Lysinuric protein intolerance

This is part of Rare diseases.

Diagnosis: Lysinuric protein intolerance

Synonyms: LPI

Publication date: 2011-12-29
Version: 1.2

ICD 10 code


The disease

Lysinuric protein intolerance is a congenital metabolic disease affecting many organs. It is caused by the increased excretion of the amino acids lysine, arginine and ornithine by the kidneys and the inability of the intestine to reabsorb them. The consequence is a deficiency of these amino acids. Low levels of arginine and ornithine limit the functioning of the urea cycle, a system which removes the toxic substance ammonia from the body. As a result, high levels of ammonia accumulate, affecting the brain and other organs. Low levels of amino acids, particularly lysine, affect the gastrointestinal tract, lungs, immune system, liver, spleen and organs producing blood. The skeleton is also affected.

Lysinuric protein intolerance is relatively common in Finland, and was described first in 1965 by Finnish paediatricians Jaakko Perheentupa och Jarmo Visakorpi.


The exact incidence of the condition is unknown. Approximately 100 people with the disease have been reported in international medical literature. Almost half of them were from Finland where occurrence is estimated at one per 60,000 inhabitants. In Sweden, only a few individuals with the disease have been identified.


In lysinuric protein intolerance, the transport tamino acids lysine, arginine and ornithine over the basal membranes of the epithelial cells of the kidneys and intestines is defective. The cause is a mutation in a gene which produces (codes for) protein y+LAT-1, which is important for certain transportation systems. The gene, known as SLC7A7, is located on the long arm of chromosome 14 (14q11.2). The mutation leads to reduced absorption of the amino acids lysine, arginine and ornithine. Studies have also shown that because the secretion process does not function normally, these amino acids may be trapped within the cells.

Abnormalities in the metabolisms of arginine and ornithine result in reduced capacity of the urea cycle. The most important function of the urea cycle is to change ammonia, produced when protein is broken down, into urea, which is then excreted in the urine. Deficiencies in the urea cycle lead to elevated levels of ammonia, a highly toxic substance which can have a detrimental effect on brain function.

Figure: The urea cycle, showing chemical reactions and enzymes.

Figure: The urea cycle, showing chemical reactions and enzymes.

The symptoms of lysinuric protein intolerance differ greatly from those caused by other urea cycle defects. Apart from deficiencies in the urea cycle, lysinuric protein intolerance also causes the excretion of lysine in the urine. The lysine deficiency is thought to cause many of the symptoms which characterise the disease, including those affecting the liver and spleen, the immune system and kidneys. Other symptoms include impaired growth, brittle bones (osteoporosis) and muscle weakness. Arginine is vital for nitric oxide synthesis and low levels may interfere with nitric oxide production. Low levels of nitric oxide may in turn cause changes in the blood vessels.


In lysinuric protein intolerance the pattern of inheritance is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


Infants with the disease do not usually show symptoms as long as they are being breast-fed. When they are given more protein-rich food, vomiting and diarrhoea may occur. They show clear signs that their bodies cannot cope with protein as they have problems eating, and do not grow or thrive as they should. Vomiting and diarrhoea are common. Gastrointestinal diseases are often suspected and for this reason the child is often tested for gluten intolerance. Common forms of infant formula are comparable with breast milk, but if children with this condition are given formula milk or gruel with high protein content, they may develop elevated ammonia levels.

Children show signs of muscle weakness (hypotonus) from an early age. They may show skin disorders similar to children with kwashiorkor, a form of malnutrition seen during famines and caused by lack of protein. In this disorder skin often becomes fragile and develops a dry rash while nails become thickened and deformed. Children may have thin, sparse hair or no hair at all (alopecia).

Elevated levels of ammonia in the blood (hyperammonemia) can result in recurring periods of brain dysfunction (encephalopathy), vomiting, unsteady movements and reduced levels of consciousness. Abdominal pain is also common. Between meals the urea cycle can often maintain near-normal ammonia levels, but after meals levels can rise dramatically. Severe hyperammonemia may result in unconsciousness. Hyperammonemia may continue for extended periods if the child has an infection, has fasted or has eaten protein-rich food, with an associated risk of serious damage to the internal organs.

