Abstracts

Rationale: MECP2 duplication syndrome (MECP+) is a neurodegenerative X-linked dominant disorder with prominent neurological phenotype that includes infantile hypotonia, severe intellectual disability, psychomotor regression, autism, and spasticity. The syndrome has 100% penetrance in males and is extremely rare in female carriers due to skewed X-inactivation. Epileptic encephalopathy is frequent but poorly understood in its prevalence, characteristics, and causality. Yet, prevalence and potential functional contribution of the MECP2 duplications to the epilepsy characteristics are unknown. Our preliminary data uncovered suspect pathogenic variants in epilepsy genes in a MECP2 duplication positive family with late onset severe epileptic encephalopathy.Methods: The study was approved by the Institutional Review Board of Baylor College of Medicine. We performed a retrospective chart review on 41 subjects with MECP2 duplication syndrome followed in the Blue Bird Clinic Rett Center. Charts of MECP+ subjects were reviewed for history of epilepsy and age of onset, classified epilepsy syndrome, length of duplication, and MRI findings. Twenty-five subjects were excluded due to insufficient documentation of history and prior workup.Results: Duplication was inherited in 12 and de novo in 2 subjects. The inheritance pattern could not be assessed in 2 adopted subjects. Length of duplication on Xq28 spanned from 0.254 to 5.910 Mb. Brain MRI were non-specific and included volume loss, white matter signal abnormalities, and callosal hypoplasia. Nine subjects (56%) had epilepsy and it was refractory in 78% of them. Age of onset of epilepsy was ranging from 7 days to 19 years (Average 7 y 2 m+/- 7 yr 7m). All seven subjects with refractory epilepsy had severe epileptic encephalopathy. Four patients were affected by Lennox Gastaut Syndrome (LGS), two by Doose syndrome, and one by unclassified severe epileptic encephalopathy. Recurrent LGS in association with MECP2+ was observed in two siblings and we performed next generation whole exome sequencing to better understand their liability to epilepsy in the face of MECP+. We uncovered multiple suspect pathogenic variants in several genes with known association with epilepsy, including CTCL1, SUCL2, DOCK8, PIGL, ALG1, PIGO, ATIC, PIGO, PGAP1, GALC, LAMC3, and AMK3.Conclusions: Our findings indicate that epilepsy in MECP2+ is common and it is often severe. The pilot data suggests that complex genetic background likely contributes to the phenotypic expression of epilepsy in this duplication syndrome. Replication of this finding in a larger cohort will be important in guiding future studies on the MECP+ syndrome natural history and to inform clinical care, and counseling.