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Lysinuric protein intolerance(LPI)

MedGen UID:
75704
Concept ID:
C0268647
Disease or Syndrome
Synonyms: Dibasicamino aciduria II; LPI
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Lysinuric protein intolerance (303852004); Hyperdibasic aminoaciduria (303852004); LPI - Lysinuric protein intolerance (303852004); Congenital lysinuria (303852004)
 
Gene (location): SLC7A7 (14q11.2)
OMIM®: 222700
Orphanet: ORPHA470

Definition

Lysinuric protein intolerance (LPI) typically presents after an infant is weaned; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth; osteoporosis; involvement of the lungs (progressive interstitial changes; pulmonary alveolar proteinosis) and of kidneys (progressive glomerular and proximal tubular disease); hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis at the bone marrow aspirate) and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Acute pancreatitis can also be seen. [from GTR]

Additional descriptions

From GeneReviews
Lysinuric protein intolerance (LPI) typically presents after an infant is weaned; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth; osteoporosis; involvement of the lungs (progressive interstitial changes; pulmonary alveolar proteinosis) and of kidneys (progressive glomerular and proximal tubular disease); hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis at the bone marrow aspirate) and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Acute pancreatitis can also be seen.  https://www.ncbi.nlm.nih.gov/books/NBK1361
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 GHR
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.People 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.The signs and symptoms of lysinuric protein intolerance typically appear after infants are weaned and receive greater amounts of protein from solid foods.  https://ghr.nlm.nih.gov/condition/lysinuric-protein-intolerance

Clinical features

Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Truncal obesity
MedGen UID:
90229
Concept ID:
C0311277
Finding
A condition of having excess fat in the abdomen. Abdominal obesity is typically defined as waist circumferences of 40 inches or more in men and 35 inches or more in women. Abdominal obesity raises the risk of developing disorders, such as diabetes, hypertension and METABOLIC SYNDROME X.
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 \
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
Abnormal enlargement 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
INFLAMMATION of the PANCREAS. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of CHRONIC PANCREATITIS (International Symposium on Acute Pancreatitis, Atlanta, 1992). The two most common forms of acute pancreatitis are ALCOHOLIC PANCREATITIS and gallstone pancreatitis.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement 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
An imbalanced nutritional status resulting from insufficient intake of nutrients to meet normal physiological requirement.
Psychotic episodes
MedGen UID:
90930
Concept ID:
C0338614
Mental or Behavioral Dysfunction
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
A decrease in the number of LEUKOCYTES in a blood sample below the normal range (LEUKOCYTE COUNT less than 4000).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A laboratory test result indicating that there is an abnormally small number of platelets in the circulating blood.
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result demonstrating decreased levels of hemoglobin in a biological specimen.
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.
Pulmonary alveolar proteinosis
MedGen UID:
18760
Concept ID:
C0034050
Disease or Syndrome
A PULMONARY ALVEOLI-filling disease, characterized by dense phospholipoproteinaceous deposits in the alveoli, cough, and DYSPNEA. This disease is often related to, congenital or acquired, impaired processing of PULMONARY SURFACTANTS by alveolar macrophages, a process dependent on GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed)
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Skeletal muscle atrophy
MedGen UID:
902598
Concept ID:
C0234958
Disease or Syndrome
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Muscle weakness
MedGen UID:
811372
Concept ID:
C3714552
Sign or Symptom
Reduced strength of muscles.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
A decrease in the number of LEUKOCYTES in a blood sample below the normal range (LEUKOCYTE COUNT less than 4000).
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
INFLAMMATION of the PANCREAS. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of CHRONIC PANCREATITIS (International Symposium on Acute Pancreatitis, Atlanta, 1992). The two most common forms of acute pancreatitis are ALCOHOLIC PANCREATITIS and gallstone pancreatitis.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement 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.
Hyperammonaemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
A laboratory test result demonstrating an increased concentration of ammonia in the blood.
Increased serum ferritin
MedGen UID:
69130
Concept ID:
C0241013
Finding
Abnormal raised concentration of ferritin, a ubiquitous intracellular protein that stores iron, in the blood.
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.
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Generalized osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
A condition of reduced bone mass, with decreased cortical thickness and a decrease in the number and size of the trabeculae of cancellous bone (but normal chemical composition), resulting in increased fracture incidence. Osteoporosis is classified as primary (Type 1, postmenopausal osteoporosis; Type 2, age-associated osteoporosis; and idiopathic, which can affect juveniles, premenopausal women, and middle-aged men) and secondary osteoporosis (which results from an identifiable cause of bone mass loss).
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.
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.
Sparse hair
MedGen UID:
349904
Concept ID:
C1860844
Sign or Symptom
Reduced density of hairs.
Generalized elastolysis
MedGen UID:
418920
Concept ID:
C2930812
Disease or Syndrome
Wrinkled, redundant, inelastic and sagging skin.

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

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
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. PMID: 24032281
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
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

Diagnosis

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
Habib A, Azize NA, Yakob Y, Md Yunus Z, Wee TK
Malays J Pathol 2016 Dec;38(3):305-310. PMID: 28028301
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
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

Therapy

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
Douda DN, Farmakovski N, Dell S, Grasemann H, Palaniyar N
Orphanet J Rare Dis 2009 Dec 23;4:29. doi: 10.1186/1750-1172-4-29. PMID: 20030831Free PMC Article

Prognosis

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. PMID: 24032281
Ogier de Baulny H, Schiff M, Dionisi-Vici C
Mol Genet Metab 2012 May;106(1):12-7. Epub 2012 Feb 17 doi: 10.1016/j.ymgme.2012.02.010. PMID: 22402328
Tanner LM, Näntö-Salonen K, Niinikoski H, Jahnukainen T, Keskinen P, Saha H, Kananen K, Helanterä A, Metso M, Linnanvuo M, Huoponen K, Simell O
J Pediatr 2007 Jun;150(6):631-4, 634.e1. doi: 10.1016/j.jpeds.2007.01.043. PMID: 17517249

Clinical prediction guides

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
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
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
Sebastio G, Sperandeo MP, Andria G
Am J Med Genet C Semin Med Genet 2011 Feb 15;157C(1):54-62. Epub 2011 Feb 9 doi: 10.1002/ajmg.c.30287. PMID: 21308987

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