Lysinuric protein intolerance 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, ... Lysinuric protein intolerance 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 (Borsani et al., 1999).
Sperandeo et al. (2008) noted that the diagnosis of LPI is often difficult because of vague clinical presentation. Classic symptoms of protein intolerance may remain unnoticed during the first and second decades of life due to unconscious avoidance ... Sperandeo et al. (2008) noted that the diagnosis of LPI is often difficult because of vague clinical presentation. Classic symptoms of protein intolerance may remain unnoticed during the first and second decades of life due to unconscious avoidance of dietary protein. However, patients usually present with gastrointestinal symptoms soon after weaning. - Prenatal Diagnosis Sperandeo et al. (1999) demonstrated the feasibility of prenatal diagnosis of LPI by linkage analysis.
Perheentupa and Visakorpi (1965) first described 3 Finnish infants with an inborn error of metabolism characterized by protein intolerance and deficient transport of basic amino acids. Blood urea was low and urinary lysine and arginine were increased. ... Perheentupa and Visakorpi (1965) first described 3 Finnish infants with an inborn error of metabolism characterized by protein intolerance and deficient transport of basic amino acids. Blood urea was low and urinary lysine and arginine were increased. Kekomaki et al. (1967) described 10 children, including several pairs of sibs, with vomiting, diarrhea, failure to thrive, hepatomegaly, diffuse cirrhosis, low blood urea, hyperammonemia, and leukopenia. Symptoms were aggravated by high protein intake and relieved by protein restriction. An excess of ornithine, arginine, and lysine, but not of cystine, was excreted in the urine. Intestinal absorption of arginine and lysine was normal. A low concentration of arginine relative to lysine in body fluids was thought responsible for the hyperammonemia and reduced urea synthesis. One of the families was consanguineous. Kekomaki et al. (1968) reported a 23-year-old man with protein intolerance who refused to eat protein-rich food. Institution of cow's milk at age 1 year resulted in prolonged watery diarrhea and retardation of physical development. He grew physically with increased protein intake in his teens, but mental function deteriorated and he had episodic attacks of stupor and asterixis. The liver was enlarged and fatty. His 15-year-old affected sister also had protein intolerance. Oyanagi et al. (1970) described severe mental retardation, physical retardation, mild intestinal malabsorption syndrome, and increased urinary excretion of lysine, ornithine, and arginine in 2 Japanese sisters with second-cousin parents. Cystine excretion was always within normal limits. Malmquist et al. (1971) stated that 13 cases of familial protein intolerance had been observed in Finland. They described a Swedish patient of Finnish origin with intellectual impairment, radiographic evidence of brain atrophy, and marked skeletal fragility. Administration of alanine resulted in elevation of blood ammonia and glucose. Urea cycle function appeared to be normal and the defect was thought to concern the mechanisms by which amino nitrogen is transferred to the urea-synthesizing system. During citrulline infusion, Rajantie et al. (1981) found that LPI patients had increased plasma citrulline levels similar to controls, but excessive excretion compared to controls. Patients had subnormal increases in plasma arginine and ornithine with massive argininuria and moderate ornithinuria. The excretion rates of the third diamino acid lysine and other amino acids remained practically unaltered, thus excluding mutual competition as the cause for the increases. The results suggested that reabsorption in the normal kidney involves partial conversion of citrulline to arginine and ornithine, and that the diamino acid transport defect in LPI is located at the basolateral cell membrane of the renal tubules. This inhibits the efflux of arginine and ornithine, increasing their cellular concentration, which in turn inhibits the metabolic disposal of citrulline, and causes leakage of arginine, ornithine, and