Rett variants: A suggested model for inclusion criteria

doi:10.1016/0887-8994(94)90082-5

Pediatric Neurology

Volume 11, Issue 1, July 1994, Pages 5-11

https://doi.org/10.1016/0887-8994(94)90082-5 Get rights and content

Abstract

A model for the clinical delineation of atypical cases of Rett syndrome is presented. It is based on the presence, at age ≥10 years, of combined clusters of at least 3 of 6 primary criteria and at least 5 of 11 supportive manifestations appearing through childhood with advancing age. The model was applied to 16 mentally retarded females, aged 11–47 years (median: 23) who were considered to manifest atypical variants of the syndrome (8 formes frustes, 6 late regression, 2 congenital variants). Two of the 16 patients had an early seizure history as the initial abnormality. In parallel, the number of supportive manifestations in a series of 41 females over 10 years of age with classic Rett syndrome are given. The differentiating power was tested on 8 patients with a chromosome-verified Angelman syndrome. It is concluded that the model applied here has the capacity to identify and distinguish Rett syndrome variants of different types, to sift out other developmental disorders in routine clinical work, and to have potential as a useful research tool.

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Cited by (190)

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome
2020, Brain and Development
Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in MECP2. The diagnostic criteria of RTT are clinical; mutations in MECP2 are neither diagnostic nor necessary, and a mutation in another gene does not exclude RTT. We attempted to correlate genotype and phenotype to see if there are significant clinical associations.
All available females diagnosed with RTT in Norway were invited to the study. Parents were interviewed, the girl or woman with RTT examined and medical records reviewed. All diagnoses were revisited according to the current diagnostic criteria and exome-based sequencing analyses were performed in individuals without an identified causative mutation. Participants were categorized according to genotypes and RTT diagnosis. Individuals with RTT with and without mutations in MECP2 were compared.
Ninety-one individuals were included. A presumed causative mutation was identified in 86 individuals, of these, mutations in MECP2 in 77 individuals and mutations in SMC1A, SYNGAP1, SCN1A, CDKL5, FOXG1 or chromosome 13q in nine. Seventy-two individuals fulfilled the diagnostic criteria for classic and 12 for atypical RTT. Significant differences in early development, loss of hand use and language, intense eye gaze and the presence of early onset epilepsy were revealed in individuals with RTT according to their MECP2 genotypic status.
Using the current diagnostic criteria, genetic and clinical variation in RTT is considerable. Significant differences between individuals with RTT with and without MECP2 mutations indicate that MECP2 is a major determinant for the clinical phenotype in individuals with RTT.
Genetic and epigenetic influences on the phenotype of Rett syndrome
2019, Chromatin Signaling and Neurological Disorders
Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene and associated with severe functional impairments and medical comorbidities. Since first described in 1966, there has been striking progress in understanding biological and clinical aspects. With the phenotype of the affected child in mind, this chapter describes the genetic cause and adverse biological effects of reduced MeCP2 production. We illustrate the clinical presentation of functional abilities and the health challenges of comorbidities, each of which can be associated with adverse effects on quality of life. We discuss the more recent field of epigenetics in relation to Rett syndrome and highlight possible therapeutic avenues that would aim to reduce adverse neighborhood effects on biological functioning and thereafter phenotype. Finally, we consider how these three fields of investigation can each contribute to insightful epidemiological datasets to accelerate the pipeline of discovery.
Phenotype Differentiation of FOXG1 and MECP2 Disorders: A New Method for Characterization of Developmental Encephalopathies
2016, Journal of Pediatrics
To differentiate developmental encephalopathies by creating a novel quantitative phenotyping tool.
We created the Developmental Encephalopathy Inventory (DEI) to differentiate disorders with complex multisystem neurodevelopmental symptoms. We then used the DEI to study the phenotype features of 20 subjects with FOXG1 disorder and 11 subjects with MECP2 disorder.
