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Lysinuric protein intolerance(LPI)

MedGen UID:
75704
Concept ID:
C0268647
Disease or Syndrome
Synonyms: Dibasicamino aciduria II; LPI
SNOMED CT: Lysinuric protein intolerance (303852004); Hyperdibasic aminoaciduria (303852004); LPI - Lysinuric protein intolerance (303852004); Congenital lysinuria (303852004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SLC7A7 (14q11.2)
 
Monarch Initiative: MONDO:0009109
OMIM®: 222700
Orphanet: ORPHA470

Disease characteristics

Excerpted from the GeneReview: Lysinuric Protein Intolerance
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. [from GeneReviews]
Authors:
Virginia Nunes  |  Harri Niinikoski   view full author information

Additional descriptions

From OMIM
Lysinuric protein intolerance is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine, and orotic aciduria (Borsani et al., 1999). See also dibasic amino aciduria I (222690).  http://www.omim.org/entry/222700
From MedlinePlus Genetics
Lysinuric protein intolerance is a disorder caused by the body's inability to digest and use certain protein building blocks (amino acids), namely lysine, arginine, and ornithine. Because the body cannot effectively break down these amino acids, which are found in many protein-rich foods, nausea and vomiting are typically experienced after ingesting protein.\n\nPeople with lysinuric protein intolerance have features associated with protein intolerance, including an enlarged liver and spleen (hepatosplenomegaly), short stature, muscle weakness, impaired immune function, and progressively brittle bones that are prone to fracture (osteoporosis). A lung disorder called pulmonary alveolar proteinosis may also develop. This disorder is characterized by protein deposits in the lungs, which interfere with lung function and can be life-threatening. An accumulation of amino acids in the kidneys can cause end-stage renal disease (ESRD) in which the kidneys become unable to filter fluids and waste products from the body effectively. A lack of certain amino acids can cause elevated levels of ammonia in the blood. If ammonia levels are too high for too long, they can cause coma and intellectual disability.\n\nThe signs and symptoms of lysinuric protein intolerance typically appear after infants are weaned and receive greater amounts of protein from solid foods.  https://medlineplus.gov/genetics/condition/lysinuric-protein-intolerance

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
Long-standing and persistent renal disease with glomerular filtration rate (GFR) less than 15 ml/min.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Pulmonary hemorrhage
MedGen UID:
57732
Concept ID:
C0151701
Pathologic Function
Pulmonary hemorrhage is a bleeding within the lungs. Older children and adults may spit blood or bloody sputum. Neonates, infants and young children usually do not spit up blood. Anemia, pulmonary infiltrates, increasingling bloody return on BAL and the presence of hemosiderin-laden macrophages in broncho-alveolar lavage (BAL) fluid or lung biopsy can diagnose lung bleeding. Alveolar macrophages contain phagocytosed red blood cells and stain positive for hemosiderin, a product of hemoglobin degradation, after about 48-72 hours following pulmonary hemorraghe. Previous or recurrent bleeding can thus be distinguished from fresh events. A differentiation into local or diffuse is of importance. Also differentiate if pulmonary hemorrhage is due to a primary lung disorder or a manifestation of a systemic disease.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Truncal obesity
MedGen UID:
1637490
Concept ID:
C4551560
Finding
Obesity located preferentially in the trunk of the body as opposed to the extremities.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency of loose or watery bowel movements.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Nausea
MedGen UID:
10196
Concept ID:
C0027497
Sign or Symptom
A sensation of unease in the stomach together with an urge to vomit.
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Malnutrition
MedGen UID:
56429
Concept ID:
C0162429
Disease or Syndrome
A deficiency in the intake of energy and nutrients.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Psychotic episodes
MedGen UID:
90930
Concept ID:
C0338614
Mental or Behavioral Dysfunction
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Pulmonary hemorrhage
MedGen UID:
57732
Concept ID:
C0151701
Pathologic Function
Pulmonary hemorrhage is a bleeding within the lungs. Older children and adults may spit blood or bloody sputum. Neonates, infants and young children usually do not spit up blood. Anemia, pulmonary infiltrates, increasingling bloody return on BAL and the presence of hemosiderin-laden macrophages in broncho-alveolar lavage (BAL) fluid or lung biopsy can diagnose lung bleeding. Alveolar macrophages contain phagocytosed red blood cells and stain positive for hemosiderin, a product of hemoglobin degradation, after about 48-72 hours following pulmonary hemorraghe. Previous or recurrent bleeding can thus be distinguished from fresh events. A differentiation into local or diffuse is of importance. Also differentiate if pulmonary hemorrhage is due to a primary lung disorder or a manifestation of a systemic disease.
Hemophagocytosis
MedGen UID:
163750
Concept ID:
C0876991
Disease or Syndrome
Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
A reduction in the strength of one or more muscles.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Skeletal muscle atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Pulmonary hemorrhage
MedGen UID:
57732
Concept ID:
C0151701
Pathologic Function
Pulmonary hemorrhage is a bleeding within the lungs. Older children and adults may spit blood or bloody sputum. Neonates, infants and young children usually do not spit up blood. Anemia, pulmonary infiltrates, increasingling bloody return on BAL and the presence of hemosiderin-laden macrophages in broncho-alveolar lavage (BAL) fluid or lung biopsy can diagnose lung bleeding. Alveolar macrophages contain phagocytosed red blood cells and stain positive for hemosiderin, a product of hemoglobin degradation, after about 48-72 hours following pulmonary hemorraghe. Previous or recurrent bleeding can thus be distinguished from fresh events. A differentiation into local or diffuse is of importance. Also differentiate if pulmonary hemorrhage is due to a primary lung disorder or a manifestation of a systemic disease.
Pulmonary alveolar proteinosis
MedGen UID:
1763046
Concept ID:
C5400698
Finding
Accumulation of amorphous PAS-positive material in the space betweem alveolar macrophages, sometimes as condensed form (oval bodies) are typically found in alveolar proteinosis.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Hemophagocytosis
MedGen UID:
163750
Concept ID:
C0876991
Disease or Syndrome
Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
An increased concentration of ammonia in the blood.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Increased serum lactate
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Cutis laxa
MedGen UID:
8206
Concept ID:
C0010495
Disease or Syndrome
Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated with skeletal and developmental anomalies and, in some cases, with severe systemic involvement. Several different forms of inherited CL have been described, differentiated on the basis of the mode of inheritance and differences in the extent of internal organ involvement, associated anomalies and disease severity.
Sparse hair
MedGen UID:
534509
Concept ID:
C0232411
Finding
Reduced density of hairs.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLysinuric protein intolerance
Follow this link to review classifications for Lysinuric protein intolerance in Orphanet.

