Inherited disorders of the Urea Cycle

Inherited disorders of the urea cycle

The urea cycle, a series of five biochemical reactions, has a dual role. It prevents the accumulation of toxic nitrogenous products, mainly ammonium and glutamine, by incorporating nitrogen not used for biosynthetic purposes into urea, the principal mammalian waste nitrogen product. The cycle also contains several biochemical reactions needed for the biosynthesis of arginine.

The steps in the cycle are shown in Figure 1. The collective incidence of the urea cycle disorders is estimated as 1 in 30 000.

Five specific diseases, with considerable genetic and phenotypic variability, are recognized, each corresponding to a defect in the biosynthesis of one of the enzymes of the urea cycle.

Four of these five diseases have signs and symptoms caused by accumulation of precursors of urea, mainly ammonium and glutamine. They are

• carbamoyl phosphate synthetase deficiency (CPSD)
• ornithine carbamoyl transferase deficiency (OCTD)
• arginosuccinate synthetase deficiency (ASD)
• arginosuccinase deficiency (ALD).

The most drastic and potentially lethal presentation of these four diseases occurs in term infants usually without obstetric risk factors, who appear normal for 24-48 hours and then develop progressive lethargy with hypothermia and apnoea, resulting from very high plasma ammonium levels. Pathologically the brain shows oedema and swollen astrocytes, attributed to osmotic shifts of water into the cell caused by intraglial accumulation of glutamine. These diseases can also present later, in infancy, childhood or even adult life, with episodic lethargy and behavioural changes which may cause diagnostic difficulty.

The fifth disease, arginase deficiency, differs from the others, with a clinical picture of progressive spastic tetraplegia (quadriplegia) and mental retardation. Symptomatic hyperammonaemia is rarer and milder than in the other four disorders.

OCTD is inherited as an X-linked condition; the carrier status of ornithine transcarbomylase mutations in women can be determined by allopurinol-induced orotidinuria. The other four diseases are inherited as autosomal recessive traits. Prenatal diagnosis in fetuses at risk is possible by various methods, specific to each disease, including enzyme analysis of fibroblasts cultured from amniocytes, in utero liver biopsy and DNA techniques. The subject was recently reviewed by Brusilow & Horwich (1995) [1].

Clinical features

The clinical presentation is broadly similar in all the disorders except arginase deficiency, which will be considered separately. There is wide variation in the severity and age of onset (Walser 1983, Brusilow 1985, Walter & Leonard 1987) [2, 3, 4] . The most severely affected children present in the neonatal period while those with mild disease may have few symptoms.

Neonates

Affected infants are healthy at birth and usually remain well for the first 24 hours, since until birth their ammonia overload is cleared through their mother's liver. Initially the symptoms are non-specific such as lethargy, irritability, tachypnoea, and feeding difficulties which are followed by vomiting, alterations in tone, vasomotor instability, convulsions, loss of reflex activity, apnoea and coma. Intracranial or intrapulmonary haemorrhage may be the terminal event. Prompt diagnosis and treatment may prevent severe and lethal brain damage.

Although neonatal screening may eventually play an important role in acute metabolic disease, experience to date has been disappointing. The Quebec Screening Program (Lemieux et al 1982)[5] tried to identify urea cycle defects by analysis of urinary orotate at 2-3 weeks of age. No cases were identified in this way, and this approach has the obvious disadvantage of not detecting the severestress that there is at present no substitute for a physician who is keenly aware that all full-term neonates are candidates for symptomatic inborn errors of metabolism.

Infants and older children

Less severe enzyme defects may present after the neonatal period with a wide variety of symptoms. Infants often present with developmental delay, failure to thrive and persistent vomiting. Older children may have an episodic or fluctuating illness, often with neurologicalmanifestations. The symptoms may be mild and non-specific, such as behavioural abnormalities (particularly tantrums), lethargy, confusion, irritability and headaches, or more severe, with ataxia, visual disturbance and focal neurological signs (such as tetraplegia or hemiplegia). When the symptoms are mild the differential diagnosis is wide, and many diagnoses may be considered including psychiatric or gastrointestinal disorders. Drug abuse or food allergy may also be suspected, the latter because the patient may `self-select' an idiosyncratic diet low in protein. When there is more obvious encephalopathy, encephalitis is often diagnosed. Illness may be precipitated by infections or other metabolic stress causing protein catabolism (for example anaesthesia) but the trigger cannot always be identified. Sodium valproate therapy may also provoke deterioration and should be avoided when metabolic disease is suspected. Although recovery may be complete, patients with more severe hyperammonaemia may be permanently handicapped or may die during an attack. It is also important to realize that patients may remain well for many years between the episodes of hyperammonaemia, so that the significance of an earlier illness may be overlooked by the doctor or its occurrence forgotten by parents.

