Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome.

Abstract

OBJECTIVES:

Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS.

METHODS:

Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24-72months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models.

RESULTS:

A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P=0.008) and the cognitive T score (P=0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study.

CONCLUSION:

This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings.

• Authors: Reem Rafik AlOlaby, Stefan R Sweha, Marisol Silva, Blythe Durbin-Johnson, Carolyn M Yrigollen, Dalyir Pretto, Randi J Hagerman, Flora Tassone
• Journal: Brain & development (Brain Dev) Vol. 39 Issue 6 Pg. 483-492 (Jun 2017) ISSN: 1872-7131 [Electronic] Netherlands
• PMID: 28242040 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Brain-Derived Neurotrophic Factor
• SLC6A4 protein, human
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Uptake Inhibitors
• Cytochrome P-450 Enzyme System
• Monoamine Oxidase
• monoamine oxidase A, human
• Matrix Metalloproteinase 9
• Sertraline

Topics

• Autism Spectrum Disorder (drug therapy, genetics)
• Biomarkers (metabolism)
• Brain-Derived Neurotrophic Factor (blood)
• Child
• Child, Preschool
• Cohort Studies
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Double-Blind Method
• Female
• Fragile X Syndrome (blood, drug therapy, genetics)
• Genotype
• Humans
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Monoamine Oxidase (genetics, metabolism)
• Serotonin Plasma Membrane Transport Proteins (genetics, metabolism)
• Selective Serotonin Reuptake Inhibitors (therapeutic use)
• Sertraline (therapeutic use)
• Severity of Illness Index