Study of the Pathophysiological Mechanisms Involved in Bleeding Events Observed in Patients With Lowe Syndrome
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 30
- Locations
- 2
- Primary Endpoint
- The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls
Study Overview
Brief 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:
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Diagnostic
- Masking
- None
Eligibility Criteria
- Ages
- 6 Years to 45 Years (Child, Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Patient with a clinical syndrome of Lowe (congenital cataracts, renal tubular dysfunction and neuromuscular damage) with a molecular defect in the gene known OCRL
- •For the centre of Necker, patients should have a weight> 10 kg. For the centre of Toulouse site, patients should have a weight> 40 kg.
- •No alteration of glomerular function (creatinine clearance> 30 ml/min/1.73m ²)
- •No significant anemia (hematocrit> 25%, hemoglobin> 8 g / L)
- •Every patient should have included a signed informed consent. For minor patients, the consent of parents or legal guardian must be obtained.
- •Patients may be included only if they receive social security coverage or CMU
Exclusion Criteria
- •Weight less than 10 kg for the centre of Necker
- •Weight less than 40 kg for the centre of Toulouse
- •Major renal insufficiency (creatinine clearance <30 ml/min/1.73m ²)
- •Profound anemia (hematocrit <25%, Hb <8g/dl)
- •Patients taking drugs interfering with hemostasis in the eight days before the survey
- •Patients with major behavior disorder making it difficult to achieve the blood sample, despite the nitrous oxide
- •Patients with a other pathology of hemostasis (hemophilia, thrombotic disease)
- •Participation in another clinical study requiring a blood sample within 4 weeks
- •Contraindication to EMLA patch: confers Summary of Product Characteristics.
- •Contraindication to KALINOX: confers Summary of Product Characteristics.
Outcomes
Primary Outcomes
The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls
Time Frame: 18 months
The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls. Various platelet responses will be studied: * The measurement of platelet closure time by PFA100 * Aggregation, retraction, secretion and adhesion
Secondary Outcomes
- Characterization of abnormalities in platelet-signalling pathways(18 months)