Study of the Pathophysiological Mechanisms Involved in Bleeding Events
Condition: Oculocerebrorenal Syndrome
MeSH terms: Oculocerebrorenal Syndrome; Syndrome; Hemorrhage
Study type: Interventional

Summary: 
      Lowe syndrome is associated with mutations in the OCRL1 gene, which encodes OCRL1, a
      phosphatidylinositol-4, 5-bisphosphate (PtdIns(4, 5)P (2))5-phosphatase. PtdIns(4, 5)P2, a
      substrate of OCRL1, is an important signaling molecule within the cell. An abnormal rate of
      hemorrhagic events was found in a retrospective clinical survey, suggesting platelet
      dysfunction.

      The main objective of the study is to confirm the presence of platelet dysfunction in Lowe
      syndrome and to characterize this abnormality.
    

Detailed description: 
      Introduction: Lowe syndrome (LS), also known as oculocerebrorenal syndrome of Lowe (OCRL), is
      a rare X-linked condition characterized by congenital cataracts, defective renal tubule cell
      function, muscular hypotonia and variable degrees of mental retardation. Patients with LS
      require frequent surgery, some of which are associated with a severe haemorrhagic risk, such
      as scoliosis reduction, hip surgery, or eye surgery. In a recent retrospective clinical
      survey of French LS patients, we observed an abnormal rate of haemorrhagic events, some of
      which had dramatic outcomes. LS is caused BYMUTATIONS in the OCRL gene, which encodes OCRL,
      an inositol polyphosphate 5-phosphatase. The preferred OCRLsubstrate is the membrane
      phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). OCRL also contains a Rho
      GTPase-activating protein(GAP)-like domain that participates in the regulation of Rho
      proteins (Rho, Rac, Cdc42), as GTPase-activating proteins or by mediating in protein-protein
      interactions. PtdIns(4,5)P2 and Rho-dependent signalling play a central role in many
      important cellular processes, including vesicular trafficking and cytoskeletal organization
      both of which are very important for platelet function. Thus, modulation of PtdIns(4,5)P2
      levels and/or Rho-dependent signalling would be expected to impact platelet function.

      Based on the clinical observation, we tested whether hemorrhagic symptom of 6 Lowe patients
      could be related to homeostasis abnormalities and we found that all the six patients had a
      prolonged closure time tested by PFA100 analyzer (Platelet Function Analyzer). These results
      were measured in absence of interfering factor such anemia, thrombopenia, or von Willebrand
      factor deficiency, thus suggesting platelet dysfunction.

      Study justification:

      The comprehension of the physiopathology implicated in the abnormal hemorrhagic risk is of
      major interest in term of prevention and clinical management in Lowe patients who requires
      frequent surgical care.

      Objectives:

      The main objective of the study is to confirm the presence of platelet dysfunction in Lowe
      syndrome and to characterize this abnormality. The secondary aims are to settle a functional
      test allowing the detection of patients with increasing hemorrhagic risk. Moreover, we could
      determinate whether platelet is an interesting cellular model, easily available, for further
      OCRL1 studies in Lowe patients.

      Methods:

      We will investigate platelet activation response in 15 Lowe cases and 15 normal cases. The
      evaluation criteria will include the PFA100, THROMBOELASTOMETRY (ROTEM), aggregation,
      secretion, adhesion in a flux system and clot retraction. We will also compare molecular
      (phospho-proteins, phospholipid...) and structural modifications of the non activated
      platelet and of activating platelet.

      Conclusion:

      The characterization of a platelet activation abnormality in Lowe patients could lead to
      major benefit for the patients with systematic homeostasis screening and special precautions
      rules before surgery, often required in this multisystemic condition. Moreover, this study
      could contribute to go further into PI(4,5)P2 signaling pathways and may provide clues to the
      interrelationship between these processes in normal metabolism and diseases states.
    

Intervention name(s): Blood sample
Intervention type(s): Other
Intervention description(s): Blood sample
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Lowe syndrome; OCRL; Haemostasis; Bleeding Disorders; Platelet Function Tests