Last Updated: May 7, 2024
Introduction to Lysinuric Protein Intolerance (LPI)
Lysinuric protein intolerance (LPI: also known as hyperdibasic aminoaciduria type 2) is an autosomal recessive disorder that results from defects in the transport of cationic amino acids across the basolateral membranes of both intestinal enterocytes (allowing transport of dietary cationic amino acids into the blood) and renal tubular cells (allowing for cationic amino acid reuptake from the glomerular filtrate). This particular cationic amino acid transporter is a heterodimeric transporter composed of proteins that are both members of the SLC family of transporter proteins.
Molecular Biology of LPI
The subunits of the cationic amino acid transporter are encoded by the SLC3A2 and the SLC7A7 genes. Mutations in the SLC7A7 gene are the causes of lysinuric protein intolerance. The SLC3A2 gene encoded protein is the heavy chain component of not only the cationic amino acid transporter but also several other amino acid transporters. The SLC3A2 encoded protein is often referred to as 4F2hc for 4F2 cell-surface antigen heavy chain. The SLC7A7 gene encoded protein is the light chain component and was originally called y+LAT1 to identify it as a component of the y+ system of Na+-independent transporters. When combined into a functional heterodimer the SLC3A2 and SLC7A7 encoded proteins form what is called the y+L amino acid transporter.
In the context of the transport of the cationic amino acids, lysine, arginine, and ornithine, the actual transport process is catalyzed by the SLC7A7 encoded protein, whereas the SLC3A2 encoded protein is required for transport of the disulfide bonded heterodimeric complex to the plasma membrane.
The SLC3A2 gene is located on chromosome 11q12.3 and is composed 14 exons the generate four alternatively spliced mRNAs that each encode a different protein isoform.
The SLC7A7 gene is located on chromosome 14q11.2 and is composed of 13 exons that generate three alternatively spliced mRNAs that all encode the same 511 amino acid protein. Expression of the SLC7A7 gene is highest in the small intestine, kidney, peripheral leukocytes, lung, placenta, and spleen.
In all individuals suspected of having LPI, mutations in the SLC7A7 gene have been identified. The vast majority of the mutations found in LPI are single nucleotide missense mutations with small deletions also being found in a few cases. Large gene deletions and splice site mutations in the SLC7A7 gene are rare but have been found. To date a total of 50 different SLC7A7 mutations have been found in nearly 150 different LPI patients.
Clinical Features of Lysinuric Protein Intolerance
The onset of symptoms of lysinuric protein intolerance (LPI) have been found to be quite broad ranging from first appearing in the neonatal period to individuals having no symptoms until adulthood. The classic form of LPI is, however, the neonatal presenting form. In affected infants symptoms will most often appear upon weaning from breastmilk or when transitioning from milk-based infant formulas due to the fact that both are enriched in fats and low in protein content.
When symptoms of LPI appear they encompass neurodigestive signs and include poor feeding and frequent episodes of vomiting and diarrhea. Both of these digestive issues combine to result in hypotonia and poor growth. If an LPI affected infant is force fed, as a means to intervene in the failure to thrive, and that feeding is with protein-rich food, this intervention can provoke vomiting and enhanced neurological signs, including possible coma.
The presence of hepatosplenomegaly, although often mild in presentation, may lead to a clinical suspicion of an inherited metabolic disorder and may most likely suggest some form of a lysosomal storage disease. In LPI the low availability of arginine and ornithine in hepatocytes causes a defect in the urea cycle resulting in hyperammonemia.
Due to the onset of vomiting and diarrhea, following protein consumption, parents avoid giving these foods to their infant and in older patients protein aversion is pronounced with a strong tendency towards a vegetarian style diet. These nutritionally inadequate diets result in malnourished infants or children that exhibit pallor, poor muscle tone, osteopenia with delayed bone growth resulting in osteoporosis with pathologic fractures.
LPI patients will progressively exhibit a celiac disease-like phenotype which is characterized by thin extremities, relatively enlarged abdomen, and sparse hair. In most LPI patients their level of mental development is normal. However, in LPI patients who experienced severe or recurrent episodes of hyperammonemia there is a high likelihood of intellectual impairment. Lung involvement in LPI is of significance to the course and severity of the disorder. Initial lung pathology is asymptomatic interstitial disease observed by conventional chest X-ray.
