Lysinuric protein intolerance (LPI) is an autosomal recessive condition caused by the deficiency of the light subunit of the y+ LAT1 transporter and biallelic pathogenic variants in the SLC7A7 gene. The y+ LAT1 transporter is most heavily expressed by renal epithelial cells and the intestinal basolateral membrane. Deficiency of this transporter in these tissues results in decreased absorption and reuptake of the cationic amino acids: lysine, ornithine, and arginine. Decreased arginine and ornithine results in secondary urea cycle dysfunction that is associated with some of the clinical features associated with LPI including hyperammonemia, protein avoidance, and poor growth. However, LPI has multiple clinical features not commonly seen in primary urea cycle disorders including osteoporosis, renal disease, interstitial lung disease, and immune dysfunction including hemophagocytic lymphohistiocytosis (HLH). In vitro studies of SLC7A7-deficient monocyte and macrophage cell lines suggest that some of the immune phenotype is driven by high levels of pro-inflammatory cytokines TNF-alpha and IL-1beta.
The proband is an 11-year-old female who was seen in general genetics clinic for evaluation of recurrent fractures and concern for osteogenesis imperfecta. She had a history of 5 lifetime fractures that were notable for prolonged healing requiring casts/braces for longer than expected. On physical exam, she had short stature and hepatomegaly. A skeletal survey was obtained that showed significant demineralization, healed/healing prior fractures, multiple compression fractures of the thoracic spine, and interstitial lung disease. The combination of demineralization and interstitial lung disease raised the question of LPI. Subsequent screening labs were performed and notable for elevated transaminases, LDH, ferritin, and zinc. Hematologic labs were notable for mild neutropenia (absolute neutrophil count 1000 cells/microliter), but normal platelets, hemoglobin, and fibrinogen. LPI was biochemically confirmed with plasma amino acids (elevated glutamine, decreased ornithine and lysine), urine amino acids (elevated lysine, arginine, and ornithine), and urine organic acids (orotic acid present). Molecular testing identified two pathogenic variants in SLC7A7 (NM_001126106.2:c.426_434del, p.Tyr142* and c.1263_1269del, p.Ile422Serfs*95), confirming the diagnosis of LPI. After diagnosis, the proband was referred to several specialists including Immunohematology, Endocrinology, Nephrology, Pulmonology, and Hepatology for further evaluation. Additional labs ordered by Immunohematology were consistent with a smoldering HLH picture, where the patient was asymptomatic but had laboratory findings consistent with severe immune dysregulation: elevated ferritin, slightly reduced CD107a, elevated sCD163 and elevations in various cytokines, including sIL2R. Interestingly, ESR and CRP were normal.
The proband’s 12-year-old full sister was noted to have similar features (short stature, multiple fractures, and protein intolerance). Initial labs obtained as part of screening for LPI when she was asymptomatic were notable for an elevated ferritin of 1447 mg/mL (normal 6-155), elevated triglycerides (450 mg/dL, normal < 90), elevated transaminases (AST 247 IU/L, ALT 149 IU/L), CBCD with mild thrombocytopenia (126,000 cells/microliter), mild neutropenia (ANC 1100 cells/μL) and normal hemoglobin and fibrinogen. Subsequent molecular testing confirmed the diagnosis of LPI in this patient as well. Her imaging was notable for hepatic steatosis and splenomegaly. A chest CT showed mild interlobular septal thickening bilaterally, likely representing early manifestation of interstitial lung disease. During her evaluation with Immunohematology, she also had evidence of smoldering chronic inflammation with laboratory features of HLH (elevated ferritin, increased S100A proteins, reduced CD107a, elevated sCD163, cytopenias and increased cytokines).
Following the LPI diagnosis, both sisters were started on a protein-restricted diet (although this was similar to their protein intake prior to diagnosis). They were also started on glycerol phenylbutyrate and supplementation of lysine, citrulline, and carnitine. Due to numerous fractures, both children were started on zoledronic acid infusions every 6 months. Based on concerns for smoldering HLH and rapidly progressive lung disease, they were started on IL-1 inhibition via canakinumab 2 mg/kg every 4 weeks. In the 6 months since canakinumab initiation, both sisters have had reductions in their ferritin levels. The older sister with higher ferritin at diagnosis, also had more dramatic decreases in her transaminases. Both sisters continue to have stable, mild neutropenia and remain asymptomatic from a HLH perspective.