Brain metabolism in rett syndrome: Age, clinical, and genotype correlations

Abstract

Objective Brain metabolism, as studied by magnetic resonance spectroscopy (MRS), has been previously shown to be abnormal in Rett syndrome (RTT). However the relationship of MRS findings to age, disease severity and genotype is unknown. This study reports MRS findings in 40 RTT girls (1–14 years old) and 12 age-matched controls. Methods Single voxel, short echo time proton MRS of left frontal lobe white matter was performed. Levels of myo-inositol (mI), total choline (Cho), glutamate/glutamine (Glx), and N-acetyl aspartate (NAA) were expressed as ratios relative to creatine (Cr). Results NAA/Cr ratios decreased and mI/Cr ratios increased with age in RTT (both p<0.03) while these ratios were stable in controls. The mean Glx/Cr ratio was 36% higher in RTT than in controls (p=0.043). The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared to those without seizures (p=0.017). NAA/Cr ratios also decreased with increasing clinical severity score (p=0.031). Compared to patients with T158X, R255X, and R294X mutations, and C-terminal deletions, patients with the R168X mutation tended to have the highest severity score (0.01≤p≤0.11) and the lowest NAA/Cr ratio (0.029≤p<0.14). Interpretation Decreasing NAA/Cr and increasing mI/Cr with age are suggestive of progressive axonal damage and astrocytosis in RTT respectively, while increased Glx/Cr ratio may be secondary to increasing glutamate-glutamine cycling at the synaptic level. The relationships between NAA/Cr, presence or absence of seizures, and disease severity suggest that MRS provides a non-invasive measure of cerebral involvement in RTT, with greatest impairment in patients with the R168X mutation.

Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice

“…Chronic sleep deprivation can lead to chronically elevated glutamate levels in the extrasynaptic space, which may be one of the reasons of the higher levels detected in the CSF of RTT patients (Lappalainen and Riikonen, 1996; Horska et al, 2009). The resulting raised glutamate itself then can act through extrasynaptic glutamate receptors and disrupt brain function and sleep structure (Hardingham and Bading, 2010).…”

Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission

“…Seizures occur in the majority of RTT patients (Jian et al 2007;Nissenkorn et al 2010), but the frequency and severity of seizures tend to decrease into adolescence and adulthood, suggesting that possible deficits in excitatory/inhibitory imbalance may be limited to early developmental stages (Steffenburg et al 2001). This epileptic activity is suggestive of cortical hyperexcitability (Glaze 2005), and, taken together with the observed decreases in the threshold for action potential firing, higher glutamate levels, and increased N-methy-D-aspartate (NMDA) receptor density in different areas of the cortex (Blue et al 1999;Eyre et al 1990;Horska et al 2009), these observations imply that the brains of RTT patients favor excitation over inhibition.…”

Altered Carbon Dioxide Metabolism and Creatine Abnormalities in Rett Syndrome

“…Even so, an 8% greater mean creatine concentration was previously found in the frontal white matter in the RTT group. This difference was not significantly different, because of a high variability in creatine levels in both RTT and control groups (Horská et al 2000(Horská et al , 2009. Nevertheless, in case of a decreased expression of SLC6A8, less creatine would be present in the brain, making this diagnosis highly unlikely in our patients (Salomons et al 2001).…”

“…According to the reference values for creatine, creatine concentrations normally decrease with increasing age (Salomons et al 2003). Furthermore, Horská and colleagues reported stable creatine concentrations with increasing age in RTT girls using proton magnetic resonance spectroscopy (Horská et al 2009). Consequently, it seems highly unlikely that the altered creatine concentrations can be explained by age.…”

“…The clinical phenotypes of RTT and an X-linked creatine transporter deficiency overlap regarding mental retardation, epilepsy, and language delay (Salomons et al 2001). However, few studies have examined the brain metabolites of RTT females using proton magnetic resonance spectroscopy (G€ okcay et al 2002;Hashimoto et al 1998;Horská et al 2000Horská et al , 2009Khong et al 2002;Pan et al 1999). Overall, N-acetylaspartate/total creatine was significantly decreased compared with age-matched controls, primarily reflecting reduced N-acetylaspartate levels.…”