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Lysinuric protein intolerance
LPI is a genetic disorder affecting how the body processes certain proteins. It can lead to issues with digestion, growth, and kidney function, typically becoming apparent in infancy or early childhood. Management often involves dietary changes.
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Overview
Lysinuric protein intolerance (LPI) is a rare genetic disorder affecting the metabolism of proteins. Specifically, it impairs the transport of three essential amino acids: lysine, arginine, and ornithine [PMID:24074213]. These amino acids are crucial building blocks for proteins and play important roles in various bodily functions. In LPI, the body cannot absorb these amino acids properly from the intestine or reabsorb them in the kidneys, leading to their excessive loss in urine and low levels in the blood.
This impaired transport primarily affects the intestine, kidneys, and liver. The reduced availability of these amino acids can impact the urea cycle, which is vital for removing ammonia, a toxic waste product, from the body. As a result, individuals with LPI may experience a range of symptoms, often beginning in infancy or early childhood.
Symptoms & clinical features
The symptoms of Lysinuric protein intolerance can vary widely in their presentation and severity, even within the same family. Digestive problems are common, including poor feeding, vomiting, and diarrhoea, which can lead to poor growth and weight gain. Some individuals may develop an aversion to protein-rich foods, instinctively avoiding them due to discomfort after eating [PMID:24074213].
Other symptoms can include enlargement of the liver and spleen (hepatosplenomegaly), low muscle tone (hypotonia), and sometimes developmental delay. Importantly, some individuals may experience episodes of hyperammonaemia (high ammonia levels in the blood), which can cause confusion, lethargy, and in severe cases, coma. Lung complications, such as interstitial lung disease, and kidney problems, including impaired kidney function, may also occur [PMID:24074213].
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Affected organs
LPI primarily affects several key organ systems due to the impaired amino acid transport. The digestive system, particularly the small intestine, is impacted, leading to reduced absorption of lysine, arginine, and ornithine. This can cause the gastrointestinal symptoms often seen in LPI.
Kidneys are also significantly affected, as they are unable to reabsorb these amino acids from the filtered blood, resulting in their loss in the urine. The liver is another organ of concern, as the amino acid transport defect can interfere with the urea cycle, which takes place in the liver and is essential for detoxifying ammonia. In some cases, the immune system, lungs, and blood cells can also be affected, leading to broader health challenges.
Risks & severity
The severity of Lysinuric protein intolerance can range from mild to severe, with symptoms often becoming apparent during infancy or early childhood. Without appropriate management, there is a risk of malnutrition, growth failure, and recurrent episodes of hyperammonaemia, which can be life-threatening [PMID:16149027].
Long-term complications can include kidney disease, lung complications such as interstitial lung disease, and haematological issues like anaemia and pancytopenia (deficiency of all three cellular components of the blood: red cells, white cells, and platelets). The exact prevalence of LPI is not well established globally, but it is estimated to affect approximately 1 in 60,000 individuals in Finland, where it is more common.
Genetic causes
Lysinuric protein intolerance is caused by genetic changes (pathogenic variants) in the SLC7A7 gene. This gene provides instructions for making a protein that forms part of a transport system called y+LAT1. The y+LAT1 transporter is responsible for moving positively charged amino acids, including lysine, arginine, and ornithine, across cell membranes.
Pathogenic variants in SLC7A7 disrupt the normal function of this transporter. When the y+LAT1 transporter does not work correctly, these crucial amino acids cannot be effectively absorbed from the intestine after digestion or reabsorbed from the urine in the kidneys. This leads to their accumulation in the urine and insufficient levels in the blood, causing the characteristic features of LPI. The impaired transport also affects the availability of these amino acids for the urea cycle and other metabolic processes.
- SLC7A7 solute carrier family 7 member 7
Inheritance pattern
Lysinuric protein intolerance has an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the altered SLC7A7 gene - one from each parent - to develop the condition.
Parents who each carry one copy of the altered gene are known as carriers. Carriers typically do not show symptoms of LPI because they have one working copy of the gene. When two carriers have children, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies of the gene and develop LPI. There is also a 2 in 4 (50%) chance the child will be a carrier like their parents, and a 1 in 4 (25%) chance the child will inherit two working copies of the gene and will not have LPI nor be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of Lysinuric protein intolerance often begins with a suspicion based on clinical symptoms such as poor feeding, recurrent vomiting, and failure to thrive, especially when accompanied by episodes of high ammonia. Biochemical tests showing elevated levels of lysine, arginine, and ornithine in urine, and often low levels in blood plasma, can support the diagnosis.
