Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature

Abstract

Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in SLC7A7. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.

Systemic Lupus Erythematosus and Hereditary Coproporphyria: Two Different Entities Diagnosed by WES in the Same Patient

“…A significant number of genes associated with autoinflammation and autoimmunity have been implicated in monogenic lupus, including SLC7A7 [ 4 – 6 ]. The compound heterozygous variants in SLC7A7 , namely, c.475C > T (p. Arg159Cys) and c.1001 T > G (p. Leu334Arg), were detected in a patient who clinically presented with immune dysregulation in the setting of early onset SLE [ 28 ]. Li et al [ 27 ] reported five mutations of SLC7A7 : c.625+1G > A, c.235G > A, c.1085 T > C, c.1387delG, and c.1215G > A, which were identified as causative mutations of SLE in 4 of 52 Chinese pediatric patients.…”

Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus

“…Mutations in this gene causes LPI, a rare recessive disorder characterized by FTT, growth retardation, muscle hypotonia and hepatosplenomegaly [ 45 ]. Mostly appeared after weaning of breastmilk, clinical manifestations of LPI can be widely variable resembling the findings in urea cycle disorders such as hyperammonemia [ 46 ]. Overlapping manifestation of LPI and SLE has been reported in several case series [ 11 , 46 ].…”

“…Mostly appeared after weaning of breastmilk, clinical manifestations of LPI can be widely variable resembling the findings in urea cycle disorders such as hyperammonemia [ 46 ]. Overlapping manifestation of LPI and SLE has been reported in several case series [ 11 , 46 ]. Renal involvement is a frequent and progressive complication in LPI.…”

“…Heterogeneous renal histological findings ranging from tubulointestinal disorder to distinct glomerulonephritis with polyclonal immunoglobulin deposition has been reported [ 47 , 48 ]. Carefully reviewed by Contreras et al, the incidence of other LPI associating manifestations including FTT, metabolic disorder, neurologic symptoms and hepatosplenomegaly in Case 2 and 3 corresponded to 52%, 52%, 25% and 43% of all cases with LPI, respectively [ 46 ]. While recessive disorder requires homozygous SLC7A7 defects to become phenotypic, the clinical phenotypes, presence of hyperammonemia, segregation analysis and the complete skipping of exon 4 revealed by complementary DNA analysis of Case 2 and 3 suggested a diagnosis of LPI.…”

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…The CMGs provided educational and networking opportunities by hosting in-person courses attended by over 300 analysts and researchers, including the Mendelian Data Analysis Workshop (University of Washington), Interpreting Genomes for Rare Disease (Broad), and McKusick Short Course in Human and Mammalian Genetics (Baylor-Hopkins). The CMGs have enabled researchers and clinicians investigating rare Mendelian diseases around the world to access gene discovery techniques, including those in countries where access to research opportunities is limited, such as the Democratic Republic of the Congo, 27 South Africa, Kenya, Egypt, 28,29 Iraq, 30 Chile, 31,32 Turkey, [33][34][35] and Lithuania. For some, this has involved training opportunities within a CMG-affiliated laboratory, whereas for others, learning happened through collaborative meetings to discuss analysis results on teleconferences.…”