Investigating genotype–phenotype relationships in Rett syndrome using an international data set

Bebbington, Ami; Anderson, Alison; Ravine, David; Fyfe, Sue; Pineda, Merçè; Klerk, Nicholas de; Ben‐Zeev, Bruria; Yatawara, Nihal; Percy, Alan K.; Kaufmann, Walter E.; Leonard, Helen

doi:10.1212/01.wnl.0000304752.50773.ec

Cited by 219 publications

(289 citation statements)

References 35 publications

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“…Whereas the latter mutations have been associated with milder presentations, earlytruncating mutations have been associated with greater severity. 9,10,30 Alhough all of the MeCP2 structural domains are necessary to mediate normal cellular actions of MeCP2, 31 it is possible that areas of the central nervous system are differentially susceptible than others to the degree of dysfunction in MeCP2 protein. A less functional protein with greater loss of genetic material could be more disruptive to brainstem and cerebellar structures than a more functional protein, 32 and may account for phenotypic differences such as muscle tone and motor function.…”

Section: Discussionmentioning

confidence: 99%

The phenotype associated with a large deletion on MECP2

et al. 2012

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Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22-0.79, P¼0.007) and to be currently walking (OR 0.53, 95% CI: 0.26-1.10, P¼0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98-3.48, P¼0.057) and epilepsy (OR 2.72, 95% CI: 1.38-5.37, P¼0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected.

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Section: Discussionmentioning

confidence: 99%

The phenotype associated with a large deletion on MECP2

et al. 2012

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“…The girls showed some variability in their functional skills, likely to have been related in part to the specific genotype [43]. Many frustrations had been experienced by these families whilst searching for a diagnosis for their daughter [44] and these frustrations continued in their current lives in terms of limited access to appropriate equipment, education and rehabilitation opportunities and poor access to information about Rett syndrome.…”

Section: Discussionmentioning

confidence: 99%

Caring for a child with severe intellectual disability in China: The example of Rett syndrome

Lim

Downs

et al. 2012

Disability and Rehabilitation

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Implications for rehabilitation Little is known about the lives of girls with Rett syndrome in China, a genetic condition associated with severe disability.  Most girls experienced home-based care with limited access to appropriate equipment, education and rehabilitation.  Limited information and discrimination and stigma from some community members reduced families' abilities to meet their child's needs.  Greater access to health, education and information services in China should be supported.

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“…2,3 The severity of the RTT phenotype varies considerably depending on the MECP2 mutation type and location. [4][5][6][7][8] The degree of X chromosome inactivation skewing has also been shown to affect phenotypic variability in Mecp2-null mice, 9 and in RTT females. 10 However, these two mechanisms only partially explain this variability.…”

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confidence: 99%