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Olli Simell - One of the best experts on this subject based on the ideXlab platform.
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exploring the transcriptomic variation caused by the finnish founder mutation of lysinuric Protein Intolerance lpi
Molecular Genetics and Metabolism, 2012Co-Authors: Maaria Tringham, Laura Tanner, Kirsti Nantosalonen, Johanna Kurko, Johannes Tuikkala, Marja Hietala, Harri Niinikoski, Olli Nevalainen, Olli SimellAbstract:Abstract Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7 . Although all Finnish patients share the same homozygous mutation, their clinical manifestations vary greatly. The symptoms range from failure to thrive, Protein aversion, anemia and hyperammonaemia, to immunological abnormalities, nephropathy and pulmonary alveolar Proteinosis. To unravel the molecular mechanisms behind those symptoms not explained directly by the primary mutation, gene expression profiles of LPI patients were studied using genome-wide microarray technology. As a result, we discovered 926 differentially-expressed genes, including cationic and neutral amino acid transporters. The functional annotation analysis revealed a significant accumulation of such biological processes as inflammatory response, immune system processes and apoptosis. We conclude that changes in the expression of genes other than SLC7A7 may be linked to the various symptoms of LPI, indicating a complex interplay between amino acid transporters and various cellular processes.
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growth hormone therapy is safe and effective in patients with lysinuric Protein Intolerance
JIMD reports, 2011Co-Authors: Harri Niinikoski, Laura Tanner, Risto Lapatto, Matti Nuutinen, Olli Simell, Kirsti NantosalonenAbstract:Background: Lysinuric Protein Intolerance (LPI) is an autosomal recessive cationic amino acid transport defect characterized by episodes of postprandial hyperammonemias and spontaneous Protein aversion. Subnormal growth is common in spite of appropriate nutritional therapy. Growth hormone (GH) therapy promotes appetite, Protein synthesis and accretion, but its possible growth-promoting effects and safety in patients with LPI are poorly known.
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combined hyperlipidemia in patients with lysinuric Protein Intolerance
Journal of Inherited Metabolic Disease, 2010Co-Authors: Laura Tanner, Kirsti Nantosalonen, Harri Niinikoski, Olli SimellAbstract:Background and aims Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder characterized by defective transport of cationic amino acids lysine, arginine, and ornithine. Low plasma concentrations of arginine and ornithine lead to impaired urea cycle function and, subsequently, decreased Protein tolerance. Patients often develop natural aversion to Protein-rich foods, which may predispose them to nutritional problems. The objective of this retrospective study was to investigate lipid values and efficacy of lipid-lowering therapy in patients with LPI.
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carnitine deficiency and l carnitine supplementation in lysinuric Protein Intolerance
Metabolism-clinical and Experimental, 2008Co-Authors: Laura Tanner, Kirsti Nantosalonen, Jaana Venetoklis, Maija Aalto, Sami Kotilainen, Kirsi Huoponen, Harri Niinikoski, Mohamed S Rashed, Olli SimellAbstract:Abstract The aim of the study was to investigate the prevalence and mechanisms of development of carnitine deficiency in patients with lysinuric Protein Intolerance (LPI). In our cohort of 37 Finnish patients with LPI, 8 (8-52 years of age) have been diagnosed with hypocarnitinemia. Their free and total serum carnitine levels, acyl carnitine profiles, renal function, diet, and medication were compared with the data from 8 age- and sex-matched patients with LPI not treated with carnitine supplementation. In patients with LPI, hypocarnitinemia was strongly associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. Of the 8 hypocarnitinemic patients, 3 complained of muscle weakness, and their symptoms disappeared during carnitine supplementation. Oral lysine supplementation did not correct hypocarnitinemia in our patients. The patients with LPI are at considerable risk for carnitine deficiency. Supplementation of hypocarnitinemic LPI patients with oral l -carnitine improved serum total carnitine values, but the ratio of free and total carnitine remained subnormal in all supplemented patients except one. Furthermore, decreased ratio of free and total serum carnitine was common even in LPI patients with normal total serum carnitine concentration.
