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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Lysinuric Protein Intolerance

Synonym: Cationic Aminoaciduria

, MD and , PhD.

Author Information
, MD
Associate Professor of Pediatrics
Department of Pediatrics
Federico II University
Naples, Italy
, PhD
Professor of Genetics, Genetics Unit
Physiological Sciences II
Faculty of Medicine - Bellvitge Campus
University of Barcelona
Senior Investigator, Molecular Genetics Laboratory IDIBELL
Chief, CIBERER U730
Barcelona, Spain
vnunes@ub.edu

Initial Posting: ; Last Revision: October 13, 2011.

Summary

Disease characteristics. Lysinuric protein intolerance (LPI) typically presents after an infant is weaned; 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 kidneys (progressive glomerular and proximal tubular disease); hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis at the bone marrow aspirate) and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Acute pancreatitis can also be seen.

Diagnosis/testing. Plasma ammonia concentration may be elevated after a protein-rich meal. Plasma concentrations of cationic amino acids (lysine, arginine, and ornithine) are usually below normal for age but may be within the normal range. Plasma concentrations of serine, glycine, citrulline, proline, alanine, and glutamine are increased. Urinary orotic acid excretion is frequently increased. Twenty-four-hour urinary excretion of cationic amino acids, especially lysine, is increased. Plasma concentrations of TBG, LDH, and ferritin are usually elevated. Hypertriglyceridemia and hypercholesterolemia are frequently observed. SLC7A7 is the only gene in which mutations are currently known to cause LPI. Molecular genetic testing identifies two SLC7A7 mutations in more than 95% of individuals with typical biochemical findings of LPI.

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; providing 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: Varicella immunization in those without previous history of chickenpox or varicella zoster; treatment of those exposed as immune-compromised persons.

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.

Agents/circumstances to avoid: Complete restriction of protein for more than 24-48 hours.

Evaluation of relatives at risk: Molecular genetic testing or biochemical testing for early diagnosis and treatment of at-risk sibs.

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 pregnancies at increased risk are possible using molecular genetic techniques if both disease-causing mutations have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

The 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 syndrome

Testing

Biochemical 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 Testing

Gene. 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 Intolerance

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SLC7A7Sequence analysisSequence variants in coding and splice sites including the Finnish founder mutation 295% 3
Targeted mutation analysisFinnish founder mutation c.895-2A>T 4100% for targeted mutation
Deletion / duplication analysis 5Exonic or whole-gene deletions 15%-20% in non-Finnish populations

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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.

Research testing

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.

Clinical Description

Natural History

Usually 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.

Complications

Lung disease. Progressive interstitial changes in the lung are frequently detected from early years without overt clinical symptoms. Progression to severe pulmonary alveolar proteinosis (PAP) is a well-known life-threatening complication.

PAP usually presents with progressive exertional dyspnea, tachypnea, and cough that are exacerbated by respiratory infections. Diminished breath sounds, inspiratory crackles, subcostal and suprasternal retractions, cyanosis and, more rarely, digital clubbing can be found on physical examination.

Diffuse reticulonodular densities are common on radiologic evaluation. Chest high-resolution computed tomography reveals ground-glass opacities with superimposed smooth septal thickening.

The pathogenesis of the PAP in LPI is poorly understood.

Renal involvement. Glomerular and tubular involvement is common. Isolated mild proteinuria is the initial sign of renal disease. Serum creatinine concentration and cystatin C concentration are frequently increased. In a study on 39 Finnish individuals with LSI, proteinuria and hematuria were observed in 74% and 38%, respectively. Elevated blood pressure, mild to moderate renal insufficiency and, in some cases, end-stage renal disease were also reported in this cohort [Tanner et al 2007].

Renal tubular acidosis or findings consistent with reduced phosphate reabsorption and generalized aminoaciduria indicate underlying complex proximal tubular disease (Fanconi syndrome).

Kidney histology reveals immune-mediated glomerulonephritis as well as chronic tubulointerstitial nephritis with glomerulosclerosis in the absence of immune deposits.

