Expanding the clinical picture of the MECP2 Duplication syndrome

Abstract

Individuals with two or more copies of the MECP2 gene, located at Xq28, share clinical features and a distinct facial phenotype known as MECP2 Duplication syndrome. We have examined perinatal characteristics, early childhood development and medical co-morbidities in this disorder. The International Rett Syndrome Phenotype Database (InterRett), which collects information from caregivers and clinicians on individuals with Rett syndrome and MECP2 associated disorders, was used as the data source. Data were available on 56 cases (49 males and 7 females) with MECP2 Duplication syndrome. Median age at ascertainment was 7.9 years (range: 1.2-37.6 years) and at diagnosis 3.0 years (range: 3 weeks-37 years). Less than a third (29%) learned to walk. Speech deterioration was reported in 34% and only 20% used word approximations or better at ascertainment. Over half (55%) had been hospitalised for respiratory infections in the first 2 years of life. Just under half (44%) had seizures, occurring daily in nearly half of this group. The majority (89%) had gastrointestinal problems and a third had a gastrostomy. Following the recent demonstration of phenotype reversal in a mouse model of MECP2 Duplication, a clear understanding of the natural history is crucial to the design and implementation of future therapeutic strategies.

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

“…Lim et al noted that chronic constipation was present in 80% of the subjects in their series 12. This is consistent with our findings (78%), but seems to be more frequent than in previous reports (table 3).…”

“…In our series, among the 32/59 patients with epilepsy, 62% were drug-resistant, compared with 76% in the series of Lim et al 12. Multiple different seizure types (table 2) and different EEG patterns (data not shown) were observed, which is consistent with other reports 24 34 35.…”

“…Recurrent and severe infections were a significant health issue for 89% of MECP2 duplication patients, as in the study by Lim et al , who found recurrent respiratory infections in 78% of affected males, three-quarters of them requiring hospital admissions within the first 2 years of life for supportive care and interventional procedures (mechanical ventilation, intravenous antibiotics, tracheostomy) 12. Van Esch, in a review of 129 affected males, reported 70% of recurrent infections, especially of the respiratory tract 10.…”

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

“…Table lists the demographics of participants in this study, along with the frequency of salient clinical features as compared to prior published studies . When parents were asked to list their chief concern about their child, many reported that lack of effective communication (27%) was their most pressing concern, while 23% reported that seizures were their greatest concern.…”

Clinical and biological progress over 50 years in Rett syndrome

“…53,[90][91][92] The phenotype of MECP2 Duplication syndrome, the clinical manifestation of overexpression, is gradually being delineated and is more commonly reported in males. 91,93 When modelled in mice, MECP2 Duplication syndrome, like RTT, has shown the potential for phenotypic reversal when MeCP2 levels are restored to normal levels. 94 Loss of MeCP2 alters the cellular levels of many gene products but the effects at the individual gene level are typically small 75,95 and likely to be cell-type specific.…”