Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the SLC7A7 gene, which encodes the y+L cationic amino acid transporter-1 (y+LAT-1). This transporter is responsible for the movement of cationic amino acids—including arginine, ornithine, and lysine—across cell membranes. Dysfunction of y+LAT-1 in polarized epithelial cells leads to impaired intestinal absorption and renal tubular reabsorption of these essential amino acids, resulting in chronic malnutrition, growth retardation, and failure to thrive from early childhood.

Beyond its metabolic manifestations, LPI is increasingly recognized as an inborn error of immunity. In non-polarized immune cells, defective y+LAT-1 function disrupts immune homeostasis and contributes to profound immune dysregulation. As a result, patients with LPI are at risk of developing severe autoimmune and hyperinflammatory complications, including systemic lupus erythematosus (SLE) and hemophagocytic lymphohistiocytosis (HLH). Additional organ involvement is common and may include pulmonary alveolar proteinosis (PAP), hepatosplenomegaly, and progressive renal impairment, all of which significantly worsen long-term prognosis.

While patients with mild LPI phenotypes may achieve partial disease control through dietary protein restriction and citrulline supplementation, conventional metabolic management is often insufficient for individuals with severe immunologic or multisystem complications. In such cases, disease progression can be relentless, and effective therapeutic options remain limited.

In this context, GoBroad Healthcare Group clinicians report a complex case of LPI complicated by SLE, PAP, and HLH, representing a severe and life-threatening disease spectrum. Notably, this case demonstrates, for the first time, the successful application of allogeneic hematopoietic stem cell transplantation (HSCT) to halt and reverse the progression of immune-mediated pathology associated with LPI. Following transplantation, the patient showed marked improvement in immune dysregulation, resolution of hyperinflammatory features, and stabilization of organ involvement.

This clinical experience provides compelling evidence that HSCT can address the underlying immune defect in LPI, rather than merely managing downstream complications. By reconstituting a functional immune system, HSCT offers a potential disease-modifying strategy for patients with severe LPI-related immunologic manifestations. These findings expand the therapeutic landscape for LPI and support consideration of HSCT in carefully selected patients with refractory or life-threatening immune complications.

This work underscores GoBroad Healthcare Group's commitment to advancing precision medicine for rare genetic and immunologic disorders, and highlights the importance of integrated metabolic, immunologic, and transplant expertise in delivering transformative care for patients with complex inherited diseases.

Refer to the original: https://doi.org/10.1016/j.jaci.2023.03.006