RARE DISEASE
Lysinuric protein intolerance
Lysinuric protein intolerance
Lysinuric protein intolerance
Synonyms: Hyperdibasic aminoaciduria, LPI
Synonyms: Hyperdibasic aminoaciduria, LPI
Synonyms: Hyperdibasic aminoaciduria, LPI
Drug discovery
1
drug
With orphan designation
Overview
Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by SLC7A7 gene variants, disrupting cationic amino acid transport (lysine, arginine, ornithine). This leads to protein intolerance, hyperammonemia, and multi-system complications: hepatosplenomegaly, osteoporosis, immune dysregulation, pulmonary alveolar proteinosis, and renal disease. Symptoms typically emerge post-weaning with vomiting, failure to thrive, and protein aversion [1][8][11].
Burden
Chronic morbidity: Progressive interstitial lung disease, osteoporosis, and renal failure in adulthood [1][11].
Immune dysregulation: High risk of hemophagocytic lymphohistiocytosis (HLH) and lupus-like syndromes [4][11].
Mortality risk: Linked to hyperammonemic crises, acute respiratory failure, or systemic immune complications [4][8][11].
Therapies
Dietary management: Protein restriction (0.5–1.5 g/kg/day) paired with citrulline supplementation (up to 100 mg/kg/day) to enhance urea cycle function [3][13][17].
Pharmacotherapy: Nitrogen-scavengers (e.g., sodium benzoate) for hyperammonemia; immunosuppressants for autoimmune complications [11][13].
Complication-specific interventions: Whole lung lavage for pulmonary alveolar proteinosis; renal replacement therapy for end-stage disease [11][13].
Categories: rare genetic diseases, rare immunological diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
80 drug discovery papers about Lysinuric protein intolerance, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
80 drug discovery papers about Lysinuric protein intolerance, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-13 | Monogenic lupus with SLC7A7 mutations: a retrospective study from a Chinese center.
BACKGROUND: Monogenic lupus is a rare but severe form of systemic lupus erythematosus (SLE) that typically manifests during childhood. Mutations in SLC7A7 cause lysinuric protein intolerance (LPI), and this gene has been implicated in monogenic lupus. This study aimed to investigate the clinical features, treatment strategies, and outcomes of pediatric patients with monogenic lupus caused by SLC7A7 mutations. METHODS: We conducted a retrospective single-center study of pediatric patients with SLE who fulfilled the 2012 SLICC and/or 2019 EULAR/ACR classification criteria and underwent next-generation sequencing because of early onset or atypical clinical features. Patients carrying biallelic pathogenic or likely pathogenic variants in SLC7A7 together with biochemical evidence of LPI were classified as having SLC7A7-associated monogenic lupus. Their clinical and immunological characteristics, treatment strategies, and outcomes were compared with those of SLE patients without identifiable monogenic variants. RESULTS: Among pediatric SLE patients who underwent next-generation sequencing for suspected monogenic etiology, six were identified with biallelic SLC7A7 variants and biochemical evidence of lysinuric protein intolerance, accounting for 31.6% of all monogenic lupus cases in this cohort. The mean age at SLE diagnosis in the SLC7A7-associated monogenic lupus group was 6.6 years, and patients were followed for an average of 5.5 years. In the overall LPI cohort (n = 12), the median age of symptom onset was 1 year and the mean age at LPI diagnosis was 7.7 years. The recurrent splice-site mutation c.625 + 1G > A was the most frequent variant, detected in 14 of 24 alleles. Compared with gene-negative SLE patients, those with SLC7A7-associated monogenic lupus more frequently exhibited protein intolerance, osteopenia, short stature, and hyperferritinemia (all p < 0.05). Treatment consisted of combined immunosuppressive and metabolic therapies, and at the last follow-up 83.3% (5/6) of patients had achieved and maintained a Lupus Low Disease Activity State (LLDAS). CONCLUSIONS: In Chinese patients with lysinuric protein intolerance, this study suggests an association with an increased susceptibility to developing SLE. Given the small LPI-SLE subgroup, these findings require validation in larger cohorts. Within this cohort, the splice-site mutation c.625 + 1G > A was the most frequently observed SLC7A7 variant. Furthermore, in children diagnosed with SLE, the presentation of a metabolic triad—protein intolerance, short stature, and osteopenia—should raise suspicion for SLC7A7-associated monogenic lupus and prompt genetic and metabolic evaluation, which could facilitate early diagnosis and timely intervention.
