Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance

Institut Curie, Lutetia Parisorum, Île-de-France, France
Journal of Pediatrics (Impact Factor: 3.79). 03/1999; 134(2):236-9. DOI: 10.1016/S0022-3476(99)70423-3
Source: PubMed


We describe 4 cases of lysinuric protein intolerance, which all fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. Mature histiocytes and neutrophil precursors participated in hemophagocytosis in the bone marrow. Moreover, serum levels of ferritin and lactate dehydrogenase were elevated, hypercytokinemia was present, and soluble interleukin-2 receptor levels were increased up to 18.6-fold. The diagnosis of lysinuric protein intolerance should therefore be considered in any patient presenting with hemophagocytic lymphohistiocytosis.

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    • "Other symptoms may include hepatomegaly, growth retardation, mental retardation, osteoporosis, and muscle weakness [5]. Some patients present with symptoms suggestive of immune system dysfunction including glomerulonephritis, pulmonary alveolar proteinosis (PAP), increased susceptibility to hemophagocytic lymphohistiocytosis and severe varicella infections [6] [7] [8]. Impaired intestinal and renal absorption of the cationic amino acids lysine, arginine and ornithine result in low plasma levels and increased urinary excretion of CAAs. "
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    ABSTRACT: Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder caused by mutations in the SLC7A7 located on the chromosome 14q11.2. LPI is most prevalent in Finland (1:50,000), Northern Japan (1:60,000) and Italy. Cases have also been reported in Spain and the United States. Here we report two siblings of Mexican descent. The older child was diagnosed at the age of three with severe chronic respiratory insufficiency leading to her demise. In contrast, the younger child was diagnosed soon after birth and dietary therapy has led to a stable life. Genetic analysis revealed a previously unreported deletion in the SLC7A7 gene. Additional research is needed to clarify the role of lysine in the pathophysiology of pulmonary proteinosis and herpes infections.
    Full-text · Article · Mar 2015 · Molecular Genetics and Metabolism Reports
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    • "Malignancies such as leukemias or lymphomas, particularly T-cell lymphomas and rarely solid tumors, are known to be potential triggers for HLH [1]. Moreover, a number of metabolic disorders, including multiple sulfatase deficiency, lysinuric protein intolerance, Wolman's disease, and disorders of proprionate metabolism, have been associated with HLH [28,32-34]. Finally, immunosuppressive therapy for malignancies, after organ trans-plantation, or for autoimmune disorders may predispose to 'secondary' HLH [28,35-37]. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.
    Full-text · Article · Jun 2012 · Arthritis research & therapy
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    • "The persistence of respiratory failure suggested patient refractoriness to WLL and induced to consider a treatment with inhaled rGM-CSF (Sargramostim, Leukine, Bayer). The treatment was preceded by a bone marrow biopsy, aimed at excluding the presence of a latent haemophagocytic syndrome, a possible feature of LPI [23]. The rGM-CSF treatment was approved by the AIFA (Italian Agency For Drugs) and by the Ethic Committee of the San Matteo Hospital. "
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    ABSTRACT: In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed. Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y+L activity was determined measuring the 1-min uptake of [3H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR. We have found that: 1) system y+L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of SLC7A7/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the SLC7A6/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of SLC7A7, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization. Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y+L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of SLC7A7 and SLC7A6. Moreover, the expression of SLC7A7 is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.
    Full-text · Article · Nov 2010 · Orphanet Journal of Rare Diseases
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