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nutrient intake in lysinuric Protein Intolerance
Journal of Inherited Metabolic Disease, 2007Co-Authors: Laura Tanner, Kirsti Nantosalonen, Jaana Venetoklis, Sami Kotilainen, Kirsi Huoponen, Harri Niinikoski, Olli SimellAbstract:Lysinuric Protein Intolerance (LPI) is a rare autosomal recessive disorder characterized by defective transport of cationic amino acids. Poor intestinal absorption and increased renal loss of arginine, ornithine and lysine lead to low plasma concentrations of these amino acids and, subsequently, to impaired urea cycle function. The patients therefore have decreased nitrogen tolerance, which may lead to hyperammonaemia after ingestion of normal amounts of dietary Protein. As a protective mechanism, most patients develop strong aversion to Protein-rich foods early in life. Oral supplementation with citrulline, which is absorbed normally and metabolized to arginine and ornithine, improves Protein tolerance to some extent, as do sodium benzoate and sodium phenylbutyrate also used by some patients. Despite effective prevention of hyperammonaemia, the patients still consume a very restricted diet, which may be deficient in energy, essential amino acids and some vitamins and minerals. To investigate the potential nutritional problems of patients with lysinuric Protein Intolerance, 77 three- to four-day food records of 28 Finnish LPI patients aged 1.5–61 years were analysed. The data suggest that the patients are clearly at risk for many nutritional deficiencies, which may contribute to their symptoms. Their diet is highly deficient in calcium, vitamin D, iron and zinc. Individualized nutritional supplementation accompanied by regular monitoring of dietary intake is therefore an essential part of the treatment of LPI.
Gianfranco Sebastio - One of the best experts on this subject based on the ideXlab platform.
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inducible slc7a7 knockout mouse model recapitulates lysinuric Protein Intolerance disease
International Journal of Molecular Sciences, 2019Co-Authors: Susanna Bodoy, Maria Pia Sperandeo, Meritxell Espinoguarch, Fernando Sotillo, Aida Ormazabal, Gianfranco Sebastio, Antonio Zorzano, Rafael Artuch, Manuel PalacinAbstract:Lysinuric Protein Intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar Proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7−/−). The Slc7a7−/− model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7−/− mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7−/− model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.
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lysinuric Protein Intolerance reviewing concepts on a multisystem disease
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2011Co-Authors: Gianfranco Sebastio, Maria Pia Sperandeo, Generoso AndriaAbstract: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. © 2011 Wiley-Liss, Inc.
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Lysinuric Protein Intolerance: reviewing concepts on a multisystem disease.
American journal of medical genetics. Part C Seminars in medical genetics, 2011Co-Authors: Gianfranco Sebastio, Maria Pia Sperandeo, Generoso AndriaAbstract: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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Growth hormone deficiency in a patient with lysinuric Protein Intolerance
European Journal of Pediatrics, 2006Co-Authors: Valentina Esposito, Teresa Lettiero, Simona Fecarotta, Giancarlo Parenti, Gianfranco Sebastio, Mariacarolina SalernoAbstract:Introduction Lysinuric Protein Intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteporosis. However, other findings have also been reported, and these suggest a multisystem involvement. Discussion We report a girl with confirmed LPI who presented with severe short stature that was unresponsive to adequate LPI treatment. The girl was found to have a classic growth hormone deficiency (GHD) and responded well to growth hormone (GH) replacement therapy. Conclusion While it is not known whether the mechanisms involved in the GHD of our patient are related to LPI, this case suggests that GH/IGF-I axis should be investigated in LPI children with persistent growth failure.
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growth hormone deficiency in a patient with lysinuric Protein Intolerance
European Journal of Pediatrics, 2006Co-Authors: Valentina Esposito, Teresa Lettiero, Simona Fecarotta, Giancarlo Parenti, Gianfranco Sebastio, Mariacarolina SalernoAbstract:Introduction Lysinuric Protein Intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteporosis. However, other findings have also been reported, and these suggest a multisystem involvement.
Generoso Andria - One of the best experts on this subject based on the ideXlab platform.
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lysinuric Protein Intolerance reviewing concepts on a multisystem disease
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2011Co-Authors: Gianfranco Sebastio, Maria Pia Sperandeo, Generoso AndriaAbstract: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. © 2011 Wiley-Liss, Inc.
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Lysinuric Protein Intolerance: reviewing concepts on a multisystem disease.