2025-11-13 | Brain fog and protein logs: unravelling encephalopathy in lysinuric protein intolerance with rare mutation and expanded phenotypic spectrum.
Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by variants in the SLC7A7 gene, leading to impaired transport of dibasic amino acids across intestinal and renal membranes. This results in postprandial hyperammonaemia due to deficiencies in lysine, arginine and ornithine, crucial substrates for the urea cycle. It commonly presents in infancy with recurrent vomiting, diarrhoea and encephalopathy. Diagnosis involves molecular genetic testing for the SLC7A7 gene variant. In this case, the rarity of the neuroimaging findings and the identification of an ultra-rare mutation contribute to the expanding clinical and genetic spectrum of LPI. Despite therapeutic advancements, the prognosis of LPI hinges on the progression of pulmonary and renal complications, underscoring the importance of comprehensive care and monitoring.
2025-11-05 | Lysinuric protein intolerance: Unusual clinical manifestations in a compound heterozygote with a novel pathogenic variant.
Lysinuric protein intolerance is an amino acid transport disorder that leads to episodic hyperammonemia especially in times of protein loading. We report a 10-year-old male with severe failure to thrive who presented to the hospital due to somnolence. The patient's overall appearance suggested that he was younger than his chronological age. He was admitted due to an ammonia level of 250 μmol/L that rose to 374 μmol/L on repeat testing. Mild transaminitis with AST and ALT in the 100-200 mg/dL range was noted. Plasma amino acids showed elevated glutamine, alanine, and ornithine, with diminished arginine. Urine organic acids were remarkable for elevated orotic acid. He was treated initially with D10 containing IV fluids, intralipids, and IV sodium benzoate/sodium phenylacetate and l-arginine. Once stable, he was converted to an oral ammonia scavenger-currently well controlled on sodium benzoate alone after not tolerating sodium phenyl glycerate. His diet was titrated to his meet his caloric and protein needs (with restriction) and supplementation with l-arginine, l-citrulline and l-lysine. The patient's hyperammonemia has since resolved and his glutamine has normalized. Molecular testing revealed two pathogenic variants in SLC7A7, confirming his diagnosis of lysinuric protein intolerance.
2025-05-12 | Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury.
Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the SLC7A7 gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia. To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure. Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays. Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. N-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity. SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.
2025-03-19 | Structural basis for the substrate recognition and transport mechanism of the human y+LAT1-4F2hc transporter complex.
Heteromeric amino acid transporters (HATs), including y+LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y+LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y+LAT1 has yet to be fully understood. In this study, we characterized the function of y+LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y+LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp243 in y+LAT1 plays a crucial role in coordination with sodium ion and substrate selectivity. Molecular dynamic (MD) simulations further revealed the different transport mechanism of cationic amino acids and neutral amino acids. These results provide important insights into the mechanisms of the substrate binding and working cycle of HATs.
proteins
2026-03-05 | P051: Clinical and biochemical characterization of a patient with lysinuric protein intolerance: A rare disorder of amino acid transport
and mortality in HPP.Early suspicion for the condition based on family history and prenatal ultrasound findings allowed for coordination with the NICU team for earlier administration of asfotase alfa.This case also highlights the importance of re-evaluating the status of VUS over time, as the maternal ALPL variant was reclassified as pathogenic between the first and second pregnancy in this case.It is reasonable to include ALPL on gene panels for craniosynostosis.Serum ALP on a standard metabolic panel is a readily available, and affordable, first-line test in patients when evaluating for HPP.Further work is being done to identify the cause of craniosynostosis in this patient's older sibling, as they do not meet a clinical or molecular diagnosis for HPP at this time.
