リジン尿性蛋白不耐症

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disorder characterized by multisystem involvement, including failure to thrive, protein intolerance, hepatosplenomegaly, osteoporosis, pulmonary and renal disease, neurological impairment, and immune-dysregulation. Although immune-abnormalities are increasingly recognized in LPI, the immunological consequences of altered amino acid homeostasis remain incompletely understood. According to this, we aimed to characterize the immunologic-phenotype of patients with LPI. Patients with LPI and age-matched healthy controls were enrolled. Peripheral lymphocyte subsets, intracellular protein and cytokine expression, and lymphocyte-proliferative responses were assessed by flow cytometry. Serum immunoglobulin levels and amino acid profiles were analyzed using high-performance-liquid-chromatography. A total of 10 patients with LPI and 18 healthy-controls were included. Patients exhibited a combined immunological and metabolic phenotype characterized by reduced B-cell and class-switched memory B-cell compartments with IgG deficiency, together with impaired lymphocyte-proliferative responses despite preserved T-cell numbers. Cytokine profiling demonstrated decreased IL-17 and IL-4 responses, whereas IFN-γ production was relatively preserved. In parallel, stimulation-dependent alterations in amino acid profiles and disease-specific correlations between amino acids and immune-parameters suggested a direct link between disrupted amino acid homeostasis and immune dysfunction. Beyond quantitative immune defects, our findings reveal disease-specific metabolic signatures accompanying lymphocyte activation in LPI. Mitogenic stimulation induced coordinated amino acid changes in healthy controls, whereas this response was altered and accompanied by distinct metabolic changes, including increased citrulline levels. Overall, our findings indicate that lysinuric protein intolerance is associated with an immune phenotype characterized by humoral and cellular immune abnormalities accompanied by metabolic alterations. Together with previous studies describing innate immune dysfunction, these findings further support immune dysregulation as an important feature of LPI.

Lysinuric protein intolerance (LPI) is a rare disorder of dibasic amino acid transport associated with secondary urea cycle defects and immune dysregulation. Pregnancy in LPI is seldom reported and presents significant management challenges. We report a 25-year-old woman with genetically confirmed LPI complicated by prior hemophagocytic lymphohistiocytosis (HLH) and systemic lupus erythematosus (SLE) who presented with an unplanned pregnancy. Early gestation was characterised by metabolic instability, including transient hyperammonaemia and elevated orotic acid, which improved with optimisation of nitrogen scavenger therapy and nutritional support. Progressive severe thrombocytopenia and anaemia developed during the second trimester and were managed as presumed immune thrombocytopenia with corticosteroids and intravenous immunoglobulin. Delivery by caesarean section at 35 weeks resulted in favourable maternal and neonatal outcomes. To our knowledge, this represents the first reported case of pregnancy in LPI complicated by established immune dysregulation (HLH and SLE) and severe thrombocytopenia, defining a previously uncharacterised high-risk phenotype with a favourable outcome.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing prevalence. Genetic factors play an important role in the etiology of ASD, and researchers and clinicians have shown increasing interest in understanding the underlying genetic mechanisms of ASD. This report describes a case of lysinuric protein intolerance (LPI), a rarely reported metabolic/genetic syndrome associated with ASD. LPI is an autosomal recessive disorder, and pathogenic variants in the responsible gene, solute carrier family 7 member 7 ( SLC7A7 ), have been identified. Although there are studies suggesting that the SLC7A7 gene is involved in the etiology of ASD, the literature review did not identify any case reports of concurrent diagnoses of ASD and LPI. This report presents the case of a 10-year-old who was diagnosed with both ASD and LPI. This case report aims to contribute to the literature on the genetic underpinnings of ASD by highlighting its potential association with LPI.

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.

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.