American journal of medical genetics. Part C Seminars in medical genetics, 2011Co-Authors: Gianfranco Sebastio, Maria Pia Sperandeo, Generoso AndriaAbstract: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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recurrent fatal pulmonary alveolar Proteinosis after heart lung transplantation in a child with lysinuric Protein Intolerance
The Journal of Pediatrics, 2004Co-Authors: Francesca Santamaria, Paola Francalanci, C Squitieri, Patrizia Dargenio, Gianluca Brancaccio, Carlo Dionisivici, Generoso Andria, Giancarlo Parenti, Gianfranco Sebastio, Francesco ParisiAbstract:We present a case of recurrent pulmonary alveolar Proteinosis after heart-lung transplantation in a child with lysinuric Protein Intolerance. The recurrence of the pulmonary disease provides further insight regarding the possible pathogenesis of pulmonary alveolar Proteinosis and therapeutic options for this complication.
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is mutated in patients with lysinuric Protein Intolerance
1999Co-Authors: Giuseppe Borsani, Maria Pia Sperandeo, Marta Manzoni, Anna Buoninconti, Mirko Riboni, Barbara Incerti, A. Pepe, Maria Teresa Bassi, Alessandro De Grandi, Generoso AndriaAbstract:Lysinuric Protein Intolerance (LPI, MIM 222700) is an autosomalrecessive multisystem disorder found mainly in Finland andItaly. On a normal diet, LPI patients present poor feeding, vom-iting, diarrhoea, episodes of hyperammoniaemic coma and fail-ure to thrive. Hepatosplenomegaly, osteoporosis and alife-threatening pulmonary involvement (alveolar Proteinosis)are also seen
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genetic homogeneity of lysinuric Protein Intolerance
European Journal of Human Genetics, 1998Co-Authors: Tuija Lauteala, Maria Pia Sperandeo, Marja-liisa Savontaus, Paolo Gasparini, Generoso Andria, Olli Simell, Gianfranco Sebastio, Juha Mykkänen, Pentti AulaAbstract:Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder in which transport of the cationic amino acids lysine, arginine and ornithine is defective at the basolateral membrane of the epithelial cells in the intestine and renal tubules. LPI is unusually common in Finland, but patients have been described on all continents. Linkage analysis in Finnish LPI families recently assigned the LPI gene locus to a 10 cM interval between markers D14S72 and MYH7 on the long arm of chromosome 14. In the present study linkage analysis of LPI families from six different non-Finnish populations strongly suggests genetic homogeneity in LPI. Peak lod scores were obtained at the chromosomal area between D14S72 and MYH7 with the same markers as in the Finnish families. The non-Finnish families showed no linkage disequilibrium except in an Italian family cluster, whereas strong allelic association in the Finnish families implies that LPI in Finland is caused by a founder mutation.
Laura Tanner - One of the best experts on this subject based on the ideXlab platform.
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inhaled sargramostim induces resolution of pulmonary alveolar Proteinosis in lysinuric Protein Intolerance
JIMD reports, 2016Co-Authors: Laura Tanner, Kirsti Nantosalonen, Johanna Kurko, Maaria Tringham, Harri Niinikoski, Juha Mykkänen, Heikki LukkarinenAbstract:Pulmonary alveolar Proteinosis (PAP) is a potentially fatal complication of lysinuric Protein Intolerance (LPI), an inherited disorder of cationic amino acid transport. The patients often present with mild respiratory symptoms, which may rapidly progress to acute respiratory failure responding poorly to conventional treatment with steroids and bronchoalveolar lavations (BALs). The pathogenesis of PAP in LPI is still largely unclear. In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group.
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exploring the transcriptomic variation caused by the finnish founder mutation of lysinuric Protein Intolerance lpi
Molecular Genetics and Metabolism, 2012Co-Authors: Maaria Tringham, Laura Tanner, Kirsti Nantosalonen, Johanna Kurko, Johannes Tuikkala, Marja Hietala, Harri Niinikoski, Olli Nevalainen, Olli SimellAbstract:Abstract Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7 . Although all Finnish patients share the same homozygous mutation, their clinical manifestations vary greatly. The symptoms range from failure to thrive, Protein aversion, anemia and hyperammonaemia, to immunological abnormalities, nephropathy and pulmonary alveolar Proteinosis. To unravel the molecular mechanisms behind those symptoms not explained directly by the primary mutation, gene expression profiles of LPI patients were studied using genome-wide microarray technology. As a result, we discovered 926 differentially-expressed genes, including cationic and neutral amino acid transporters. The functional annotation analysis revealed a significant accumulation of such biological processes as inflammatory response, immune system processes and apoptosis. We conclude that changes in the expression of genes other than SLC7A7 may be linked to the various symptoms of LPI, indicating a complex interplay between amino acid transporters and various cellular processes.