2026-03-05 | Two siblings with lysinuric protein intolerance misdiagnosed as glycogen storage disease in resource-limited setting: A case report from Sri Lanka
No abstract available
2025-01-30 | Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.
2024-11-14 | Rare genetic interstitial lung diseases: a pictorial essay.
The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations.
2024-03-06 | A novel variant in a Chinese boy with lysinuric protein intolerance: A case report and literature review.
We report a case of a 4-year-old boy with lysinuric protein intolerance in China. The patient presented with interstitial lung disease with obvious clubbing of the fingers and toes. During the course of diagnosis and treatment, we found he was averse to a high-protein diet, intolerant to activity, and had a history of diarrhea and fractures. Physical examination revealed hepatosplenomegaly and clubbing of the fingers and toes. Next-generation sequencing revealed compound heterozygous mutations (c.1387delG, c.958T > C) in SLC7A7, which was confirmed as a disease-causing gene for lysinuric protein intolerance. After a literature review, we found that c.958T > C had not been previously reported, and summarized the clinical and genetic characteristics of patients from different continents. His symptoms improved significantly after 3 months of being on a low-protein diet, supplementation with lysine, citrulline, carnitine, and trace elements, and oral corticosteroid treatment for 2 months. The patient is still under follow-up.
cell therapies
2025-12-04 | Lysinuric protein intolerance: Allogeneic peripheral blood stem cell transplantation for an inborn error of metabolism and immunity.
Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmune disorders (e.g. systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocystosis (HLH)). Recently, one case of allogeneic hematopoietic stem cell transplantation (allo-HSCT) reversing SLE and HLH in a LPI patient was reported. We present 21 years of follow-up in a second LPI patient having undergone allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for HLH.
2022-10-09 | Improving a Rare Metabolic Disorder Through Kidney Transplantation: A Case Report of a Patient With Lysinuric Protein Intolerance
Lysinuric protein intolerance (LPI) is a rare metabolic disorder with reduced renal and intestinal reabsorption of ornithine, lysine, and arginine. It is due to variants in SLC7A7, the gene encoding y+L amino acid transporter 1 (y+LAT1), which lead to urea cycle defects with protein intolerance. Chronic kidney disease in lysinuric protein intolerance is common and can progress to kidney failure and initiation of kidney replacement therapy. Kidney transplantation could in theory improve urine levels and, consequently, plasma levels of these amino acids and therefore improve clinical symptoms, as well as protein intolerance, in patients with lysinuric protein intolerance. However, data on kidney transplantation in patients with lysinuric protein intolerance are limited, and up until now no data on clinical and biochemical improvement after kidney transplantation have been reported. In this case report we describe a rare case of kidney transplantation in a lysinuric protein intolerance patient with substantial improvement in protein tolerance; in plasma and urine levels of ornithine, lysine, and arginine; and in lysinuric protein intolerance symptoms.
small molecules
2026-03-13 | Monogenic lupus with SLC7A7 mutations: a retrospective study from a Chinese center.