The pathogenesis of the renal involvement is unknown.

Hematologic complications and bone marrow anomalies. A clinical presentation resembling hemophagocytic lymphohistiocytosis/macrophagic activation syndrome has been repeatedly observed.

Erythroblastophagocytosis and decreased megakaryocytes may be found in bone marrow aspirate. Hematologic findings also include slight normochromic or hypochromic anemia, leukopenia, thrombocytopenia, and sub-clinical intravascular coagulation.

Hypercholesterolemia and hypertriglyceridemia. Increased plasma concentrations of cholesterol and triglycerides are relatively common in individuals with LPI [Tanner et al 2010]. No clear explanation has been proposed for this dyslipidemic state; a higher-carbohydrate diet may contribute to the increased plasma concentration of triglycerides, but it is not sufficient to explain either the hypercholesterolemia or the severe hypertriglyceridemia (triglycerides >1,000 mg/dL or >11 mmol/L).

Autoimmunity and immunologic abnormalities. Various immunologic abnormalities including impaired function of lymphocytes, the presence of lupus erythematosus (LE) cells, antinuclear and anti-DNA antibodies, hypergammaglobulinemia or low serum immune globulin concentrations, hypocomplementemia, and life-threatening varicella infection can be observed.

Growth, growth hormone (GH) deficiency. Growth retardation is commonly observed in children with LPI and is usually related to protein malnutrition. In some cases, growth hormone deficiency or arginine depletion causing impaired secretion of growth hormone is observed [Esposito et al 2006].

Pancreatitis. Acute pancreatitis is a life-threatening complication in some persons with LPI. A clear relationship with severe hypertriglyceridemia has not been defined.

Pregnancy and childbirth. A Finnish study demonstrated that maternal LPI is associated with increased risk of anemia and toxemia during pregnancy and increased risk of bleeding complications during delivery. Intrauterine growth retardation was noted in a significant number of unaffected neonates born to mothers with LPI [Tanner et al 2006].

Pathophysiology. LPI is an inborn error of metabolism caused by mutation of SLC7A7, the gene encoding the light chain of system y+L. This system mediates the transport of cationic amino acids at the basolateral membrane of enterocytes and renal tubular cells. Most of the clinical findings of LPI may be related to the metabolic abnormality originating from altered absorption and reabsorption of cationic amino acids. In this respect, hyperammonemia is caused by functional impairment of the urea cycle probably resulting from an intracellular deficiency of ornithine in the liver. However, nutritional imbalance of cationic amino acids does not explain the complex multiorgan involvement of LPI, especially the complications affecting lung, kidney, and immune and hematologic systems.

System y+L activity has recently been shown to be markedly reduced in monocytes and alveolar macrophages from an individual with LPI [Barilli et al 2010]. This could explain the pathogenesis of the severe complications of LPI including those affecting lung and kidney. A paradox may occur in LPI: on one hand, mutations of SLC7A7 cause a general depletion of cationic amino acid secondary to defective intestinal uptake and renal reuptake; additionally, in immunocompetent cells the impairment of system y+L activity may cause intracellular arginine accumulation, with a potential risk of surcharging the nitric oxide pathway [Sebastio et al 2011]. A lower dosage of citrulline supplementation is now recommended, given that citrulline is converted into arginine, notably in kidney.

Genotype-Phenotype Correlations

Genotype-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].

Prevalence

Over 140 individuals with LPI have been reported; one third are of Finnish origin [Sperandeo et al 2008, Font-Llitjós et al 2009]. Clusters of affected individuals have also been isolated in Southern Italy and Japan.

The disorder is found worldwide: individuals with LPI originate from at least 25 countries [Cimbalistiene et al 2007, Sperandeo et al 2008, Font-Llitjós et al 2009]. A founder effect for specific alleles underlies the observed occurrence of LPI in Finland (c.895-2A>T) and in Japan (c.1228C>T).Surprisingly, this mutation was also found in a Moroccan individual [Font-Llitjós et al 2009].

The incidence has been estimated at 1:60,000 newborns in Finland and 1:57,000 in Japan [Koizumi et al 2000].