Adults

It is now recognized that even adults with apparently mild disease may develop episodes of severe hyperammonaemia which may prove fatal (Tallan et al 1983, Di Magno et al 1986)[6, 7]. Other adults may be identified who have never been symptomatic or who have no more than a dislike of proteinrich foods.

Enzyme deficiencies

Carbamoyl phosphate synthetase deficiency (CPSD)

While the clinical features of CPSD are varied, most patients develop symptoms in the neonatal period, in association with almost total absence of the enzyme, and a rapidly fatal outcome (Walser 1983) [2]. Partial deficiency is linked to a more slowly progressive form with a residual enzyme activity greater than 10%.

Ornithine carbamoyl transferase deficiency (OCTD)

This condition is the commonest urea cycle disorder with an estimated incidence of 1:30 000 births, and an X-linked mode of inheritance. Many affected males have no residual enzyme activity and develop symptoms soon after birth. However, males with mild disease are not uncommon (Drogari & Leonard 1988) [8], with a spectrum of disease very similar to that of the female heterozygotes, who rarely develop symptoms in the neonatal period (Brusilow 1985) [3]. The most severely affected girls usually develop symptoms during early infancy, while the least affected remain asymptomatic although they may still have mild protein intolerance and a slight reduction in IQ (Batshaw et al 1980) [9].

In an unusual case a girl with OCTD presented with recurrent stroke-like episodes from the age of 2 years 8 months (Christodoulou et al 1993) [10].

Most autopsy studies in OCTD have been of children with fairly advanced disease (e.g. Harding et al 1984) [11] , in whom widespread cortical destruction, loss of white matter and gliosis are found, probably related to episodes of hypotension, cardiac arrest and ventilator dependence. Neuropathological changes acquired in utero have been reported in an infant boy who died aged 17 days. Multiple bilateral cystic areas of infarction extended from below the molecular layer of the cortical surface into the subjacent white matter. These lesions appeared to be at least 8 or more weeks of age and may represent the earliest irreversible CNS lesions caused by the metabolic disturbances of the disease (Filloux et al 1986) [12] .

Arginosuccinate synthetase deficiency (A SD: citrullinaemia)

This disorder most commonly presents in fulminant fashion in the neonatal period in western countries, although mild variants are not infrequent (Walser 1983). A more subacute form may start in infancy with episodic vomiting, ataxia and seizures, leading to mental retardation. A craving for peanuts, beans and peas may reflect a relative arginine deficiency (McKusick 1991) [13] . A late onset form, commoner in Japan, is associated with reduced enzymatic activity only in the liver.

Argininosuccinic aciduria (ASLD)

These patients may present in the neonatal period or later with neurological problems including fits, intermittent ataxia, irritability and delayed development. Some of them have short friable hair with the characteristic microscopic appearance of trichorrhexis nodosa. Very mild forms of this disorder also exist (Walser 1983) [2] .

Arginase deficiency (AD)

The presentation of this disorder usually differs from the other urea cycle disorders as the children most commonly present in childhood with a progressive spastic diplegia or tetraplegia and mental retardation (Walser 1983)[2] . The diagnosis is often delayed because they are assumed to have cerebral palsy. One patient has been described with a fulminant course in the neonatal period (Jorda et al 1986) [14] .

Diagnosis of urea cycle disorders

Physical examination

There are no diagnostic physical signs. Short friable hair with trichorrhexis nodosa in a mentally retarded child suggests the diagnosis of ASLD but this is not specific. This feature is less specific in the USA, perhaps due to a higher content of arginine in the average diet (Handler et al 1996) [15] . In all the urea cycle disorders hepatomegaly may be present, particularly during acute attacks. Neurological signs are variable and may fluctuate. Focal signs such as hemiplegia or paraparesis may be present during hyperammonaemic episodes.

Biochemical tests

Routine biochemistry, including liver function tests, often shows no abnormality except for raised aminotransferases (transaminases). The plasma urea may be low in urea cycle disorders presenting in the neonatal period but is usually normal in those presenting later. A respiratory alkalosis may be present, especially during the early stages of a hyperammonaemic episode, and can be a useful diagnostic clue.

Plasma ammonium concentrations

The single most important investigation is the measurement of the plasma ammonium concentration. Blood should be collected in ammonia-free heparinized tubes and plasma separated immediately. The analysis should be undertaken without delay, but if storage of samples is unavoidable, they should be frozen at - 70°C because breakdown of some nitrogenous compounds occurs at - 20°C. Haemolysis and muscular exercise both raise plasma ammonium concentrations.

