Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysinuric protein intolerance is an autosomal recessive disease, due to a defect in intestinal, renal and hepatic dibasic amino acid transport. Two new cases in the same family are reported. The disease appears progressively during the first months of life with failure to thrive, anorexia, vomiting, diarrhea, hepatosplenomegaly, muscular weakness, osteoporosis, anemia, leukothrombocytopenia, hyperammonemia and orotic aciduria after a high-protein intake. Hyperdibasicamino-aciduria was associated with subnormal plasma concentrations of the same aminoacids. Oral l-arginine, l-ornithine, l-lysine, and lysyl-glycine loads confirmed the diagnosis. The supplementation of the diet with l-citrulline resulted in normal levels of blood ammonia. However, hepatosplenomegaly, muscular weakness, osteoporosis remained unchanged and growth was not improved. These may be due to lysine deficiency.
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PMID:[Lysinuric protein intolerance: a severe hyperammonemia secondary to l-arginine deficiency (author's transl)]]. 680 Mar 34

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.
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PMID:Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. 1008 Jan 82

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive multisystem disorder found mainly in Finland and Italy. On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive. Hepatosplenomegaly, osteoporosis and a life-threatening pulmonary involvement (alveolar proteinosis) are also seen. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine and orotic aciduria. The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined. We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region. Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI. In five Italian patients, we found either an insertion or deletion in the coding sequence, which provides evidence of a causative role of SLC7A7 in LPI. Furthermore, we detected a splice acceptor change resulting in a frameshift and premature translation termination in four unrelated Finnish patients. This mutation may represent the founder LPI allele in Finland.
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PMID:SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. 1008 Jan 83

Lysinuric protein intolerance (LPI) is characterized by defective cellular transport of the dibasic amino acids, secondary dysfunction of the urea cycle, aversion to dietary protein, failure to thrive, hepatosplenomegaly and osteoporosis. Because several patients have suffered from recurrent respiratory infections and/or severe generalized varicella, and a few have developed systemic lupus, vasculitis or other autoimmune diseases, we have now evaluated the function of patients' immune systems. Serum concentrations of one to three IgG subclasses were decreased in 10 of the 12 patients studied. Antibody titres against diphtheria, tetanus and Haemophilus influenzae (Hib) were below the detection limit of the assay in four, three and eight of the 11 patients examined, respectively. (Re)vaccination of these 11 patients led to satisfactory responses against tetanus, but two patients still failed to develop measurable antibodies against diphtheria, two against Hib and six against one or more of the three serotypes of 23-valent pneumococcus vaccine. The proportions of T cells of all lymphocytes and the proliferative responses of the peripheral blood mononuclear cells were normal. In conclusion, humoral immune responses in some patients with LPI are defective and these patients may benefit from intravenous immunoglobulin therapy.
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PMID:B and T cell immunity in patients with lysinuric protein intolerance. 1036 Dec 30

Renal Fanconi syndrome developed rapidly in a 3-year-old Moroccan girl with established lysinuric protein intolerance. She was hospitalized because of lowered consciousness, uncoordinated movements and hepatosplenomegaly after a febrile period. Laboratory investigations revealed plasma ammonia 270 micromol/L (normal <70 micromol/L), ferritin 159 micromol/L (normal 2-59 micromol/L), LDH 1180 U/L (normal 26-534 U/L). LPI was diagnosed based on the findings of reduced plasma ornithine, arginine and lysine, and an increased level of glutamine. Urinary orotic acid (645 micromol/mmol creatinine; normal <3.6) was strongly increased. A defect in the SLC7A7 amino acid transporter was established (homozygous c.726G > A mutation). Detailed renal function tests including an acid challenge test, bicarbonate loading, and tubular maximal reabsorption of glucose showed complex tubular dysfunction. No evidence of respiratory chain defects was found in muscle or kidney tissue. No morphological abnormalities were demonstrated in the mitochondria. Ultrastructural analysis of proximal tubular cells showed vacuolization and sloughing of the apical brush border (Fig. 1). Renal involvement in LPI has only been described in a few reports; however, no detailed studies of the renal acidification mechanism were performed. Our patient had evidence of a full-blown Fanconi syndrome. Surprisingly, a metabolic acidosis was found with a moderately increased serum anion gap combined with repeatedly normal plasma organic acid values. This finding is in contrast with the diagnosis of renal tubular acidosis. Patients with hyperlysinaemia have a similar heavy load on the renal tubules; they never develop a renal Fanconi syndrome. Therefore, we consider the intratubular accumulation of lysine an unlikely candidate for the development of the renal Fanconi syndrome.
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PMID:Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance. 1753 Apr 37

