title: Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood.
abstract: Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit y+LAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management.
  
  
  
  Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16).
  
  
  
  As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Mauhin
authors.affiliation: Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Habarou
authors.affiliation: Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gobin
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.|Nephrology Unit, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Servais
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Brassier
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Coraline
authors.initials: C
authors.lastname: Grisel
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Célina
authors.initials: C
authors.lastname: Roda
authors.affiliation: Endocrinoloy Unit, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Graziella
authors.initials: G
authors.lastname: Pinto
authors.affiliation: Paediatric Immunology, Haematology and Rheumatology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Gastroenterology, Kremlin Bicêtre Hospital, AP-HP, University Paris Sud, Paris, France.
authors.forename: Fahd
authors.initials: F
authors.lastname: Ghalim
authors.affiliation: Nephrology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Krug
authors.affiliation: Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Deltour
authors.affiliation: Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Pontoizeau
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dubois
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Assoun
authors.affiliation: Anatomopathology, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Galmiche
authors.affiliation: Molecular Genetics, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.affiliation: Metabolic Biochemistry, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Pneumology, Hospital Necker Enfants Malades, AP-HP, University Paris Descartes, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: de Blic
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Arnoux
authors.affiliation: Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France. pascale.delonlay@aphp.fr.|Reference Center of Metabolic Disease Unit, Université Paris Descartes, Hôpital Necker-Enfants Malades, Institute Imagine, INSERM-U781, 149 rue de Sèvres, 75015, Paris, France. pascale.delonlay@aphp.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
mesh_terms: D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000097:blood / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000097:blood; D000071069:Multiple Chronic Conditions; D009154:Mutation; D009203:Myocardial Infarction / Q000097:blood / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D011649:Pulmonary Alveolar Proteinosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D008239:Lysine
keywords: Amyloidosis; Hemophagocytic lymphohistiocytosis; Hyperammonemia; Inborn error of metabolism; Lupus; Lysine; Lysinuric protein intolerance; Myocardial infarction; Pulmonary alveolar proteinosis; Urea Cycle disorder