Neonates In healthy term neonates the plasma ammonium concentrations are less than 40 µmol/l, but in small-for-dates and premature babies the concentrations may be up to 65 µmol/l (Batshaw & Brusilow 1978) [16] . In inborn errors of the urea cycle presenting in the neonatal period, the plasma ammonium concentration is often above 300 µmol/l when first measured and may rise rapidly thereafter, often exceeding 1000 µcool/l. Any severe illness can be associated with raised plasma ammonia, but the concentrations are usually less than 175 µmol/l. Levels above 400 µmol/l result in coma, and above 500 in brain swelling and irreversible brain damage (Brenningstall 1986) [17] .

Infants and children In normal children plasma levels are less than 40 µmol/l and with serious illness they may rise to between 50 and 80 µmol/l. Values over 100 µmol/l require further investigation, although lower values may be significant, particularly if the patient has been on a lowprotein diet or intravenous fluids for several days. In the urea cycle disorders the plasma ammonium concentration is usually more than 150 µmol/l during acute episodes but is often normal at other times.

Amino acids and other investigations

In patients with hyperammonaemia, it is essential to measure the plasma amino acids since these may be diagnostic (Table 7.1). Plasma citrulline concentrations are helpful diagnostically as they are moderately raised in ASLD (100-300 µmol/1), very high in ASD (> 1 mmol/1), and reduced or absent in CPSD and OCTD. In all of the disorders glutamine and alanine, the precursors of ammonia, are raised.

Urinary orotic acid should be assayed in all children with hyperammonaemia. Carbamoyl phosphate (CP) is a substrate both for the urea cycle and for the synthesis of pyrimidines (Fig. 7.1). In all the urea cycle disorders except CPSD, CP accumulates causing an increase in pyrimidine synthesis. This can most readily be detected by measuring orotic acid, an intermediate in this pathway (Bachmann & Colombo 1980) [18] .

Enzyme diagnosis

In ASLD, ASD and arginase deficiency the diagnosis can be confirmed by assay of the enzyme activity in red blood cells, leucocytes or skin fibroblasts (Table 7.1). In CPSD, in which only plasma glutamine and alanine are raised without orotic aciduria, needle biopsy of the liver is normally required to confirm the diagnosis. In OCTD, if two members of the family have the characteristic biochemical changes, a liver biopsy is not usually necessary unless there is any doubt about the diagnosis or there are unusual findings.

Imaging

The appearance of the CT brain scan in urea cycle disorders is very variable. During acute episodes of encephalopathy, it may be normal or may show cerebral oedema. Focal areas of low attenuation may also be seen (Kendall et al 1983) [19] .

Liver histology

The liver in children with urea cycle defects may be normal microscopically or may show mild histological changes such as fatty infiltration with focal changes (La Brecque et al 1979) [20] . Fibrosis, or even cirrhosis, may rarely develop and can cause diagnostic confusion.

Neuropathology

Macroscopically, the brain in urea cycle disorders shows a wide variety of changes which often reflect the duration of the metabolic disorder. If the patient has died of acute hyperammonaemia the brain is often congested and oedematous. Uncal herniation may be found in association with cerebral oedema. If there has been prolonged hyperammonaemia, extensive brain destruction may be seen (Bruton et al 1970)[21] .

Microscopically, many changes have been described, but the most consistent finding in patients dying after the neo- natal period appears to be glial proliferation (Hopkins et al 1969, Solitaire et al 1969) [22, 23]. In one series it seemed that some of the neuropathological changes were prenatal in onset (Harding et al 1984) [11] .

Differential diagnosis

Hyperammonaemia may develop in a number of disorders, both inherited and acquired.

Neonates

In the neonate, the most important causes of hyperammonaemia, apart from urea cycle disorders, are organic acidaemias and transient hyperammonaemia of the newborn. This latter condition usually develops in premature neonates within the first 24 hours of life, presenting with respiratory distress and encephalopathy (Ballard et al 1978) [24]. The aetiology is unknown; it has been proposed that perfusion of the liver is abnormal (Eggermont et al 1980) [25] , but another hypothesis is an immaturity of the mechanisms regulating ATP homeostasis (Hudak et al 1985) [26] . It has been suggested that this syndrome can usually be distinguished from inborn errors of the urea cycle on clinical grounds (Hudak et al 1985), but this is not always easy.

Infants and older children

In addition to urea cycle disorders, two further inborn errors can lead to raised plasma ammonia concentrations:lysinuric protein intolerance and HHH syndrome (hyperornithinaemia, hyperammonaemia and homocitrullinuria).

