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:
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.
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
2025-12-04 | 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.
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.
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.
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
2025-12-04 | 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.
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.
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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