Lysinuric protein intolerance

Mendelian MONDO:0009109 Pathograph 18 Show in embeddings browser Inborn error of metabolism Inborn disorder of amino acid transport

Lysinuric protein intolerance (LPI) is an autosomal recessive inborn error of metabolism caused by biallelic loss-of-function variants in SLC7A7, which encodes the y+LAT-1 light-chain subunit of the heterodimeric cationic amino acid transporter. Defective transport of the dibasic (cationic) amino acids lysine, arginine, and ornithine at the basolateral membrane of intestinal and renal tubular epithelium causes their urinary loss and systemic deficiency. Depletion of the urea-cycle intermediates arginine and ornithine impairs ammonia detoxification, producing protein-induced postprandial hyperammonemia. Beyond the metabolic phenotype, LPI is a multisystem disease with pulmonary alveolar proteinosis, renal glomerular and tubular disease, hematologic and immune dysregulation resembling hemophagocytic lymphohistiocytosis, growth failure, and osteoporosis.

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1
Mappings
1
Inheritance
8
Pathophys.
16
Phenotypes
18
Pathograph
1
Genes
5
Medical Actions
1
References
🔗

Mappings

MONDO
MONDO:0009109 lysinuric protein intolerance
skos:exactMatch MONDO
MONDO exact match for OMIM:222700 and Orphanet:470.
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:8163273 SUPPORT Human Clinical
"Lysinuric protein intolerance is an autosomal recessive disease caused by defective transport of cationic amino acids."
Directly states autosomal recessive inheritance.
PMID:20301535 SUPPORT Human Clinical
"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."
GeneReviews genetic counseling section provides the autosomal recessive sib recurrence risk.
⚙

