Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome

Abstract

ObjectiveWe characterized the epilepsy features and contribution to cognitive regression in 47 patients with MECP2 duplication syndrome (MDS) and reviewed these characteristics in over 280 MDS published cases.MethodsThe institutional review board approved this retrospective review of medical records and case histories of patients with MDS.ResultsThe average age at enrollment was 10 ± 7 years. Patients with epilepsy were older (13 ± 7 years vs 8 ± 5 years, p = 0.004) and followed for a longer time (11.8 ± 6.5 years vs 6.3 ± 4.2 years, p = 0.003) than patients without a seizure disorder. Epilepsy affected 22/47 (47%) patients with MDS. It was treatment-refractory and consistent with epileptic encephalopathy in 18/22 (82%) cases. Lennox-Gastaut syndrome (LGS) was present in 12/22 (55%) patients and manifested between late childhood and adulthood in 83% of cases. The emergence of neurologic regression coincided with the onset of epilepsy. The MECP2 duplication size and gene content did not correlate with epilepsy presence, type, age at onset, or treatment responsiveness.ConclusionEpilepsy in MDS is common, often severe, and medically refractory. LGS occurs frequently and may have a late onset. Developmental regression often follows the onset of epilepsy. The MECP2 duplication extent and gene content do not discriminate between patients with or without epilepsy. Our findings inform clinical care and family counseling with respect to early epilepsy recognition, diagnosis, specialty referral, and implementation of aggressive seizure therapy to minimize detrimental effect of uncontrolled seizures on cognitive functions or preexisting neurologic deficits.

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

“…However, while severity of MECP2 mutations is linked to the RTT clinical phenotype, MECP2 duplication size and gene content predict neither presence of epilepsy, seizure type, age of seizure onset or responsiveness to treatment. Mechanisms by which MECP2 gene duplications modulate the spectrum and severity of neurocognitive phenotype remain unclear [ 199 ].…”

Phenotypic features in MECP2 duplication syndrome: Effects of age

“…Our previous studies have shown there is a possibility of regression in MDS (Peters, Hundley, Wilson, Carvalho, et al, 2013) that occurs at a much older age as compared to RTT. Developmental regression is likely to coincide with the onset of epilepsy in MDS (Marafi et al, 2019), and both are increasingly likely as participants age (Marafi et al, 2019; Peters et al, 2019). A recent study indicated that epilepsy affected around 47% of participants with MDS, disproportionately affected those who were older, and it was treatment‐refractory and consistent with epileptic encephalopathy in a high percentage of those cases (Marafi et al, 2019).…”

“…Developmental regression is likely to coincide with the onset of epilepsy in MDS (Marafi et al, 2019), and both are increasingly likely as participants age (Marafi et al, 2019; Peters et al, 2019). A recent study indicated that epilepsy affected around 47% of participants with MDS, disproportionately affected those who were older, and it was treatment‐refractory and consistent with epileptic encephalopathy in a high percentage of those cases (Marafi et al, 2019). Lennox–Gastaut Syndrome (LGS), a classic epileptic encephalopathy, was diagnosed in almost 25% of the sample.…”

Identification of hsa-miR-1275 as a Novel Biomarker Targeting MECP2 for Human Epilepsy of Unknown Etiology

“…MECP2 is reported to be associated with a severe epileptic seizure phenotype in Rett syndrome (RTT) and in MECP2 duplication syndrome (MDS). 48,49 RTT is an X-linked neurodevelopmental disorder that primarily occurs in females. 50 Mutations of the gene encoding MECP2, which have been identified in 90%-95% of RTT cases, are considered to be the foremost cause of typical RTT.…”