Neurofibromin/dopamine signaling as a biomarker for cognitive and behavioral problems in children with neurofibromatosis type 1 (nf1)

Abstract

The present disclosure is generally related to neurofibromatosis type 1. More particularly, disclosed herein are methods for detecting behavioral disorders, methods for detecting cognitive impairment, and methods for detecting brain neurofibromin-dependent dopaminergic signaling associated with neurofibromatosis type 1.

What is claimed is: 
     
         1 . A method for detecting a behavioral disorder in a subject having or suspected of having neurofibromatosis type 1 (NF1), the method comprising:
 obtaining an expression level of neurofibromin in a sample obtained from the subject having or suspected of having neurofibromatosis type 1 (NF1);   obtaining a reference expression level of neurofibromin from a healthy subject;   identifying a difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin, wherein the difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin indicates a memory defect in a subject having or suspected of having neurofibromatosis type 1 (NF1).   
     
     
         2 . The method of  claim 1  further comprising identifying an expression level of dopamine. 
     
     
         3 . The method of  claim 1  further comprising identifying phosphorylation of dopamine and cAMP regulated neuronal phosphoprotein (DARPP-32). 
     
     
         4 . The method of  claim 1  further comprising detecting a point mutation in a neurofibromin exon wherein the exon is selected from the group consisting of exon 18, exon 21 and combinations thereof. 
     
     
         5 . The method of  claim 4  wherein the point mutation in exon 18 is c.2041C>T of human Nf1 gene. 
     
     
         6 . The method of  claim 4  wherein the point mutation in exon 21 is c.2542G>C of human Nf1 gene. 
     
     
         7 . The method of  claim 1  wherein the behavioral disorder is selected from the group consisting of attention deficit/hyperactivity disorder (ADHD), autism, learning difficulties, and combinations thereof. 
     
     
         8 . A method for detecting a cognitive impairment in a subject having or suspected of having neurofibromatosis type 1 (NF1), the method comprising:
 obtaining an expression level of neurofibromin in a sample obtained from the subject having or suspected of having neurofibromatosis type 1 (NF1);   obtaining a reference expression level of neurofibromin from a healthy subject;   identifying a difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin, wherein the difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin indicates a memory defect in a subject having or suspected of having neurofibromatosis type 1 (NF1).   
     
     
         9 . The method of  claim 8  further comprising identifying an expression level of dopamine. 
     
     
         10 . The method of  claim 8  further comprising identifying phosphorylation of dopamine and cAMP regulated neuronal phosphoprotein (DARPP-32). 
     
     
         11 . The method of  claim 8  further comprising detecting a point mutation in a neurofibromin exon wherein the exon is selected from the group consisting of exon 18, exon 21 and combinations thereof. 
     
     
         12 . The method of  claim 11  wherein the point mutation in exon 18 is c.2041C>T of human Nf1 gene. 
     
     
         13 . The method of  claim 11  wherein the point mutation in exon 21 is c.2542G>C of human Nf1 gene. 
     
     
         14 . The method of  claim 8  wherein the cognitive impairment is selected from the group consisting of a learning disability, attention deficit, autistic-like behavior, visuospatial learning/memory problem and combinations thereof. 
     
     
         15 . A method for detecting altered brain neurofibromin-dependent dopaminergic signaling in a subject having or suspected of having neurofibromatosis type 1 (NF1), the method comprising:
 obtaining an expression level of neurofibromin in a sample obtained from the subject having or suspected of having neurofibromatosis type 1 (NF1);   obtaining a reference expression level of neurofibromin from a healthy subject;   identifying a difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin, wherein the difference between the expression level of the neurofibromin in the sample obtained from the subject and the reference expression level of the neurofibromin indicates a memory defect in a subject having or suspected of having neurofibromatosis type 1 (NF1).   
     
     
         16 . The method of  claim 15  further comprising identifying an expression level of dopamine. 
     
     
         17 . The method of  claim 16  further comprising identifying phosphorylation of dopamine and cAMP regulated neuronal phosphoprotein (DARPP-32). 
     
     
         18 . The method of  claim 16  further comprising detecting a point mutation in a neurofibromin exon wherein the exon is selected from the group consisting of exon 18, exon 21 and combinations thereof. 
     
     
         19 . The method of  claim 18  wherein the point mutation in exon 18 is c.2041C>T of human Nf1 gene. 
     
     
         20 . The method of  claim 18  wherein the point mutation in exon 21 is c.2542G>C of human Nf1 gene.