Recent clinical studies

Etiology

Zhang G, Cao L
Pediatr Pulmonol 2017 Nov;52(11):E94-E96. doi: 10.1002/ppul.23760. PMID: 29058386Free PMC Article
Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, Roda C, Pinto G, Moshous D, Ghalim F, Krug P, Deltour N, Pontoizeau C, Dubois S, Assoun M, Galmiche L, Bonnefont JP, Ottolenghi C, de Blic J, Arnoux JB, de Lonlay P
Orphanet J Rare Dis 2017 Jan 5;12(1):3. doi: 10.1186/s13023-016-0550-8. PMID: 28057010Free PMC Article
Ghilain V, Wiame E, Fomekong E, Vincent MF, Dumitriu D, Nassogne MC
Eur J Paediatr Neurol 2016 Sep;20(5):777-81. Epub 2016 Jun 8 doi: 10.1016/j.ejpn.2016.05.016. PMID: 27321952
Valimahamed-Mitha S, Berteloot L, Ducoin H, Ottolenghi C, de Lonlay P, de Blic J
J Inherit Metab Dis 2015 Mar;38(2):257-63. Epub 2014 Oct 22 doi: 10.1007/s10545-014-9777-5. PMID: 25335805
Güzel-Ozantürk A, Ozgül RK, Unal O, Hişmi B, Aydın Hİ, Sivri S, Tokatlı A, Coşkun T, Aksöz E, Dursun A
Gene 2013 Jun 1;521(2):293-5. Epub 2013 Mar 28 doi: 10.1016/j.gene.2013.03.033. PMID: 23542076

Diagnosis

Zhang G, Cao L
Pediatr Pulmonol 2017 Nov;52(11):E94-E96. doi: 10.1002/ppul.23760. PMID: 29058386Free PMC Article
Estève E, Krug P, Hummel A, Arnoux JB, Boyer O, Brassier A, de Lonlay P, Vuiblet V, Gobin S, Salomon R, Piètrement C, Bonnefont JP, Servais A, Galmiche L
Hum Pathol 2017 Apr;62:160-169. Epub 2017 Jan 11 doi: 10.1016/j.humpath.2016.12.021. PMID: 28087478
Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, Roda C, Pinto G, Moshous D, Ghalim F, Krug P, Deltour N, Pontoizeau C, Dubois S, Assoun M, Galmiche L, Bonnefont JP, Ottolenghi C, de Blic J, Arnoux JB, de Lonlay P
Orphanet J Rare Dis 2017 Jan 5;12(1):3. doi: 10.1186/s13023-016-0550-8. PMID: 28057010Free PMC Article
Ghilain V, Wiame E, Fomekong E, Vincent MF, Dumitriu D, Nassogne MC
Eur J Paediatr Neurol 2016 Sep;20(5):777-81. Epub 2016 Jun 8 doi: 10.1016/j.ejpn.2016.05.016. PMID: 27321952
Noguchi A, Nakamura K, Murayama K, Yamamoto S, Komatsu H, Kizu R, Takayanagi M, Okuyama T, Endo F, Takasago Y, Shoji Y, Takahashi T
Pediatr Int 2016 Oct;58(10):979-983. Epub 2016 Jun 8 doi: 10.1111/ped.12946. PMID: 26865117

