation of the extremities should be treated. DNA
`diagnosis is employed in most of the disorders and has been
`
`FIGURE 3 Blood ammonium levels at onset and long-term prog-
`noses.
`
`effectively used for assessments of severity, inheritance patterns,
`carrier detection, and prenatal diagnosis of UCDs.
`
`Conclusion
`
`Although advances in the diagnosis and treatment of UCDs
`are responsible for saving many lives, the mental development
`of many patients is still affected. Liver transplantation is
`a promising cure for enzyme deficiency; however, brain damage
`caused by the initial hyperammonemia attack is inevitable in
`many patients even with newborn screening systems. New
`strategies for diagnosis and prevention of the initial attack must
`be considered.
`
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