Newborn screening in northern Japan revealed a carrier rate of 1:119 [Koizumi et al 2000].

Differential Diagnosis

The 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations 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 Manifestations

The 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 Crises

Pharmacologic 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 Treatment

Dietary 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 Complications

While 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 Manifestations

The 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 Complications

The 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.

Surveillance

Individuals 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 function
  • Attention to early clinical signs of lung involvement
  • Serum 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 Avoid

Large boluses of protein or amino acids should be avoided.

It is not clear whether prolonged fasting may trigger hyperammonemic crises.

Evaluation of Relatives at Risk

If 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 Investigation

Alendronate. 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.

Other

No treatment, including strict compliance with dietary regimen, citrulline supplementation, or high-dose corticosteroids, is effective in influencing the clinical course of the renal disease.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lysinuric protein intolerance (LPI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with LPI are obligate heterozygotes (carriers) for a disease-causing mutation in SLC7A7.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members using molecular genetic techniques is possible once the mutations have been identified in the family.

Biochemical genetic testing. Biochemical tests (e.g., plasma concentration of amino acids or urinary excretion of orotic acid) cannot distinguish carriers from controls.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Urea Cycle Disorders Foundation
    75 South Grand Avenue
    Pasadena CA 91105
    Phone: 800-386-8233 (toll-free); 626-578-0833
    Fax: 626-578-0823
    Email: info@nucdf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD)

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC7A714q11​.2Y+L amino acid transporter 1Finnish Disease Database (SLC7A7)SLC7A7

Data 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)

222700LYSINURIC PROTEIN INTOLERANCE; LPI
603593SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 7; SLC7A7

Normal 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 Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.726G>A 2p.Trp242XNM_003982​.3
NP_003973​.3
c.895-2A>T 3
(1181-2A>T or 1136-2A>T)
c.1228C>Tp. Arg410X
c.1381_1384dupATCA
(1670insATCA or 1384_1385insATCA)
p.Arg462Asnfs*7

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. 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].

References

Literature Cited

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  2. Borsani G, Bassi MT, Sperandeo MP, De Grandi A, Buoninconti A, Riboni M, Manzoni M, Incerti B, Pepe A, Andria G, Ballabio A, Sebastio G. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat Genet. 1999;21:297–301. [PubMed: 10080183]
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  23. Sperandeo MP, Annunziata P, Ammendola V, Fiorito V, Pepe A, Soldovieri MV, Taglialatela M, Andria G, Sebastio G. Lysinuric protein intolerance: identification and functional analysis of mutations of the SLC7A7 gene. Hum Mutat. 2005;25:410. [PubMed: 15776427]
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  26. Tanner LM, Näntö-Salonen K, Niinikoski H, Jahnukainen T, Keskinen P, Saha H, Kananen K, Helanterä A, Metso M, Linnanvuo M, Huoponen K, Simell O. Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance. J Pediatr. 2007;150:631–4. [PubMed: 17517249]
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Suggested Reading

  1. Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev. 2008;88:249–86. [PubMed: 18195088]
  2. Morris SM Jr. Arginine metabolism: boundaries of our knowledge. J Nutr. 2007;137:1602S–9S. [PubMed: 17513435]
  3. Bröer S, Palacin M. The role of amino acid transporters in inherited and acquired diseases. Biochem J. 2011;436:193–211. [PubMed: 21568940]

Chapter Notes

Acknowledgments

MICINN (SAF 2009-12606-C02-02) and SGR01490 to VN

Author History

Simona Fecarotta, MD; Federico II University (2006-2011)
Virginia Nunes, PhD (2011-present)
Gianfranco Sebastio, MD (2006-present)
Maria Pia Sperandeo, PhD; Federico Il University (2006-2011)

Revision History

  • 13 October 2011 (cd) Revision: targeted mutation analysis for the c.895-2A>T founder mutation available clinically
  • 31 May 2011 (me) Comprehensive update posted live
  • 21 December 2006 (me) Review posted to live Web site
  • 22 September 2006 (gs) Original submission
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