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growth hormone therapy is safe and effective in patients with lysinuric Protein Intolerance
JIMD reports, 2011Co-Authors: Harri Niinikoski, Laura Tanner, Risto Lapatto, Matti Nuutinen, Olli Simell, Kirsti NantosalonenAbstract:Background: Lysinuric Protein Intolerance (LPI) is an autosomal recessive cationic amino acid transport defect characterized by episodes of postprandial hyperammonemias and spontaneous Protein aversion. Subnormal growth is common in spite of appropriate nutritional therapy. Growth hormone (GH) therapy promotes appetite, Protein synthesis and accretion, but its possible growth-promoting effects and safety in patients with LPI are poorly known.
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combined hyperlipidemia in patients with lysinuric Protein Intolerance
Journal of Inherited Metabolic Disease, 2010Co-Authors: Laura Tanner, Kirsti Nantosalonen, Harri Niinikoski, Olli SimellAbstract:Background and aims Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder characterized by defective transport of cationic amino acids lysine, arginine, and ornithine. Low plasma concentrations of arginine and ornithine lead to impaired urea cycle function and, subsequently, decreased Protein tolerance. Patients often develop natural aversion to Protein-rich foods, which may predispose them to nutritional problems. The objective of this retrospective study was to investigate lipid values and efficacy of lipid-lowering therapy in patients with LPI.
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carnitine deficiency and l carnitine supplementation in lysinuric Protein Intolerance
Metabolism-clinical and Experimental, 2008Co-Authors: Laura Tanner, Kirsti Nantosalonen, Jaana Venetoklis, Maija Aalto, Sami Kotilainen, Kirsi Huoponen, Harri Niinikoski, Mohamed S Rashed, Olli SimellAbstract:Abstract The aim of the study was to investigate the prevalence and mechanisms of development of carnitine deficiency in patients with lysinuric Protein Intolerance (LPI). In our cohort of 37 Finnish patients with LPI, 8 (8-52 years of age) have been diagnosed with hypocarnitinemia. Their free and total serum carnitine levels, acyl carnitine profiles, renal function, diet, and medication were compared with the data from 8 age- and sex-matched patients with LPI not treated with carnitine supplementation. In patients with LPI, hypocarnitinemia was strongly associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. Of the 8 hypocarnitinemic patients, 3 complained of muscle weakness, and their symptoms disappeared during carnitine supplementation. Oral lysine supplementation did not correct hypocarnitinemia in our patients. The patients with LPI are at considerable risk for carnitine deficiency. Supplementation of hypocarnitinemic LPI patients with oral l -carnitine improved serum total carnitine values, but the ratio of free and total carnitine remained subnormal in all supplemented patients except one. Furthermore, decreased ratio of free and total serum carnitine was common even in LPI patients with normal total serum carnitine concentration.
Harri Niinikoski - One of the best experts on this subject based on the ideXlab platform.
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inhaled sargramostim induces resolution of pulmonary alveolar Proteinosis in lysinuric Protein Intolerance
JIMD reports, 2016Co-Authors: Laura Tanner, Kirsti Nantosalonen, Johanna Kurko, Maaria Tringham, Harri Niinikoski, Juha Mykkänen, Heikki LukkarinenAbstract:Pulmonary alveolar Proteinosis (PAP) is a potentially fatal complication of lysinuric Protein Intolerance (LPI), an inherited disorder of cationic amino acid transport. The patients often present with mild respiratory symptoms, which may rapidly progress to acute respiratory failure responding poorly to conventional treatment with steroids and bronchoalveolar lavations (BALs). The pathogenesis of PAP in LPI is still largely unclear. In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group.
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exploring the transcriptomic variation caused by the finnish founder mutation of lysinuric Protein Intolerance lpi
Molecular Genetics and Metabolism, 2012Co-Authors: Maaria Tringham, Laura Tanner, Kirsti Nantosalonen, Johanna Kurko, Johannes Tuikkala, Marja Hietala, Harri Niinikoski, Olli Nevalainen, Olli SimellAbstract:Abstract Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7 . Although all Finnish patients share the same homozygous mutation, their clinical manifestations vary greatly. The symptoms range from failure to thrive, Protein aversion, anemia and hyperammonaemia, to immunological abnormalities, nephropathy and pulmonary alveolar Proteinosis. To unravel the molecular mechanisms behind those symptoms not explained directly by the primary mutation, gene expression profiles of LPI patients were studied using genome-wide microarray technology. As a result, we discovered 926 differentially-expressed genes, including cationic and neutral amino acid transporters. The functional annotation analysis revealed a significant accumulation of such biological processes as inflammatory response, immune system processes and apoptosis. We conclude that changes in the expression of genes other than SLC7A7 may be linked to the various symptoms of LPI, indicating a complex interplay between amino acid transporters and various cellular processes.
