Clinical Guidance

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 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 . The pathogenic variant 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 .

Source: GeneReviews — "Lysinuric Protein Intolerance"

Diagnostic Criteria

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

Source: GeneReviews — "Lysinuric Protein Intolerance"

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. 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.

Source: GeneReviews — "Lysinuric Protein Intolerance"

Management Guidelines

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 radiograph, 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.

Treatment of Acute Hyperammonemic Crises

Pharmacologic management. Blocking of...

Source: GeneReviews — "Lysinuric Protein Intolerance"

Clinical Guidance

Large boluses of protein or amino acids should be avoided. It is not clear whether prolonged fasting may trigger hyperammonemic crises.

Source: GeneReviews — "Lysinuric Protein Intolerance"

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.

Source: GeneReviews — "Lysinuric Protein Intolerance"

Surveillance Guidelines

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.

Source: GeneReviews — "Lysinuric Protein Intolerance"