Lysinuric Protein Intolerance: A Treatable Cause of Developmental Delay with Multiple Complications

Discussion

Lysinuric protein intolerance (LPI, OMIM # 222700) is frequently under or misdiagnosed due to its highly variable, often nonspecific phenotype and often subtle biochemical abnormalities [2]. LPI is relatively common in Finland, with a prevalence of 1/60,000. It is also found in Southern Italy, Northern Japan and sporadically all over the world [2, 3, 4, 5]. It is caused by mutations in the SLC7A7 gene, which encodes the yþLAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family [1, 2, 3, 4]. The reduced activity of the transporter (SLC7A7) leads to reduced absorption of arginine, ornithine and lysine in the kidney and intestine [5, 6]. LPI is a multi organ disease with a variety of clinical symptoms. Protein malnutrition and lysine deficiency contribute to the patient’s failure to thrive, as deficiency of arginine and ornithine result in dysfunction of the urea cycle with resultant hyperammonaemia and its developmental sequelae [2, 5]. On weaning, patients usually display an aversion to high-protein foods and show delayed bone growth, osteoporosis, hepatosplenomegaly and muscle hypotonia [2, 4, 5]. These clinical features were all present in the index case. Some patients experience chronic congenital diarrhoea due to the osmotic effect of high concentration of amino acids in the intestine [7]. Immune dysfunction attributable to nitric oxide (NO) overproduction secondary to intracellular trapping of arginine (due to defective efflux from the cell) is also a major feature. This may be a crucial Pathophysiological explanation for many LPI complications including severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis (HLH) with subsequent activation of macrophages (MAS), various auto-immune disorders and an incompletely characterized immune deficiency [2, 3, 5, 8]. The index case experienced pneumonia at a young age and frequent respiratory tract infections. The diagnosis of LPI is based on the combination of increased urinary excretion and low plasma concentrations of the cationic amino acids [2, 5, 6]. It is vital that both urine & plasma amino acids are quantitated so as not to miss the diagnosis. This is illustrated in the sibling of the index case where plasma arginine and lysine were within the normal range with only ornithine mildly reduced. However the urine amino acids showed marked excretion of lysine, arginine and ornithine. Patients are treated with low-protein diet and supplementation of L-citrulline, which is absorbed by neutral amino acid transporters and serves to correct the urea cycle dysfunction. Citrulline is partially converted to arginine and ornithine. It is proposed that citrulline increases the intracellular synthesis of arginine and may further stimulate the immune cascade in renal tubular, glomerular and mesangial cells, alveolar macrophages and pulmonary epithelial cells and the reticular endothelial system. Thus regularly monitoring of plasma ammonia, glutamine and urinary orotic acid should be undertaken. If hyperammonemia develops, more severe protein restriction with or without nitrogen scavengers must be used [2, 5]. By giving early and aggressive treatment, the number of hyperammonaemic episodes can be reduced significantly thereby preventing intellectual disability [1, 2, 6, 8]. Given the multi-systemic nature of this disorder, care should be taken to monitor for, and to treat early, manifestation of HLH, MAS, nephropathy and immune dysfunction. A multi- disciplinary team approach is required in order to treat these patients successfully [2, 3]. In summary, we described a case series of LPI patients with a range of non-specific symptoms. In order to avoid missing the diagnosis we recommend careful quantitative evaluation of both plasma and urine amino acids. Marked clinical improvement can be achieved by diet and medication which is best achieved through early detection and treatment. Surveillance for other LPI associated complications should be part of the management of these patients.