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Lysinuric protein intolerance (LPI) is mainly found in Japan and Finland where the prevalence is approximately 1/60,000. More than 200 cases have been reported in the literature.

The metabolic disturbance in LPI causes increased renal excretion and reduced absorption from intestine of dibasic amino acids and orotic aciduria. Patients affected by LPI may present with nausea and vomiting after protein ingestion, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteopenia, episodes of hyperammoniaemic coma, altered immune response, autoimmune manifestations, cytopenias associated with macrophagic activation syndrome, chronic renal disease, and lung involvement (interstitial lung disease due to alveolar proteinosis).

It is caused by defective dibasic amino acids transport at the basolateral membrane of epithelial cells in the kidney and intestine. LPI is caused by at least 69 affecting-function variants in the gene coding for solute carrier family 7A member 7 (SLC7A7) located at chromosome 14q11.2, with no clear genotype-phenotype correlation found so far.

Diagnosis requires amino acid assays in plasma and urine where increased urinary excretion and low plasma concentration of lysine, arginine, and ornithine indicate positive diagnosis, but these signs may vary over time. Macrophagic activation syndrome is a constant finding, with hepatosplenomegaly, hyperferritinemia and elevated LDH. Identification of biallelic pathogenic variants (by single-gene testing or multigene panel depending on the clinical findings) can help confirm the diagnosis.

The differential diagnoses include other causes of hyperammonemia, lysosomal storage diseases, other causes of macrophage activation syndrome, and some autoimmune disorders such as systemic lupus erythematosus.

Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Acute hyperammonemic manifestations are treated by intravenous administration of nitrogen-scavenger drugs, dextrose infusion and/or extra-renal depuration following the usual guidelines for hyperammonemia management. Due to HLH, intravenous lipids should be avoided. Long term treatment revolves around protein-restricted diet (1-1.5 g/kg/day in children and 0.5-0.8 g/kg/day in adults) and supplement of citrulline (<100 mg/kg/day), and monitoring of biochemical markers. The complication of pulmonary alveolar proteinosis has been reported to be successfully treated by whole lung lavage.

Prognosis varies depending on early identification of the disease, hyperammonemia and pulmonary complications. Pulmonary involvement represents a major cause of impaired clinical course and fatal outcome. In adulthood, chronic kidney failure is common, and may require dialysis followed by renal transplantation. Long-term outcomes are also related to the unpredictable risk of occurrence of autoimmune and/or dysimmune manifestations, independent from the metabolic management.

Last update: January 2024 - Expert reviewer(s): Dr Juliette BOUCHEREAU | MetabERN* - Pr Manuel SCHIFF

* European Reference Network