Lysinuric protein intolerance

{{Infobox medical condition (new)

| name = Lysinuric protein intolerance

| synonyms =Hyperdibasic aminoaciduria type 2,Cationic aminoaciduria or Familial protein intolerance

| image = L-lysine-2D-skeletal.png

| caption = Lysine

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Lysinuric protein intolerance (LPI) is an autosomal recessive{{cite journal |pmid=1155480 |date=August 1975 |vauthors=Simell O, Perheentupa J, Rapola J, Visakorpi JK, Eskelin LE |title=Lysinuric protein intolerance |volume=59 |issue=2 |pages=229–240 |journal=The American Journal of Medicine |url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+56-41-7 |format=Free full text |doi=10.1016/0002-9343(75)90358-7}} metabolic disorder affecting amino acid transport. It is characterised by the body's inability to properly digest and use certain proteins. {{Citation |last=Simell |first=O. |title=Lysinuric Protein Intolerance |date=1990 |work=Inborn Metabolic Diseases |pages=577–583 |url=http://dx.doi.org/10.1007/978-3-662-02613-7_44 |access-date=2024-07-22 |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |doi=10.1007/978-3-662-02613-7_44 |isbn=978-3-662-02615-1}} This condition leads to various metabolic complications and is typically diagnosed in infancy or early childhood.{{Citation |last=Simell |first=O. |title=Lysinuric Protein Intolerance |date=1990 |work=Inborn Metabolic Diseases |pages=577–583 |url=http://dx.doi.org/10.1007/978-3-662-02613-7_44 |access-date=2024-07-22 |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |doi=10.1007/978-3-662-02613-7_44 |isbn=978-3-662-02615-1}}

About 140 patients have been reported, almost half of them of Finnish origin. Individuals from Japan, Italy, Morocco and North Africa have also been reported plus one in Bixby, Oklahoma.

Signs and symptoms

Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis and osteopenia,{{OMIM|222700}} delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and kidney complications. High levels of plasma glutamine and glycine are observed.{{citation needed|date=September 2020}}

Genetic Basis

LPI has been associated with SLC7A7.{{cite journal |vauthors=Borsani G, Bassi MT, Sperandeo MP, etal |title=SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance |journal=Nat. Genet. |volume=21 |issue=3 |pages=297–301 |date=March 1999 |pmid=10080183 |doi=10.1038/6815|s2cid=38960307 }} LPI is caused by mutations in the SLC7A7 gene, which encodes for a protein involved in the transport of amino acids across cell membranes. Mutations in this gene impair the transport function, leading to the characteristic amino acid imbalances seen in LPI patients.{{Cite journal |last1=Borsani |first1=Giuseppe |last2=Bassi |first2=Maria Teresa |last3=Sperandeo |first3=Maria Pia |last4=Grandi |first4=Alessandro De |last5=Buoninconti |first5=Anna |last6=Riboni |first6=Mirko |last7=Manzoni |first7=Marta |last8=Incerti |first8=Barbara |last9=Pepe |first9=Antonio |last10=Andria |first10=Generoso |last11=Ballabio |first11=Andrea |last12=Sebastio |first12=Gianfranco |date=March 1999 |title=SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance |url=http://dx.doi.org/10.1038/6815 |journal=Nature Genetics |volume=21 |issue=3 |pages=297–301 |doi=10.1038/6815 |pmid=10080183 |issn=1061-4036}}

Mechanism

Image:autorecessive.svg pattern of inheritance.]]

In LPI, urinary excretion of cationic amino acids (ornithine, arginine and lysine) is increased and these amino acids are poorly absorbed from the intestine. Therefore, their plasma concentrations are low and their body pools become depleted. Deficiency of arginine and ornithine restricts the function of the urea cycle and leads to hyperammonemia after protein-rich meals. Deficiency of lysine may play a major role in the skeletal and immunological abnormalities observed in LPI patients.{{citation needed|date=September 2020}}

Clinical Features

The symptoms of LPI typically appear after weaning from breast milk to a protein-rich diet. Common symptoms include poor growth, muscle weakness, enlarged liver and spleen, and frequent infections. Neurological symptoms such as confusion and seizures can also occur.{{Cite journal |last1=Douda |first1=David N |last2=Farmakovski |first2=Nicole |last3=Dell |first3=Sharon |last4=Grasemann |first4=Hartmut |last5=Palaniyar |first5=Nades |date=December 2009 |title=SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance |journal=Orphanet Journal of Rare Diseases |volume=4 |issue=1 |page=29 |doi=10.1186/1750-1172-4-29 |doi-access=free |pmid=20030831 |pmc=2807424 |issn=1750-1172}}

Diagnosis

The diagnosis is based on the biochemical findings (increased concentrations of lysine, arginine and ornithine in urine and low concentrations of these amino acids in plasma, elevation of urinary orotic acid excretion after protein-rich meals, and inappropriately high concentrations of serum ferritin and lactate dehydrogenase isoenzymes) and the screening of known mutations of the causative gene from a DNA sample.{{Cite journal |last1=Sebastio |first1=Gianfranco |last2=Schiff |first2=Manuel |last3=de Baulny |first3=Hélène Ogier |date=September 2016 |title=Lysinuric Protein Intolerance and Hartnup Disease |url=http://dx.doi.org/10.1093/med/9780199972135.003.0025 |journal=Oxford Medicine Online |doi=10.1093/med/9780199972135.003.0025}}

Treatment

Treatment of LPI consists of protein-restricted diet and supplementation with oral citrulline.{{cite web |last1=Nunes |first1=Virginia |last2=Niinikoski |first2=Harri |title=Lysinuric Protein Intolerance |url=https://www.ncbi.nlm.nih.gov/books/NBK1361/ |website=GeneReviews® |publisher=University of Washington, Seattle |access-date=26 September 2024 |date=1993}} Citrulline is a neutral amino acid that improves the function of the urea cycle and allows sufficient protein intake without hyperammonemia.{{Cite journal |last1=Sebastio |first1=Gianfranco |last2=Schiff |first2=Manuel |last3=de Baulny |first3=Hélène Ogier |date=September 2016 |title=Lysinuric Protein Intolerance and Hartnup Disease |url=http://dx.doi.org/10.1093/med/9780199972135.003.0025 |journal=Oxford Medicine Online |doi=10.1093/med/9780199972135.003.0025}}

Prognosis

Under proper dietary control and supplementation, the majority of the LPI patients are able to have a nearly normal life. However, severe complications including pulmonary alveolar proteinosis and chronic kidney disease may develop even with proper treatment.{{cite journal |vauthors=Tanner LM, Näntö-Salonen K, Niinikoski H, etal |title=Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance |journal=J. Pediatr. |volume=150 |issue=6 |pages=161–164 |date=June 2007 |pmid=17517249 |doi=10.1016/j.jpeds.2007.01.043}}Fertility appears to be normal in women, but mothers with LPI have an increased risk for complications during pregnancy and delivery.{{cite journal |vauthors=Tanner LM, Näntö-Salonen K, Niinikoski H, etal |title=Hazards associated with pregnancies and deliveries in lysinuric protein intolerance |journal=Metabolism |volume=55 |issue=2 |pages=224–231 |date=February 2006 |pmid=16423630 |doi=10.1016/j.metabol.2005.08.016}}