citrulline into the tubular lumen. Carpenter et al. (1985) emphasized that childhood osteopenia and osteoporosis were nearly constant complications of lysinuric protein intolerance. Laboratory studies suggested defective transport of ornithine and arginine across the plasma membrane of liver cells and across the basolateral membrane of renotubular cells. The defect in transport of dibasic amino acids results in lack of sufficient ornithine to support activity of hepatic ornithine transcarbamylase (OTC; 300461). Episodic hyperammonemia occurs, similar to that observed in OTC deficiency (311250). Shaw et al. (1989) described a 36-year-old man and his 32-year-old brother who presented in adult life with hyperammonemic coma due to lysinuric protein intolerance. They were of normal intellect and had maintained good health, until presentation in their thirties, by unconscious dietary protein avoidance. Parto et al. (1994) described the clinical courses and autopsy findings of 4 pediatric LPI patients. All had developed acute respiratory insufficiency. In addition to pulmonary hemorrhages, 3 of them had pulmonary alveolar proteinosis and 1 had cholesterol granulomas. Three patients had clinically obvious renal insufficiency, but all 4 showed histologic signs of immune complex-mediated glomerulonephritis. The patients also developed hepatic insufficiency with fatty degeneration or cirrhosis. All patients showed anemia, thrombocytopenia, and a severe bleeding tendency. Bone marrow of 3 patients was hypercellular, but the number of megakaryocytes was decreased in 2 cases. Amyloid was present in the lymph nodes and spleen. Bone specimens showed osteoporosis. Parto et al. (1994) concluded that in addition to being at risk of protein malnutrition in the active growth phase, probably due to higher requirements for total nitrogen and amino acids, pediatric patients with lysinuric protein intolerance are predisposed to develop pulmonary alveolar proteinosis and glomerulonephritis. McManus et al. (1996) reported a 21-year-old woman who had presented at 8 months of age with persistent vomiting and failure to thrive. At that time there was a marked increase in urinary lysine excretion and ornithine and arginine to a lesser extent. The urinary orotic acid concentration was also raised and casein protein loading tests increased the concentrations of all plasma amino acids except lysine, ornithine, and arginine. A protein-restricted diet was recommended and supplements of lysine, arginine, and citrulline were prescribed. During the teenage years, compliance with the diet and amino acid supplements was poor, and she developed osteoporosis. She showed gradual deterioration with episodic disturbances of liver function and hyperammonemia 2 years before her death. Immediately before death she became comatose, had persistently raised serum ammonia concentrations, metabolic acidosis, and a coagulopathy. She died despite intensive therapy, including intravenous arginine for the hyperammonemia. Postmortem examination revealed hepatic micronodular cirrhosis with extensive fatty changes. The lungs showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy revealed glomerulonephritis with predominant IgA deposition. McManus et al. (1996) suggested that the glomerulopathy may have been related to the failure of the normal role of the liver in clearance of immune complexes from the circulation. Pulmonary hemorrhage and alveolar proteinosis had also been previously described in Finnish cases. In a 3-year-old boy of Norwegian descent with LPI and immune complex disease consistent with systemic lupus erythematosus (SLE; 152700), Parsons et al. (1996) presented evidence suggesting that the immune complex disease may be the basis of the respiratory problems. In 4 patients with LPI, Duval et al. (1999) found features that fulfilled the diagnostic criteria for familial hemophagocytic lymphohistiocytosis (HPLH1; 267700). Mature histiocytes and neutrophil precursors participated in hemophagocytosis in the bone marrow. 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. Duval et al. (1999) suggested that the diagnosis of LPI should be considered in any patient presenting with hemophagocytic lymphohistiocytosis.