As the disease progresses there is the appearance of interstitial reticulonodular densities that are best evaluated using high-resolution chest CT scan. Bronchoalveolar lavage will find that the airways are invaded with foamy macrophages filled with proteinaceous material suggestive of pulmonary alveolar proteinosis. The involvement of the lungs in LPI can progress to respiratory insufficiency. Renal dysfunction is also often apparent in LPI patients and evidenced by proteinuria and hematuria.
A major contributor to the broad pathophysiology observed in LPI patients is most likely unbalanced metabolism of intracellular arginine. Arginine serves a critical role in the function of the urea cycle, the biosynthesis of the polyamines, the biosynthesis of creatine, and the biosynthesis of the amino acids proline and glutamate. In addition, and of critical clinical significance, arginine is the precursor of nitric oxide (NO) which is a regulator of vascular pressure, immune function, and numerous other important biological processes.
As indicated above, dietary cationic amino acid transport into the blood (efflux) from intestinal enterocytes and renal re-uptake of these same amino acids is the function of the y+L amino acid transporter which is a heteromeric complex composed of the SLC3A2 and SLC7A7 encoded proteins. Intracellular arginine homeostasis is controlled by different transport systems that are dependent upon cell type.
The uptake (influx) of arginine from the lumen of the intestines (at the apical membrane) into intestinal enterocytes and the reabsorption of arginine via renal tubular cells involves the heteromeric transporter whose subunits are encoded by the SCL3A1 (encoding the rBAT protein) and SLC7A9 (encoding the b0,+AT protein) genes. In addition to arginine transport the SLC3A1/SLC7A9 transporter transports cystine (disulfide bonded cysteines). Mutations in either the SLC3A1 or the SLC7A9 gene result in cystinuria (type 1 and non-type 1, respectively). The basolateral membrane efflux transporter of arginine, the SLC3A2 and SLC7A7 encoded transporter, is also responsible for arginine efflux in human airway epithelial cells. The fact that this transporter functions in the regulation of intracellular arginine in airway epithelial cells likely explains the involvement of the lungs in the pathology of LPI.
A correct diagnosis of LPI requires correct clinical suspicion and an overall understanding of the disorder. Diagnosis is difficult due to the variable clinical presentation. Almost all LPI patients present with signs of a urea cycle disorder. In addition, many patients have abnormal signs of macrophage activation. Characteristic postprandial plasma results for LPI patients are hyperammonemia and high glutamine along with low levels of the cationic amino acids, arginine, ornithine and lysine. In contrast, urinary excretion of these three cationic amino acids is elevated in LPI. In addition to these plasma and urinary abnormalities, LPI patients exhibit hypercitrullinemia, cystinuria and orotic aciduria. Additional laboratory data may reinforce the suspicion of the diagnosis of LPI and includes evaluation of complete blood count and of serum protein levels. Delayed bone age, along with osteoporosis and lung involvement is often seen in X-rays.
Treatment of Lysinuric Protein Intolerance
Treatment of patients with LPI requires a protein-controlled diet principally to reduce the risk for hyperammonemia. Dietary supplementation with citrulline, coupled with the use of nitrogen-scavenging drugs commonly used to treat urea cycle disorders (e.g. sodium benzoate), can effectively correct the hyperammonemia and improve some of the nutritional aspects of LPI. However, due to the potential for intracellular trapping of arginine, and a consequent excess of NO production, the level of citrulline supplementation should be kept low at around 100 mg/kg/day.
Since lysine is a critical amino acid for muscle protein synthesis as well as a high energy amino acid, the potential for its deficiency in LPI needs to be addressed with low dose lysine supplementation (10–40 mg/kg/day). Lysine is also the precursor for carnitine and so carnitine supplementation is recommended in patients with LPI. Linear growth delay is a common feature of LPI and may be associated with growth hormone deficiency potentially necessitating growth hormone treatments. Steroids and immunosuppressant drugs are commonly required to treat the lung pathology observed in LPI patients.