Pathophysiology

8
SLC7A7 Loss of Function
Biallelic SLC7A7 pathogenic variants abolish function of y+LAT-1, the catalytic light-chain subunit that, together with the 4F2hc heavy chain, mediates y+L system cationic amino acid transport. This is the initiating molecular lesion in LPI.
SLC7A7 hgnc:11065 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC7A7 (hgnc:11065). hgnc:11065 is a gene from the HUGO Gene Nomenclature Committee.
amino acid transmembrane transporter activity GO:0015171 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased amino acid transmembrane transporter activity (GO:0015171). GO:0015171 is a molecular function from the Gene Ontology. ↓ DECREASED
basolateral plasma membrane GO:0016323 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves basolateral plasma membrane (GO:0016323). GO:0016323 is a cellular component from the Gene Ontology.
Downstream
Defective Cationic Amino Acid Transport Loss of y+LAT-1 abolishes basolateral efflux of cationic amino acids from intestinal and renal epithelium.
Show evidence (2 references)
PMID:17764084 SUPPORT Human Clinical
"LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family."
Establishes the causal SLC7A7/y+LAT-1 molecular defect.
PMID:17764084 SUPPORT Human Clinical
"Coexpression of 4F2hc (the heavy chain subunit) and y(+)LAT-1 induces y(+)L activity (CAA transport)."
Defines the y+LAT-1/4F2hc heterodimer as the functional cationic amino acid transporter.
Defective Cationic Amino Acid Transport
Impaired basolateral transport of the dibasic amino acids lysine, arginine, and ornithine at the intestinal and renal proximal tubular epithelium causes massive urinary loss of cationic amino acids and reduced intestinal absorption, producing systemic depletion despite dibasic aminoaciduria.
amino acid transport GO:0006865 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased amino acid transport (GO:0006865). GO:0006865 is a biological process from the Gene Ontology. ↓ DECREASED
L-lysine transmembrane transporter activity GO:0015189 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased L-lysine transmembrane transporter activity (GO:0015189). GO:0015189 is a molecular function from the Gene Ontology. ↓ DECREASED
kidney epithelium UBERON:0004819 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney epithelium (UBERON:0004819). UBERON:0004819 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Urea Cycle Substrate Deficiency Systemic depletion of arginine and ornithine limits availability of urea-cycle intermediates required for ammonia detoxification.
Alveolar Macrophage Dysfunction and Pulmonary Alveolar Proteinosis y+LAT1-dependent cationic amino acid transport is required in macrophage-lineage cells, linking the transporter defect to alveolar macrophage dysfunction and PAP.
Renal Involvement Defective cationic amino acid transport in renal epithelium causes renal aminoaciduria and is linked to progressive renal disease in LPI.
Hematologic and Immune Dysregulation The systemic LPI transport defect is associated with hematologic cytopenias and HLH-like immune dysregulation.
Skeletal and Growth Involvement Chronic cationic amino acid deficiency and metabolic disease contribute to poor growth and osteoporosis.
Show evidence (1 reference)
PMID:17764084 SUPPORT Human Clinical
"Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney."
Localizes the transport defect to the basolateral membrane of intestinal and renal epithelium.
Urea Cycle Substrate Deficiency
Depletion of the urea-cycle intermediates arginine and ornithine impairs hepatic ammonia detoxification, functionally producing a urea-cycle defect that manifests as protein-triggered hyperammonemia.
urea cycle GO:0000050 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased urea cycle (GO:0000050). GO:0000050 is a biological process from the Gene Ontology. ↓ DECREASED
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Postprandial Hyperammonemic Decompensation Protein loading overwhelms the impaired urea cycle, precipitating acute hyperammonemia with stupor and coma.
Show evidence (1 reference)
PMID:31653080 SUPPORT Model Organism
"LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication."
Confirms hyperammonemia as a core feature of the LPI phenotype in the recapitulating model.
Postprandial Hyperammonemic Decompensation
Ingestion of protein in the setting of urea-cycle substrate deficiency causes acute hyperammonemia, the intoxication-type metabolic decompensation shared with the urea-cycle disorders, presenting with vomiting, stupor, and coma.
Downstream
Hyperammonemia Acute decompensation produces frank hyperammonemia.
Coma Severe hyperammonemia after protein intake can progress to stupor and coma.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"In acute hyperammonemic crises: intravenous administration of arginine chloride and nitrogen-scavenger drugs"
Acute hyperammonemic crises are managed as urea-cycle metabolic decompensations.
Alveolar Macrophage Dysfunction and Pulmonary Alveolar Proteinosis
LPI is complicated by pulmonary alveolar proteinosis (PAP), attributed to disturbed function and activity of alveolar macrophages that fail to clear surfactant, leading to intraalveolar phospholipid-proteinaceous accumulation and progressive respiratory insufficiency.
alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves abnormal alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology. ⚠ ABNORMAL
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pulmonary alveolar proteinosis Alveolar macrophage dysfunction leads to intraalveolar phospholipid-proteinaceous accumulation.
Show evidence (2 references)
PMID:27783330 SUPPORT Human Clinical
"In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group."
Attributes LPI-associated PAP to alveolar macrophage dysfunction.
PMID:8163273 SUPPORT Human Clinical
"We conclude that pediatric patients with lysinuric protein intolerance are predisposed to develop pulmonary alveolar proteinosis and glomerulonephritis."