In 31 Finnish patients with lysinuric protein intolerance, Torrents et al. (1999) identified homozygosity for a founder mutation in the SLC7A7 gene (603593.0001). Borsani et al. (1999) defined the Finnish mutation as a splice acceptor change resulting in ... In 31 Finnish patients with lysinuric protein intolerance, Torrents et al. (1999) identified homozygosity for a founder mutation in the SLC7A7 gene (603593.0001). Borsani et al. (1999) defined the Finnish mutation as a splice acceptor change resulting in a frameshift and premature translation termination. Torrents et al. (1999) identified compound heterozygosity for 2 SLC7A7 mutations (603593.0005; 603593.0006) in a Spanish LPI patient. In affected members of 2 unrelated Italian LPI families, Borsani et al. (1999) identified 2 different homozygous mutations in the SLC7A7 gene (603593.0002 and 603593.0003, respectively). Noguchi et al. (2000) identified SLC7A7 mutations (603593.0008; 603593.0009) in Japanese LPI patients. Mykkanen et al. (2000) performed mutation screening of 20 non-Finnish LPI patients and found 10 novel mutations in the SLC7A7 gene. Sperandeo et al. (2008) identified 9 novel mutations in the SLC7A7 gene, and noted that a total of 43 different mutations had been identified in over 100 patients with LPI. Mutations were spread throughout the gene with no apparent genotype/phenotype correlations. Font-Llitjos et al. (2009) identified 11 mutations in the SLC7A7, including 7 novel mutations, in 11 patients from 9 unrelated families with LPI. Two of the mutations were large deletions involving exons 4 to 11 and exons 6 through 11 (603593.0011), respectively. These deletions were identified using multiplex ligation probe amplification (MLPA) assays and were found to result from the recombination of Alu repeats at introns 3 and 5, respectively, and the same AluY sequence in the 3-prime region of the SLC7A7 gene. Patients with the large deletions had the most severe phenotypes, likely resulting from dramatic loss of transport function.
The diagnosis of lysinuric protein intolerance (LPI) relies on clinical and biochemical findings [Simell 2002] and, recently, on molecular genetic testing....
DiagnosisClinical DiagnosisThe diagnosis of lysinuric protein intolerance (LPI) relies on clinical and biochemical findings [Simell 2002] and, recently, on molecular genetic testing.LPI typically presents after weaning of breast-fed or formula-fed infants as a variable and nonspecific progressive clinical picture that includes the following: Recurrent vomiting with episodes of diarrhea Episodes of stupor and coma after a protein-rich meal Poor feeding Aversion to protein-rich food Failure to thrive Enlargement of the liver and spleen Muscular hypotonia The diagnosis of LPI is usually not suspected by clinical findings alone and may be missed during infancy and childhood unless the presence of neurologic involvement triggers a diagnostic laboratory evaluation that includes determination of plasma ammonia concentration. In some cases, the diagnosis is established in adulthood. Over time, additional clinical findings or clinical presentations appear:Poor growth Early (often severe) osteoporosis Subclinical or overt pulmonary involvement Renal involvement Hemophagocytic lymphohistiocytosis/macrophagic activation syndromeTestingBiochemical Testing Affected individuals Plasma ammonia concentration may be elevated after a protein-rich meal. Fasting values are usually normal. Urinary orotic acid excretion is frequently increased. Note: (1) In some affected individuals elevated urinary orotic acid excretion occurs in the absence of hyperammonemia. (2) Urinary orotic acid excretion may be within the normal range if an untreated person has had a prolonged fast or has excluded protein-rich food from the diet.Plasma amino acid concentrations Cationic amino acid (lysine, arginine, and ornithine) concentrations are usually below normal for age, but may be within the normal range. Serine, glycine, citrulline, proline, alanine, and glutamine concentrations are increased. Urinary amino acid excretion. Twenty-four-hour urinary excretion of cationic amino acids, especially lysine, is increased. Note: (1) In some affected individuals, calculation of the renal clearances of cationic amino acids (lysine, arginine, and ornithine) may be necessary to clarify the urinary loss of these amino acids. (2) Renal clearance of an amino acid is calculated using the same formula as for creatinine clearance, but substituting creatinine values with values of 24-hour urinary amino acid excretion and of the fasting plasma amino acid concentrations. (3) Mean values and ranges of the renal clearances of cationic amino acids in individuals with LPI are reported in Simell [2002]. (4) Serine, glycine, citrulline, proline, alanine, and glutamine are found in excess in urine but have normal renal clearances. Other Plasma concentrations of thyroxine-binding globulin (TBG), LDH, and ferritin are usually elevated. Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings. Hypertriglyceridemia and hypercholesterolemia are frequently observed.Carriers. Biochemical analyses cannot be used to determine carrier status. Molecular Genetic TestingGene. SLC7A7 is currently the only gene in which mutation is known to cause LPI [Borsani et al 1999, Torrents et al 1999]. Table 1. Summary of Molecular Genetic Testing Used in Lysinuric Protein IntoleranceView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC7A7Sequence analysisSequence variants in coding and splice sites including the Finnish founder mutation 295% 3Clinical Targeted mutation analysisFinnish founder mutation c.895-2A>T 4100% for targeted mutationDeletion / duplication analysis 5Exonic or whole-gene deletions 15%-20% in non-Finnish populationsResearch testing 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Presently, of 236 alleles of persons in whom LPI is suspected, only 12 have not been characterized, giving a detection rate of about 95%.4. The mutation c.895-2A>T is the most frequent as a result of a founder effect originating in the Finnish population; this mutation is very rare elsewhere. (See Molecular Genetics for other recurrent mutations).5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.6. See following section.Research testingDeletion/duplication analysis. Several groups have reported deletion and duplication mutations of SLC7A7 [Kamada et al 2001, Shoji et al 2002, Sperandeo et al 2005].When the multiplex ligation-dependent probe amplification (MLPA) assay was used to screen for copy number changes of SLC7A7 in individuals with LPI, two deletions of 12 kb and 4.6 kb were identified that resulted from an Alu-mediated recombination [Font-Llitjós et al 2009]. The number of rearrangements found in this study is higher than that previously reported in non-Finnish groups (i.e., 21.4% vs 5.1%) [Cimbalistiene et al 2007, Sperandeo et al 2008]. It has been estimated that MLPA detects 15%-20% of partial- or whole-gene deletions in non-Finnish populations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. If clinical and biochemical findings are suggestive of LPI, the diagnosis can be confirmed by molecular genetic testing of SLC7A7. Molecular genetic testing begins with sequence analysis of SLC7A7. If no mutation or only one mutation is identified, deletion/duplication analysis is performed. The identification of two mutant alleles confirms the diagnosis of LPI. Note: Testing may begin with targeted mutation analysis for the Finnish founder mutation, c.895-2A>T, in individuals of Finnish ancestry. For individuals of other ancestry, targeted mutation analysis for a known recurrent mutation in those populations may be performed (see Molecular Genetics, Pathologic allelic variants). When only one mutant allele is detected, clinical and biochemical findings are crucial to the diagnosis of LPI. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations of SLC7A7.
Usually infants with lysinuric protein intolerance (LPI) present with gastrointestinal symptoms (feeding difficulties, vomiting, and diarrhea) soon after weaning from breast milk or formula. ...
Natural HistoryUsually infants with lysinuric protein intolerance (LPI) present with gastrointestinal symptoms (feeding difficulties, vomiting, and diarrhea) soon after weaning from breast milk or formula. Most affected infants show failure to thrive early in life. Neurologic presentation with episodes of coma is less common. Moderate hepatosplenomegaly is present. Muscular hypotonia and hypotrophy are observed from early infancy. Poor growth and delayed skeletal maturation are common after the first year of life. Osteoporosis may result in pathologic fractures.Mental development is normal unless episodes of prolonged coma cause neurologic damage. Classic symptoms of protein intolerance may remain unnoticed during the first and second decades of life because of subconscious avoidance of dietary protein. Treatment with a low-protein diet and supplementation with citrulline and nitrogen-scavenging drugs (see Management, Treatment of Manifestations) significantly improve symptoms related to the metabolic abnormality. However, some complications, representing the major causes of morbidity and mortality, are not amenable to treatment.
Genotype-phenotype correlations have not been found....
