Neurons and neuronal systems involved in the pathophysiologies of Rett syndrome

It has long been suspected that the Rett syndrome (RS) is associated with abnormality of monoaminergic systems, particularly in the brainstem and midbrain, with spread to basal ganglia and cerebral cortex. Early investigators found no significant abnormality in the level of metabolites of noradrenaline, dopamine or serotonin in the spinal fluid, but autopsy brain studies revealed reduced levels of these substances and their metabolites as well as cortical choline acetyltransferase (ChAT) and microtubule-associated proteins (MAP). Levels of Substance P in spinal fluid of RS girls have been reported to be low, while levels of glutamate are raised. Attempts to assess dopaminergic activity by positron emission tomography (PET) in RS have given variable results with different reagents, including [18F] 6-fluorodopa. Our group investigated nine RS patients after the age of 12 years and control girls of similar age. Volumetric scans of basal ganglia with Magnetic Resonance Imaging showed a significant reduction in the size of caudate heads and thalami in RS (but not in the size of lentiform nuclei). PET scans with [11C] raclopride and with [18F] 6-fluorodopa under intravenous propofol anesthesia showed the mean uptake of fluorodopa to be reduced by 13.1% in caudate and by 12.4% in putamen as compared to the controls, whereas dopamine D2 receptor binding, as indicated by raclopride binding, was significantly increased by 9.7% in caudate and by 9.6% in putamen.