Autopsy series documents PAP as a characteristic pulmonary complication.
Renal Involvement
Progressive glomerular and proximal tubular disease, including immune complex-mediated glomerulonephritis, is a recognized renal complication of LPI that can progress to chronic kidney disease.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Chronic kidney disease Progressive glomerular and tubular disease can advance to chronic kidney disease.
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis."
Autopsy series documents renal insufficiency and immune-complex glomerulonephritis.
Hematologic and Immune Dysregulation
LPI is associated with normochromic or hypochromic anemia, leukopenia, and thrombocytopenia, with erythroblastophagocytosis and a presentation resembling hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
Downstream
Anemia Hematologic dysregulation produces normochromic or hypochromic anemia.
Thrombocytopenia Hematologic dysregulation produces thrombocytopenia with bleeding tendency.
Leukopenia Hematologic dysregulation includes decreased leukocyte counts.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"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"
GeneReviews documents the hematologic and HLH-like immune features.
Skeletal and Growth Involvement
Chronic amino acid deficiency and metabolic disease contribute to failure to thrive, poor growth, and osteoporosis.
Downstream
Osteoporosis Chronic metabolic disease contributes to reduced bone mineral density.
Growth delay Chronic metabolic disease and amino acid deficiency contribute to poor growth.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"failure to thrive, hepatosplenomegaly, and muscular hypotonia"
GeneReviews documents failure to thrive as a presenting feature.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Lysinuric protein intolerance Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Blood 3
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
Anemia documented in the autopsy series.
Leukopenia Decreased total leukocyte count HP:0001882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukopenia, annotated with Decreased total leukocyte count (HP:0001882). HP:0001882 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"hematologic abnormalities (normochromic or hypochromic anemia, leukopenia"
GeneReviews lists leukopenia among the hematologic abnormalities in LPI.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
Thrombocytopenia documented in the autopsy series.
Cardiovascular 1
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"failure to thrive, hepatosplenomegaly, and muscular hypotonia"
Hepatosplenomegaly is a recognized feature.
Digestive 2
Protein aversion and recurrent vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013), qualified as temporality recurrent. HP:0002013 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"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"
Recurrent vomiting and protein aversion are typical presenting features.
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014), qualified as temporality recurrent. HP:0002014 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"recurrent vomiting and episodes of diarrhea"
GeneReviews lists recurrent diarrhea among typical presenting findings.
Genitourinary 1
Chronic kidney disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622), qualified as course progressive. HP:0012622 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis."
Renal insufficiency and glomerulonephritis documented at autopsy.
Metabolism 3
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987), qualified as temporality recurrent. HP:0001987 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:31653080 SUPPORT Model Organism
"LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication."
Hyperammonemia is a defining metabolic feature of LPI.
Hypercholesterolemia HP:0003124 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercholesterolemia (HP:0003124). HP:0003124 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen."
GeneReviews lists hypercholesterolemia among additional LPI findings.
Hypertriglyceridemia HP:0002155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertriglyceridemia (HP:0002155). HP:0002155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen."
GeneReviews lists hypertriglyceridemia among additional LPI findings.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular hypotonia, annotated with Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"failure to thrive, hepatosplenomegaly, and muscular hypotonia"
Muscular hypotonia is a recognized feature.
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"Bone specimens showed osteoporosis."
Osteoporosis documented at autopsy.
Nervous System 1
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259), qualified as temporality acute. HP:0001259 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"episodes of stupor and coma after a protein-rich meal"
Protein-triggered hyperammonemic decompensation can progress to stupor and coma.
Growth 2
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"poor feeding, aversion to protein-rich food, failure to thrive"
Failure to thrive is a typical presenting feature.
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"Over time, findings include: poor growth"
GeneReviews documents poor growth as a later LPI feature.
Other 1
Pulmonary alveolar proteinosis Intraalveolar phospholipid accumulation HP:0006517 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary alveolar proteinosis, annotated with Intraalveolar phospholipid accumulation (HP:0006517), qualified as course progressive. HP:0006517 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:8163273 SUPPORT Human Clinical
"In addition to pulmonary hemorrhages, three of the patients had pulmonary alveolar proteinosis and one had cholesterol granulomas."
Autopsy documentation of PAP in LPI patients.
🧬