Genotype-Phenotype CorrelationsGenotype-phenotype correlations have not been found.Variable expressivity is observed in individuals of Finnish origin who are homozygous for the same founder mutation. In a large Italian pedigree, homozygosity for the same private mutation c.1381_1384dupATCA gave rise to different clinical presentations: severe short stature with pancreatic and renal involvement in a girl; early pulmonary alveolar proteinosis causing death in a boy; a very mild clinical presentation in another boy whose brother had a similar clinical picture but died suddenly after a flu-like episode [Sperandeo et al 2000].Mutation c.726G>A (p.Trp242X) was found in 13 individuals belonging to nine independent families from Italy, Morocco, and North Africa. Five of the 13 had a severe phenotype with pulmonary alveolar proteinosis [Sperandeo et al 2008].
The phenotypic variability of lysinuric protein intolerance (LPI) has resulted in various misdiagnoses....
Differential DiagnosisThe phenotypic variability of lysinuric protein intolerance (LPI) has resulted in various misdiagnoses.Hyperammonemia. Hyperammonemia and clinical manifestations related to it are shared by other metabolic diseases, notably the urea cycle disorders (see Urea Cycle Disorders Overview). Increased orotic aciduria and hyperexcretion of cationic amino acids help to distinguish LPI from other hyperammonemic conditions. Lysosomal storage diseases (LSDs). Hepatosplenomegaly, interstitial lung disease, and hematologic manifestation may suggest LSDs such as Niemann-Pick disease type B and Gaucher disease [Parenti et al 1995]. Malabsorptive diseases. The occurrence of gastrointestinal symptoms (e.g., vomiting, diarrhea) as well as of hypoproteinemia and failure to thrive suggests celiac disease. LPI should be included in the differential diagnosis of malabsorptive diseases. Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Failure to thrive, hepatosplenomegaly, fever, hypertriglyceridemia, increased serum ferritin concentration, anemia, and other blood abnormalities suggest acquired or familial hemophagocytic lymphohistiocytosis. Autoimmune disorders. Clinical and biochemical findings consistent with diagnosis of an autoimmune disorder such as systemic lupus erythematosus (SLE) were reported in individuals with LPI and, in some cases, were the presenting features. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with lysinuric protein intolerance, the following evaluations are recommended: ...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with lysinuric protein intolerance, the following evaluations are recommended: History for evidence of hyperammonemic crises with overt neurologic manifestations (vomiting, drowsiness, coma) and of respiratory involvement (cough, dyspnea, recurrent lower respiratory tract infections) Neurologic evaluation to detect secondary neurologic damage Respiratory evaluation including chest x-ray, pulmonary high-resolution computed tomography, and function tests Evaluation and follow-up of growth parameters Liver and spleen ultrasound examination to monitor liver structural changes and spleen enlargement Hematologic evaluation (bone marrow aspirate may be required) Immunologic assessment including plasma concentrations of immune globulins and, when clinically indicated, detection of autoimmune antibodies and immune complexes Renal function studies Bone density evaluation Treatment of ManifestationsThe management of individuals with LPI is similar to that described in urea cycle disorders. In LPI, the severity of hyperammonemic crises rarely requires extreme treatments such as dialysis and hemofiltration. It is recommended that individuals with LPI be cared for by a specialized metabolic team.Treatment of Acute Hyperammonemic CrisesPharmacologic management. Blocking the production of ammonia is accomplished by the intravenous administration of arginine chloride and of a combination of the nitrogen scavenger drugs sodium phenylacetate and sodium benzoate. An intravenous loading dose is followed by an oral maintenance dose of nitrogen scavenger drugs when the individual is stable. Depletion of branched chain amino acids (BCAAs) may occur as a consequence of the therapy with sodium phenylacetate [Scaglia 2010]. Persistence of BCAA deficiency hampers protein synthesis and induces catabolism. Therefore, careful evaluation of BCAA serum levels is recommended and specific supplementation may be required. Various detailed protocols for the treatment of intercurrent hyperammonemia in individuals with urea cycle disorders and, more generally, with hyperammonemia may be adopted [Singh 2007, Häberle 2011]. Reducing the amount of excess nitrogen in