The DEI identified core domains of fine motor and expressive language that were severely impaired in both disorders. Individuals with FOXG1 disorder were overall more severely impaired. Subjects with FOXG1 disorder were less able to walk, had worse fine motor skills, more disability in receptive language and reciprocity, and had more disordered sleep than did subjects with MECP2 disorder (P <.05). Covariance, cluster, and principal component analysis confirmed a relationship between impaired awareness, reciprocity, and language in both disorders. In addition, abnormal ambulation was a first principal component for FOXG1 but not for MECP2 disorder, suggesting that impaired ambulation is a strong differentiating factor clinically between the 2 disorders.
We have developed a novel quantitative developmental assessment tool for developmental encephalopathies and propose this tool as a method to identify and illustrate core common and differential domains of disability in these complex disorders. These findings demonstrate clear phenotype differences between FOXG1 and MECP2 disorders.
Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome
2015, Free Radical Biology and Medicine
Rett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders, although in many cases it is not clear whether OS is a cause or a consequence of the pathology. Fairly recently, the presence of a systemic OS has been demonstrated in RTT patients with a strong correlation with the patients’ clinical status. The link between MECP2 mutation and the redox imbalance found in RTT is not clear. Animal studies have suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and reexpression of Mecp2 gene in the brain of null mice restored oxidative damage, suggesting that Mecp2 loss of function can be involved in oxidative brain damage. Starting from the evidence that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, could be caused by OS. We also analyzed whether therapies that at least partially treated some RTT symptoms can play a role in defense against OS. At this stage we can propose that OS could be one of the main causes of the dysfunctions observed in RTT. In addition, the major part of the therapies recommended to alleviate RTT symptoms have been shown to interfere with oxidative homeostasis, suggesting that MeCP2 could somehow be involved in the protection of the brain from OS.
Variant Rett syndrome in a girl with a pericentric X-chromosome inversion leading to epigenetic changes and overexpression of the MECP2 gene
2015, International Journal of Developmental Neuroscience
Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome −46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55 ± 0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98 ± 0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.
Antiepileptic drugs in Rett Syndrome
2015, European Journal of Paediatric Neurology
We investigated drugs most often used to treat epilepsy in Rett Syndrome and their efficacy in a large cohort of Italian patients.
This is a multi-centre retrospective study. Data of 165 Rett subjects were collected from the patients' files, and hospital charts. The efficacy of antiepileptic drugs (AEDs) was classified as follows: not effective; decrease in seizure frequency ≥50% for at least 6 months; seizure-free for at least 2 years. Phenotypic and genetic categorization of patients was performed and it was considered in AEDs efficacy evaluation.
There were 130 epileptic patients.Sodium valproate (VPA) was the most commonly administered AED (44.3%) at seizure onset, followed by Carbamazepine (CBZ) (25.4%) and Phenobarbital (PB) (13%). Monotherapy was the first treatment option in most patients. VPA and CBZ proved to be equally effective in Rett patients who presented seizures within the typical age range (4–5 years), while Lamotrigine (LTG) was effective for patients in whom epilepsy started later. Overall, the frequency of side effects was low and the most often observed ones were restlessness and somnolence.
Our study suggests that LTG, VPA and CBZ can be used as drugs of first choice in Rett Syndrome. The association of four drugs should be avoided since it did not result in any significant clinical improvement.

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^☆: The study was supported by the W:6 Rett Research Programme and Gunnar and Märta Bergendahl's Foundation, Göteborg, Sweden; and by the Co-ordination Council for the Mentally Retarded, Norway.

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Review articleRett variants: A suggested model for inclusion criteria☆

Abstract

Pediatr Neurol

Brain Dev (Tokyo)

Brain Dev

Electroencephalogr Clin Neurophysiol

Clinical criteria, stages and natural history

Rett variants—Rettoid phenotypes

Diagnostic criteria for Rett syndrome

Ann Neurol

Review article
Rett variants: A suggested model for inclusion criteria☆