Genetic Associations

1
SLC7A7
Gene: SLC7A7 hgnc:11065 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC7A7 (hgnc:11065). hgnc:11065 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:17764084 SUPPORT Human Clinical
"LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family."
Identifies SLC7A7 as the causal gene encoding the y+LAT-1 transporter subunit.
💊

Medical Actions

5
Dietary protein restriction
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Long-term restriction of dietary protein to limit nitrogen load and prevent hyperammonemic decompensation.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"Long-term: dietary protein restriction; oral supplementation with citrulline and nitrogen-scavenger drugs, L-lysine-HCl, and carnitine"
Dietary protein restriction is the mainstay of long-term management.
Citrulline supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: L-citrulline CHEBI:16349 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-citrulline (CHEBI:16349). CHEBI:16349 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral L-citrulline replenishes urea-cycle intermediates (regenerating arginine and ornithine) to support ammonia detoxification without a cationic amino acid transport requirement.
Show evidence (1 reference)
PMID:31653080 SUPPORT Model Organism
"Hyperammonemia is currently prevented by citrulline supplementation."
Citrulline supplementation prevents hyperammonemia in LPI.
Nitrogen-scavenger therapy for acute hyperammonemia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Acute hyperammonemic crises are managed with intravenous arginine chloride and nitrogen-scavenger drugs (sodium benzoate, sodium phenylacetate) with reduction of nitrogen intake and carbohydrate-based energy provision.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"In acute hyperammonemic crises: intravenous administration of arginine chloride and nitrogen-scavenger drugs (sodium benzoate, sodium phenylacetate) to block ammonia production"
Nitrogen scavengers plus arginine are used for acute hyperammonemic crises.
Whole-lung lavage for pulmonary alveolar proteinosis
Action: therapeutic procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is therapeutic procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Whole-lung lavage removes accumulated intraalveolar material to improve respiratory function in patients with LPI-associated pulmonary alveolar proteinosis.
Show evidence (1 reference)
PMID:20301535 SUPPORT Human Clinical
"whole-lung lavage to improve respiratory function in persons with pulmonary alveolar proteinosis"
Whole-lung lavage is used for LPI-associated PAP.
Inhaled GM-CSF (sargramostim) for pulmonary alveolar proteinosis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Inhaled recombinant human GM-CSF (sargramostim) can induce resolution of LPI-associated PAP by augmenting alveolar macrophage number and activity.
Show evidence (1 reference)
PMID:27783330 SUPPORT Human Clinical
"In conclusion, inhaled rhuGM-CSF might be of benefit in patients with LPI-associated PAP."
Inhaled GM-CSF is an emerging therapy for LPI-associated PAP.
📈

