Neurophysiology of Rett syndrome

Neurophysiological evaluations have been widely applied in the study of Rett syndrome (RS) to provide information concerning the developmental aspects of RS; the character and extent of involvement of the central, peripheral, and autonomic nervous system pathways; and evaluation of the clinical symptomatology of RS. The electroencephalogram (EEG) is invariably abnormal and shows characteristic, though not diagnostic, changes: loss of expected developmental features; the appearance of focal, multifocal, and generalized epileptiform abnormalities; and the occurrence of rhythmic slow (theta) activity primarily in the frontal-central regions. Epileptic seizures are reported to occur frequently in RS, and partial and generalized seizures may be experienced by RS girls. However, many events presumed to be seizures have no EEG correlate during video-EEG monitoring, suggesting the possibility of a nonepileptic mechanism. Such monitoring may be necessary to determine appropriate use of antiepileptic drugs. Evoked potentials typically demonstrate intact peripheral auditory and visual pathways and suggest dysfunction of central or "higher" cortical pathways. Somatosensory-evoked potentials may be characterized by "giant" responses, suggesting cortical hyperexcitability. An increased incidence of long QT intervals during electrocardiographic recordings and diminished heart-rate variability, suggesting impairment of the autonomic nervous system, are described in RS. With the discovery of the genetic basis of RS, neurophysiological studies will provide parameters for phenotype-genotype correlations and characterization of animal models.     

Neuropathology of Rett syndrome

Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72-76.     

Clinical manifestations and stages of Rett syndrome

The presentation and clinical diagnosis of Rett syndrome at various ages and stages are reviewed. In addition to the classical form, variability in phenotype between different atypical Rett forms is given. Obligatory, supportive, and differential diagnostic criteria are summarized. Long-term follow-up findings in ageing Rett women are addressed.     

Behavioral competition in a case of Rett syndrome

Major behavioral features of Rett syndrome are the loss of instrumental reaching and grasping and the presentation of some variant of hand-hand or hand-mouth stereotypy. As part of an experimental home intervention program, a 3-year-old girl with Rett syndrome was exposed to four types of contingency games designed to elicit instrumental reaching, kicking, vocalization, and eye movement, respectively. Parent and subject performance were videorecorded on seven occasions over the initial 2-month period. Evaluation of these records provided evidence of contingency learning in all but the vocalization games. Stereotypic hand clasping was examined in relation to the performance of instrumental behavior (reaching, kicking, looking). Coincidental (short-term mutual inhibition arising by chance co-occurrence), associative (short-term mutual inhibition arising by having elicitor in common), and foundational (long-term mutual inhibition arising by having neural network in common) forms of specific behavioral competition were defined and examined. Evidence for coincidental and foundational competition was found in the relation between reaching and hand clasping. Implications for the support of functional hand use are discussed.     

The phenotypic consequences of MECP2 mutations extend beyond Rett syndrome

Although MECP2 was initially identified as the causative gene in classic Rett syndrome (RTT), the gene has now been implicated in several phenotypes that extend well beyond the clinically defined disorder. MECP2 mutations have been found in people with various disorders, including neonatal onset encephalopathy, X-linked recessive mental retardation (MRX), classic and atypical RTT, autism, and Angelman syndrome, as well as mildly affected females and normal carrier females. To make matters more complex, in approximately 20% of classic sporadic RTT cases and more than 50% of affected sister pairs, no mutation in MECP2 has been found. X-chromosome inactivation patterns can clearly affect the phenotypic expression in females, while the effect of the type and position of the mutation is more apparent in the broader phenotype than in RTT. Both males and females are at risk, although an excess of paternally derived mutations are found in most cases of classic RTT. Thus, because of the range of disparate phenotypes, the gene may account for a relatively large portion of mental retardation in the population.     

Case study: Noninvasive behavioral treatment of self-injurious hand stereotypy in a child with Rett syndrome

Treatment of stereotypic hand mouthing in a 3-year-old girl with Rett syndrome by differential reinforcement of competing functional responses plus response interruption is described and evaluated in this case study. A package of graduated guidance with social and edible reinforcers successfully established stable rates of functional hand movements to activate toys, gross motor responses to verbal prompts, palmar grasp and release, and some vocal imitation. Contingent response interruption virtually eliminated hand mouthing during instructional sessions. Instruction alone did not maintain hand mouthing suppression when interruption was withdrawn, and treatment gains appeared highly discriminated. Post-hoc comparison indicated differential reinforcement plus response interruption (DR1 + 1) to be superior to hand splints in reducing hand stereotypies, with approximately equivalent increases in collateral tongue thrusting.