TTCT 1471 mutation in lysnuric protein intolerance: clinical features of a Tunisian paediatric series.


Elhem Jbebli
Yosra Jbeli
Rym Amdouni
Rim Ben Abdelaziz
Héla Boudabous
Amel Ben Chehida
Slim Abdelmoula


Introduction: Lysinuric protein intolerance (LPI) is a rare inherited metabolic disease. It is caused by a deficiency in cationic amino acid transport caused by mutations in SLC7A7 gene.

Aim: To identify the clinical, diagnostic and therapeutic features of lysnuric protein intolerance.

Methods: This was a retrospective study conducted in the pediatric department of La Rabta Hospital over a period of 30 years (1992 to 2022). We included patients with clinical signs suggestive of lysinuric protein intolerance and orotic acid in the urine.

Results: We enrolled seven patients. The median age at disease onset was nine months. The median age at positive diagnosis was 21 months. Growth retardation, hepatosplenomegaly and haematological abnormalities were the main features of the disease. Hyperammonia and increased urinary orotic acid were present in all patients. Molecular biology revealed the del TTCT 1471 mutation in five patients. All patients were prescribed a low protein diet and citrulline supplementation. Complications of the disease were growth retardation (n=7), psychomotor or intellectual retardation (n=5), haemophagocytic lymphohistiocytosis (n=4) and osteoporosis (n=3). After a median follow-up of 11 years, six of our patients are still alive. One patient died from acute hyperammonemic encephalopathy.

Conclusion: In this paediatric series, delays in diagnosis and treatment of LPI were responsible for long-term sequelae, particularly bone and neurological. The delTTCT1471 mutation appears to be the mutation of paediatric-onset forms in Tunisia. This mutation was not associated with pulmonary involvement, which is a prognostic factor and the main cause of death.


Hereditary metabolic disease , Urea cycle, Macrophagic activation, Osteoporosis



  1. Sebastio G, Sperandeo MP, Andria G. Lysinuric protein intolerance: reviewing concepts on a multisystem disease. Am J Med Genet C Semin Med Genet. 15 févr 2011;157C(1):54‑62.
  2. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. mai 2012;106(1):12‑7.
  3. The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K. W., and Vogelstein, B., eds., 8th ed., McGraw-Hill, New-York, 2001, 7012 p., $550.00). Biochem Mosc. 1 mai 2002;67(5):611‑2.
  4. Rajantie J, Simell O, Rapola J, Perheentupa J. Lysinuric protein intolerance: a two-year trial of dietary supplementation therapy with citrulline and lysine. J Pediatr. déc 1980;97(6):927‑32.
  5. Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, et al. Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood. Orphanet J Rare Dis. 5 janv 2017;12(1):3.
  6. Nunes V, Niinikoski H. Lysinuric Protein Intolerance. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., éditeurs. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cité 19 déc 2023]. Disponible sur:
  7. Kurko J, Tringham M, Tanner L, Näntö-Salonen K, Vähä-Mäkilä M, Nygren H, et al. Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI). Metabolism. sept 2016;65(9):1361‑75.
  8. Esseghir N, Bouchlaka C, Fredj S, Chehida A, Azzouz H, Fontaine M, et al. 1471 delTTCT a Common Mutation of Tunisian Patients with Lysinuric Protein Intolerance. Clin Lab [Internet]. 2015 [cité 18 déc 2023];61(12/2015). Disponible sur:
  9. Font-Llitjós M, Rodríguez-Santiago B, Espino M, Sillué R, Mañas S, Gómez L, et al. Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat. Eur J Hum Genet. janv 2009;17(1):71‑9.
  10. Esseghir N, Bouchlaka CS, Fredj SH, Chehida AB, Azzouz H, Fontaine M, et al. First Report of a Molecular Prenatal Diagnosis in a Tunisian Family with Lysinuric Protein Intolerance. In: JIMD Reports - Case and Research Reports, 2011/1: Case and Research Reports [Internet]. Berlin, Heidelberg: Springer; 2011 [cité 18 déc 2023]. p. 37‑8. (JIMD Reports). Disponible sur:
  11. Niinikoski H, Lapatto R, Nuutinen M, Tanner L, Simell O, Näntö-Salonen K. Growth hormone therapy is safe and effective in patients with lysinuric protein intolerance. JIMD Rep. 2011;1:43‑7.
  12. Palacín M, Bertran J, Chillarón J, Estévez R, Zorzano A. Lysinuric protein intolerance: mechanisms of pathophysiology. Mol Genet Metab. avr 2004;81 Suppl 1:S27-37.
  13. Noguchi A, Nakamura K, Murayama K, Yamamoto S, Komatsu H, Kizu R, et al. Clinical and genetic features of lysinuric protein intolerance in Japan. Pediatr Int. oct 2016;58(10):979‑83.
  14. Parto K, Penttinen R, Paronen I, Pelliniemi L, Simell O. Osteoporosis in lysinuric protein intolerance. J Inherit Metab Dis. 1993;16(2):441‑50.
  15. Svedström E, Parto K, Marttinen M, Virtama P, Simell O. Skeletal manifestations of lysinuric protein intolerance. A follow-up study of 29 patients. Skeletal Radiol. 1993;22(1):11‑6.
  16. Doireau V, Fenneteau O, Duval M, Perelman S, Vilmer E, Touati G, et al. [Lysinuric dibasic protein intolerance: characteristic aspects of bone marrow involvement]. Arch Pediatr Organe Off Soc Francaise Pediatr. sept 1996;3(9):877‑80.
  17. Duval M, Fenneteau O, Doireau V, Faye A, Emilie D, Yotnda P, et al. Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr. févr 1999;134(2):236‑9.
  18. Tanner LM, Niinikoski H, Näntö-Salonen K, Simell O. Combined hyperlipidemia in patients with lysinuric protein intolerance. J Inherit Metab Dis. déc 2010;33 Suppl 3:S145-150.
  19. Parenti G, Sebastio G, Strisciuglio P, Incerti B, Pecoraro C, Terracciano L, et al. Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course. J Pediatr. févr 1995;126(2):246‑51.