Progression

1
Infantile-onset multisystem metabolic disease
Age: Typically after weaning through adulthood
LPI typically becomes symptomatic after an infant is weaned from breast milk or formula onto higher-protein foods, with recurrent vomiting, protein aversion, failure to thrive, and hyperammonemic episodes; multisystem pulmonary, renal, hematologic, and skeletal complications accrue over time. Clinical presentation is highly variable with no established genotype-phenotype correlation.
Show evidence (2 references)
PMID:20301535 SUPPORT Human Clinical
"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..."
GeneReviews summarizes the typical age of onset and presenting features.
PMID:17764084 SUPPORT Human Clinical
"LPI patients show extreme variability in clinical presentation, and no genotype-phenotype correlations have been defined."
Documents the variable course and lack of genotype-phenotype correlation.
📊

Prevalence

1
Finland
Birth Prevalence 1.4 per 100,000 1–9 per 100,000
LPI is enriched in the Finnish population due to a founder splice variant (c.895-2A>T); the classic Finnish birth incidence is approximately 1 in 60,000.
Show evidence (1 reference)
PMID:17764084 SUPPORT Human Clinical
"A genuine founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895-2A>T."
The founder mutation underlies the elevated Finnish disease frequency.
{ }

Source YAML

click to show 
name: Lysinuric protein intolerance
creation_date: "2026-07-07T16:30:00Z"
category: Mendelian
synonyms:
- LPI
- Hyperdibasic aminoaciduria type 2
- Cationic aminoaciduria
- y+LAT-1 deficiency
- SLC7A7 deficiency
description: >-
  Lysinuric protein intolerance (LPI) is an autosomal recessive inborn error of
  metabolism caused by biallelic loss-of-function variants in SLC7A7, which
  encodes the y+LAT-1 light-chain subunit of the heterodimeric cationic amino
  acid transporter. Defective transport of the dibasic (cationic) amino acids
  lysine, arginine, and ornithine at the basolateral membrane of intestinal and
  renal tubular epithelium causes their urinary loss and systemic deficiency.
  Depletion of the urea-cycle intermediates arginine and ornithine impairs
  ammonia detoxification, producing protein-induced postprandial hyperammonemia.
  Beyond the metabolic phenotype, LPI is a multisystem disease with pulmonary
  alveolar proteinosis, renal glomerular and tubular disease, hematologic and
  immune dysregulation resembling hemophagocytic lymphohistiocytosis, growth
  failure, and osteoporosis.
disease_term:
  preferred_term: lysinuric protein intolerance
  term:
    id: MONDO:0009109
    label: lysinuric protein intolerance
parents:
- Inborn error of metabolism
- Inborn disorder of amino acid transport
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009109
      label: lysinuric protein intolerance
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO exact match for OMIM:222700 and Orphanet:470.
references:
- reference: PMID:20301535
  title: "Lysinuric Protein Intolerance."
  tags:
  - GeneReviews
prevalence:
- population: Finland
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.4
  notes: >-
    LPI is enriched in the Finnish population due to a founder splice variant
    (c.895-2A>T); the classic Finnish birth incidence is approximately 1 in
    60,000.
  evidence:
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genuine founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895-2A>T."
    explanation: The founder mutation underlies the elevated Finnish disease frequency.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysinuric protein intolerance is an autosomal recessive disease caused by defective transport of cationic amino acids."
    explanation: Directly states autosomal recessive inheritance.
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At \nconception, each sib of an affected individual has a 25% chance of being \naffected, a 50% chance of being an asymptomatic carrier, and a 25% chance of \nbeing unaffected and not a carrier."
    explanation: GeneReviews genetic counseling section provides the autosomal recessive sib recurrence risk.
genetic:
- name: SLC7A7
  gene_term:
    preferred_term: SLC7A7
    term:
      id: hgnc:11065
      label: SLC7A7
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family."
    explanation: Identifies SLC7A7 as the causal gene encoding the y+LAT-1 transporter subunit.
progression:
- phase: Infantile-onset multisystem metabolic disease
  age_range: Typically after weaning through adulthood
  notes: >-
    LPI typically becomes symptomatic after an infant is weaned from breast milk
    or formula onto higher-protein foods, with recurrent vomiting, protein
    aversion, failure to thrive, and hyperammonemic episodes; multisystem
    pulmonary, renal, hematologic, and skeletal complications accrue over time.
    Clinical presentation is highly variable with no established
    genotype-phenotype correlation.
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews summarizes the typical age of onset and presenting features.
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPI patients show extreme variability in clinical presentation, and no genotype-phenotype correlations have been defined."
    explanation: Documents the variable course and lack of genotype-phenotype correlation.
pathophysiology:
- name: SLC7A7 Loss of Function
  description: >-
    Biallelic SLC7A7 pathogenic variants abolish function of y+LAT-1, the
    catalytic light-chain subunit that, together with the 4F2hc heavy chain,
    mediates y+L system cationic amino acid transport. This is the initiating
    molecular lesion in LPI.
  genes:
  - preferred_term: SLC7A7
    term:
      id: hgnc:11065
      label: SLC7A7
  molecular_functions:
  - preferred_term: amino acid transmembrane transporter activity
    term:
      id: GO:0015171
      label: amino acid transmembrane transporter activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: basolateral plasma membrane
    term:
      id: GO:0016323
      label: basolateral plasma membrane
  evidence:
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family."
    explanation: Establishes the causal SLC7A7/y+LAT-1 molecular defect.
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coexpression of 4F2hc (the heavy chain subunit) and y(+)LAT-1 induces y(+)L activity (CAA transport)."
