Argininosuccinate lyase deficiency

Amniotic fluid has limited value in prenatal diagnosis for the aminoacid-opathies. Unlike the organic acid disorders, in most amino acid disorders the metabolites do not accumulate before birth. Abnormal amino acid patterns in amniotic fluid have only been found in two of the urea cycle disorders, namely argininosuccinate lyase deficiency (argininosuccinic acidemia) and argininosuccinate synthetase deficiency (citrullinemia). 

CitrullLne B T H Argininosuccinic aciduria (argininosuccinate lyase deficiency)... 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

Quantitation of plasma amino acids, especially of citrullinc, is the first step in determining the precise enzyme or transport protein defect in patients with a UCD. If the defect involves N-acetyglutamate synthetase (NAGS), CPSI, or OTC, then plasma citrulline concentration will be low. Marked hypercitrullinemia (>2000 pmol/I.) is seen in argininosuccinate synthetase (AS) deficiency, while moderate increases (>200 pmol/L, normal undetectable) are found in argininosuccinate lyase (AL) and citrin deficiencies. In AL deficiency, the presence of argininosuccinic acid and its anhydrides further distinguishes this disorder. 

It is significant that the ornithine transcarbamylase activity in the intestinal mucosa of one patient was only 20% of the mean normal compared to a reduction to less than 5% of the mean normal in the liver of the same patient (L8) (Table 7). This manifestation of an enzyme deficiency in more than one organ in the body has a parallel in argininosuccinic aciduria, where lyase deficiency has been shown to occur both in the liver and in the red cells and, in one case, in red cells, brain, and kidney. 

A number of inherited diseases are associated with the urea cycle. The mutations result in changes in either Vm or Km as defective proteins are produced. These include disruptions of N- acety 1 gl utam ate synthase, carbamoyl phosphate synthetase, ornithine transcarbamoylase (the most prevalent of the urea cycle deficiencies), argininosuccinate synthetase, argininosuccinate lyase, and arginase. In these diseases, when applicable, treatments are low-protein diets, to put less strain on urea cycle flux and, when appropriate, addition of amino acids as required, such as ornithine and/or arginine. 

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... 

ASL deficiency aigininosuccinic aciduria (ASA) Argininosuccinic add lyase ASL Elevated Elevated... 

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