Comparison of Core Features in Four Developmental Encephalopathies in the Rett Natural History Study
Open accessAbstract
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.
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LOF of MECP2 leads to Rett syndrome in girls and duplication typically leads to DEE with profound impairment in boys.
“Key genes include MECP2, a ubiquitously expressed methyl-CpG binding protein, for which LOF leads to Rett syndrome in girls and duplication typically leads to DEE with profound impairment in boys 136 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [136]
The Introduction (page not provided) associates MECP2 loss of function with Rett syndrome and says MECP2 duplication causes a distinct disorder primarily affecting males. The Abstract’s Objective classifies MECP2 Duplication Disorder as a developmental encephalopathy, but the paper does not establish that it typically causes profound impairment; its Abstract Results report the lowest severity scores for that group among the four disorders compared. (LLM, conf=0.87)
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- Authors
- Cutri‐French, C., Armstrong, D., Saby, J., Gorman, C., Lane, J., Fu, C., Peters, S. U., Percy, A., Neul, J. L., & Marsh, E. D.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Civitan International (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Marsh, Eric D.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2020-06-29
- Volume
- 88
- Issue
- 2
- Pages
- 396-406
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC8882337
- OpenAlex
- W3028930497
- Cited by
- 45
- References
- 41
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 8 · 2020: 3
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD086984, U54HD061222, P50HD103537, U54HD083211)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Rett syndrome, CDKL5 deficiency disorder, MECP2 duplication syndrome, developmental encephalopathy, clinical severity, developmental regression, seizure onset age, seizure types, head circumference, disease classification
- MeSH terms
- Epileptic Syndromes, Adolescent, Brain Diseases, Child, Child, Preschool, Female, Humans, Male, Nerve Tissue Proteins, Spasms, Infantile, Rett Syndrome, X-Linked Intellectual Disability, Forkhead Transcription Factors, Young Adult, Neurodevelopmental Disorders
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