    explanation: Defines the y+LAT-1/4F2hc heterodimer as the functional cationic amino acid transporter.
  downstream:
  - target: Defective Cationic Amino Acid Transport
    description: Loss of y+LAT-1 abolishes basolateral efflux of cationic amino acids from intestinal and renal epithelium.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31653080
      reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter."
      explanation: An inducible Slc7a7 knockout mouse links loss of the transporter to defective cationic amino acid transport recapitulating LPI.
- name: Defective Cationic Amino Acid Transport
  description: >-
    Impaired basolateral transport of the dibasic amino acids lysine, arginine,
    and ornithine at the intestinal and renal proximal tubular epithelium causes
    massive urinary loss of cationic amino acids and reduced intestinal
    absorption, producing systemic depletion despite dibasic aminoaciduria.
  biological_processes:
  - preferred_term: amino acid transport
    term:
      id: GO:0006865
      label: amino acid transport
    modifier: DECREASED
  molecular_functions:
  - preferred_term: L-lysine transmembrane transporter activity
    term:
      id: GO:0015189
      label: L-lysine transmembrane transporter activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-lysine
    term:
      id: CHEBI:18019
      label: L-lysine
    modifier: DECREASED
  - preferred_term: L-arginine
    term:
      id: CHEBI:16467
      label: L-arginine
    modifier: DECREASED
  - preferred_term: ornithine
    term:
      id: CHEBI:18257
      label: ornithine
    modifier: DECREASED
  locations:
  - preferred_term: kidney epithelium
    term:
      id: UBERON:0004819
      label: kidney epithelium
  evidence:
  - reference: PMID:17764084
    reference_title: "Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney."
    explanation: Localizes the transport defect to the basolateral membrane of intestinal and renal epithelium.
  downstream:
  - target: Urea Cycle Substrate Deficiency
    description: Systemic depletion of arginine and ornithine limits availability of urea-cycle intermediates required for ammonia detoxification.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: Urinary loss of cationic amino acids (including the urea-cycle intermediates) underlies the substrate deficiency.
  - target: Alveolar Macrophage Dysfunction and Pulmonary Alveolar Proteinosis
    description: y+LAT1-dependent cationic amino acid transport is required in macrophage-lineage cells, linking the transporter defect to alveolar macrophage dysfunction and PAP.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - y+LAT1-dependent arginine transport in macrophages and monocytes.
    - Impaired alveolar macrophage surfactant clearance.
    evidence:
    - reference: PMID:31653080
      reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The y+LAT1-CD98 heterodimer also mediates arginine transport in non-polarized cells, such as macrophages and monocytes, and is essential for the correct function of these cells"
      explanation: Mouse-model paper links y+LAT1 to macrophage/monocyte function, providing the upstream connection to PAP.
  - target: Renal Involvement
    description: Defective cationic amino acid transport in renal epithelium causes renal aminoaciduria and is linked to progressive renal disease in LPI.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Renal tubular cationic amino acid reabsorption defect.
    - Progressive glomerular and proximal tubular disease.
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "involvement of the lungs (progressive interstitial \nchanges, pulmonary alveolar proteinosis) and of the kidneys (progressive \nglomerular and proximal tubular disease)"
      explanation: GeneReviews ties renal glomerular and proximal tubular disease to the LPI clinical syndrome.
  - target: Hematologic and Immune Dysregulation
    description: The systemic LPI transport defect is associated with hematologic cytopenias and HLH-like immune dysregulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hematologic abnormalities \n(normochromic or hypochromic anemia, leukopenia, thrombocytopenia, \nerythroblastophagocytosis in the bone marrow aspirate), and a clinical \npresentation resembling the hemophagocytic lymphohistiocytosis/macrophagic \nactivation syndrome."
      explanation: GeneReviews documents hematologic and immune dysregulation as part of LPI.
  - target: Skeletal and Growth Involvement
    description: Chronic cationic amino acid deficiency and metabolic disease contribute to poor growth and osteoporosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic lysine, arginine, and ornithine deficiency.
    - Protein aversion and restricted protein tolerance.
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Over time, findings include: \npoor growth, osteoporosis"
      explanation: GeneReviews documents poor growth and osteoporosis as later LPI findings.
- name: Urea Cycle Substrate Deficiency
  description: >-
    Depletion of the urea-cycle intermediates arginine and ornithine impairs
    hepatic ammonia detoxification, functionally producing a urea-cycle defect
    that manifests as protein-triggered hyperammonemia.
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
    modifier: DECREASED
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:31653080
    reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication."
    explanation: Confirms hyperammonemia as a core feature of the LPI phenotype in the recapitulating model.
  downstream:
  - target: Postprandial Hyperammonemic Decompensation
    description: Protein loading overwhelms the impaired urea cycle, precipitating acute hyperammonemia with stupor and coma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "episodes of stupor and coma after a protein-rich meal"
      explanation: Protein-triggered hyperammonemic decompensation is the hallmark metabolic crisis of LPI.
- name: Postprandial Hyperammonemic Decompensation
  description: >-
    Ingestion of protein in the setting of urea-cycle substrate deficiency
    causes acute hyperammonemia, the intoxication-type metabolic decompensation
    shared with the urea-cycle disorders, presenting with vomiting, stupor, and
    coma.
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In acute hyperammonemic crises: intravenous administration of arginine chloride and nitrogen-scavenger drugs"
