Early motor disturbances in Rett syndrome and its pathophysiological importance

doi:10.1016/j.braindev.2004.11.010

Brain and Development

Volume 27, Supplement 1, November 2005, Pages S54-S58

https://doi.org/10.1016/j.braindev.2004.11.010 Get rights and content

Abstract

Assessment of the development of motor function of Rett syndrome (RTT) revealed hypotonia with failure of crawling and disturbance in skillful hand manipulation are shown as early motor signs. Clinical evaluation has revealed the former as postural hypotonia with failure in locomotion and neurophysiological examinations have showed this to be due to hypofunction of the aminergic neurons of the brainstem. The latter signs are considered to indicate dysfunction of the corticospinal tract at higher levels. As the signs appear along with deceleration of head growth, dysfunction of the noradrenergic neuron, which is involved in synaptogenesis in the cerebral cortex, is postulated as the cause. The characteristic stereotyped hand movements appear in early childhood after loss of purposeful hand use and are underlain by rigid hypertonus. Neurophysiological examinations have indicated that these are due to hypofunction of the nigrostriatal (NS) dopamine (DA) neuron. By comparison with animal experimental work the neurohistochemical changes in the substantia nigra of the autopsied brain of RTT suggest a lesion caused by the dysfunction of the pedunculopontine nucleus, induced by dysfunction of the brainstem aminergic neurons which modulate postural tone and locomotion. Hypofunction of the aminergic neurons also cause ‘leakage’ of atonia into nonREM stages which lead to disturbances in the autonomic nervous system through inhibition of the reflex system. The grade of disturbance of locomotion closely matches the grade in abnormalities of higher cortical function as indicated by the development of meaningful words. The loci of missense mutation of methyl CPG binding domain of MECP 2gene which affect locomotion severely also markedly impaired their effects on the formation of the heterochromatin. Thus, dysfunction of the aminergic neurons of the brainstem which regulate postural tone and locomotion is proposed as the primary lesion.

Introduction

Rett syndrome (RTT) is characterized by stereotyped hand movement with dystonic posture, appearing in early childhood after the loss of purposeful hand use. However, in infancy hypotonia, failure in crawling and lack of skill in fine finger movements are noticeable. To evaluate the pathophysiology of these early motor signs and their age dependent changes advances understanding of the neurons or neuronal systems primarily affected and the basic neuronal patho-mechanism underlying the age related occurrence of the particular signs in RTT.

Furthermore, demonstration of the neuron or neurons involved in the initial signs assists elucidation of the primary lesion or lesions in RTT and making it possible to understand how the mutations in the Methyl-CpG-binding protein 2 (MeCP 2) gene cause RTT.

In this report, we review our previous studies on early motor signs, demonstrate their pathophysiologies based on clinical and neurophysiological studies and suggest the early or primary lesion to be hypofunction of the aminergic neurons of the brainstem which provide postural augmentation system and locomotion and influences synaptogenesis of the cerebral cortex. Furthermore, we discussed how these dysfunction leads to particular age dependent signs.

Section snippets

Early motor symptoms

Evaluation of the motor milestones of 38 patients with RTT revealed delay from infancy. Head control was delayed in 5 patients (13.1%) in early infancy and became more evident in mid infancy with delay in rolling over in 13 (34.2%) and in adoption of the sitting position in 10 patients (30.3%) [1]. Delay in motor milestone became more obvious as regards crawling. Only 4 patients (10.4%) could crawl before 10 months. This was delayed in 7 (19.4%) and in 27 patients (71.1%) crawling with on all

Pathophysiology of early motor symptoms

Hypotonia and failure in crawling are not due to abnormalities of the skeletal muscles nor motor neurons, because in RTT tendon reflexes are preserved and muscle atrophy or muscle weakness is not observed [2].

