Rett syndrome in Spain: mutation analysis and clinical correlations

doi:10.1016/S0387-7604(01)00374-6

Brain and Development

Volume 23, Supplement 1, December 2001, Pages S251-S253

https://doi.org/10.1016/S0387-7604(01)00374-6 Get rights and content

Abstract

Rett syndrome (RTT) is an X-linked neurodevelopmental disease that affects girls almost exclusively. In a high proportion of patients the disease is caused by de novo mutations at the MECP2 gene, encoding methyl-CpG-binding protein 2. With the aim to characterize the spectrum of mutations in a series of sporadic RTT patients, including an affected male, and to relate the genetic results to the clinical features of the disease, a clinical checklist and a score system were elaborated to evaluate the clinical severity of the disease. Mutation analysis of the MECP2 coding region was done by direct sequencing. De novo mutations were found in 60% of the patients, including both classic and atypical forms. The change R133H was identified in a 13-year-old boy showing a classic RTT phenotype and normal karyotype. Significant differences were observed among missense and truncating mutations regarding disease severity, age of onset of stereotypies, and the ability of the patients to sit alone and to walk.

Section snippets

Objectives

The aim of this study was to characterize the spectrum of MECP2 mutations in a series of Spanish sporadic Rett syndrome (RTT) patients and to evaluate the contribution of the type of mutation to the final phenotype. With this purpose in mind, a clinical checklist and a score system to test the clinical variables were elaborated.

We present preliminary results on the spectrum of MECP2 mutations found in our population, including our case of a 13-year-old male with classical RTT. Clinical features

Subjects and genetic methods

Forty-six sporadic female patients and one affected male with known MECP2 mutations are presented. Healthy parents and unaffected sisters were also analyzed. Informed consent was obtained from all subjects. DNA was prepared from peripheral blood lymphocytes by standard methods. The coding region of the MECP2 gene was studied by direct sequencing.

Clinical data management

All patients were submitted to a strict selection and were diagnosed according to the Rett Syndrome Diagnostic Criteria Work Group. We analyzed 34 females and one male with classical RTT, and ten atypical female cases (five congenital, four preserved language and one form fruste). For genotype/phenotype correlations, patients were classified according to the type of mutation. A score was assigned to each clinical variable, following the criteria summarized in Table 1. Higher scores indicate

Spectrum and distribution of MECP2 mutations

The 47 mutations found in our patients are summarized in Fig. 1.

MECP2 mutation in a classical RTT male patient

We report the first described case of a male with classical RTT and normal 46, XY karyotype. At 7 years of age he fulfilled 8/9 necessary criteria, 7/8 supportive criteria and no exclusion criteria. Necessary criteria include normal prenatal and perinatal period, normal neurodevelopment until 12 months of age, acquired microcephaly, loss of purposeful hand use, complete loss of language skills, stereotypic hand movements (wringing,

Conclusions

From the present work we can conclude that

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Mutations at the MECP2 coding region cause the broad spectrum of classical and atypical forms of RTT.
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Males can be affected by classical RTT.
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Significant differences can be found between missense and truncating mutations in relation to the following clinical features: sitting alone (age of acquisition and conservation); ambulation (age of acquisition and conservation); age of onset of stereotypies.
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Missense mutations are associated with milder forms of RTT.

Acknowledgements

We thank the Asociación Valenciana and Catalana de Sı́ndrome de Rett for their support, all RTT patients and families for their enthusiastic participation, and M. Naudó for technical assistance. This work was supported by Fondo de Investigación Sanitaria FIS99/0235 and by the Asociación Valenciana y Catalana de SÍndrome de Rett. J.A. is the recipient of a fellowship from Fondo de Investigación Sanitaria FIS99/0235.

References (0)

