Argininosuccinic aciduria

Argininosuccinic aciduria results from a defective argininosuccinate lyase, mediating the cleavage of argininosuccinic acid to arginine and fumaric acid (Fig. 8). 

The first three children described with this condition had hair which was described as dry and brittle, so that it remained characteristically short (Al, L2). In this form of trichorrhexis nodosa, the breaks in the hair fluoresced red with acridine orange, as distinct from the more usual form of this condition in which the fluorescence is green (L2). In one of these children, the skin was rough in patches and there were numerous creases on the palms of the hand and soles of the feet. The disorder of the hair, originally thought to be a constant feature of argininosuccinic aciduria, is present in fewer than half, even of the older children. 

Because of this characteristic onset and course in several infants, it has been suggested that there is, in addition to the less severe condition in the older child, a very severe and usually fatal variant of the disease 

---

Figure 32, Chromatograms of plasma and urine samples with various abnormalities, A, Phenylalaninemia B, tyrosinemia C, elevated plasma methionine seen in homocystinuria D, glycinemia E, normal urine F, argininosuccinic aciduria G, homocystinuria H, hyperglycinuria I, hyperlysinuria.

Except for patients with argininosuccinic aciduria, who may demonstrate varying degrees of hepatic fibrosis, there... 

Argininosuccinic aciduria. Patients manifest high levels of argininosuccinate in urine, blood and cerebrospinal fluid. Neonates have a stormy clinical course. Almost all have died or sustained severe brain injury. A peculiar finding is trichorrhexis nodosa, or dry brittle hair with nodular protrusions that are best visible with light microscopy. The precise cause is unknown. 

Patients who survive the neonatal period can be maintained with a low-protein diet and sodium benzoate. A useful therapeutic adjunct for citrullinemia and argininosuccinic aciduria is dietary arginine supplementation, which enhances the ability to eliminate nitrogen as either citrulline or argininosuccinate. Maintaining normal arginine levels also facilitates protein synthesis. 

Argininosuccinic aciduria p ASAt.Citt.Glnt, Argt... 

Millington DS, Maltby DA, Roe CR (1986) Rapid detection of argininosuccinic aciduria and citrullinuria by fast atom bombardment and tandem mass spectrometry. Clin Chim Acta 155 173-178... 

Using this isotope labeling approach, metabolites in human plasma have been quantified (38) and altered metabolites have been detected in urine that are due to metabolic disorders such as tyrosinemia type II, argininosuccinic aciduria, homocystinuria, and phenylketonuria (20). Most recently, a smart isotope tag, 15N-cholamine, has been developed for effective detection of the same metabolites using both NMR and MS methods. This approach maximizes the combined strengths of two powerful analytical techniques for a variety of metabolomics applications. 15N-cholamine possesses dual characteristics an NMR-sensitive heteronuclear isotope with good chemical shift dispersion and a permanent charge that improves MS sensitivity (48). 

The specific syndrome arising from a severe deficiency of ornithine transcarbamylase has been termed hyperammonemia (L2) (Fig. 9). Next to argininosuccinic aciduria, this in the most frequently reported of the enzymatic disturbances of the urea cycle eleven proved examples... 

The clinical manifestations of hyperammonemia are very similar to those of argininosuccinic aciduria or citrullinemia, but differ in that the neurological manifestations are in general more severe. 

As in argininosuccinic aciduria, there are two main clinical categories, an infantile and an adult type. Adults with hyperammonemia may be symptom free, having only an aversion to protein foods. In the infant, symptoms are usually severe. Vomiting is frequently the first symptom. It may occur in the first few weeks of life, especially if artificial feeding... 

The abnormal hair or skin of argininosuccinic aciduria are not found in hyperammonemia. 

Biochemical Findings in Inborn Errors of the Urea Cycle 10.1. Argininosuccinic Aciduria... 

Fia. 13. Two-way chromatogram of urine from a case of argininosuccinic aciduria. The free acid and the two anhydrides are indicated (L2). 

Argininosuccinic Aciduria Amino Acid Levels in Plasma, Cerebrospinal Fluid (CSF), and Urine IN a IO-Year-Ouo Child (Nonfasting) on Low Protein Diet... 

In one infant with the fulminating variant of the disease the level of ammonia in the cerebrospinal fluid was 114 / g/100 ml when the blood level was over 800 /xg/100 ml (L5, L9) (Table 3). The only other reference to ammonia levels in cerebrospinal fluid or blood was by Carton et al. (C3), who observed in a neonate with argininosuccinic aciduria that the ammonia levels in both blood and cerebrospinal fluid as judged by column chromatography were high or very high. 

Protein Intake and Urea Excretion. Levin et al. (L7) were the first to show that urea excretion and therefore presumably urea synthesis was increased with increased protein intake in argininosuccinic aciduria. They showed in their patient that an increase of 2.5 times in the protein intake resulted in a 4- or 5-fold increase in urea output. From the results of a feeding trial, in which the infant was given a casein hydrolyzate from which most of the arginine had been removed, they concluded from the small amount of arginine present and the relatively high amount of urea excreted daily, that most of the urea was derived from a urea cycle, presumably in the liver. Conversely, reduction of protein intake resulted in a marked decrease in the output of both urea and argininosuccinic acid. 

Liver and Red Cell. The identification by Westall (W3, W4) of the amino acid excreted in large amounts as an intermediate in the urea cycle led him to postulate a deficiency of argininbsuccinate lyase in this condition. He confirmed this in the red cells of two affected children. In all other cases of argininosuccinic aciduria in which this assay has been performed, no enzyme activity has been detected in the red cells... 

Argininosuccinate Lyase Activity in Red Blood Cells of Patients with Argininosuccinic Aciduria and Their Families... 

Inheritance o/ Argininosuccinic Aciduria and Detection of the Heterozygote State... 

---