Lysinuric protein intolerance presents with failure to thrive, feeding problems, diarrhoea and vomiting. Hepatosplenomegaly, leucopenia, osteoporosis and mental retardation are common features of this condition (Walser 1983) [2] , which is caused by a defect in the transport of dibasic amino acids at the basolateral cell membrane (Rajantie et al 1981). Hyperammonaemia is variable and usually develops after eating protein.

A combination of hyperornithinaemia, hyperammonaemia and homocitrullinuria (HHH syndrome) has been reported in several patients with vomiting and lethargy when given protein (Valle & Simell 1983) [27] . Seizures arecommon and the intellect varies from low normal to severely retarded. Some patients have had a progressive spastic quadriplegia (Rodes et al 1987) [28].

Acquired

Hyperammonaemic encephalopathy is probably more common than is generally recognized. Hyperammonaemia is one of the key findings in Reye's syndrome and can be a complication of other disorders including leukaemia (Watson et al 1985) [29], liver failure, sodium valproate therapy (Gerber et al 1979) [30] and urinary tract infection with ureasplitting organisms (Drayna et al 1981) [31]. Plasma ammonium concentrations may also be raised in children with recurrent fits and severe systemic illness.

Treatment of urea cycle disorders

There are three main strategies in the long-term treatment of urea cycle disorders: restriction of dietary protein, arginine supplements and the use of alternative pathways for nitrogen excretion. Keto-acids are no longer used as they appear to be ineffective.

Dietary protein restriction

The aim of this is to control hyperammonaemia and yet to provide sufficient amino acids for normal growth. In mild disease modest protein restriction (1.5-2 g/kg/d) may be enough to give good metabolic control, but in more severe cases this is not adequate, and protein intake should then be restricted to between 0.75 and 1.5 g/kg/d depending on age and protein tolerance. The energy intake is kept high. Natural protein intake can be further reduced while still meeting the needs for normal growth by giving an essential amino acid supplement (Snyderman et al 1976) [32] .

Arginine supplements

Since arginine is normally synthesized in the urea cycle, it is not an essential amino acid, but in patients with urea cycle defects it becomes essential or semi-essential because of reduced synthesis. Arginine deficiency may partly explain the developmental retardation and skin rashes seen in some patients (Danks et al 1974, Kline et al 1981) [33, 34] . In CPSD and OCTD, arginine 50-150 mg/kg/d is given orally. In severely affected patients this may be replaced by citrulline 1 mmol/kg/d (175 mg/kg/d) as this is converted to arginine utilizing an additional nitrogen atom (Brusilow 1985) [3] .

In ASD and ASLD, the metabolic block reduces the recycling of ornithine in the urea cycle, and arginine is given in a dose of up to 4 mmol/kg/d (700 mg/kg/d) to replenish the ornithine, thereby improving the control of plasma ammonium concentrations (Brusilow & Batshaw 1979) [35] .

Alternative pathways of nitrogen excretion

In 1979, Brusilow et al introduced the concept of using alternative pathways of nitrogen excretion by giving sodium benzoate and sodium phenylacetate. Benzoic acid is conjugated with glycine in the liver to form hippuric acid, a compound whose renal clearance is five times that of the glomerular filtration rate. Since glycine contains one atom of nitrogen, 1 mmol of benzoate emoves 1 mmol of nitrogen. Sodium benzoate in doses up to 1.75 mmol/kg/d (250 mg/kg/d) is well tolerated and significantly improves metabolic control. Phenylacetate is conjugated with glutamine to form phenylacetylglutamine, which is also rapidly excreted and removes 2 mol nitrogen for each mol phenylacetate. However, sodium phenylacetate has an unpleasant, clinging, mousy smell which severely limits its use. Sodium phenylbutyrate, which undergoes betaoxidation in the liver to form phenylacetate, is more accept- able although less water soluble. In ASLD, the use of sodium benzoate may not be needed because arg- inosuccinate has a high renal clearance and contains the same two nitrogen atoms as urea (Brusilow 1985). Sodium benzoate, and often sodium phenylbutyrate, may be needed in ASD, as citrulline which accumulates has a low renal clearance and contains only one atom of waste nitrogen. Both benzoate and phenylbutyrate are necessary in the severe forms of CPSD and OCTD.

Rarely, when severe and recurrent acute metabolic decompensation cannot be prevented despite optimal treatment, liver transplantation may be the only effective therapeutic approach. This was performed in a girl with OCTD (Largilliere et al 1989).