BACKGROUND: Monogenic lupus is a rare but severe form of systemic lupus erythematosus (SLE) that typically manifests during childhood. Mutations in SLC7A7 cause lysinuric protein intolerance (LPI), and this gene has been implicated in monogenic lupus. This study aimed to investigate the clinical features, treatment strategies, and outcomes of pediatric patients with monogenic lupus caused by SLC7A7 mutations. METHODS: We conducted a retrospective single-center study of pediatric patients with SLE who fulfilled the 2012 SLICC and/or 2019 EULAR/ACR classification criteria and underwent next-generation sequencing because of early onset or atypical clinical features. Patients carrying biallelic pathogenic or likely pathogenic variants in SLC7A7 together with biochemical evidence of LPI were classified as having SLC7A7-associated monogenic lupus. Their clinical and immunological characteristics, treatment strategies, and outcomes were compared with those of SLE patients without identifiable monogenic variants. RESULTS: Among pediatric SLE patients who underwent next-generation sequencing for suspected monogenic etiology, six were identified with biallelic SLC7A7 variants and biochemical evidence of lysinuric protein intolerance, accounting for 31.6% of all monogenic lupus cases in this cohort. The mean age at SLE diagnosis in the SLC7A7-associated monogenic lupus group was 6.6 years, and patients were followed for an average of 5.5 years. In the overall LPI cohort (n = 12), the median age of symptom onset was 1 year and the mean age at LPI diagnosis was 7.7 years. The recurrent splice-site mutation c.625 + 1G > A was the most frequent variant, detected in 14 of 24 alleles. Compared with gene-negative SLE patients, those with SLC7A7-associated monogenic lupus more frequently exhibited protein intolerance, osteopenia, short stature, and hyperferritinemia (all p < 0.05). Treatment consisted of combined immunosuppressive and metabolic therapies, and at the last follow-up 83.3% (5/6) of patients had achieved and maintained a Lupus Low Disease Activity State (LLDAS). CONCLUSIONS: In Chinese patients with lysinuric protein intolerance, this study suggests an association with an increased susceptibility to developing SLE. Given the small LPI-SLE subgroup, these findings require validation in larger cohorts. Within this cohort, the splice-site mutation c.625 + 1G > A was the most frequently observed SLC7A7 variant. Furthermore, in children diagnosed with SLE, the presentation of a metabolic triad—protein intolerance, short stature, and osteopenia—should raise suspicion for SLC7A7-associated monogenic lupus and prompt genetic and metabolic evaluation, which could facilitate early diagnosis and timely intervention.
2025-11-13 | Brain fog and protein logs: unravelling encephalopathy in lysinuric protein intolerance with rare mutation and expanded phenotypic spectrum.
Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by variants in the SLC7A7 gene, leading to impaired transport of dibasic amino acids across intestinal and renal membranes. This results in postprandial hyperammonaemia due to deficiencies in lysine, arginine and ornithine, crucial substrates for the urea cycle. It commonly presents in infancy with recurrent vomiting, diarrhoea and encephalopathy. Diagnosis involves molecular genetic testing for the SLC7A7 gene variant. In this case, the rarity of the neuroimaging findings and the identification of an ultra-rare mutation contribute to the expanding clinical and genetic spectrum of LPI. Despite therapeutic advancements, the prognosis of LPI hinges on the progression of pulmonary and renal complications, underscoring the importance of comprehensive care and monitoring.
2025-11-05 | Lysinuric protein intolerance: Unusual clinical manifestations in a compound heterozygote with a novel pathogenic variant.
Lysinuric protein intolerance is an amino acid transport disorder that leads to episodic hyperammonemia especially in times of protein loading. We report a 10-year-old male with severe failure to thrive who presented to the hospital due to somnolence. The patient's overall appearance suggested that he was younger than his chronological age. He was admitted due to an ammonia level of 250 μmol/L that rose to 374 μmol/L on repeat testing. Mild transaminitis with AST and ALT in the 100-200 mg/dL range was noted. Plasma amino acids showed elevated glutamine, alanine, and ornithine, with diminished arginine. Urine organic acids were remarkable for elevated orotic acid. He was treated initially with D10 containing IV fluids, intralipids, and IV sodium benzoate/sodium phenylacetate and l-arginine. Once stable, he was converted to an oral ammonia scavenger-currently well controlled on sodium benzoate alone after not tolerating sodium phenyl glycerate. His diet was titrated to his meet his caloric and protein needs (with restriction) and supplementation with l-arginine, l-citrulline and l-lysine. The patient's hyperammonemia has since resolved and his glutamine has normalized. Molecular testing revealed two pathogenic variants in SLC7A7, confirming his diagnosis of lysinuric protein intolerance.
2025-05-12 | Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury.
Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the SLC7A7 gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia. To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure. Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays. Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. N-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity. SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.
2025-03-19 | Structural basis for the substrate recognition and transport mechanism of the human y+LAT1-4F2hc transporter complex.
