Diagnostic methods for determining susceptibility to convulsive conditions

Abstract

The present invention exploits the discovery that amounts of uracil and thymine metabolites, especially β-aminoisobutyric acid, in various bodily fluids, especially urine, are correlated with the occurrence of epilepsy when compared to matched control subjects. Analytical and diagnostic protocols, including a novel high performance liquid chromatography system, for use in the invention are disclosed.

1 . A method of diagnosing a convulsive condition or susceptibility thereto in a subject comprising the steps of a. analyzing a bodily fluid from a subject for the presence or amount of a neuro-active molecule, or the relative amounts of neuro-active molecules, associated with a convulsive condition; and b. ediagnosing the subject as at risk of a convulsive condition or susceptibility thereto when the amount of said compound indicates a likelihood of same in said subject.  
   
   
       2 . A method of modulating the onset of a convulsive condition in a subject comprising the steps of analyzing a bodily fluid from a subject at risk of a convulsive condition for the presence or amount of a neuro-active molecule, or the relative amounts of neuro-active molecules, associated with a convulsive condition; determining from the amount of said compound in said bodily fluid whether said subject is at risk of a convulsive condition; and treating said subject, if at risk of a convulsive condition, to modulate the onset of said convulsive condition in said subject.  
   
   
       3 . A method of diagnosing a convulsive condition or susceptibility thereto in a subject comprising the steps of analyzing a bodily fluid from a subject for the presence or amount of a .beta.-amino acid, or the relative amount of .beta.-amino acid; and diagnosing the subject as at risk of a convulsive condition when the amount of said .beta.-amino acid indicates a likelihood of same in said subject.  
   
   
       4 . (canceled)  
   
   
       5 . The method of  claim 1 , wherein said neuro-active molecule is a metabolite of uracil or thymine, or a derivative thereof.  
   
   
       6 . The method of  claim 1 , wherein said compound is an amino acid or a derivative thereof.  
   
   
       7 . The method of  claim 5 , wherein said metabolite is a β-amino carboxylic acid.  
   
   
       8 . The method of  claim 5 , wherein said .beta.-amino acid is selected from β-aminoisobutyric acid and derivatives thereof.  
   
   
       9 . The method of  claim 1 , wherein said convulsive condition is selected from the group consisting of epileptogenic associated disorders, epileptogenesis, and non-epileptic convulsions.  
   
   
       10 . The method of  claim 1 , wherein said convulsive condition is an epileptogenic-associated disorder selected from epilepsy, head trauma, stroke, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, motor neuron disease, Alzheimer's disease, chicken-pox, measles, encephalitis, pertussis encephalitis, infections of the CNS, meningitis, encephalitis, subdural haematoma, brain tumour, birth defects, anoxic brain injury dementia, or other disorders in which altered activity of neuro-active molecules is a cause, at least in part, of the disorder.  
   
   
       11 . The method of  claim 1 , wherein said convulsive condition is selected from the group consisting of epilepsy and non-epileptic convulsions.  
   
   
       12 . The method of  claim 1 , wherein said subject has not yet developed seizures.  
   
   
       13 . The method of  claim 1 , wherein said treatment step comprises administering an effective amount of an anti-convulsive pharmaceutical composition.  
   
   
       14 . The method of  claim 1 , wherein said treatment step comprises administering an effective amount of an anti-epileptogenic pharmaceutical composition.  
   
   
       15 . The method of  claim 1 , further comprising the steps of deproteinizing said bodily fluid.  
   
   
       16 . The method of  claim 15 , wherein said deproteinizing step is ultrafiltration, ultracentrifugation, or chemical precipitation.  
   
   
       17 . The method of  claim 16 , wherein said chemical precipitation step employs sulfosalicylic acid, perchloric acid, trichloroacetic acid, picric acid, acetonitrile, ethanol, acetone, or methanol.  
   
   
       18 . The method of  claim 1 , further comprising derivatizing said amino acid prior to analyzing it.  
   
   
       19 . The method of  claim 18 , wherein said derivatizing step covalently attaches a chromophore to said amino acid.  
   
   
       20 . The method of  claim 18 , wherein said derivatizing step employs o-phthalaldehyde, 9-fluorenylmethylchloroformate, phenyl isothiocyanate, or 1-dimethylaminonaphthalene-5-sulphonyl chloride.  
   
   
       21 . The method of  claim 1 , wherein said bodily fluid is urine, blood, plasma, blood serum, cerebrospinal fluid, sweat, lymph, amniotic fluid, synovial fluid, conjunctival fluid, salivary fluid, vaginal fluid, stool, seminal fluid, bile, tears, or mixtures thereof.  
   
   
       22 - 40 . (canceled)