Rett syndrome in females with CTS hot spot deletions: A disorder profile

Smeets, Eric; Terhal, Pauline; Casaer, Paul; Peters, A. C. B.; Midro, Alina T.; Schollen, E; Roozendaal, Kees van; Moog, Ute; Matthijs, Gert; Herbergs, Jos; Smeets, H.; Curfs, Leopold; Schrander-Stumpel, C. T. R. M.; Fryns, Jean‐Pierre

doi:10.1002/ajmg.a.30410

Cited by 68 publications

(67 citation statements)

References 19 publications

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“…However, these apparently milder mutations also appear to be more likely to have other behavioural problems [32]. C terminal mutations are usually mild in severity [33]; they also had a low prevalence of sleep problems. We found that cases with a large MECP2 deletion were the most likely to have a sleep problem and night-time laughter was reported in all cases.…”

Section: Discussionmentioning

confidence: 98%

Sleep problems in Rett syndrome

Young

Nagarajan

Klerk

et al. 2007

Brain and Development

120

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Rett syndrome (RTT) is a severe neurological disorder, affecting mainly females. It is generally caused by mutations in the MECP2 gene. Sleep problems are thought to occur commonly in Rett syndrome, but there has been little research on prevalence or natural history. An Australian population-based registry of cases born since 1976 has been operating since 1993, with current ascertainment at 300. The Australian Rett Syndrome Database (ARSD) consists of information about Rett syndrome cases including their functional ability, behaviour, sleep patterns, medical conditions and genotype. The cases range in age from two to 29 years.The aim of this study was to investigate the type and frequency of sleep problems, relationships with age and MECP2 mutation type and to evaluate changes over time.Parents or carers of the subjects with Rett syndrome were asked to complete a questionnaire about sleep problems on three separate occasions (2000, 2002 and 2004). Regression modelling was used to investigate the relationships between sleep problems, age and mutation type. Sleep problems were identified in over 80% of cases. The prevalence of night-time laughter decreased with age and the prevalence of reported night-time seizures and daytime napping increased with age. The prevalence of sleep problems was highest in cases with a large deletion of the MECP2 gene and in those with the p.R294X or p.R306C mutations.Sleep problems are common in Rett syndrome and there is some variation with age and mutation type.

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Section: Discussionmentioning

confidence: 98%

Sleep problems in Rett syndrome

Young

Nagarajan

Klerk

et al. 2007

Brain and Development

120

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“…The identified mutation was an 86 bp deletion in the deletion-prone region at the C-terminus of the fourth exon (1140del86). The boundaries of this deletion hot-spot region are located between nucleotides 1050 and 1200, giving rise to intragenic deletions of various sizes and accounting for approximately 10% of RTT mutations in females (13). Although the late truncation of the MeCP2 protein results in intact methyl-binding and transcriptional repression capacity, it nevertheless prevents the highest level of chromatin compaction (19).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of causative alterations (including missense, nonsense, and frameshift mu-tations) occur in exons 3 and 4, which encode the MeCP2 functional domains, the MBD and the TRD domain, respectively (12). The C-terminal region located downstream of the TRD is prone to deletions of various sizes resulting in the production of truncated proteins (13). Large rearrangements encompassing even whole exons and more specifically duplications ranging from 400 to 800 kilobases (Kb) have also been detected in RTT patients, accounting for ϳ10% of RTT cases.…”

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confidence: 99%

Phenotypic and Genotypic Variability in Four Males With MECP2 Gene Sequence Aberrations Including a Novel Deletion

et al. 2010

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ABSTRACT:The MECP2 gene mutations cause Rett syndrome (RTT) (OMIM: 312750), an X-linked dominant disorder primarily affecting girls. Until RTT was considered lethal in males, although now approximately 60 cases have been reported. Males with MECP2 mutations present with a broad spectrum of phenotypes ranging from neonatal encephalopathy to nonsyndromic mental retardation (MR). Four boys (aged, 3-11 y) were evaluated for MR. Patient 1 had autistic features. Patients 2 and 3 were brothers both presenting with psychomotor delay. Patient 4 showed dysmorphic features and behavioral problems reminiscent of FXS. All patients had a normal 46, XY karyotype and three were tested for FXS with negative results. MECP2 gene analysis of exons 3 and 4 was performed using methods based on the PCR, including Enzymatic Cleavage Mismatched Analysis (ECMA) and direct sequencing. Patient 1 presented somatic mosaicism for the classic RTT p.R106W mutation and patient 4 carried the p.T203M polymorphism. Analysis of the mothers in both cases revealed normal DNA sequences. Patients 2 and 3 had a novel deletion (c.1140del86) inherited from their unaffected mother. MECP2 gene mutations may be considered a rare cause of MR in males although great phenotypic variation hinders genotype-phenotype correlation. (Pediatr Res 67: 551-556, 2010) R ett syndrome (RTT) (OMIM: 312750) is a severe Xlinked dominant neurodevelopmental disorder, typically affecting females. It is characterized by apparently normal psychomotor development during the first 6 months of life, followed by gradual loss of acquired skills, deceleration of head growth, initiation of stereotypic hand movements, and autistic behavior by the age of 3-4 y (1). During the course of the disease multiple clinical problems emerge such as seizures, scoliosis, breathing abnormalities, and severe mental retardation (MR) (1). The prevalence of RTT is 1:10 -15.000 live births per year and 99% of the cases are considered sporadic (1).Although the diagnosis of classic RTT is based on welldefined criteria, several atypical RTT forms also exist (2). In the majority of cases, the syndrome is caused by heterozygous mutations in the MECP2 gene, which is located on chromosome X (Xq28) and encodes a methyl-CpG binding protein 2 (MeCP2). The protein is thought to selectively bind methyl-CpG islands in the mammalian genome, functioning as a regulator (mostly a repressor) of gene expression. Mutations of the MECP2 gene have been reported in a broad phenotypic spectrum of mentally retarded individuals (3). The first case was molecularly documented in 1999 after the discovery of the MECP2 gene. Generally, males were considered not to survive due to the X-linked mode of inheritance of the disease (4), but to date, more than 60 male patients with MECP2 mutations have been reported (5), suggesting that mutations in this gene may be included among the causes of MR in males. Recent data show that the frequency of MECP2 mutations among mentally retarded males is approximately 1.3 to 1.7% (5).The clinical phenotype...

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“…Roughly 57.1% (8/14) of the patients with atypical RTT possessed mutations in their MECP2 sequences. Recent reports described a range of 65-79% for the mutation detection rate among patients with atypical RTT (Smeets et al , 2005. Kanmmoun et al recommended selecting well-defined clinical criteria while searching for MECP2 mutations, as all individual variables did not exhibit similar weights (Kammoun et al 2004).…”

Section: Cdkl5 Mutation Detection By Dhplc Analysismentioning

confidence: 99%

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

Pan

Bao

et al. 2006

J Hum Genet

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Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46ins-GGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

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Rett syndrome in females with CTS hot spot deletions: A disorder profile

Cited by 68 publications

References 19 publications

Sleep problems in Rett syndrome

Sleep problems in Rett syndrome

Phenotypic and Genotypic Variability in Four Males With MECP2 Gene Sequence Aberrations Including a Novel Deletion

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

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