Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Collins, Bridget E.; Neul, Jeffrey L.

doi:10.2147/ndt.s371483

Cited by 32 publications

(22 citation statements)

References 223 publications

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“…Accordingly, missense variations such as R106W, T158M, p.Thr158Ala (T158A) and p.Tyr120Asp (Y120D) express reduced protein levels compared to the wild-type product ( Goffin et al, 2012 ; Johnson et al, 2017 ; Lamonica et al, 2017 ; Gandaglia et al, 2019 ). Interestingly, among nonsense mutations, the R294X produced stable truncated proteins whereas the R168X, R255X, and R270X did not yield to a detectable product ( Collins and Neul, 2022 ). It is subject of debate whether global MeCP2 deficiency correctly recapitulates the molecular features of the disease.…”

Section: Mouse Models Of Mecp2 -Related Disordersmentioning

confidence: 99%

Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

2023

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Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT.

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Section: Mouse Models Of Mecp2 -Related Disordersmentioning

confidence: 99%

Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

2023

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“…There is extensive literature on the use of mouse models in RTT and MDS [61]. Previous work has shown that even mild overexpression of MeCP2 can lead to progressive neurological deterioration in mice [62].…”

Section: Other Considerationsmentioning

confidence: 99%

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

Singh

Goodman-Vincent

Santosh

2023

IJMS

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This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.

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“…Gene dosage disorders, in which either too much or too little of a gene cause disease, are strongly linked to psychiatric, cognitive, and behavioral impairments (Genovese & Butler, 2023; Levitis et al, 2024; Morris, 2023; Vicari, 2006). One well‐studied example of gene dosage disorders are diseases caused by the X‐linked MECP2 (methyl CpG‐binding protein‐2) gene, a transcriptional regulator of thousands of genes (Collins & Neul, 2022). MECP2 is associated with two major neurodevelopmental disorders: Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) (Sandweiss et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2‐related disorders

Suter,

Pehlivan,

et al. 2024

Autism Research

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The methyl CpG‐binding protein‐2 (MECP2) gene is located on the Xq28 region. Loss of function mutations or increased copies of MECP2 result in Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. Individuals with both disorders exhibit overlapping autism symptoms, yet few studies have dissected the differences between these gene dosage sensitive disorders. Further, research examining sensory processing patterns in persons with RTT and MDS is largely absent. Thus, the goal of this study was to analyze and compare sensory processing patterns in persons with RTT and MDS. Towards this goal, caregivers of 50 female individuals with RTT and 122 male individuals with MDS, between 1 and 46 years of age, completed a standardized measure of sensory processing, the Sensory Experiences Questionnaire. Patterns detected in both disorders were compared against each other and against normative values. We found sensory processing abnormalities for both hyper‐ and hypo‐sensitivity in both groups. Interestingly, abnormalities in MDS were more pronounced compared with in RTT, particularly with items concerning hypersensitivity and sensory seeking, but not hyposensitivity. Individuals with MDS also exhibited greater sensory symptoms compared with RTT in the areas of tactile and vestibular sensory processing and for both social and nonsocial stimuli. This study provides a first description of sensory symptoms in individuals with RTT and individuals with MDS. Similar to other neurodevelopmental disorders, a variety of sensory processing abnormalities was found. These findings reveal a first insight into sensory processing abnormalities caused by a dosage sensitive gene and may ultimately help guide therapeutic approaches for these disorders.

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Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Cited by 32 publications

References 223 publications

Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2‐related disorders

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