MECP2 Gene Study in a Large Cohort

Maortua, Hiart; Martínez-Bouzas, Cristina; García-Ribes, Ainhoa; Martínez, María-Jesús; Guillén, Encarna; Domingo, Maria-Rosario; Calvo, María Teresa; Guitart, Míriam; Gabau, Elisabeth; Botella, María-Pilar; Gener, Blanca; Rubio, Izaskun; López-Aríztegui, María-Asunción; Tejada, María-Isabel

doi:10.1016/j.jmoldx.2013.05.002

Cited by 5 publications

(3 citation statements)

References 55 publications

(38 reference statements)

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“…MECP2 mutation type is a strong predictor of disease severity [12,17,41]. Interestingly, plasma amounts of both 4-F 4t -NeuroP and 10-F 4t -NeuroP showed different abundance as a function of MECP2 gene mutation type.…”

Section: Discussionmentioning

confidence: 98%

Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

Signorini

Leoncini

Galano

et al. 2021

IJMS

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Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F4t-neuroprostane (4-F4t-NeuroP) and 10(RS)-10-F4t-neuroprostane (10-F4t-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F4t-NeuroP and 10-F4t-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F4t-NeuroP and 10-F4t-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p ≤ 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p ≤ 0.002); and (iv) deficiency in walking (p ≤ 0.0003). This study indicates the biological significance of 4-F4t-NeuroP and 10-F4t-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype–phenotype associations in RTT.

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Section: Discussionmentioning

confidence: 98%

Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

Signorini

Leoncini

Galano

et al. 2021

IJMS

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“…Newborn screening for RTT would also need to consider the alterations of the MECP2 gene within the healthy population. Reduced gene expression can increase the vulnerability to stress in healthy females [7], and variations in healthy control populations have also been described [90]. Any newborn screening strategy will need to have a threshold at which MECP2 becomes pathogenic.…”

Section: Discussionmentioning

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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“…Morphological changes in neurons with MeCP2 loss of function include small neurons, less complex dendrites and reduced synaptic density (Leonard et al, 2017). Different kinds of mutations have been found in RTT: missense and nonsense point mutations, indels, intronic variants and large deletions (Maortua et al, 2013). Strong associations between genotype and phenotype in both classic and atypical RTT have been described Neul et al, 2008).…”

Section: Mecp2mentioning

confidence: 99%

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome

Henriksen

Breck

Sejersted

et al. 2020

Brain and Development

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Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females. Epilepsy is a major clinical feature, but its long-term course in RTT has not been sufficiently explored. This study addresses the development of the epilepsy in adults with RTT. Methods: Available females diagnosed with RTT in Norway were asked to participate. Parents/caregivers were interviewed, the girls/women were examined and their medical records reviewed. Participants were categorized according to age, epilepsy, seizure patterns and mutation severity groups. RTT severity was assessed (epilepsy score excluded). Results: 70 females with classic RTT were included. A presumed pathogenic mutation in MECP2 was found in 96%. The presence of active epilepsy (seizures last five years) was similar in all age groups above the age of ten: 11 (65%) in adolescents (11-20 years), 9 (60%) in young adults (21-30 years) and 14 (67%) in participants above 30 years of age. Tonic-clonic seizures within the last year were present in 55, 67 and 64%, and ≥ weekly seizures occurred in 27, 45 and 50% in the respective age groups. Among participants with active epilepsy, 69% had unremitting seizures, whereas 31% had experienced remissions for more than six months during the last five years. In the oldest group (> 30 years), only 19% had obtained seizure control for > 5 years, and 14% had never experienced seizures. Seizure activity correlated with RTT severity score, whereas the relationship to mutation type remained ambiguous. Conclusion: Epilepsy continues to be a major concern in adults with RTT. Two thirds of women above 30 years of age remained with active epilepsy and 50% of them had seizures at least weekly.

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MECP2 Gene Study in a Large Cohort

Cited by 5 publications

References 55 publications

Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

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

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome

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