Metabolic Disorders Are Associated With Each Reaction Of The Urea Cycle

Metabolic disorders of urea biosynthesis, while extremely rare, illustrate four important principles: (1) Defects in any of several enzymes of a metabolic pathway enzyme can result in similar clinical signs and symptoms. (2) The identification of intermediates and of ancillary products that accumulate prior to a metabolic block provides insight into the reaction that is impaired. (3) Precise diagnosis requires quantitative assay of the activity of the enzyme thought to be defective. (4) Rational therapy must be based on an understanding of the underlying biochemical reactions in normal and impaired individuals.

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some cova-lent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels.

Hyperammonemia Type 1. A consequence of carbamoyl phosphate synthase I deficiency (reaction 1, Figure 29-9), this relatively infrequent condition (estimated frequency 1:62,000) probably is familial.

Hyperammonemia Type 2. A deficiency of or-nithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia.

Citrullinemia. In this rare disorder, plasma and cerebrospinal fluid citrulline levels are elevated and 1-2 g of citrulline are excreted daily. One patient lacked detectable argininosuccinate synthase activity (reaction 3, Figure 29-9). In another, the Km for citrulline was 25 times higher than normal. Citrulline and argini-nosuccinate, which contain nitrogen destined for urea synthesis, serve as alternative carriers of excess nitrogen. Feeding arginine enhanced excretion of citrulline in these patients. Similarly, feeding benzoate diverts ammonia nitrogen to hippurate via glycine (see Figure 31-1).

Argininosuccinicaciduria. A rare disease characterized by elevated levels of argininosuccinate in blood, cerebrospinal fluid, and urine is associated with friable, tufted hair (trichorrhexis nodosa). Both early-onset and late-onset types are known. The metabolic defect is the absence of argininosuccinase (reaction 4, Figure 29-9). Diagnosis by measurement of erythrocyte argini-nosuccinase activity can be performed on umbilical cord blood or amniotic fluid cells. As for citrullinemia, feeding arginine and benzoate promotes nitrogen excretion.

Hyperargininemia. This defect is characterized by elevated blood and cerebrospinal fluid arginine levels, low erythrocyte levels of arginase (reaction 5, Figure 29-9), and a urinary amino acid pattern resembling that of lysine-cystinuria. This pattern may reflect competition by arginine with lysine and cystine for reabsorption in the renal tubule. A low-protein diet lowers plasma ammonia levels and abolishes lysine-cystinuria.

Gene Therapy Offers Promise for Correcting Defects in Urea Biosynthesis

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.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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