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lysinuric Protein Intolerance
2011Co-Authors: Virginia Nunes, Harri NiinikoskiAbstract:Clinical characteristics Lysinuric Protein Intolerance (LPI) typically presents after an infant is weaned from breast milk or formula; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a Protein-rich meal, poor feeding, aversion to Protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth, osteoporosis, involvement of the lungs (progressive interstitial changes, pulmonary alveolar Proteinosis) and of the kidneys (progressive glomerular and proximal tubular disease), hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis in the bone marrow aspirate), and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen. Diagnosis/testing The diagnosis is established in an individual with clinical and laboratory features suggestive of LPI including elevated 24-hour urinary excretion of cationic amino acids, especially lysine. Identification of biallelic SLC7A7 pathogenic variants confirms the diagnosis. Management Treatment of manifestations: In acute hyperammonemic crises: intravenous administration of arginine chloride and nitrogen-scavenger drugs (sodium benzoate, sodium phenylacetate) to block ammonia production; reduction of excess nitrogen in the diet; provision of energy as carbohydrates to reduce catabolism. Long-term: dietary Protein restriction; oral supplementation with citrulline and nitrogen-scavenger drugs, L-lysine-HCl, and carnitine; whole-lung lavage to improve respiratory function in persons with pulmonary alveolar Proteinosis. Prevention of primary manifestations: Long-term Protein restriction and administration of citrulline and nitrogen-scavenging drugs. Prevention of secondary complications: Minimize the risk of respiratory infections; vaccination against influenza is recommended. Varicella immunization in those without previous history of chickenpox or varicella zoster; treatment of those exposed as immune-compromised persons; revaccination may be required if poor response to polysaccharide-containing vaccines. Surveillance: Plasma concentration of amino acids to identify deficiencies of essential amino acids secondary to Protein-restricted diet; fasting and postprandial blood ammonia concentrations and attention to signs of hyperammonemia, urinary orotic acid excretion; periodic evaluation of renal function; evaluation of lung involvement; periodic serum LDH and ferritin. Agents/circumstances to avoid: Large boluses of Protein or amino acids. Evaluation of relatives at risk: It is appropriate to evaluate at-risk sibs of a proband by molecular genetic testing or biochemical testing in order to reduce morbidity and mortality through early diagnosis and treatment. Genetic counseling LPI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for a pregnancy at increased risk are possible using molecular genetic techniques if both pathogenic variants have been identified in an affected family member.
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growth hormone therapy is safe and effective in patients with lysinuric Protein Intolerance
JIMD reports, 2011Co-Authors: Harri Niinikoski, Laura Tanner, Risto Lapatto, Matti Nuutinen, Olli Simell, Kirsti NantosalonenAbstract:Background: Lysinuric Protein Intolerance (LPI) is an autosomal recessive cationic amino acid transport defect characterized by episodes of postprandial hyperammonemias and spontaneous Protein aversion. Subnormal growth is common in spite of appropriate nutritional therapy. Growth hormone (GH) therapy promotes appetite, Protein synthesis and accretion, but its possible growth-promoting effects and safety in patients with LPI are poorly known.
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combined hyperlipidemia in patients with lysinuric Protein Intolerance
Journal of Inherited Metabolic Disease, 2010Co-Authors: Laura Tanner, Kirsti Nantosalonen, Harri Niinikoski, Olli SimellAbstract:Background and aims Lysinuric Protein Intolerance (LPI) is an autosomal recessive disorder characterized by defective transport of cationic amino acids lysine, arginine, and ornithine. Low plasma concentrations of arginine and ornithine lead to impaired urea cycle function and, subsequently, decreased Protein tolerance. Patients often develop natural aversion to Protein-rich foods, which may predispose them to nutritional problems. The objective of this retrospective study was to investigate lipid values and efficacy of lipid-lowering therapy in patients with LPI.
