A 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 μM (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 μM (3–5 times normal) and numerous other amino acids were also high. Plasma ammonia was generally normal, but rose to 250 μg/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
The pathogenesis of the neurologic abnormalities in patients with arginase deficiency may in part be the perturbation of intra-cellular amino acid levels secondary to the elevated levels of arginine.