the diet and reducing catabolism through the introduction of energy supplied by carbohydrates and fat. In acutely ill individuals, energy should be provided as carbohydrate and fat, either intravenously as glucose and Intralipid® or orally as protein-free formula. Patients should be transitioned from parenteral to enteral feeds as soon as possible. Nasogastric tube feeding may be required to ensure adequate caloric and nutritional intake. Therapy with ondansetron can be started to decrease vomiting.Complete restriction of protein for more than 24-48 hours is not recommended as the individual will become protein catabolic for essential amino acids. Long-Term TreatmentDietary protein restriction and citrulline supplementation. Current treatment consists of dietary protein restriction (0.8-1.5 g/kg/day in children and 0.5-0.8 g/kg/day in adults) and supplementation with citrulline (100 mg/kg/day, in four doses taken with meals). Nitrogen scavenger drugs such as sodium benzoate (100-250 mg/kg/day in four divided doses) should be added to keep the lowest effective dosage of citrulline. As in the management of other inherited metabolic disorders, diet must be tailored on the basis of individual tolerance for the protein charge and carefully monitored to avoid disturbances of both growth and nutritional status.Measurement of orotic aciduria appears to be a sensitive tool for adjustment of treatment.Lysine supplementation. As lysine deficiency may contribute to the development of pathologic signs in LPI, oral supplementation with L-lysine-HCl should be attempted. Taking into account the defective intestinal absorption of lysine in LPI, small doses of L-lysine-HCl (0.05-0.5 mmol/kg, three times per day) are given and may normalize plasma lysine concentrations [Lukkarinen et al 2003]. Carnitine supplemetation. In a recent survey of 37 Finnish patients, hypocarnitemia was found to be associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. When documented, hypocarnitemia should be corrected (25-50 mg/kg/day) [Korman et al 2002, Tanner et al 2008].Additional therapies. Modification of the diet and fish oil supplementation should be tried in individuals with dyslipidemia before pharmacologic treatment of dyslipidemia is started. Treatment of Late ComplicationsWhile hyperammonemia can be efficiently prevented and treated, no effective therapy has been established for late complications. Treatment of lung disease in LPI remains controversial: high-dose corticosteroid treatment was effective in a few patients when started early, whereas no response was noted in others. In individuals with pulmonary alveolar proteinosis (PAP), treatment with granulocyte/monocyte colony stimulating factor (GM-CSF) was shown to be ineffective or even to worsen the clinical course [Santamaria et al 2004]. Recently, increased GM-CSF and decreased bioavailability of surfactant protein D have been proposed as a part of the mechanism underlying PAP in LPI [Douda et al 2009]. Whole lung lavage still remains the best therapeutic approach for PAP in LPI [Ceruti et al 2007]; however, relapses may require serial lavage. Heart-lung transplantation was attempted with a temporary successful result, but it did not prevent a fatal return of the lung disease [Santamaria et al 2004]. Bone marrow transplantation has been discussed as a possible treatment for PAP in LPI. The rationale of this therapeutic approach would rely on the hypothesis of a defective function of lung macrophages [Barilli et al 2010, Sebastio et al 2011].Treatment of renal disease in LPI should follow the standard guidelines under direction of the nephrologist. Treatment of hemophagocytic lymphohistiocytosis/macrophagic activation syndrome in LPI should be planned under the direction of the specialist.Prevention of Primary ManifestationsThe prevention of metabolic abnormality is the goal of the treatment. Long-term management is based on protein-restricted diet and administration of citrulline (see Treatment of Manifestations). Prevention of Secondary ComplicationsThe onset and the clinical course of the secondary complications, such as lung and renal involvement, seem to be poorly influenced by early treatment. Efforts to minimize the risk of respiratory infections should be promoted. An individual with LPI without previous history of chickenpox or varicella zoster should be vaccinated or, if exposed to varicella, treated as an immune-compromised person. Some individuals with LPI may respond poorly to polysaccharide-containing vaccines. Therefore, revaccination may be required if specific antibody titers are non-protective.SurveillanceIndividuals with LPI should be referred for follow-up to physicians with