Lysinuric Protein Intolerance

Clinical Definition

Lysinuric protein intolerance (LPI) is an uncommon autosomal recessive disorder characterized by postprandial hyperammonemia caused by a primary defect in the transport of the cationic amino acids lysine, arginine and ornithine in the epithelial cells of the kidneys and gastrointestinal tract and secondarily by a disturbance of the urea cycle.

The disease was first described in 1965. By far the highest incidence (1/60,000) is found among the Laplander descent of Finland.

Clinical Course

Because of the increased urinary excretion and decreased intestinal absorption of cationic amino acids in general and of the essential amino acid lysine in particular, the bodies of patients with lysinuric protein intolerance are progressively depleted of these amino acids.

Deficiency of ornithine subsequently leads to an impairment of the urea cycle. Affected patients experience episodes of hyperammonanemia and accordingly develop nausea and vomiting and avoid protein-rich foods.

Newborns and infants after the breast-feeding period fail to thrive, and symptoms of protein malnutrition are further aggravated by lysine deficiency.

Subsequently, patients develop hepatosplenomegaly, osteoporosis Opens in new window and bone fractures, sparse hair, muscle hypotonia, anemia Opens in new window and coagulopathies and pulmonary, renal and sometimes central nervous system disorders.

Gene Involvement

Lysinuric protein intolerance has been found to be caused by mutations in the amino acid transporter gene SLC7A7, located on chromosome 14q.

In patients with lysinuric protein intolerance, the plasma concentration of cationic amino acids in plasma is low and the concentrations of glutamine, alanine, serine, proline, citrulline and glycine may be elevated.

The urinary excretion of lysine is excessive and that of arginine and ornithine is also elevated. Serum ammonia increases after protein-containing meals but is normal under fasting conditions.

Several cases of pancreatitis have been reported in patients with lysinuric protein intolerance, and the morphologic alterations in the pancreas can include inflammatory changes, necrosis, intraductal protein plugs, atrophy and fibrosis.

The underlying defect is thought to be the severe protein deficiency, because similar pancreatic changes have been found in patients with kwashiorkor.

In at least one kindred that was previously classified as having familial pancreatitis, the underlying cause may have been either primary lysinuric protein intolerance or co-inheritance of lysinuric protein intolerance together with one of other gene mutations that predispose to familial pancreatitis.


Patients with lysinuric protein intolerance are treated with a proten-restricted and citrulline-supplemented diet and usually respond with an improvement of symptoms, although the aversion to dietary proteins remains.

Patients with lysinuric protein intolerance-associated pulmonary disease, but not with renal complications, have been reported to respond to steroids.

  1. Perheentupa J, Visakorpi JK (1965) Protein intolerance with deficient transport of basic amino acids: another inborn error of metabolism. Lancet 2:813-816
  2. Simell O, Perheentupa J, Rapola J et al. (1975) Lysinuric protein intolerance. Am J Med 59:229-240.
  3. Carpenter TO, Levy HL, Holtrop ME et al. (1985) Lysinuric protein intolerance presenting as childhood osteoporosis. Clinical and skeletal response to citrulline therapy. N Engl J Med 312:290-294.
  4. Tanner LM, Niinikoski H, Nanto-Salonen K, Simell O (2010) Combined hyperlipidemia in patients with lysinuric protein intolerance. J inherit Metab Dis, EPub ahead of print.
  5. Yoshida Y, Machigashira K, Suehara M et al. (1995) Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci 134:178-182.
  6. Lukkarinen M, Parto K, Ruuskanen O et al. (1999) B and T cell immunity in patients with lysinuric protein intolerance. Clin Exp Immunol 116:430-434.
  7. Kamoda T, Nagai Y, Shigeta M et al (2001) Lysinuric protein intolerance in siblings: complication of systemic lupus erythematosus in the elder sister. Eur J Pediatr 160:522-523
  8. Parenti G, Sebastio G, Strisciuglio P et al. (1995) Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course. J Pediatr 126:246-251.