We report on an 18-year-old Lithuanian girl with hepatosplenomegaly noticed at birth, which progressed thereafter. The patient had to wait about 17 years for an accurate diagnosis and appropriate therapy. Lactase deficiency, congenital cataract of the right eye, and osteoporosis were observed. Episodes of drowsiness were caused by intake of high-protein food. Laboratory findings included slight hyperammonaemia, high plasma Citr, Ala, Gly, Glu, Ser levels, as well as citrullinuria, lysinuria, glutaminuria, alaninuria, argininuria, prolinuria, hydroxyprolinuria, ornithinuria, and orotic aciduria. Aversion to high-protein diet strongly suggested a disorder resulting in hyperammonaemia. Citrullinaemia was suspected. Subsequently the diagnosis of LPI was made on the basis of biochemical and clinical features. Molecular genetic testing revealed a mutation in the SLC7A7 gene, confirming the diagnosis.
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PMID:First reported case of lysinuric protein intolerance (LPI) in Lithuania, confirmed biochemically and by DNA analysis. 1766 82

Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y(+)LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y(+)LAT-1 protein, is mutated in LPI patients. Mutation analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625+1G>C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3' region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3' region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.
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PMID:Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat. 1871 12

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.
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PMID:Lysinuric protein intolerance: reviewing concepts on a multisystem disease. 2130 87

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disease, caused by defective transport of dibasic amino acids. Failure to thrive, hepatosplenomegaly, hematological abnormalities, and hyperammonemic crisis are major clinical features. However, there has been no reported Korean patient with LPI as of yet. We recently encountered a 3.7-yr-old Korean girl with LPI and the diagnosis was confirmed by amino acid analyses and the SLC7A7 gene analysis. Her initial chief complaint was short stature below the 3rd percentile and increased somnolence for several months. Hepatosplenomegaly was noted, as were anemia, leukopenia, elevated levels of ferritin and lactate dehydrogenase, and hyperammonemia. Lysine, arginine, and ornithine levels were low in plasma and high in urine. The patient was a homozygote with a splicing site mutation of IVS4+1G > A in the SLC7A7. With the implementation of a low protein diet, sodium benzoate, citrulline and L-carnitine supplementation, anemia, hyperferritinemia, and hyperammonemia were improved, and normal growth velocity was observed.
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PMID:The first Korean case of lysinuric protein intolerance: presented with short stature and increased somnolence. 2287 67

Lysinuric protein intolerance is an autosomal recessive metabolic disorder caused by defective transport of the cationic amino acids lysine, arginine and ornithine in the epithelial cells of the basolateral membrane in the small intestine and renal tubules. Mutations in the solute carrier family 7, member 7, SLC7A7, gene cause this multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. In the present study, genomic structure of SLC7A7 in six Turkish patients with lysinuric protein intolerance was examined in order to detect disease causing mutations by denaturing high pressure liquid chromatography and direct sequencing. Four novel mutations were identified in SLC7A7: c.223insGTC, p.Val74_Ile75insVal; c.283insTGG, p.Glu94_Thr95insTrp; c.344_347delTTGC, p.Leu115LeufsX53; and c.1099insT, p.Ile367TyrfsX16. Clinical and biochemical findings were evaluated together with these molecular analyses.
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PMID:Molecular and clinical evaluation of Turkish patients with lysinuric protein intolerance. 2354 76


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