expertise in the treatment of inborn errors of metabolism. The age of the patient and the severity of the clinical features determine the frequency of clinical visits and monitoring. Monitoring should include the following:Plasma concentrations of amino acids to identify deficiencies of essential amino acids induced by the protein-restricted diet (similar to that used in urea cycle disorders) Attention to early signs of hyperammonemia including lethargy, nausea, vomiting, and poor feeding in young children, and headache and mood changes in older children Fasting and postprandial blood ammonia concentrations Urinary orotic acid excretion Evaluation of renal functionAttention to early clinical signs of lung involvementSerum concentrations of LDH and ferritin The development of a multiorgan pathology in LPI requires careful surveillance of several complications including lung and renal diseases and osteoporosis. No specific guidelines have been proposed. Therefore, a tailored approach is necessary for the follow-up of a specific complication. Agents/Circumstances to AvoidLarge boluses of protein or amino acids should be avoided.It is not clear whether prolonged fasting may trigger hyperammonemic crises.Evaluation of Relatives at RiskIf the disease-causing mutations have been identified in an affected family member, it is appropriate to offer molecular genetic testing to at-risk sibs in order to reduce morbidity and mortality through early diagnosis and treatment. When molecular testing is not available, early diagnosis of at-risk sibs relies on careful clinical evaluation and determination of plasma and urinary amino acid concentrations and orotic acid urinary excretion. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAlendronate. Osteopenia leading to osteoporosis is a major feature of LPI. Many individuals with LPI show osteopenia or osteoporosis despite treatment. Treatment with alendronate has recently been attempted in a child with LPI [Gomez et al 2006]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherNo treatment, including strict compliance with dietary regimen, citrulline supplementation, or high-dose corticosteroids, is effective in influencing the clinical course of the renal disease.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Lysinuric Protein Intolerance: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC7A714q11.2Y+L amino acid transporter 1Finnish Disease DatabaseSLC7A7Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Lysinuric Protein Intolerance (View All in OMIM) View in own window 222700LYSINURIC PROTEIN INTOLERANCE; LPI 603593SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 7; SLC7A7Normal allelic variants. SLC7A7 has 11 exons and is 46.5 kbp in length. More than 90 normal allelic variants have been identified in intronic regions of SLC7A7 (www.ncbi.nih.gov/projects/SNP). Pathologic allelic variants. To date, more than 50 SLCA7 mutations have been identified as causative of lysinuric protein intolerance (LPI) [Borsani et al 1999, Torrents et al 1999, Shoji et al 2002, Sperandeo et al 2008, Font-Llitjós et al 2009]. Most mutations reported in these five studies are private, except for the Finnish founder mutation c.895-2A>T found in 38 individuals, the c.726G>A mutation found in 13, and the c.1228C>T mutation found in persons of Japanese heritage and one of Moroccan origin. All types of mutations have been observed: missense and nonsense mutations, deletions, insertions, splicing mutations, and large genomic rearrangements.Table 2. Selected SLC7A7 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequencesc.726G>A 2p.Trp242XNM_003982.3 NP_003973.3c.895-2A>T 3(1181-2A>T or 1136-2A>T)c.1228C>Tp. Arg410Xc.1381_1384dupATCA (1670insATCA or 1384_1385insATCA)p.Arg462Asnfs*7See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Described in Italian and North African individuals. See Genotype-Phenotype Correlations.3. Founder mutation of Finnish population; previously reported as 1181-2A>T by Torrents et al [1999] and as 1136-2A>T by Borsani et al [1999]Normal gene product. SLC7A7 encodes the Y+L amino acid transporter 1 (y+LAT-1) protein; y+LAT-1 is linked by a disulfide bond to solute carrier family 3 member 2 (SLC3A2, also known as 4F2hc), which represents the heavy chain subunit of the heterodimeric amino acid transporter defective in LPI. This transporter, located at the basolateral membrane of epithelial cells, induces a system y+L activity. Abnormal gene product. Expression studies in cell culture systems demonstrated that the tested SLC7A7 mutations are functionally different from the wild type and that most of them abolish the y+L activity [Mykkänen et al 2000, Sperandeo et al 2005].