    explanation: Acute hyperammonemic crises are managed as urea-cycle metabolic decompensations.
  downstream:
  - target: Hyperammonemia
    description: Acute decompensation produces frank hyperammonemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31653080
      reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hyperammonemia is currently prevented by citrulline supplementation."
      explanation: Establishes hyperammonemia as the treated metabolic endpoint.
  - target: Coma
    description: Severe hyperammonemia after protein intake can progress to stupor and coma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Ammonia neurotoxicity during acute decompensation.
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "episodes of stupor and coma after a protein-rich meal"
      explanation: Links protein-triggered decompensation to encephalopathic coma.
- name: Alveolar Macrophage Dysfunction and Pulmonary Alveolar Proteinosis
  description: >-
    LPI is complicated by pulmonary alveolar proteinosis (PAP), attributed to
    disturbed function and activity of alveolar macrophages that fail to clear
    surfactant, leading to intraalveolar phospholipid-proteinaceous accumulation
    and progressive respiratory insufficiency.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
    modifier: ABNORMAL
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:27783330
    reference_title: "Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group."
    explanation: Attributes LPI-associated PAP to alveolar macrophage dysfunction.
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that pediatric patients with lysinuric protein intolerance are predisposed to develop pulmonary alveolar proteinosis and glomerulonephritis."
    explanation: Autopsy series documents PAP as a characteristic pulmonary complication.
  downstream:
  - target: Pulmonary alveolar proteinosis
    description: Alveolar macrophage dysfunction leads to intraalveolar phospholipid-proteinaceous accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8163273
      reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition to pulmonary hemorrhages, three of the patients had pulmonary alveolar proteinosis and one had cholesterol granulomas."
      explanation: Autopsy documentation of PAP in LPI patients.
- name: Renal Involvement
  description: >-
    Progressive glomerular and proximal tubular disease, including immune
    complex-mediated glomerulonephritis, is a recognized renal complication of
    LPI that can progress to chronic kidney disease.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis."
    explanation: Autopsy series documents renal insufficiency and immune-complex glomerulonephritis.
  downstream:
  - target: Chronic kidney disease
    description: Progressive glomerular and tubular disease can advance to chronic kidney disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Immune complex-mediated glomerulonephritis and proximal tubular disease.
    evidence:
    - reference: PMID:8163273
      reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis."
      explanation: Renal insufficiency progressing from glomerulonephritis.
- name: Hematologic and Immune Dysregulation
  description: >-
    LPI is associated with normochromic or hypochromic anemia, leukopenia, and
    thrombocytopenia, with erythroblastophagocytosis and a presentation
    resembling hemophagocytic lymphohistiocytosis/macrophage activation
    syndrome.
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: GeneReviews documents the hematologic and HLH-like immune features.
  downstream:
  - target: Anemia
    description: Hematologic dysregulation produces normochromic or hypochromic anemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8163273
      reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
      explanation: Autopsy series documents anemia and thrombocytopenia.
  - target: Thrombocytopenia
    description: Hematologic dysregulation produces thrombocytopenia with bleeding tendency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8163273
      reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
      explanation: Autopsy series documents thrombocytopenia.
  - target: Leukopenia
    description: Hematologic dysregulation includes decreased leukocyte counts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hematologic abnormalities \n(normochromic or hypochromic anemia, leukopenia, thrombocytopenia"
      explanation: GeneReviews explicitly includes leukopenia among LPI hematologic abnormalities.
- name: Skeletal and Growth Involvement
  description: >-
    Chronic amino acid deficiency and metabolic disease contribute to failure to
    thrive, poor growth, and osteoporosis.
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, hepatosplenomegaly, and muscular hypotonia"
    explanation: GeneReviews documents failure to thrive as a presenting feature.
  downstream:
  - target: Osteoporosis
    description: Chronic metabolic disease contributes to reduced bone mineral density.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:8163273
      reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bone specimens showed osteoporosis."
      explanation: Osteoporosis documented at autopsy.
  - target: Growth delay
    description: Chronic metabolic disease and amino acid deficiency contribute to poor growth.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic amino acid deficiency.
    - Protein aversion and restricted protein tolerance.
    evidence:
    - reference: PMID:20301535
      reference_title: "Lysinuric Protein Intolerance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Over time, findings include: \npoor growth"
      explanation: GeneReviews documents poor growth as a later LPI finding.
phenotypes:
- name: Hyperammonemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
    temporality: RECURRENT
  evidence:
  - reference: PMID:31653080
    reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication."
    explanation: Hyperammonemia is a defining metabolic feature of LPI.
- name: Protein aversion and recurrent vomiting
  category: Gastrointestinal
  description: Aversion to protein-rich food with recurrent vomiting after protein intake.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: Recurrent vomiting and protein aversion are typical presenting features.
- name: Diarrhea
