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Using Precision Medicine to Disentangle Genotype-Phenotype Relationships in Twins with Rett Syndrome: A Case Report
Jatinder Singh1,2,3, Georgina Wilkins1,2,3, Ella Goodman-Vincent1,2,3
1Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Current Issues in Molecular Biology
|August 28, 2024
Summary
Rett syndrome twins with the same MECP2 mutation showed different outcomes due to BDNF gene variations. Buspirone improved autonomic function and symptoms in the more severely affected twin.
Area of Science:
- Neuroscience
- Genetics
- Paediatrics
Background:
- Rett syndrome (RTT) is a complex neurodevelopmental disorder with significant heterogeneity.
- Understanding genotype-phenotype relationships in RTT is challenging due to variable clinical presentations.
- Identical mutations can lead to discordant neurodevelopmental profiles, necessitating advanced assessment methods.
Purpose of the Study:
- To investigate genotype-phenotype correlations in RTT using a precision medicine approach.
- To compare clinical and physiological profiles of RTT twins with an identical MECP2 mutation.
- To assess the impact of buspirone treatment on autonomic function and clinical severity.
Main Methods:
- Case report of RTT twins with an identical pathogenic MECP2 mutation.
- Targeted genotyping, including assessment of BDNF gene variants (rs6265 polymorphism).
- Longitudinal monitoring of heart rate variability (HRV) using Empatica E4 wristband.
- Clinical severity assessment using RTT-anchored Clinical Global Impression Scale (RTT-CGI) and Multi-System Profile of Symptoms Scale (MPSS).
Main Results:
- Twin A exhibited impaired BDNF function and poorer autonomic health (autonomic inflexibility) compared to Twin B.
- Twin A presented with worse clinical severity scores (hospitalization, RTT-CGI-S, MPSS).
- Buspirone treatment improved Twin A's autonomic profile from inflexible to flexible, reducing autonomic and cardiac symptoms.
Conclusions:
- A co-occurring BDNF polymorphism, combined with autonomic and clinical profiles, influenced RTT prognosis in genetically identical twins.
- Buspirone demonstrated efficacy in improving autonomic flexibility and mitigating symptoms in an RTT patient.
- Precision medicine, integrating wider genotype profiling and objective physiological monitoring, is crucial for understanding RTT and other neurodevelopmental disorders.
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