Activation in a Subgroup of Patients with Tourette Syndrome

To determine whether blood gene expression patterns distinguish heritable neurologic diseases for which no causative gene has been identified, we measured blood gene expression profiles in patients with familial Tourette syndrome (TS). TS is a chronic, childhood-onset disorder characterized by motor and vocal tics, which are

VPA resistant VPA responsive Drug free

Patient Groups

Figure 3.6 Hierarchical cluster analysis of 461 genes regulated by chronic VPA monotherapy.

A parametric f-test (BRB-Array Tools 2.0) was performed on 5053 genes that were highly expressed in blood to derive a group of 461 genes that were significantly regulated in the VPA group (n = 11) compared to the drug-free group (n = 7) (FDR < 0.1). Each gene was normalized to the median of 18 measurements so that its relative expression in each sample was indicated by the fold change relative to the median as represented by the density of the squares. The cluster analysis yielded three distinct clusters that correlate with whether the patients were drug free, seizure free while on VPA (VPA responsive), or continued having seizures while on VPA (VPA resistant). (From Tang, Y. et al., Acfa Neurol. Scand. 109(3), 2004. With permission.)

VPA resistant VPA responsive Drug free

Patient Groups

Figure 3.6 Hierarchical cluster analysis of 461 genes regulated by chronic VPA monotherapy.

A parametric f-test (BRB-Array Tools 2.0) was performed on 5053 genes that were highly expressed in blood to derive a group of 461 genes that were significantly regulated in the VPA group (n = 11) compared to the drug-free group (n = 7) (FDR < 0.1). Each gene was normalized to the median of 18 measurements so that its relative expression in each sample was indicated by the fold change relative to the median as represented by the density of the squares. The cluster analysis yielded three distinct clusters that correlate with whether the patients were drug free, seizure free while on VPA (VPA responsive), or continued having seizures while on VPA (VPA resistant). (From Tang, Y. et al., Acfa Neurol. Scand. 109(3), 2004. With permission.)

often accompanied by obsessive compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD).1718 Multigenerational family, twin, and adoption studies show evidence of autosomal dominant inheritance with varying penetrance and a more severe phenotype in cases of bilineal transmission.19-21 Despite the identification of large kindreds, the search for genes and linkage has been inconclusive to date.22

A variety of nongenetic factors are also associated with the onset or increased severity of tics and co-morbid OCD in patients with TS.23-28 In addition, it has been suggested that a subgroup of patients suffers from an autoimmune form of this disorder, termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).2930 Modeled on the paradigm of Sydenham's chorea, the PANDAS phenotype is characterized clinically by the temporal association of symptom onset or exacerbations with Group A beta hemolytic streptococcal (GABHS) infections.31 Thus, it appears possible that a number of environmental factors could modulate gene(s) that influence the vulnerability to or otherwise affect the TS phenotype. It is also possible that the TS phenotype has multiple genotypes, some of which confer susceptibility to contributing environmental factors.

In this study, we tried to use blood genomic profiling to detect the effects of possible genetic and environmental factors in TS. We reasoned that a high-throughput genomic approach might identify TS or TS subtypes that could then be subjected to further genetic analysis.

Permutation analysis showed that the blood gene expression pattern associated with TS has a p value = 0.2. In other words, 20% of random permutations of class label generated the same number of up- and downregulated genes. Thus, no evidence was found that the clinical diagnosis of TS is associated with a single, unique gene expression profile in whole blood that is significantly different from normal or diseased controls.

Subgroup analysis, however, showed that there were six upregulated genes and one downregulated gene in TS (p < 0.05 for each of 8 comparisons). Expression levels of these genes in TS are shown in Figure 3.4. These were all genes known to be expressed by lymphocytes, especially natural killer (NK) cells. Granzyme B (tested and confirmed by real-time polymerase chain reaction (RT-PCR) on 16 TS and 16 age-matched controls with 1.8-fold increase and Student's t test p = 0.09) is involved in the target killing process of cytotoxic T cells (CTL) or Natural Killer cells (NK) (Lord, 2003). NKG2E encodes a lectin-like receptor, which plays a role in the recognition of the MHC molecules by NK cells and some CTL cells. CD94 is also preferentially expressed by NK cells and forms heterodimers with NKG subunits.33 NK-p46 participates in NK-cell-mediated lysis of cells infected with intracellular bacteria.34

The one downregulated gene, IMPA2, is also of interest. IMPA2 plays a crucial role in the phosphatidylinositol signaling pathway. In the brain, its expression is substantially higher in subcortical regions, most prominently in the caudate, a region shown in many neuroimaging studies to be involved in TS and OCD.3536 It is also considered to be a strong candidate gene for bipolar disorder.3738

Although these genes are significantly regulated in TS compared to other groups, they all have a large variance within the TS group, which raised the question whether these genes might serve as markers to identify a subgroup of patients with TS. Using ^-means cluster analysis, TS and control samples were stratified into two clusters with samples in cluster A that are low expressers and samples in cluster B that are high expressers of these 6 CTL/NK genes (Figure 3.7 and Figure 3.8). Although there are a few higher expressers (cluster B) in each control group, the proportion of TS subjects in the higher expression group was significantly greater than the proportions in the control groups (chi square, p < 0.05). Permutation-based analysis showed that less than 4% of random permutations generated the same number of differentially expressed genes as those in clusters A and cluster B. This analysis suggests that the differences in expression profiles between the two TS clusters are not due to chance (p < 0.05).

Was this article helpful?

0 0
Understanding And Treating ADHD

Understanding And Treating ADHD

Attention Deficit Disorder or ADD is a very complicated, and time and again misinterpreted, disorder. Its beginning is physiological, but it can have a multitude of consequences that come alongside with it. That apart, what is the differentiation between ADHD and ADD ADHD is the abbreviated form of Attention Deficit Hyperactive Disorder, its major indications being noticeable hyperactivity and impulsivity.

Get My Free Ebook


Post a comment