To determine which amino acids in a high casein diet are responsible for induction of the five urea cycle enzyme activities in rat liver, we tube-fed 21 L-amino acids singly to rats over 2 days at maximum doses which did not cause toxicity. The results were compared with the 1.3- to 1.9-fold increases (units/100 g rat) obtained by tube-feeding 2 g N/kg for 2 days as casein hydrolysate. Ala (2 g N/kg), Gly /2 g N/kg), Met (0.2--0.4 g N/kg) and Cys (0.4 g N/kg) were the only amino acids which increased all five activities. Moreover, Met. Ala, Gly and casein hydrolysate in these doses increased immuno-precipitable arginase as much as they increased its activity. A combination of Met, Ala and Gly (2 g N/kg) increased all five activities more than 2 g N/kg of casein hydrolysate. Met (0.05 g N/kg) + Ala (0.08 g N/kg) + Gly (0.1 g N/kg), the amounts of these contained in 2 g N/kg of casein, increased all five enzymes in 2 days as much as this dose of casein hydrolysate. Met (0.06 g N/kg) alone increased all five activities (units/100 g rat) 1.2 to 1.4-fold over controls by increasing g liver/100 g rat. Ammonium citrate or acetate tube-feedings over 8 days at 2 g N/kg increased only AS. The keto-acid of alanine, pyruvate, or the alpha-hydroxy acid of methionine did not increase any enzyme whereas the same molar dose of their amino acids increased all five activities. Thus three amino acids of casein, Ala, Gly and especially Met, account for the enzyme adaptation of the urea cycle on a high casein diet.

SummaryA female and a male sibling aged 15 and 8 yr developed almost normally for 3 yr, then gradually deteriorated intellectually and physically. Both patients showed marked hyperargininuria (up to 370 times normal), prominent lysinuria, cystinuria, and ornithinuria, and a milder generalized amino aciduria. In plasma, arginine was 600-1000 pM (4-7 times normal), but other amino acids were not increased. The levels did not change in response to increased protein intake from 1-3 g/kg/day. In cerebrospinal fluid (CSF), arginine was 70-100 pM (3-5 times normal) and numerous other amino acids were also high. Plasma ammonia was generally normal, but rose to 250 pg/dl(5 times normal) after increased protein intake and, occasionally, other stresses. The erythrocyte arginase activity level was <1% of normal and half normal in the mother and three healthy siblings. White blood cell arginase activity was less than 5% of the lowest normal control. Liver obtained at open biopsy in the older sibling was deficient in arginase activity (1.5% of normal), but had levels of the other four urea cycle enzymes that were within the normal range. Electron microscopic and histochemical studies revealed patchy severe hydropic changes, increased cellular glycogen, normal mitochondria, and dilated endoplasmic reticulum. Speculation said to be normal. The patient was irritable beginning in the 4th week of life and development was thought to be on the slow side of normal. By age 3, she was able to walk, run, and speak in phrases and occasional short sentences. At this time, increasing clumsiness was noted, the growth rate diminished, and mental deterioration began. When seen at UCLA at age 6, she was bilingual (English and Spanish), was able to go to a normal school, but could walk only with the aid of braces. Severe spasticity and hyperreflexia of the lower extremities was noted, and a history of periods of heightened irritability was obtained. She was small for her age, and her height and weight have remained constant for the subsequent 9 yr. Since then, physical and intellectual deterioration has been slow and continuous. There was no history of apparent seizures.The height (110 cm) and weight (18.3 g) were far below the third percentile, and the head circumference was 50 cm (