The gait of RTT is characterized by lack of coordinated movements of upper extremities. The child advances by rocking of the trunk side by side with wide based posture [1], [3]. This gait has been called gait apraxia with ataxia. However, in gait apraxia a subject cannot walk but can

How the initial motor signs relate to other signs of RTT particularly to the hypertonus and the characteristic stereotyped hand movement in early childhood

The stereotyped hand movement, the most diagnostic sign of RTT, is characterized by rubbing, wringing or clapping of both hands at the midline in front of the chest or around the mouth. The postures of hands and fingers are unnatural and dystonic; that is adducted thumbs, flexed fingers, deviated wrists either to the ulnar or radial side and pronated or supinated forearms [3]. Rigid hypertonus and fine tremulous movements often underlie this hand stereotypy. This can be detected clinically and

Conclusion

Early motor symptoms of RTT are postural hypotonia, failure in locomotion and disturbance in fine finger movements. The first two are considered to be caused by dysfunction of the 5HT and the NA neuron, which modulate the postural augmentation system and locomotion. The latter is caused by dysfunction of the NA neuron, which leads to failure in the synaptogenesis of the cerebral cortex and results in deceleration of head growth. Polysomnographic studies in RTT suggest disturbances of aminergic

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Sleep and the Social Profiles of Individuals With Rett Syndrome
2024, Pediatric Neurology
This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness.
Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness.
The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: “interactive motricity,” “mood change,” “anxiety/agitation,” and “gazing.” Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness.
The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.
Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome
2020, Brain and Development
Citation Excerpt :
Multivariate analysis revealed that only meaningful word acquisition was robustly related to walking ability when patients were over 10 years old. A previous study reported that walking was delayed in 30/38 RTT patients (79%); of these, 18 patients could not crawl until 4 years of age [14]. Furthermore, 55% of patients began to walk without having acquired the ability to crawl [14].
To investigate walking ability in Japanese patients with Rett syndrome (RTT).
Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database.
Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X.
Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.
A New Scale to Evaluate Motor Function in Rett Syndrome: Validation and Psychometric Properties
2019, Pediatric Neurology
Citation Excerpt :
A genotype-phenotype correlation study with a large sample of patients (more than 1000) showed that large deletions, splice sites, p.Arg270X, and p.Arg.168X are more frequently associated with locomotion impairment.13 Children with RTT present a typical pattern of abnormal or delayed (loco-)motor function14 that have been described in detail by Nomura and Segawa.15-17 In particular, some patients start walking without ever crawling, whereas others present both delayed crawling and delayed walking.
We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs.
We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis.
Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment.
Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.
Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?
2018, Experimental Neurology
Citation Excerpt :
The similarities between the results for mice and human PET studies indicate that the Mecp2-deficient mice serve as an adequate model for dopaminergic deficits in RTT. Stereotyped hand-wringing, progressive rigidity, dyskinesia, and dystonia are symptoms found in RTT that are thought to reflect perturbed dopaminergic neurotransmission (Chiron et al., 1993; Dunn, 2001; Humphreys and Barrowman, 2016; Jellinger et al., 1988; Segawa, 2005). The present human and mouse PET findings demonstrated reduced D2R numbers in striatum of females with RTT and brains of Mecp2-deficient mice.
We tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D₂ receptors (D₂R) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and D₁R and D₂R density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced D₂R density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in D₂R density of 7–10 week-old hemizygous (Mecp2-null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of D₂R declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of D₁R and D₂R in the caudate and putamen of RTT versus normal control subjects. 4) In humans and in the mouse model, PET revealed only marginal group differences in DAT. The results confirm that dopaminergic dysfunction in RTT is also present in Mecp2-deficient mice and that reductions in D₂R more likely explain the impaired ambulation and progressive rigidity observed rather than alterations in DAT.
