Diagnostic tools for charcot-marie-tooth disease

Abstract

The present invention relates in particular to methods of detecting predisposition to or diagnosis and/or prognosis of Charcot-Marie-Tooth disease (CMT) and related disorders. More specifically, the invention relates to development, validation and application of new biomarkers which can be used for detecting the presence or risk of CMT disease and related disorders. In particular, the present invention relates to metabolite, lipid, carbohydrate and proteinaceous biomarkers that can be measured in biological body fluids and easily available extracts of biopsies, which can be used to aid in the detection, prediction of drug treatment and follow-up of this treatment of neurodegenerative disorders, including CMT disease. The present invention also relates to methods for identification of CMT disease subtypes and assessing the responsiveness to treatments and the efficacy of treatments in subjects having CMT or a related disorder.

We claim: 
     
         1 . A method for predicting the responsiveness to a treatment of CMT disease and for treating an individual suffering from CMT, the method comprising:
 i) determining in vitro the free cholesterol level in a biological sample from said individual,   ii) predicting the responsiveness of said individual to said treatment by comparing the free cholesterol level obtained in i) to a reference value of a responder or non-responder group, and   iii) treating said individual predicted to be responsive with said treatment.   
     
     
         2 . The method of  claim 1 , wherein said reference value is a reference value of a non-responder group and wherein a lower free cholesterol level in the individual as compared to the reference value is indicative that the individual shall respond to the treatment. 
     
     
         3 . The method of  claim 2 , wherein said lower free cholesterol level is at least 5% lower than said reference value. 
     
     
         4 . The method of  claim 1 , wherein said biological sample is a plasma sample and wherein said reference value of a responder or non-responder group is the free cholesterol level in plasma of a responder or non-responder group. 
     
     
         5 . The method of  claim 4 , wherein the reference value of free cholesterol level in plasma in a responder group is less than 483 μg/ml. 
     
     
         6 . The method of  claim 4 , wherein the reference value of free cholesterol level in plasma in a non-responder group is superior to 520 μg/ml. 
     
     
         7 . The method of  claim 4 , wherein a free cholesterol level in said plasma sample in said individual superior to 520 μg/ml is indicative that the individual shall not respond to said treatment. 
     
     
         8 . The method of  claim 4 , wherein a free cholesterol level in said plasma sample in said individual below or equal to 483 μg/ml is indicative that the individual shall respond to said treatment. 
     
     
         9 . The method of  claim 1 , wherein said treatment of CMT disease comprises administering baclofen, naltrexone and sorbitol, or salts thereof, to said individual. 
     
     
         10 . The method of  claim 1 , wherein said CMT disease is CMT1A. 
     
     
         11 . The method of  claim 1 , wherein said reference value is a reference value of a responder group with similar age, sex, condition, and/or any ongoing treatment. 
     
     
         12 . An in vitro method for assessing efficacy of a treatment against CMT in a subject, the method comprising determining in a fluid biological sample from the subject, during the treatment, the (relative) amount or alteration of free cholesterol level and comparing said amount or alteration to a level of free cholesterol determined before treatment or at an earlier stage of treatment in said individual, wherein a deviation is indicative of the efficacy of the treatment. 
     
     
         13 . The method of  claim 12 , wherein said amount or alteration is a decrease of free cholesterol in regard of total cholesterol. 
     
     
         14 . The method of  claim 12 , wherein the relative amount or the presence of at least a second biomarker is determined, simultaneously or sequentially. 
     
     
         15 . The method of  claim 14 , wherein said at least one second biomarker is selected from LDL cholesterol, alanine, α-aminobutyric acid, citrulline, cystine, glutamine, hydroxyproline, lysine, methionine, proline, threonine, tryptophan, tyrosine, T4 thyroid hormone, testosterone, iron, LTB4, adrenaline, dopamine or serotonin. 
     
     
         16 . The method of  claim 14 , wherein the level of said biomarker(s) is compared to a reference value and wherein the deviation from said value is indicative of the efficacy of said treatment. 
     
     
         17 . The method of  claim 12 , wherein CMT disease is CMT1A. 
     
     
         18 . The method of  claim 12 , wherein the treatment is continued in an individual in whom a deviation of the (relative) amount or alteration of free cholesterol level is determined. 
     
     
         19 . The method of  claim 12 , wherein said treatment against CMT comprises administering baclofen, naltrexone and sorbitol, or salts thereof, to said individual. 
     
     
         20 . The method of  claim 12 , wherein the time interval between the measures of free cholesterol level is at least 2 months, preferably 3 or 4 months.