Study of the Pathophysiological Mechanisms Involved in Bleeding Events Observed in Patients With Lowe Syndrome
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.
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.
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.
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.
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.
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls
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
Geneviève Baujat, MD, PhD
Hôpital Necker Enfants Malades, Paris
France: Ministry of Health