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Methyl-CpG-binding protein 2 (MeCP2) is of utmost importance in neuronal function. We aim to characterize phenotypic traits in the sleep of individuals with Rett Syndrome (RTT, OMIM # 312750), a rare disorder predominantly caused by mutations of the MECP2 gene.
An overnight polysomnographic recording was performed. Outcomes investigated were parameters of nocturnal sleep macrostructure, and sample stratification per genetic and clinical characteristics, and six key features of clinical severity was applied.
The sleep of our 21 RTT female subjects with a mutant MECP2 gene, aged 8.8 ± 5.4 years, showed no significant differences within strata. However, compared to a normative dataset, we found longer duration of wake time after sleep onset and total sleep time (TST) but shorter sleep onset latency, in RTT. Regarding the proportion of sleep stages per TST, higher stage N3 (%) with lower stage N2 (%) and REM (%) were generally seen. Such abnormalities became more uniformly expressed at the severe level of clinical features, particularly for hand functioning and walking.
RTT girls with MECP2 mutations in our study demonstrated an increased deep sleep and reduced rapid eye movement sleep proportion, which is mostly allied with their hand dysfunction severity. Poor sleep-on/off switching in RTT since embryogenesis is possibly linked to (psycho)motor impairment in the cases with MECP2 mutations.
MECP2-related conditions in males: A systematic literature review and 8 additional cases
2021, European Journal of Paediatric Neurology
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We also excluded the more recent publication of a duplicated report. Additionally, the classical variants p.(Arg133Hys) and p.(Arg133Cys), recurrently reported in females with RS, have been published in males with classical presentation of RS [31] or X-linked mental retardation [46]. Nevertheless, somatic mosaicism could not be ruled out in those patients.
To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant.
We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well-characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999–2020).
The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X).
In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2-associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs∗7) and p.(Tyr132Cys)] were detected.
In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2.
The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome
2019, European Journal of Paediatric Neurology
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Patients or their parents gave signed informed consent for genetic studies, and blood samples from patients and controls were obtained according to the Helsinki Declaration of 1964, as revised in 2004.12 Patients had been diagnosed following the usual clinical parameters13 and according to the recently revised RTT Search International Consortium criteria and nomenclature.6 Patients who almost completely fulfilled the criteria, including the main features, such as psychomotor delay with or without regression stereotypic hand movements and absent language or limited to only a few words, were also included.
Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that is caused by mutations in the MECP2 gene; however, defects in other genes (CDKL5 and FOXG1) can lead to presentations that resemble classic RTT, although they are not completely identical. Here, we attempted to identify other monogenic disorders that share features of RTT. A total of 437 patients with a clinical diagnosis of RTT-like were studied; in 242 patients, a custom panel with 17 genes related to an RTT-like phenotype was run via a HaloPlex-Target-Enrichment-System. In the remaining 195 patients, a commercial TruSight-One-Sequencing-Panel was analysed. A total of 40 patients with clinical features of RTT had variants which affect gene function in six genes associated with other monogenic disorders. Twelve patients had variants in STXBP1, nine in TCF4, six in SCN2A, five in KCNQ2, four in MEF2C and four in SYNGAP1. Genetic studies using next generation sequencing (NGS) allowed us to study a larger number of genes associated with RTT-like simultaneously, providing a genetic diagnosis for a wider group of patients. These new findings provide the clinician with more information and clues that could help in the prevention of future symptoms or in pharmacologic therapy.
First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation
2018, Biochemical and Biophysical Research Communications
Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10 000 to 15 000 live female births. This disease is characterized by a period of apparently normal development until 6–18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2.
This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695 G > T; c.880C > T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome.
Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695 G > T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions.
Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region.
Rett Syndrome: Crossing the Threshold to Clinical Translation
2016, Trends in Neurosciences
Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders.
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2016, Brain and Development
To relate functional outcomes to mutation type and age at evaluation in patients with Rett syndrome (RTT).
We identified 96 RTT patients with mutations in the MECP2 (methyl-CpG-binding protein 2) gene. Chart analysis, clinical evaluation, and functional measures were completed.
Among 11 mutation groups, a statistically significant group effect of mutation type was observed for self-care, upper extremity function, and mobility, on standardized measures administered by occupational and physical therapists. Patients with R133C and uncommon mutations tended to perform best on upper extremity and self-care items, whereas patients with R133C, R306C and R294X had the highest scores on the mobility items. The worst performers on upper extremity and self-care items were patients with large deletions, R255X, R168X, and T158M mutations. The lowest scores for mobility were found in patients with T158M, R255X, R168X, and R270X mutations. On categorical variables as reported by parents at the time of initial evaluation, patients with R133C and R294X were most likely to have hand use, those with R133C, R294X, R306C and small deletions were most likely to be ambulatory, and those with R133C were most likely to be verbal.
Functional performance in RTT patients may relate to the type of mutation. Knowledge of these relationships is useful for developing appropriate rehabilitation strategies and prognosis.

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Original articleRett syndrome in Spain: mutation analysis and clinical correlations