Rett syndrome: new clinical and molecular insights

Williamson, Sarah; Christodoulou, John

doi:10.1038/sj.ejhg.5201580

Cited by 104 publications

(105 citation statements)

References 78 publications

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“…While beyond the scope of the present study, this could be explained by a pathogenic mechanism involving the interference of maternal autoantibodies with neurodevelopmental pathways for which compensatory mechanisms exist, but are ultimately overwhelmed, leading to disease symptoms. Such a pathogenesis is noted in Rett syndrome, where mutations in the gene Mecp2 manifest in behavioral regression around 18 months of age (Williamson and Christodoulou, 2006). Finally, it is important to note that the presence of maternal autoantibodies to both the 37 kDa and 73 kDa proteins does not provide an etiologic mechanism for all cases of regressive autism, and their presence is strongly associated with the regressive phenotype only in a sub-population of individuals.…”

Section: Discussionmentioning

confidence: 99%

Autism: Maternally derived antibodies specific for fetal brain proteins

et al. 2007

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Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73kDa and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands correlated with a diagnosis of behavioral regression in the child when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09 -15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.

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Section: Discussionmentioning

confidence: 99%

Autism: Maternally derived antibodies specific for fetal brain proteins

et al. 2007

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“…4 Mutations in the X-linked gene methyl CpG-binding protein 2 (MECP2) have been found in most patients. 5 Recently other genes (CDKL5 6 and Netrin G1 7 ) have been linked to this disease. Male lethality and uniparental disomy have been proposed as possible explanations for the sex bias.…”

Section: Introductionmentioning

confidence: 99%

An explanation for another familial case of Rett syndrome: maternal germline mosaicism

Venâncio¹,

Santos

Pereira

et al. 2007

Eur J Hum Genet

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Rett syndrome (RTT; OMIM#312750) is a severe neurodevelopmental disorder that affects mainly girls. It has an estimated incidence of 1:10 000 -15 000 females. Mutations in the X-linked gene methyl CpGbinding protein 2 (MECP2) have been found in most patients. The most accepted explanation for the sex bias is that the Rett mutation in sporadic cases has its origin in the paternal germline X chromosome and can thus only be transmitted to females. The majority of cases are sporadic (99.5%) but some familial cases have been described. These cases can either be explained by germline mosaicism or by asymptomatic carrier mothers with skewing of X-inactivation towards the wild-type MECP2 allele. We describe one of the few familial cases of RTT in which a maternal germline mosaicism is the most likely explanation. The mutation p.Arg270fs (c.808delC) was identified in both a girl with classical RTT and her brother who had the severe neurological phenotype usually described in males. The mutation was absent in DNA extracted from blood of both parents. These type of events must be taken into consideration in the genetic counselling of families after the diagnosis of a first case of RTT in a female or a MECP2 mutation in a male.

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“…MECP2 mutations cause a wide spectrum of phenotypes, including classical RTT and RTT‐variants such as congenital form, early‐onset seizure type to preserved speech variant (PSV), and the forms frustes (FF); and other kinds of intellectual disabilities, such as autism, nonspecific XLMR, schizophrenia, Fragile‐X‐like Syndrome (FXS), learning disability, and Angelman‐like syndrome (Gomot et al, 2003; Zoghbi, 2005). However, the elaborate pathogenic mechanism of MECP2 leading to RTT phenotype remains unclear (Chahrour & Zoghbi, 2007; Williamson & Christodoulou, 2006; Zhang, Bao, Zhang, et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Familial cases and male cases with MECP2 mutations

Zhang

Zhao

Bao

et al. 2017

American J of Med Genetics Pt B

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This is the first report of Chinese familial cases with Rett syndrome (RTT) or X‐linked mental retardation (XLMR). RTT is a neurodevelopmental disorder that almost exclusively affects females. Most RTT cases are sporadic. We have studied eight cases with MECP2 mutations in six Chinese families, including three females and five males with RTT or XLMR. All shared identical MECP2 mutations with their mothers. The three females fulfilled the diagnostic criteria for RTT, while the five males were XLMR. A random X‐chromosome inactive (XCI) pattern was seen in all the three female patients and two mothers while a skewed XCI in the rest four mothers. The clinical manifestations and pathogenic gene spectrum between male and female patients were different. The different MECP2 mutations and different XCI pattern may be the determinants of the phenotypic heterogeneity between the family members.

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Rett syndrome: new clinical and molecular insights

Cited by 104 publications

References 78 publications

Autism: Maternally derived antibodies specific for fetal brain proteins

Autism: Maternally derived antibodies specific for fetal brain proteins

An explanation for another familial case of Rett syndrome: maternal germline mosaicism

Familial cases and male cases with MECP2 mutations

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