Treatment of acute hyperammonaemia in urea cycle disorders

Neonates Severe hyperammonaemia is a medical emergency. All dietary protein should be withdrawn and intravenous glucose started. Treatment needs to be started before the precise diagnosis is known, but sodium benzoate is widely considered to be contraindicated in patients with organic acidaemias. Thus, in neonates who are not acidotic, a trial of arginine should be given intravenously. However, control of hyperammonaemia is difficult even with specific therapy, and dialysis, preferably haemodialysis, should be started early (Wiegand et al 1980, Donn et al 1979) [36, 37]. The results of tests for plasma amino acids, urine organic acids and orotic acid should be obtained as soon as possible since subsequent treatment depends on the diagnosis. Although there are concerns about the use of sodium benzoate in the neonatal period, the outlook for patients with severe urea cycle disorders is so poor (Snyderman et al 1976, McReynolds et al 1978) [32, 38] that intravenous or oral sodium benzoate and sodium phenylacetate (or phenylbutyrate) should be tried in those in whom the diagnosis has been established. For more details see Walter & Leonard (1987) [4] , Collins (1990) [39] and Brusilow & Horwich (1995) [40] .

Infants and older children In order to try to prevent hyperammonaemia, all children with urea cycle disorders should have an emergency regimen for use with intercurrent infection or other metabolic stress. The usual lowprotein diet is replaced by one with greatly reduced protein with generous calories, arginine and sodium benzoate. If encephalopathy develops, then glucose, arginine and sodium benzoate should be given intravenously. Dialysis should be undertaken if the ammonia level continues to rise. Since fluid restriction often needs to be combined with a high calorie intake, it may be necessary to give the glucose as 15 or 20% solution via a central line.

Raised intracranial pressure is a common complication of hyperammonaemia. If there is any suspicion that this is developing, intracranial pressure monitoring, if available, should be started without delay.

Treatment of arginase deficiency

The treatment of AD consists of a very low protein diet, essential amino acids and sodium benzoate. Treatment is difficult and the outcome of only a few patients has been reported. Nevertheless, several authors have reported significant improvement (Brusilow 1985) [3] . One patient treated from birth developed normally (Snyderman et al 1979) [41] .

Outcome of urea cycle disorders

The outcome for neonatal hyperammonaemic coma, despite aggressive therapy, remains poor with a very high incidence of neurological deficit in survivors (McReynolds et al 1978, Donn et al 1979, Msall et al 1984) [37, 38, 42] . However, five infants treated prospectively from birth had normal psychomotor development (Brusilow 1985) [3] . The newer forms of therapy, together with the prompt treatment of hyperammonaemic crises, have increased the survival of those presenting in infancy and later childhood. These children do well provided the diagnosis is made before neurological damage occurs.

Some infants presenting in the newborn period with urea cycle and other metabolic disorders will die. If they die before a precise diagnosis is made, their parents can be given no explanation of the tragedy and no hope of prenatal diagnosis in any future pregnancies. Collins (1990) [39] has stressed the importance, when metabolic disease is suspected, of intensive investigations performed in the hope of making an eventual posthumous diagnosis. Blood (10- 20 ml) and as much urine as possible should be collected, separated and frozen at - 70°C, and a skin biopsy taken for fibroblast culture. A liver biopsy should be taken for histopathology, electromicroscopy and storage for enzyme analysis.

Genetic aspects

All the disorders are autosomal recessive apart from OCTD, the commonest, which is X-linked. Most boys with OCTD have no residual enzyme activity and present in the neonatal period with severe hyperammonaemia. The clinical phenotype in females is very varied, depending on the relative proportion of the mutant-to-normal X-chromosomes active in the liver cells. Those with the highest proportion of mutant X-chromosomes present in infancy with hyperammonaemia, while those with a high proportion of normal X-chromosomes have few, if any, symptoms. Whenever the diagnosis of OCTD is made, detailed family studies are essential to identify carriers. Urinary orotic acid excretion following standard protein load has been used (Haan et al 1982), but in some patients the allopurinol challenge test is a safer method of detecting faulty orotic acid excretion than protein challenge (Brusilow & Valle 1987) [43] .

Prenatal diagnosis

ASLD, ASD and probably AD can be diagnosed by chorionic villus biopsy. While it may be possible to diagnose CPSD and OCTD on chorionic villus biopsy using very sensitive assay (Shin et al 1987) [44] , cDNA gene probes for OCTD are now available and can be used in informative families. For those families in whom the probes are not informative, prenatal liver biopsy at 18 weeks' gestation can be done but is not widely available (Rodeck et al 1982) [45] . Molecular and other approaches to prenatal diagnosis were discussed recently by Brusilow & Horwich (1995) [40] .

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