Intellectual disability is uncommon but may occur as a result of hyperammonemia. Lysine deficiency may also affect the brain and is considered a possible cause of cognitive disability.

People with the disease almost always have anaemia as well as reduced levels of white blood cells (leukopenia) and platelets (thrombocytopenia). Lysinuric protein intolerance can also affect the immune system. There is a risk that the common childhood disease, chickenpox, develops into a severe, life-threatening disease.

After the first years of life children continue to grow slowly and are less tall than their peers. Despite current treatments with reduced protein intake and normalisation of ammonia levels, most children with the disease do not become as tall as they would otherwise. It has been established that some of the children have a growth hormone deficiency causing growth abnormalities. In such cases they are treated with growth hormone. Lysine deficiency is also suspected as a possible cause of restricted growth. Brittle bones occur in most people with the disease and bone fractures are not uncommon.

Lung abnormalities are common complications and can cause both acute and chronic breathing problems. In isolated cases they can lead to serious lung disease involving changes to lung tissue (pulmonary fibrosis) and organ failure. Symptoms of lung abnormalities include fatigue, coughing, breathlessness during exertion, fever and sometimes coughing up blood. The liver, spleen, kidneys and pancreas may also be affected. Cirrhosis of the liver may manifest, and some people with the disease develop pancreatis. Kidney function is reduced, particularly in adults with the disease. In isolated cases a kidney transplantation may be necessary.

The disease is associated with elevated levels of blood fats, including both cholesterol and triglycerides. Hence, elevated blood fat levels are not usually the result of bad nutritional choices. The combination of elevated levels of blood fats, chronically reduced kidney function and low levels of arginine and nitric oxide, significantly increases the risk of heart and lung diseases.

Lysinuric protein intolerance is also associated with an increased risk of carnitine deficiency. Carnitine is essential to the process by which fat is converted into energy. Carnitine deficiency may worsen the muscle weakness associated with the disease.

In some people, symptoms are similar to those of haemophagocytic lymphohistiocytosis and include an enlarged liver and spleen, low levels of fibrinogen in the blood and high levels of triglycerides and ferritin. Many people also have substantially elevated levels of zinc. Separate information on haemophagocytic lymphohistiocytosis is available in the rare disease database of the Swedish National Board of Health and Welfare. Lysinuric protein intolerance has been mistaken, among other diseases, for Niemann-Pick disease (a lipid storage disease).

Some people with lysinuric protein intolerance choose to keep to a low-protein diet while they are growing up as they find they feel better doing so. This can mean that symptoms of the disease do not manifest until adulthood, for example during pregnancy and delivery.

The condition of women with lysinuric protein intolerance may deteriorate during pregnancy, with the risk of developing severe anaemia and trombocytopenia. There are increased risks of high blood pressure (hypertonia) and pre-eclampsia. Pre-existing kidney conditions can worsen. Specialist pre-natal care is therefore essential. Generally, the foetus develops normally but there is a risk of growth abnormalities. Delivery causes a major protein overload for the mother when the uterus, a very large muscle, returns to normal size by breaking down excess tissue. Possible complications include bleeding and acute blood poisoning, the result of increased levels of ammonia. Women with the disease should deliver the baby at a hospital where there is experience of inherited metabolic diseases, as they require careful monitoring and treatment.


The diagnosis is made by analysing amino acids in plasma and urine as well as organic acids and orotic acid in urine. Levels of lysine, arganine and ornithine in the plasma are often low, while levels excreted in the urine are elevated, particularly lysine. Plasma levels of the neutral amino acids serine, glycine, citrulline, proline and alanine are elevated, as are glutamine levels. Levels of lactate dehydrogenase (LD), ferritin and zinc are also often very high. Triglycerides and chlorestorol levels may also be significantly higher than normal. Numbers of white blood cells may be reduced, while haemoglobin levels (Hb) and thrombocyte numbers are also usually low.

