Abstract
Introduction: Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the Rett syndrome spectrum (RSS). Our awareness of the considerable overlap with pediatric-onset epilepsies and epileptic/developmental encephalopathies (EE/DE) genes is also growing, and the presence of variable clinical features inside a general frame of commonalities has drawn renewed attention into deep phenotyping. Methods: We decided to review the medical literature on atypical Rett syndrome and “Rett-like” phenotypes, with special emphasis on described cases with pediatric-onset epilepsies and/or EE-DE, evaluating Neul’s criteria for Rett syndrome and associated movement disorders and notable stereotypies. Results: “Rett-like” features were described in syndromic and non-syndromic monogenic epilepsy- and DE/EE-related genes, in “intellectual disability plus epilepsy”-related genes and in neurodegenerative disorders. Additionally, prominent stereotypies can be observed in monogenic complex neurodevelopmental disorders featuring epilepsy with or without autistic features outside of the RSS. Conclusions: Patients share a complex neurodevelopmental and neurological phenotype (developmental delay, movement disorder) with impaired gait, abnormal tone and hand stereotypies. However, the presence and characteristics of regression and loss of language and functional hand use can differ. Finally, the frequency of additional supportive criteria and their distribution also vary widely.
Highlights
Rett syndrome (RTT) was first described in the 60s, and atypical forms were identified
As the rate of developmental and epileptic encephalopathies (DE/EE) genes causing complex neurological phenotypes with reported “RTT-like” features is high, we reviewed the literature with the aim of describing the clinical and genetic characteristics of patients harboring pathogenic or likely pathogenic variants in genes causative of DE/EE and epileptic phenotypes and described as having a “RTT-like” or atypical Rett phenotype, in order to describe how this label is used in clinical and research practice with respect to current diagnostic criteria (Neul’s criteria) and what underlying conditions have been most frequently implicated
Epilepsy before 1 year of age is present in almost all patients carrying cyclin-dependent kinase-like 5 (CDKL5) variants who are affected by epilepsy [3,4]
Summary
Rett syndrome (RTT) was first described in the 60s, and atypical forms were identified. The term “Rett-like” spread in the medical literature to describe patients presenting with overlapping features but not satisfying criteria either for typical or atypical RTT [2]. The dramatic evolution in the number of potentially involved genes, paralleling the advent of next-generation-sequencing (NGS)-based techniques, promoted the term “Rett syndrome spectrum (RSS)”, in order to better account for heterogeneity [2]. Following this input from implemented genetic testing, there has been renewed interest in distinguishing clinical features, in order to enhance diagnostic accuracy and reduce pitfalls in data interpretation. Brain injury secondary to trauma, neurometabolic diseases, or severe infection causing neurological problems
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