Proteomic analysis of the Rett syndrome experimental model mecp2<sup>Q63X</sup> mutant zebrafish
2017, Journal of Proteomics
Citation Excerpt :
Overall, the present findings underscore the critical role of OS in RTT [18,46,47], translatable to the zebrafish mecp2-deficient model, being mitochondrial dysfunction a possible main source of aberrant redox homoeostasis [48,49]. Early motor disturbances and skeletal muscle mitochondrial dysfunction are reported in RTT patients [50,51]. Previous findings in a RTT mouse model suggest that mitochondrial abnormalities in the skeletal muscle may contribute to the progressive deterioration in mobility through accumulation of free radicals [49].
Rett syndrome (RTT) is a severe genetic disorder resulting from mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Recently, a zebrafish carrying a mecp2-null mutation has been developed with the resulting phenotypes exhibiting defective sensory and thigmotactic responses, and abnormal motor behavior reminiscent of the human disease. Here, we performed a proteomic analysis to examine protein expression changes in mecp2-null vs. wild-type larvae and adult zebrafish. We found a total of 20 proteins differentially expressed between wild-type and mutant zebrafish, suggesting skeletal and cardiac muscle functional defects, a stunted glycolysis and depleted energy availability. This molecular evidence is directly linked to the mecp2-null zebrafish observed phenotype. In addition, we identified changes in expression of proteins critical for a proper redox balance, suggesting an enhanced oxidative stress, a phenomenon also documented in human patients and RTT murine models. The molecular alterations observed in the mecp2-null zebrafish expand our knowledge on the molecular cascade of events that lead to the RTT phenotype.
We performed a proteomic study of a non-mammalian vertebrate model (zebrafish, Danio rerio) for Rett syndrome (RTT) at larval and adult stages of development. Our results reveal major protein expression changes pointing out to defects in energy metabolism, redox status imbalance, and muscle function, both skeletal and cardiac. Our molecular analysis grants the mecp2-null zebrafish as a valuable RTT model, triggering new research approaches for a better understanding of the RTT pathogenesis and phenotype expression. This non-mammalian vertebrate model of RTT strongly suggests a broad impact of Mecp2 dysfunction.
Altered somatosensory barrel cortex refinement in the developing brain of Mecp2-null mice
2013, Brain Research
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. In previous studies, monoaminergic dysfunctions have been detected in patients with RTT and in a murine model of RTT, the Mecp2-null mouse. Therefore, the pathogenesis of RTT is thought to involve impairments in the monoaminergic systems. However, there have been limited data showing that the impairment of monoamines leads to early symptoms during development. We used histochemistry to study the somatosensory barrel cortex in the B6.129P2(C)-Mecp2^tm1.1Bird mouse model of RTT. The barrel cortex is widely used to investigate neuronal development and its regulation by various neurotransmitters including 5-HT. 5-HT levels were measured by high performance liquid chromatography with electrochemical detection (HPLC/EC), and serotonin transporter (SERT) and 5-HT_1B receptor mRNAs were measured in the somatosensory cortex, thalamus and striatum on postnatal days (P) 10, P20 and P40. Mecp2-null mice (Mecp2−/y) had significantly smaller barrel fields than age-matched wild-type controls (Mecp2+/y) on P10 and P40, but the topographic map was accurately formed. Levels of 5-HT, and SERT and 5-HT_1B receptor mRNA expression in the somatosensory cortex did not differ significantly between the Mecp2-null and wild-type mice on P10. However, thalamic 5-HT was reduced in Mecp2-null mice. Our data indicate that a lack of MeCP2 may disturb the refinement of the barrel cortex in the early postnatal period. Our findings suggest that a decrease in thalamic 5-HT might be involved in this phenomenon.

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Review articleEarly motor disturbances in Rett syndrome and its pathophysiological importance

Abstract

Introduction

Section snippets

Early motor symptoms

Pathophysiology of early motor symptoms

How the initial motor signs relate to other signs of RTT particularly to the hypertonus and the characteristic stereotyped hand movement in early childhood

Conclusion

Brain Dev

Brain Dev

Neurosci Lett

Brain Dev

Neurosci Lett

Behav Brain Res

Brain Dev

Brain Dev

Brain Dev

Brain Dev

Brain Dev

Brain Dev

Motor symptoms of the Rett syndrome: abnormal muscle tone, posture, locomotion and stereotyped movement

Brain Dev

The function of long propriospinal pathways in the co-ordination of quadrupedal stepping in the cat

Anatomy of Rett syndrome

Am J Med Genet

Review article
Early motor disturbances in Rett syndrome and its pathophysiological importance