Therapy

Zhang G, Cao L
Pediatr Pulmonol 2017 Nov;52(11):E94-E96. doi: 10.1002/ppul.23760. PMID: 29058386Free PMC Article
Ko JM, Shin CH, Yang SW, Seong MW, Park SS, Song J
J Korean Med Sci 2012 Aug;27(8):961-4. Epub 2012 Jul 25 doi: 10.3346/jkms.2012.27.8.961. PMID: 22876067Free PMC Article
Shinawi M, Dietzen DJ, White FV, Sprietsma L, Weymann A
J Pediatr Gastroenterol Nutr 2011 Dec;53(6):695-8. doi: 10.1097/MPG.0b013e318227b02d. PMID: 21716135
Barilli A, Rotoli BM, Visigalli R, Bussolati O, Gazzola GC, Kadija Z, Rodi G, Mariani F, Ruzza ML, Luisetti M, Dall'Asta V
Orphanet J Rare Dis 2010 Nov 26;5:32. doi: 10.1186/1750-1172-5-32. PMID: 21110863Free PMC Article
Tanner LM, Niinikoski H, Näntö-Salonen K, Simell O
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S145-50. Epub 2010 Feb 23 doi: 10.1007/s10545-010-9050-5. PMID: 20177788

Prognosis

Noguchi A, Takahashi T
J Hum Genet 2019 Sep;64(9):849-858. Epub 2019 Jun 18 doi: 10.1038/s10038-019-0620-6. PMID: 31213652
Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, Roda C, Pinto G, Moshous D, Ghalim F, Krug P, Deltour N, Pontoizeau C, Dubois S, Assoun M, Galmiche L, Bonnefont JP, Ottolenghi C, de Blic J, Arnoux JB, de Lonlay P
Orphanet J Rare Dis 2017 Jan 5;12(1):3. doi: 10.1186/s13023-016-0550-8. PMID: 28057010Free PMC Article
Noguchi A, Nakamura K, Murayama K, Yamamoto S, Komatsu H, Kizu R, Takayanagi M, Okuyama T, Endo F, Takasago Y, Shoji Y, Takahashi T
Pediatr Int 2016 Oct;58(10):979-983. Epub 2016 Jun 8 doi: 10.1111/ped.12946. PMID: 26865117
Valimahamed-Mitha S, Berteloot L, Ducoin H, Ottolenghi C, de Lonlay P, de Blic J
J Inherit Metab Dis 2015 Mar;38(2):257-63. Epub 2014 Oct 22 doi: 10.1007/s10545-014-9777-5. PMID: 25335805
Mikołajek-Bedner W, Torbé A, Kwiatkowski S, Michalczyk M, Gizewska M, Rokicki D, Rzepka R, Konstanty-Kurkiewicz V, Domański M, Czajka R
Ginekol Pol 2013 Jul;84(7):654-6. doi: 10.17772/gp/1621. PMID: 24032281

Clinical prediction guides

Stroup BM, Marom R, Li X, Hsu CW, Chang CY, Truong LD, Dawson B, Grafe I, Chen Y, Jiang MM, Lanza D, Green JR, Sun Q, Barrish JP, Ani S, Christiansen AE, Seavitt JR, Dickinson ME, Kheradmand F, Heaney JD, Lee B, Burrage LC
Hum Mol Genet 2020 Aug 3;29(13):2171-2184. doi: 10.1093/hmg/ddaa107. PMID: 32504080Free PMC Article
Pitkänen HH, Kärki M, Niinikoski H, Tanner L, Näntö-Salonen K, Pikta M, Kopatz WF, Zuurveld M, Meijers JCM, Brinkman HJM, Lassila R
Haemophilia 2018 Sep;24(5):e312-e321. Epub 2018 Aug 2 doi: 10.1111/hae.13543. PMID: 30070418
Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, Roda C, Pinto G, Moshous D, Ghalim F, Krug P, Deltour N, Pontoizeau C, Dubois S, Assoun M, Galmiche L, Bonnefont JP, Ottolenghi C, de Blic J, Arnoux JB, de Lonlay P
Orphanet J Rare Dis 2017 Jan 5;12(1):3. doi: 10.1186/s13023-016-0550-8. PMID: 28057010Free PMC Article
Kurko J, Tringham M, Tanner L, Näntö-Salonen K, Vähä-Mäkilä M, Nygren H, Pöhö P, Lietzen N, Mattila I, Olkku A, Hyötyläinen T, Orešič M, Simell O, Niinikoski H, Mykkänen J
Metabolism 2016 Sep;65(9):1361-75. Epub 2016 May 27 doi: 10.1016/j.metabol.2016.05.012. PMID: 27506743
Noguchi A, Nakamura K, Murayama K, Yamamoto S, Komatsu H, Kizu R, Takayanagi M, Okuyama T, Endo F, Takasago Y, Shoji Y, Takahashi T
Pediatr Int 2016 Oct;58(10):979-983. Epub 2016 Jun 8 doi: 10.1111/ped.12946. PMID: 26865117

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