MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.
Keywords: MECP2 duplication syndrome; Functional skills; Intellectual disability; Neurodevelopmental; Regression; X-linked.
© 2025. The Author(s).