Comparison of Core Features in Four Developmental Encephalopathies in the Rett Natural History Study

Abstract

Objective Rett syndrome, CDKL5‐deficiency disorder, FOXG1 disorder, and MECP2 duplication disorder are developmental encephalopathies with shared and distinct features. Although they are historically linked, no direct comparison has been performed. The first head‐to‐head comparison of clinical features in these conditions is presented. Methods Comprehensive clinical information was collected from 793 individuals enrolled in the Rett and Rett‐Related Disorders Natural History Study. Clinical features including clinical severity, regression, and seizures were cross‐sectionally compared between diagnoses to test the hypothesis that these are 4 distinct disorders. Results Distinct patterns of clinical severity, seizure onset age, and regression were present. Individuals with CDKL5‐deficency disorder were the most severely affected and had the youngest age at seizure onset (2 months), whereas children with MECP2 duplication syndrome had the oldest median age at seizure onset (64 months) and lowest severity scores. Rett syndrome and FOGX1 were intermediate in both features. Smaller head circumference correlates with increased severity in all disorders and earlier age at seizure onset in MECP2 duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median = 18 months) but only 23 to 34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 deficiency disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed among groups. Interpretation Although these developmental encephalopathies share many clinical features, clear differences in severity, regression, and seizures warrant considering them as unique disorders. These results will aid in the development of disease‐specific severity scales, precise therapeutics, and future clinical trials. ANN NEUROL 2020;88:396–406.

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

“…Most studies resulting from our search concerned epileptiform abnormalities/seizures in RTT ( Figure 1 , Table 1 ). Seizures of various semiology were described, with the most common being generalized seizures, tonic-clonic seizures and complex partial seizures [ 41 , 42 , 43 , 44 , 45 ]. Reports on the prevalence of epilepsy in patients with RTT ranged between 50 and 90%, and about 30–50% of cases were drug-resistant [ 41 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

“…Nevertheless, causal relationships between seizures and developmental trajectory of RTT disorder remains unclear. For example, a recent large-scale study of 793 individuals reported that there were no significant associations between age of developmental regression and age of seizure onset in patients with RTT or in patients with so-called RTT-like disorders [ 42 ]. Thus, findings of the above correlative nature do not ascertain whether the epilepsy plays a crucial role in deteriorated cognitive abilities in RTT, or if it alternatively reflects the more severe underlying pathophysiology [ 105 ].…”

“…MECP2 duplication syndrome has the lowest severity scores, and the greatest median age of seizure onset (6 years) among developmental encephalopathies. The available reports suggest epilepsy in patients with MECP2 duplication to be mostly drug-resistant [ 42 , 58 , 197 ]. A recent report suggested that valproic acid (VPA) monotherapy can be efficient in managing epilepsy in these patients [ 198 ].…”

Phenotypic features in MECP2 duplication syndrome: Effects of age

“…Our prior studies reveal considerable variability in severity of many symptom domains within MDS including ambulation, hand function, and non‐verbal communication (Ramocki, Tavyev, & Peters, 2010) that could be related to gene duplication size and content (Peters et al, 2019). Developmental regression occurs in approximately half of the population with highly variable age of onset (Cutri‐French et al, 2020; Peters et al, 2013a). A comprehensive picture of the natural history and severity of MDS is needed as disease‐modifying therapies may be possible, as demonstrated by the recent report of phenotypic reversal after antisense oligonucleotide treatment (ASO) in an animal model of MDS (Sztainberg et al, 2015).…”

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

“…Patients with FOXG1 mutations are currently classified with Rett. However, as these rare FOXG1 mutation patients present with disease from birth and have other symptoms that do not overlap with Rett, a proposal to classify these patients as a separate syndrome was recently submitted (Cutri-French et al, 2020). Therefore, with few exceptions, any discussion about Rett syndrome phenotypes is about how defective MECP2/Mecp2 expression presents in patients and animal models and manifests as a neurodevelopmental disease.…”