Reversal of SLE and hemophagocytic lymphohistiocytosis caused by lysinuric protein intolerance through allogeneic hematopoietic stem cell transplantation

Lysinuric protein intolerance (LPI; Online Mendelian Inheritance in Man [OMIM] identifier 222700) is a rare autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes for y+L cationic amino acid (including arginine, ornithine, and lysine) transporter-1 (y+LAT-1) protein.1Tangye S.G. Al-Herz W. Bousfiha A. Chatila T. Cunningham-Rundles C. Etzioni A. et al.Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40: 66-81Crossref PubMed Scopus (485) Google Scholar The malfunction of y+LAT-1 in polarized cells impairs the intestinal absorption and renal tubular reabsorption of cationic amino acid, resulting in malnutrition and failure to thrive.2Noguchi A. Takahashi T. Overview of symptoms and treatment for lysinuric protein intolerance.J Hum Genet. 2019; 64: 849-858Crossref PubMed Scopus (23) Google Scholar LPI is also classified as an inborn error of immunity owing to the immune dysregulation caused by malfunction of the y+LAT-1 protein, the defect in nonpolarized cells, developing autoimmune disorders such as SLE and hemophagocytic lymphohistiocystosis (HLH).3Sebastio G. Sperandeo M.P. Andria G. Lysinuric protein intolerance: reviewing concepts on a multisystem disease.Am J Med Genet C Semin Med Genet. 2011; 157C: 54-62Crossref PubMed Scopus (86) Google Scholar Additionally, patients with LPI may develop other complications, including pulmonary alveolar proteinosis (PAP), hepatosplenomegaly, and kidney failure.4Contreras J.L. Ladino M.A. Aranguiz K. Mendez G.P. Coban-Akdemir Z. Yuan B. et al.Immune dysregulation mimicking systemic lupus erythematosus in a patient with lysinuric protein intolerance: case report and review of the literature.Front Pediatr. 2021; 9673957Crossref PubMed Scopus (6) Google Scholar Whereas mild LPI cases can be managed with a low-protein diet and citrulline supplementation, severe cases with the aforementioned complications have a poorer prognosis.2Noguchi A. Takahashi T. Overview of symptoms and treatment for lysinuric protein intolerance.J Hum Genet. 2019; 64: 849-858Crossref PubMed Scopus (23) Google Scholar Herein, we present the case of a patient with LPI as well as SLE, PAP, and HLH, and for the first time, we demonstrate the successful use of allogeneic hemopoietic stem cell transplantation (HSCT) to reverse the progression of immunologic disorders caused by LPI. The patient, who was 6 years old, was admitted to our center for the first time in 2017. She fulfilled the classification criteria of SLE, including neurologic symptoms such as seizure and irritability, pancytopenia, renal involvement, decreased complement level, and positive result of testing for antinuclear antibodies and anti–double-stranded DNA. A renal biopsy suggested focal proliferative lupus nephritis combined with membranous lupus nephritis. The patient was initially diagnosed with SLE and treated with prednisone plus cyclophosphamide (CTX), which relieved all of her symptoms transiently. However, the symptoms flared up again 1 year later, and PAP gradually developed. Further review of the patient's medical history revealed that since childhood, she had an aversion to protein-rich meals and once experienced transient loss of consciousness with hyperammonemia (314 μmol/L) after eating fried chicken. These clues strongly suggested an unidentified inborn metabolic disorder. Subsequently, amino acid analyses and whole exome sequencing were performed. The results indicated elevated levels of urine orotate, lysine, and uracil (175, 11, and 6.7 times higher, respectively), as well as genetic variants in the gene SLC7A7 (NM_003982.4, paternal c.625+1G>A and maternal c.182G>T [p.G61V]); the former variant was previously reported as pathogenic, whereas the latter variant was a novel variant that was not found in the Exome Aggregation Consortium database, 1000 Genomes catalog, Genome Aggregation Database, or mBiobank (http://www.mbiobank.com [a database for the Chinese population]). Prediction tools suggested that the latter variant was deleterious, probably damaging, and deleterious in Mutation Taster, Polyphen-2, and SIFT, respectively. According to the American College of Medical Genetics guideline, the variant is classified as likely pathogenic (PM1, PM2, PM3, and PP3). No other potential variants that could explain the patient's phenotype were identified. All of the clinical and laboratory data supported the diagnosis of LPI. The patient did not respond to rigorous immune suppression treatment with methylprednisone pulse therapy plus mycophenolate mofetil and intravenous immunoglobulin infusions as well as the citrulline supplementation for LPI. The patient’s pancytopenia worsened, and she developed fever, hepatosplenomegaly, hyperferritinemia, and hypofibrinogenemia, fulfilling the diagnostic criteria of HLH. After consultation with transplantation specialists, HSCT was deemed a potential treatment option. In November 2019, the patient underwent HSCT from her 31-year-old father with a 9/10 HLA match. The conditioning regimen included thymoglobulin (5 mg/kg in total) from day –10 to day –8, CTX (30 mg/kg) on day –7, busulfan (3.2 mg/kg per day) intravenously from day –7 to day –5, thiotepa (10 mg/kg) on day –4, and fludarabine (40 mg/m2 per day) from day –6 to day –2. To prevent posttransplant lymphoproliferative disorder, the patient received rituximab (375 mg/m2) on day –1. For graft-versus-host disease (GVHD) prophylaxis, CTX (50 mg/kg per day) was given on day 3 to 4, mycophenolate mofetil (45 mg/kg per day) was given from day 5 until 1 month after the transplant, and tacrolimus (0.03 mg/kg per day) was given on day 5 for 3 months before switching to sirolimus (2.5 mg/m2) with gradual tapering. Ursodiol was used for prophylaxis of hepatic venoocclusive disease until the end of the third month after the transplant. On day 0, the patient received granulocyte CSF mobilized peripheral blood stem cells with mononuclear cells in a concentration of 28.2 × 108/kg and CD34+ cells in a concentration of 7.6×106/kg. The donor cells engrafted quickly, with neutrophil engraftment occurring on day 19 and platelet engraftment on day 14. Donor cell chimerism was regularly checked after the transplant, and the outcomes suggested full donor cell constant engraftment. The patient experienced grade II to III cutaneous acute GVHD on day 28, which was controlled soon after by a small dose of glucocorticoids (0.2 mg/kg per day). No other GVHD was observed. Shortly after transplantation, the patient’s fever was controlled and all HLH-related markers returned to their normal ranges. Additionally, the patient's hepatosplenomegaly improved, with the right hepatic oblique diameter decreasing from 13.4 cm to 10.5 cm and the length of the spleen dropping from 3.7 cm to 2.6 cm. SLE activity was evaluated regularly. About 1 month after transplantation, the results of testing for autoantibodies, including antinuclear antibodies and anti–double-stranded DNA, were negative, and the patient's erythrocyte sedimentation rate returned to normal. Hypocomplementemia and anemia were corrected 3 months after transplantation, whereas thrombocytopenia disappeared at 6 months after transplantation. As for renal involvement, the results of urine protein and 24-hour urine protein testing turned negative at 6 and 10 months, respectively (Table I). A second renal biopsy was performed 1 year after HSCT and showed an absorption of dense deposit in the basal membrane. No episode of seizures or delirium occurred after transplantation, and magnetic resonance imaging indicated a decrease in abnormal signals in bilateral frontal lobes. Computed tomography scans showed that ground glass was gradually absorbed after transplantation. The patient was able to discontinue taking glucocorticoids in October 2021 and sirolimus in January 2022 while continuing citrulline supplementation.Table IChanges in laboratory data during the follow-up periodParameterBefore HSCTAfter 1 monthAfter 3 monthsAfter 6 monthsAfter 1 yearAfter 3 yearsNormal rangeHb (g/L)7997109111125148110-160PLT (×109/L)8811457100175365100-300ESR (mm/h)8010202197≤20C3 (g/L)0.350.631.210.961.421.3540.9-1.8C4 (g/L)0.030.230.330.260.350.1930.1-0.424hUP (g)1.080.330.3170.2850.1010.08≤0.2LDH (U/L)2106262248285264214≤300Fibrinogen (g/L)1.382.752.61.711.873.11.8-3.5Ferritin (ng/mL)1953168512073323014914-307TG3.992.162.492.551.42≤2.26Ammonia (umol/L)5942403931≤51ANA1:1280＜1:80＜1:80＜1:80＜1:80＜1:80＜1:80Anti-dsDNA1:20NegativeNegativeNegativeNegativeNegativeNegativeCD3+ (%)88.381.292.984.180.459.5-75.6CD3+CD4+ (%)22.521.83127.62928.5-41.4CD3+CD8+ (%)56.961.160.854.446.833.5-32.4CD3–CD19+ (%)1.5000.24.410.5-21.8CD3–CD16+ (%)7.8186.815.314.97.8-21.0ANA, Antinuclear antibody; anti-dsDNA, anti–double-stranded DNA; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; TG, triglyceride; 24hUP, 24-hour urine protein. Open table in a new tab ANA, Antinuclear antibody; anti-dsDNA, anti–double-stranded DNA; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; TG, triglyceride; 24hUP, 24-hour urine protein. It is important to note that HSCT does not directly correct the defects in intestinal epithelial cells or renal tubular cells. Therefore, regular evaluations of kidney function and metabolism were conducted. The patient's renal function was regularly monitored, and the results consistently showed values within the normal range. Urine amino acids analysis indicated some improvement after transplantation, with the patient's urine lysine level decreasing from 167 to 21 times higher than normal whereas her orotate and uracil levels returned to normal. In terms of growth, the patient’s height was consistently around the third percentile before disease onset. However, her growth was stunted during 2018 and 2019. Following transplantation, her height increased from 118 cm to 128 cm over a 2-year period. We achieved positive outcomes by performing the first allogeneic HSCT for a patient with LPI, eliminating her autoimmune symptoms and reversing the progression of PAP. Although allogeneic HSCT has been widely accepted for other congenital metabolic disorders such as mucopolysaccharidosis,5Wang J. Luan Z. Jiang H. Fang J. Qin M. Lee V. et al.Allogeneic hematopoietic stem cell transplantation in thirty-four pediatric cases of mucopolysaccharidosis--a ten-year report from the China Children Transplant Group.Biol Blood Marrow Transplant. 2016; 22: 2104-2108Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar its potential for LPI is still unclear. However, the involvement of the mononuclear phagocyte system in LPI is now well recognized. Our results indicate that allogeneic HSCT may be a promising therapy for replacing pathogenic myeloid cells with healthy ones, particularly for those patients with LPI who have severe immunologic disorders. We would like to thank the patient and her parents for their participation.