Citrullinemia urea cycle

Citrullinemia Urea Cycle Enzyme Levels in Liver and Kidney"... 

Gene therapy for rectification of defects in the enzymes of the urea cycle is an area of active investigation. Encouraging preliminary results have been obtained, for example, in animal models using an adenoviral vector to treat citrullinemia. 

Figure 20.9 The urea cycle. The bicarbonate is marked by an asterisk to facilitate its tracing through the pathway a, b, c, d, and e indicate urea cycle lesions, hyperammonemia I and II, citrullinemia, arginosuccinic aciduria, and argininemia, respectively.

A number of inherited disorders of urea cycle metabolism are known. Hy per-ammonemia I and II are associated with CPS I and ornithine transcarbamylase deficiencies, respectively. Citrullinemia, arginosuccinic aciduria, and argininemia are associated with low levels of arginosuccinic acid synthetase, arginosuccinase, and arginase, respectively. All such disorders are associated with mental retardation, convulsions, and failure to thrive if not treated. Treatment involves the feeding of low-protein diets or, experimentally, the administration of a-keto analogs of essential amino acids instead of protein. 

Citrullinemia Unclear Urea cycle Arginosuccinate synthetase... 

Citrin is an aspartate-glutamate antiporter that has a role both in the urea cycle and in the malate aspartate shuttle. It is necessary for the transport of aspartate produced in the mitochondria into the cytosol, where it is used by AS. Its role in the malate-aspartate shuttle is to transport cytosolic NADH reducing equivalents into the mitochondria, where they are used in oxidative phosphorylation. Defects in citrin cause citrullinemia type II. Patients manifest later-onset intermittent hyperammonemic encephalopathy as in HHH syndrome. 

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). 

There are difficulties in accepting this alternative pathway. Reactions (4), (5), and (6) are speculative, and the postulated enzymes mediating them have not been identified. Furthermore, although the hypothetical cycle would explain the normal urea formation in argininosuccinic aciduria, it could hardly be satisfactory, for example, in citrullinemia, in which the necessary intermediate, argininosuccinic acid, is not formed at all. 

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