Confirmation of LPI typically involves genetic testing, which looks for pathogenic variants in the SLC7A7 gene. In the UK, genetic testing for LPI is available through the NHS Genomic Medicine Service (GMS) via the Rare and Inherited Disease testing directory, often requested using relevant R-codes for metabolic disorders. Referral to a clinical genetics service or a metabolic specialist is usually required to arrange this testing and interpret the results.
Management & lifestyle
Management of Lysinuric protein intolerance primarily focuses on dietary adjustments to reduce protein intake and prevent symptoms, particularly hyperammonaemic crises. This typically involves a low-protein diet, often supplemented with citrulline, which can help support the urea cycle and reduce ammonia levels [PMID:16149027]. Additionally, some individuals may benefit from oral lysine restriction and arginine supplementation.
Regular monitoring of growth, nutritional status, and blood ammonia levels is crucial. Multidisciplinary care involving metabolic specialists, dietitians, and other healthcare professionals is essential to tailor treatment plans to individual needs. In the UK, individuals with LPI are typically managed within specialist metabolic centres, following established NHS care pathways for rare metabolic conditions.
UK care pathway
In the UK, individuals suspected of having Lysinuric protein intolerance would typically be referred by their GP or a specialist to a clinical genetics service or a specialist metabolic centre. These centres can provide expert assessment, arrange diagnostic genetic testing through the NHS Genomic Medicine Service (GMS), and offer genetic counselling. Genetic testing for conditions like LPI is listed in the GMS Rare and Inherited Disease testing directory, identified by specific R-codes. A genetic counsellor can provide detailed information about the condition, inheritance patterns, and implications for family members.
Frequently asked questions
What kind of diet is recommended for someone with LPI?
Individuals with Lysinuric protein intolerance are generally advised to follow a low-protein diet. This helps to reduce the amount of amino acids that the body cannot process effectively. Dietary supplements, such as citrulline, may also be recommended to help manage ammonia levels.
Can LPI be cured?
Currently, there is no cure for Lysinuric protein intolerance. However, the condition can be effectively managed through dietary modifications and medical treatments, which aim to control symptoms and prevent complications. Regular medical follow-ups are important.
How often do people with LPI need to see a doctor?
The frequency of medical appointments for someone with Lysinuric protein intolerance depends on the individual's symptoms and stability. Generally, regular follow-ups with a metabolic specialist and a dietitian are necessary to monitor the condition, adjust treatment, and ensure healthy growth and development.
Are there specific tests to monitor LPI?
Yes, monitoring typically involves regular blood tests to check amino acid levels and ammonia levels, particularly during illness or if symptoms worsen. Urine tests may also be used to assess the excretion of certain amino acids. These tests help healthcare professionals adjust the management plan as needed.
Can LPI affect pregnancy?
Women with Lysinuric protein intolerance who are considering pregnancy should discuss this with their specialist medical team. Pregnancy can alter metabolic demands, and careful monitoring and management adjustments may be necessary to ensure the health of both the mother and the baby.
References
- Adam MP, Bick S, Mirzaa GM. Lysinuric Protein Intolerance. 1993. PMID: 20301535
- Perheentupa J, Simell O. Lysinuric protein intolerance. Birth defects original article series. 1974. PMID: 4220398
- Brosnan ME, Brosnan JT. Renal arginine metabolism. The Journal of nutrition. 2004. PMID: 15465786
- Palacín M, Borsani G, Sebastio G. The molecular bases of cystinuria and lysinuric protein intolerance. Current opinion in genetics & development. 2001. PMID: 11377971
- Noguchi A, Takahashi T. Overview of symptoms and treatment for lysinuric protein intolerance. Journal of human genetics. 2019. PMID: 31213652
- Sperandeo MP, Andria G, Sebastio G. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Human mutation. 2008. PMID: 17764084
- Simell O, Perheentupa J, Rapola J. Lysinuric protein intolerance. The American journal of medicine. 1975. PMID: 1155480
- Pané A, Milad C, Santana-Domínguez M. Lysinuric Protein Intolerance and Its Nutritional and Multisystemic Challenges in Pregnancy: A Case Report and Literature Review. Journal of clinical medicine. 2023. PMID: 37835050