Argininosuccinic Aciduria

Argininosuccinic aciduria

Argininosuccinic aciduria (ASA) is one of the autosomal recessive hereditary urea cycle disorders (UCD), an inborn errors of hepatic metabolism with complex phenotype that caused by the deficiency of the cytosolic enzyme -- argininosuccinase or argininosuccinate lyase (ASL). Human ASL gene which is located on chromosome 7q11.21, is expressed predominantly in liver but is also detected in many other tissues, including kidney, small intestine, pancreas and muscle, heart, brain, skin fibroblasts, and erythrocytes (Hu et al. 2013). ASL catalyzes the fourth reaction in urea cycle and the first degradative step, that is, the breakdown of argininosuccinic acid (also known as argininosuccinate) to arginine and fumarate (Figure 1). Mutations in human ASL gene lead to produce malfunctioning enzymes and cause the deficiencies in the urea cycle.  The pathognomonic hallmark of ASA is the accumulation of ammonia, argininosuccinic acid and citrulline in tissues, causing hyperammonemia, excretion of argininosuccinic acid in urine, and decreased synthesis of arginine. ASA was first reported by Allan et al. (1958) as a probably hereditary disease, characterized by severe mental deficiency and a constant gross abnormality of amino acid metabolism. The clinical characteristics originally described included mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and trichorrhexis nodosa.

Figure 1. The urea cycle consists of five sequential enzymatic steps. ASA occurs when the enzyme, ASL is lacking or not functioning. CPS1, carbamyl phosphate synthetase 1; OTC, ornithine transcarbamylase; AS, argininosuccinate synthetase; ASL, argininosuccinate lyase.

Table 1. The clinical findings on the related metabolites concentration in plasma and the symptoms of ASA (Nagamani, Lee & Erez 2012).

As shown in Table 1, elevated plasma ammonia concentration (>150 µmol/L, normal range: <60 µmol/L), elevated plasma citrulline concentration (100-300 µmol/L, normal range: 6-40 µmol/L), and elevated argininosuccinic acid and its anhydrides in the plasma (50-11- µmol/L) or urine (>10000µmol/g) can be significantly observed for the diagnosis of ASL deficiency. In contrast, plasma arginine level might decrease in ASA patient. Generally, argininosuccinic acid is not detectable in body fluids of normal individual, plus the abnormalities in other metabolites, may give rise to several clinical features (Nagamani, Lee & Erez 2012).

 There are mainly two forms of clinical presentations for ASA: a severe neonatal form and a late onset form. ASA usually becomes evident in the first few days of life. The most severe cases present in the neonatal period suffer from lethargy, vomiting, hypothermia, hyperventilation, hepatomegaly, respiratory alkalosis and progressive encephalopathy. Mortality is high but neurological damage is frequent in survivors (Ficicioglu, Mandell & Shih 2009). In contrast, the disease may also be manifested later in childhood with an acute encephalopathy that often is precipitated by infection or high protein intake, to cognitive impairment, behavioral abnormalities and learning disabilities in patients without any documented episodes of hyperammonemia (Erez, Nagamani & Lee 2011) (Table 1). It is suggested that the complex phenotype observed in ASA may result in part from the substrate accumulation upstream of the enzymatic blockade (ammonia, citrulline and argininosuccinate), the deficiency of the metabolites downstream of the blockade (arginine), and their interactions with other metabolic cycles, which is outside of ureagenesis, especially the arginine metabolism (Nagamani, Lee & Erez 2012). Due to the fact that secreted argininosuccinic acid is a nitrogen-rich compound, patients with ASA typically tend to have fewer hyperammonemic episodes as compared with those proximal enzymatic blocks of ureagenesis such as CPS1 and OTC deficiencies. However, it is demonstrated that patients with ASA have a greater risk for poor neurocognitive outcome, hypertension, and hepatic disease (Batshaw 1984) (Table 2).    

Table 2. The long-term complications and unique features of ASA.

        Today, there are many ASA diagnosis tests can be done to prevent or allow early treatment on disease progression, especially in the late onset form such as newborn screening, urinary and plasma analysis, molecular testing and genetic testing (Nagamani, Lee & Erez 2012). Basically, there are two different scenarios in the ASA treatment and management, which are the rapid control of hyperammonemia during metabolic decompensations and the chronic long-term management to help prevent episodes of hyperammonemia and the long- term complications. In short, the management of hyperammonemia includes discontinuing or limiting the oral protein intake, caloric supplementation with intravenous glucose and/or lipids to scavenge ammonia and suppress protein catabolism (Enns et al. 2007). Chronic management of ASA includes protein dietary restriction and arginine supplementation to promote the excretion of nitrogen. Patients who have had frequent metabolic decompensations or elevated ammonia are candidates for additional oral nitrogen scavenging therapy with either sodium benzoate or sodium phenyl butyrate. Additionally, Nagamani, Lee & Erez (2012) proposed that the NO donor therapy is beneficial in ASA especially in the treatment of hypertension and neurocognitive issues because the anions nitrate (NO3−) and nitrite (NO2−) can be recycled in vivo to form NO. This nitrate-nitrite-NO pathway represents an important alternative source of NO to the classical arginine-NO-synthase pathway. In individuals where there is no improvement or where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through hemodialysis may be necessary. Lastly, for those who have progressive liver disease, experience recurrent medical crises and hospitalizations despite therapy, or who have a poor quality of life, a liver transplant may be recommended as a last option (Menkes, Sarnat & Maria 2006).