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.

Suggestive Findings

Lysinuric protein intolerance (LPI) should be suspected in an infant who presents after weaning from breast milk or formula with the following features.

Early clinical features

• 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

Later clinical features. In some individuals, the diagnosis is established in adulthood. Over time, additional clinical features appear:

• Poor growth
• Early (often severe) osteoporosis
• Subclinical or overt pulmonary involvement
• Renal involvement
• Hemophagocytic lymphohistiocytosis/macrophagic activation syndrome

Biochemical laboratory features

• Elevated plasma ammonia after a protein-rich meal. Fasting values are usually normal.
• Increased urinary orotic acid*
• 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. 24-hour urinary excretion of cationic amino acids, especially lysine, is 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.

**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 were reported in Simell [2001]. (4) Serine, glycine, citrulline, proline, alanine, and glutamine are found in excess in urine but have normal renal clearances.

Other laboratory features

• Plasma concentrations of LDH, ferritin, and zinc are usually elevated.
• Normochromic or hypochromic anemia, leukopenia, and thrombocytopenia are nonspecific hematologic findings.
• Hypertriglyceridemia and hypercholesterolemia are frequently observed.

Establishing the Diagnosis

The diagnosis of LPI is established in a proband with the above clinical and laboratory features. Identification of biallelic pathogenic variants in SLC7A7 by molecular genetic testing confirms the diagnosis (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of LPI has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

Intellectual development is usually 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, occurring as early as childhood in many individuals with LPI [Valimahamed-Mitha et al 2015, Mauhin et al 2017]. Pulmonary fibrosis may develop independently from PAP.

PAP usually presents with progressive exertional dyspnea, tachypnea, and cough that are exacerbated by respiratory infections and complicated by viral or bacterial pneumonia. 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, but may be associated with intracellular nitric oxide accumulation [Mauhin et al 2017].

Renal involvement. Glomerular and tubular involvement is common. Isolated mild proteinuria is the initial sign of renal disease leading to proximal tubular dysfunction and nephrocalcinosis [Estève et al 2017, Mauhin et al 2017]. Serum creatinine concentration and cystatin C concentration are frequently increased. In a study on 39 Finnish individuals with LPI, 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]. Urine beta2-microglobulin may serve as an early marker of renal involvement in LPI [Kärki et al 2016].

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 [Estève et al 2017].

The pathogenesis of the renal involvement is unknown but may be associated with nitric oxide overproduction [Nicolas et al 2016].

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 subclinical 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 cells, antinuclear and anti-DNA antibodies, hypergammaglobulinemia or low serum immune globulin concentrations, hypocomplementemia, and life-threatening varicella and bacterial infections can be observed.

Growth, growth hormone 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. Growth hormone has been used in several individuals with good response [Niinikoski et al 2011].

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 pathogenic variants in 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 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, pathogenic variants in 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 variant.

In a large Italian pedigree, homozygosity for 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]. The pathogenic variant c.726G>A 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].

In 35 individuals with LPI of Japanese ancestry, no correlation between genotype and phenotype was observed [Noguchi et al 2016].

Nomenclature

Lysinuric protein intolerance has also been referred to as cationic aminoaciduria.

Prevalence

More than 200 individuals with LPI have been reported; one third are of Finnish origin [Sperandeo et al 2008, Font-Llitjós et al 2009, Carpentieri et al 2015]. Isolated clusters of affected individuals have also been identified in southern Italy and Japan.

The disorder is found worldwide: individuals with LPI originate from at least 25 countries [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, the variant c.1228C>T was also found in a Moroccan individual [Font-Llitjós et al 2009].

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

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with lysinuric protein intolerance, the following evaluations are recommended if they have not already been completed:

• 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 pulmonary 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
• Consultation with a biochemical geneticist and/or genetic counselor

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.

Prevention of Primary Manifestations

The prevention of metabolic abnormality is the goal of 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 (e.g., lung and renal involvement) appear to be poorly responsive to early treatment.

Efforts to minimize the risk of respiratory infections should be promoted. Vaccination against influenza (and possibly pneumococci) is recommended.

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

It is appropriate to evaluate at-risk sibs of a proband in order to reduce morbidity and mortality through early diagnosis and treatment:

• If the pathogenic variants in the family are known, molecular genetic testing of at-risk sibs should be performed. Plasma and urine amino acid and urinary orotic acid analyses are recommended in individuals with suspected LPI while awaiting molecular genetic results.
• If the pathogenic variants in the family are not known, early diagnosis of at-risk sibs relies on detailed 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.

Pregnancy Management

Pregnancy management should be performed in a center familiar with metabolic diseases. Frequent plasma amino acid and ammonia measurements are recommended as well as overall well-being of the mother and fetus. Most infants with LPI are born prematurely (between gestational weeks 31 and 39) [Tanner et al 2006]. Pregnant women with LPI are at risk of toxemia and bleeding complications during and after delivery.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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.

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 (i.e., carriers of one SLC7A7 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with LPI are obligate heterozygotes (carriers) for a pathogenic variant in SLC7A7.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC7A7 pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the SLC7A7 pathogenic variants in the family.

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the SLC7A7 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Biochemical testing cannot currently be used to distinguish between affected and unaffected fetuses.

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Acknowledgments

Spanish Health Institute Carlos III Grants: FIS PI13/00121-R-FEDER and PI16/00267-R-FEDER (to V.N.), Generalitat de Catalunya Grants SGR2009-1490 (to V.N.)

Author History

Simona Fecarotta, MD; Federico II University (2006-2011)
Harri Niinikoski, MD, PhD (2018-present)
Virginia Nunes, PhD (2011-present)
Gianfranco Sebastio, MD; Federico Il University (2006-2018)
Maria Pia Sperandeo, PhD; Federico Il University (2006-2011)

Revision History

• 12 April 2018 (sw) Comprehensive update posted live
• 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 live
• 22 September 2006 (gs) Original submission