Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients

Abstract

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.

Further delineation of theMECP2duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

“…We had previously described the OFC values in a smaller series of 30 patients and shown that there were nearly as many with microcephaly (13%) as with macrocephaly (17%) 31. In the present series, we found that 7.5% of the patients were microcephalic and 17% were macrocephalic, which confirms that the OFC is not a key clinical feature in this syndrome (table 1).…”

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome

“…For example, duplications in FLNA have previously been associated with increased severity of gastrointestinal features and while it was not clearly associated with increased overall severity in this study, the severity of gastrointestinal issues was not specifically measured (the presence/absence of constipation was noted, but not as part of the severity scale). In addition, mutations in L1CAM have been associated with cerebral ventricle dilation as well as hypoplasia of the corpus callosum both relatively common findings on brain imaging in MDS which was not systematically documented in this study. Finally, future studies should examine X‐inactivation patterns in females with MDS (this could contribute to differing levels of severity).…”

“…SRPK3 is involved in muscle growth and homeostasis with overexpression causing muscle degeneration in mice . A neurological phenotype because of L1CAM overexpression has not been reported, but loss of function mutations are associated with corpus callosum abnormalities on neuroimaging that are also seen in MDS . Duplications in FLNA are associated with bowel dysfunction that is also very common in MDS …”

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

“…Proportions appear as dark blue bars in males and as pink bars in females. From Van Esch et al and El Chehadeh et al . [Color figure can be viewed at wileyonlinelibrary.com]…”

“…Other authors have also reported rare cases of severely affected females carrying an intraC dupMECP2 or an Xq28 triplication . Figure summarizes the different clinical features in affected females with an interstitial duplication, including those in this study, as compared with the largest review of males .…”