Heteromeric amino acid transporters (HATs), including y+LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y+LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y+LAT1 has yet to be fully understood. In this study, we characterized the function of y+LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y+LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp243 in y+LAT1 plays a crucial role in coordination with sodium ion and substrate selectivity. Molecular dynamic (MD) simulations further revealed the different transport mechanism of cationic amino acids and neutral amino acids. These results provide important insights into the mechanisms of the substrate binding and working cycle of HATs.
proteins
2026-03-05 | P051: Clinical and biochemical characterization of a patient with lysinuric protein intolerance: A rare disorder of amino acid transport
and mortality in HPP.Early suspicion for the condition based on family history and prenatal ultrasound findings allowed for coordination with the NICU team for earlier administration of asfotase alfa.This case also highlights the importance of re-evaluating the status of VUS over time, as the maternal ALPL variant was reclassified as pathogenic between the first and second pregnancy in this case.It is reasonable to include ALPL on gene panels for craniosynostosis.Serum ALP on a standard metabolic panel is a readily available, and affordable, first-line test in patients when evaluating for HPP.Further work is being done to identify the cause of craniosynostosis in this patient's older sibling, as they do not meet a clinical or molecular diagnosis for HPP at this time.
2026-03-05 | Two siblings with lysinuric protein intolerance misdiagnosed as glycogen storage disease in resource-limited setting: A case report from Sri Lanka
No abstract available
2025-01-30 | Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.
2024-11-14 | Rare genetic interstitial lung diseases: a pictorial essay.
The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations.
2024-03-06 | A novel variant in a Chinese boy with lysinuric protein intolerance: A case report and literature review.
We report a case of a 4-year-old boy with lysinuric protein intolerance in China. The patient presented with interstitial lung disease with obvious clubbing of the fingers and toes. During the course of diagnosis and treatment, we found he was averse to a high-protein diet, intolerant to activity, and had a history of diarrhea and fractures. Physical examination revealed hepatosplenomegaly and clubbing of the fingers and toes. Next-generation sequencing revealed compound heterozygous mutations (c.1387delG, c.958T > C) in SLC7A7, which was confirmed as a disease-causing gene for lysinuric protein intolerance. After a literature review, we found that c.958T > C had not been previously reported, and summarized the clinical and genetic characteristics of patients from different continents. His symptoms improved significantly after 3 months of being on a low-protein diet, supplementation with lysine, citrulline, carnitine, and trace elements, and oral corticosteroid treatment for 2 months. The patient is still under follow-up.
cell therapies
2025-12-04 | Lysinuric protein intolerance: Allogeneic peripheral blood stem cell transplantation for an inborn error of metabolism and immunity.
Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmune disorders (e.g. systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocystosis (HLH)). Recently, one case of allogeneic hematopoietic stem cell transplantation (allo-HSCT) reversing SLE and HLH in a LPI patient was reported. We present 21 years of follow-up in a second LPI patient having undergone allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for HLH.
2022-10-09 | Improving a Rare Metabolic Disorder Through Kidney Transplantation: A Case Report of a Patient With Lysinuric Protein Intolerance
Lysinuric protein intolerance (LPI) is a rare metabolic disorder with reduced renal and intestinal reabsorption of ornithine, lysine, and arginine. It is due to variants in SLC7A7, the gene encoding y+L amino acid transporter 1 (y+LAT1), which lead to urea cycle defects with protein intolerance. Chronic kidney disease in lysinuric protein intolerance is common and can progress to kidney failure and initiation of kidney replacement therapy. Kidney transplantation could in theory improve urine levels and, consequently, plasma levels of these amino acids and therefore improve clinical symptoms, as well as protein intolerance, in patients with lysinuric protein intolerance. However, data on kidney transplantation in patients with lysinuric protein intolerance are limited, and up until now no data on clinical and biochemical improvement after kidney transplantation have been reported. In this case report we describe a rare case of kidney transplantation in a lysinuric protein intolerance patient with substantial improvement in protein tolerance; in plasma and urine levels of ornithine, lysine, and arginine; and in lysinuric protein intolerance symptoms.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Lysinuric protein intolerance.
1 orphan drug designation for Lysinuric protein intolerance.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium benzoate | small molecules | EMA | 2016-08-29 | — | Lucane Pharma SA |
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