Lysinuric protein intolerance: reviewing concepts on a multisystem disease.

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.

Aminoaciduria of phosphate depletion manifests at the renal brush border membrane.

Vitamin-D deficiency is associated with secondary hyperparathyroidism, hypophosphatemia, generalized aminoaciduria, phosphaturia and, late in its course, hypocalcemia. The tubulopathy has been attributed to the elevated levels of circulating parathyroid hormone. To further delineate the mechanisms responsible for aminoaciduria, vitamin-D deficiency and/or phosphate depletion were induced by placing weanling Sprague-Dawley rats on one of the following diets for 5 weeks: (1) control = 0.7% P, 5.5 micrograms % vitamin D; (2) D-P- = 0.1% P, 0 microgram % vitamin D; (3) D+P- = 0.1% P, 5.5 micrograms % vitamin D; (4) D-P+ = 0.3% P, 0 microgram % vitamin D, and (5) D-P++ = 0.7% P, 0 microgram % vitamin D. Short-term P depletion was produced in a group of animals fed D-P++ for 4 weeks, then fed D-P- for another week. To study the effects of acute supplementation with a pharmacological dose of calcitriol on the transport of amino acids by renal brush border membrane vesicles, the latter experimental group received 500 pmol of calcitriol (and is known as the SUPP group), or an equal amount of the vehicle (and is referred to as the ETH group). The uptake of taurine and proline by renal brush border membrane vesicles was blunted by 50 +/- 3 and 40 +/- 5%, respectively, at the peak of the overshoot, in all diets except D-P++. No changes were observed in vesicle size or Vmax.(ABSTRACT TRUNCATED AT 250 WORDS)

Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline.

Lysinuric protein intolerance (LPI) is an autosomal recessive defect of diamino acid transport characterised by massive diaminoaciduria, especially lysinuria, with hyperammonaemia after heavy nitrogen intake. The defect has previously been demonstrated in the kidney, and is probably present in the liver cells. To evaluate the effect of the LPI gene on the net intestinal absorption of the diamino acids and citrulline, separate oral loads of each were given to controls, and to subjects heterozygous and homozygous for LPI. In the affected subjects the plasma concentrations of the loaded diamino acids showed lower increments after the loads than in the controls, the difference being marked in the homozygotes and moderate in the heterozygotes. Urinary excretion failed to explain these differences. Thus, the diamino acid transport defect of LPI is also present in the intestine. After citrulline loads, in contrast, plasma citrulline levels rose similarly in controls and homozygotes. Thus, LPI is associated with intact citrulline absorption. The ornithinopenic hyperammonaemia of LPI is probably preventable by supplementing dietary protein with the ornithine precursor citrulline.

Lysinuric protein intolerance.

Lysinuric protein intolerance (LPI), an autosomal recessive defect of diamino acid transport, is characterized chemically by renal hyperdiaminoaciduria, especially lysinuria, and by impaired formation of urea with hyperammonemia after protein ingestion. Our 20 patients thrived during breast-feeding, but ingestion of cow's milk caused diarrhea and vomiting. When able to select their diet, they rejected all protein-rich foods. They were short staturated and had weak atrophic muscles, osteoporosis, hepatomegaly and often splenomegaly. Four patients were mentally retarded. Fifteen patients had leukocyte counts below 4,000/mm3, and 17 patients had platelet counts below 150,000/mm3. Serum lactate dehydrogenase activity was constantly increased, and transaminase and aldolase activities were often increased. In the infants' livers, changes were only revealed by electron microscopy: increased and vesicular smooth endoplasmic reticulum, and abundance of glycogen particles in the hepatocytes. In the older patients, light microscopy demonstrated clearly limited areas where hepatocytes had large pale cytoplasm and small pyknotic nuclei. The diamino acids lysine, arginine and ornithine had plasma concentrations only one-third to one-half the normal mean; the renal clearances were clearly increased. Oral diamino acid loading tests suggested impaired intestinal absorption. Urea is built in the liver through transformation of ornithine to arginine, and cleavage of arginine to ornithine and urea. The addition of ornithine to an intravenous I-alanine loading prevented the hyperammonemia and normalized the urea production. Therefore, the diet has been supplemented with arginine, and more protein has been added. This therapy has lead to a remarkable catch-up growth in some patients. The pathophysiology of LPI is explained. Because of defective intestinal absorption and incrased renal loss, the diamino acids have a low plasma concentration. Their transport from plasma to hepatocytes is also impaired, and the liver becomes deficient in ornithine. This retards the urea cycle, and leads to postprandial hyperammonemia and protein aversion. The presence of the transport defect in the hepatocytes distinguishes LPI from other hyperdibasicaminoacidurias.