The Role of Susceptibility to Thrombosis in the Pseudotumor Cerebri of Nephropathic Cystinosis: A Case-Control Study
Condition: Pseudotumor Cerebri; Cystinosis
MeSH terms: Pseudotumor Cerebri; Fanconi Syndrome; Thrombosis; Cystinosis; Disease Susceptibility
Study type: Observational

Summary: 
      This study will examine whether the tendency to have thrombosis, or the formation of blood
      clots inside blood vessels, has a role in the development of pseudotumor cerebri (PTC). PTC
      causes symptoms and signs of isolated elevated blood pressure in the cranium, or covering of
      the brain. The disorder can lead to significant, negative effects on the visual system.
      Increased pressure of the cerebrospinal fluid, that is, fluid around the brain, is a factor,
      but the cause of the disorder is not clear. There has been documentation of clustering of PTC
      within families. It suggests that potential genetic polymorphisms-abilities to take on
      different forms-may become evident after exposure to conditions known to trigger PTC.

      Thrombosis comes about by interactions between genetic and environmental or acquired factors,
      or both, resulting in a blood clot at a specific time and location. Because the disease
      occurs in episodes, the interaction of the genetic and nongenetic risk factors is important.
      Cystinosis is a recessive disorder caused by deposits of cystine within the lysosomes of
      cells-that is, sac-like cell parts that contain various enzymes. Involvement of the kidneys
      remains the primary characteristic, eventually leading to renal failure. Of all of the risk
      factors that make it easier for blood clotting, a high level of a substance called
      homocysteine is of particular interest. Too much homocysteine in blood plasma is a common
      finding in patients with kidney failure, and it has been recently identified as an
      independent risk factor for diseases of the blood vessels.

      Participants of all ages who meet the Dandy criteria for PTC may be eligible for this study.
      Pregnant women will be excluded. There will also be a control group of nephropathic
      cystinosis patients who do not have PTC.

      Participants will be asked to undergo the following tests and procedures:

        -  Medical history.

        -  Physical examination, to evaluate the eye and nervous systems.

        -  Collection of blood for DNA and other tests.

        -  Collection of cerebrospinal fluid, through a procedure called lumbar puncture or spinal
           tap.

      The evaluation of patients will generally last 3 to 4 days. For the collection of
      cerebrospinal fluid, the patient's skin on the back will be numbed with a local anesthetic. A
      special needle will be inserted into the back, and a small amount of the fluid will be drawn
      through the needle. There will be pain for a minute, although there can be a headache lasting
      24 hours. Also, there may be bruising, local pain, bleeding, or infection where the needle
      enters. Patients may also have a magnetic resonance imaging scan of their head. During the
      MRI scan, patients will lie still on a table that slides in and out of a metal cylinder
      surrounded by a strong magnetic field. Patients will be able to communicate with the MRI
      staff at all times and may ask to be moved out of the machine at any time.
    

Detailed description: 
      During the follow-up of cystinosis patients under protocol #78-HG-0093 "Use of Cysteamine in
      the Treatment of Cystinosis", we found that 6 of our NIH patients developed papilledema and
      were diagnosed with pseudotumor cerebri (PTC), whose occurrence has not been previously
      reported in cystinosis. The goal of this protocol is to identify the role of thrombosis
      susceptibility in the development of PTC in nephropathic cystinosis patients in view of our
      recent findings regarding genetic susceptibility to thrombosis in PTC in general. We propose
      a case-control study. A total of 9 nephropathic cystinosis patients who developed PTC and 9
      control nephropathic cystinosis patients without PTC will be screened based upon a thrombosis
      susceptibility screening panel, including total homocysteine, protein C and S, antithrombin
      III, fibrinogen, Factor VIII, Factor IX, Factor XI levels, testing for PT, PTT, activated
      protein C resistance, antiphospholipid antibodies (ACA panel and Lupus AC) and screening for
      FV Leiden mutation, FV G1628A polymorphism, FV R2 allele, Prothrombin 20210 mutation and
      5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with
      severe homocysteinemia (greater than or equal to 100 micro mol/l).

      We will compare the prevalence of the factors that lead to thrombosis susceptibility in the
      cases and controls.
    

Keywords: Thrombophilia; Idiopathic Intracranial Hypertension; Kidney Involvement; Lysosomal Storage Disorder; Cystine; Pseudotumor Cerebri; Susceptibility to Thrombosis; Nephropathic Cystinosis; PTC; Intracranial Hypertension