The diagnosis can be confirmed by a DNA analysis. Foetal diagnosis, and on occasion embryo diagnosis, is possible if the mutation in the family has been identified.


The aim of treatment is to help compensate for deficiencies in lysine, arginine and ornithine, hence reducing detrimental effects on blood production, and on the brain, liver, spleen, pancreas, kidney, lungs and bones.

It is most important that the patient is given the amino acid citrulline, another substance in the urea cycle, which is taken up in the intestine and kidneys via another transport system than that of dibasic amino acids. By providing additional amounts of this amino acid, arginine and ornithine deficiencies are remedied and the urea cycle works more or less normally. Citrullin dosage is adjusted to the individual and doses are administered three or four times per day. Citrullin treatment is combined with a protein-reduced diet. It is important to eat regularly and not to wait too long between meals. With this treatment, elevated levels of ammonia can be reduced and arginine and ornithine levels may be normalised. If ammonia levels are not normalised by citrulline treatment, treatment with sodium benzoate supplements may be necessary. Sodium benzoate reduces ammonia levels in the blood by binding it to a safe, water-based solution which is excreted in the urine.

Lysine levels in the blood are not affected by citrulline treatment.To normalise their levels, lysine supplements are necessary. The side effects of lysine treatment may be severe and take the form of gastrointestinal problems. It has recently been stated that low doses of lysine are sufficient to achieve positive effects on lysine levels, but evidence is still limited. Lysine should be given in combination with citrulline. It is also important to recognise that excessively high levels of lysine can interfere with the urea cycle.

High levels of blood fats may require treatment with statins.

Growth hormone deficiency can be treated with daily subcutaneous injections of growth hormone.

High doses of cortisone have been used with some success to treat lung problems, but this treatment does not help everyone. If organ failure occurs different medical experts, including lung and kidney specialists, need to collaborate.

Children with lysinuric protein intolerance should be vaccinated like their peers. Everyone with lysinuric protein intolerance should be vaccinated against chicken pox if they have not had the disease.

Treatment for brittle bones may be necessary.

Advice and support from a dietician familiar with the disease are necessary. Others in contact with the child, including teachers, preschool staff and school catering staff must also be informed about the disorder and the importance of adhering to the diet. Specialist expertise is also required in the support team, including the attending physician, clinical pathologist, nurse, psychologist and social worker. They should be able to give support and practical advice to the person with the disease and to the family, as dietary treatment affects everyday family life.

If the child has an intellectual disability the extent of the disability determines the nature of the habilitation necessary. In order to stimulate the child’s development and help compensate for loss of function, measures should start at an early age. A habilitation team includes professionals with special expertise in different aspects of the disability and how it affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields.

Psychological and social support is important, both for the person affected and for the family. It is important to provide those in contact with the child, including personnel at day care and school, with clear information to increase understanding of the condition.

Practical advice


National and regional resources in Sweden

Special teams for people with congenital metabolic diseases, including a specialist physician, dietician, nurse, psychologist and social worker, may be found at Sweden’s five largest university hospitals. Treatment is carried out in close collaboration with the local hospital.

Resource personnel

Senior Physician Maria Halldin Stenlid, Centre for Inherited Metabolic Diseases (CMMS), University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: maria.halldin@kbh.uu.se.

Senior dietician Agnes Pal, Centre for Inherited Metabolic Diseases (CMMS),ÿ University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: agnes.pal@akademiska.se.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations

There is no Swedish association for people with lysinuric protein intolerance.

Courses, exchanges of experience for personnel


Research and development (R&D)

Research into lysinuric protein intolerance is carried out primarily in Finland, where the disease is most commonly found.

Information material

An information leaflet on lysinuric protein intolerance summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-9-18). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.


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Database references

OMIM (Online Mendelian Inheritance in Man)
Search: lysinuric protein intolerance, LPI

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: lysinuric protein intolerance

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Maria Halldin Stenlid, Senior physician, The Children’s Hospital, Uppsala University Hospital, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2011-12-29
Version: 1.2
Publication date of the Swedish version: 2010-11-16

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.