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: RECURRENT
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent vomiting and episodes of diarrhea"
    explanation: GeneReviews lists recurrent diarrhea among typical presenting findings.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, hepatosplenomegaly, and muscular hypotonia"
    explanation: Hepatosplenomegaly is a recognized feature.
- name: Hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, hepatosplenomegaly, and muscular hypotonia"
    explanation: Muscular hypotonia is a recognized feature.
- name: Pulmonary alveolar proteinosis
  category: Respiratory
  phenotype_term:
    preferred_term: Pulmonary alveolar proteinosis
    term:
      id: HP:0006517
      label: Intraalveolar phospholipid accumulation
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to pulmonary hemorrhages, three of the patients had pulmonary alveolar proteinosis and one had cholesterol granulomas."
    explanation: Autopsy documentation of PAP in LPI patients.
- name: Coma
  category: Neurologic
  description: Stupor and coma during acute hyperammonemic decompensation after protein intake.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
    temporality: ACUTE
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "episodes of stupor and coma after a protein-rich meal"
    explanation: Protein-triggered hyperammonemic decompensation can progress to stupor and coma.
- name: Chronic kidney disease
  category: Renal
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis."
    explanation: Renal insufficiency and glomerulonephritis documented at autopsy.
- name: Anemia
  category: Hematologic
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
    explanation: Anemia documented in the autopsy series.
- name: Leukopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hematologic abnormalities \n(normochromic or hypochromic anemia, leukopenia"
    explanation: GeneReviews lists leukopenia among the hematologic abnormalities in LPI.
- name: Thrombocytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed anemia, thrombocytopenia, and a severe bleeding tendency."
    explanation: Thrombocytopenia documented in the autopsy series.
- name: Osteoporosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:8163273
    reference_title: "Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone specimens showed osteoporosis."
    explanation: Osteoporosis documented at autopsy.
- name: Failure to thrive
  category: Constitutional
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor feeding, aversion to protein-rich food, failure to thrive"
    explanation: Failure to thrive is a typical presenting feature.
- name: Growth delay
  category: Constitutional
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over time, findings include: \npoor growth"
    explanation: GeneReviews documents poor growth as a later LPI feature.
- name: Hypercholesterolemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypercholesterolemia, hypertriglyceridemia, and acute \npancreatitis can also be seen."
    explanation: GeneReviews lists hypercholesterolemia among additional LPI findings.
- name: Hypertriglyceridemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypercholesterolemia, hypertriglyceridemia, and acute \npancreatitis can also be seen."
    explanation: GeneReviews lists hypertriglyceridemia among additional LPI findings.
treatments:
- name: Dietary protein restriction
  description: >-
    Long-term restriction of dietary protein to limit nitrogen load and prevent
    hyperammonemic decompensation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term: dietary protein restriction; oral supplementation with citrulline and nitrogen-scavenger drugs, L-lysine-HCl, and carnitine"
    explanation: Dietary protein restriction is the mainstay of long-term management.
- name: Citrulline supplementation
  description: >-
    Oral L-citrulline replenishes urea-cycle intermediates (regenerating
    arginine and ornithine) to support ammonia detoxification without a cationic
    amino acid transport requirement.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-citrulline
      term:
        id: CHEBI:16349
        label: L-citrulline
  evidence:
  - reference: PMID:31653080
    reference_title: "Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hyperammonemia is currently prevented by citrulline supplementation."
    explanation: Citrulline supplementation prevents hyperammonemia in LPI.
- name: Nitrogen-scavenger therapy for acute hyperammonemia
  description: >-
    Acute hyperammonemic crises are managed with intravenous arginine chloride
    and nitrogen-scavenger drugs (sodium benzoate, sodium phenylacetate) with
    reduction of nitrogen intake and carbohydrate-based energy provision.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In acute hyperammonemic crises: intravenous administration of arginine chloride and nitrogen-scavenger drugs (sodium benzoate, sodium phenylacetate) to block ammonia production"
    explanation: Nitrogen scavengers plus arginine are used for acute hyperammonemic crises.
- name: Whole-lung lavage for pulmonary alveolar proteinosis
  description: >-
    Whole-lung lavage removes accumulated intraalveolar material to improve
    respiratory function in patients with LPI-associated pulmonary alveolar
    proteinosis.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:20301535
    reference_title: "Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whole-lung lavage to improve respiratory function in persons with pulmonary alveolar proteinosis"
    explanation: Whole-lung lavage is used for LPI-associated PAP.
- name: Inhaled GM-CSF (sargramostim) for pulmonary alveolar proteinosis
  description: >-
    Inhaled recombinant human GM-CSF (sargramostim) can induce resolution of
    LPI-associated PAP by augmenting alveolar macrophage number and activity.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:27783330
    reference_title: "Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, inhaled rhuGM-CSF might be of benefit in patients with LPI-associated PAP."
    explanation: Inhaled GM-CSF is an emerging therapy for LPI-associated PAP.
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References & Deep Research

References

1
PMID:20301535
Lysinuric Protein Intolerance.
No top-level findings curated for this source.