Fragile X syndrome (FXS) is a neurodevelopmental disorder and the most common form of inherited intellectual disability (ID) and monogenic cause of Autism Spectrum Disorder (ASD). It is caused by the full mutation as well as highly localized methylation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the long arm of the X chromosome. The normal range of CGG trinucleotide repeats in the FMR1 gene is 5–44, and it encodes Fragile X Messenger Ribonucleoprotein 1 protein (FMRP). FMRP has a variety of functions, many of which are critical for neurological development and function. However, full mutation and methylation of the FMR1 gene cause the absence of FMR in FXS. The prevalence rate of FXS is estimated at 1 in 4.000 males and 1 in 8.000 females. The clinical presentation of FXS differs by gender. Males are generally more affected, while females tend to present with a less severe phenotype due to compensatory activation of the unaffected X chromosome. In general, FXS manifests as a variety of neurobehavioral conditions. In addition to ASD and ID, children with FXS are commonly co-diagnosed with attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. During early childhood, physical and developmental features of FXS become more apparent. Delays in motor, speech and language development and autistic features are typical by 3- to 4-year-old, and should lead to diagnosis. Nevertheless, health professionals are often unfamiliar with these features and FXS. Genetic testing for FXS is available and genetic kits have created easy-to-use, accessible, and high performance methods for laboratories. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.
Keywords: fragile X syndrome, FMR1 gene mutations, inherited intellectual disability, Autism Spectrum Disorder
Acknowledgment of the project: This research is supported by the Science Fund of the Republic of Serbia, Program IDEA #GRANT № 7673781, “Polyphenols as potential targeted treatments in Drosophila melanogaster model of fragile X syndrome”, POLYFRAX_Drosophila.
Prof. Dr. Dragana Protic. MD, PhD is associated professor of pharmacology and clinical pharmacology at the University of Belgrade, Faculty of Medicine, Institute of Pharmacology, Clinical Pharmacology and Toxicology. She is a clinical pharmacologist at Special Hospital for Cerebral Palsy and Developmental Neurology.
She completed her Ph.D. studies in Molecular Medicine and residency in Clinical Pharmacology at the University of Belgrade, Faculty of Medicine in 2013. Her research portfolio is mainly focused on translational investigation, from bench to bedside. Accordingly, she has gained valuable knowledge, skills, and attitudes in research, education, and medical practice. In the last few years, she spent valuable time as a visiting scientist and scholar at the Johns Hopkins School of Medicine and University of California at Davis. These educational visits enhanced her knowledge and skills in the area of Fragile X. Since 2016, thanks to her efforts, Belgrade’s Faculty of Medicine, established stronger collaborations with US institutions in the field of fragile X. Thanks to all efforts, the first Fragile X Clinic in South-Eastern Europe was established in Belgrade in 2018. She also established Fragile X Society-Balkans and organized children with FXS and their parents from a whole region. She was the main organizer of the international conference on Autism and Fragile X-associated disorders which was held in Belgrade in 2019. The conference brought world-renowned experts in the field to Serbia to share knowledge with professionals from Serbia and other European countries and to meet with patients with FXS and their families. Specifically, she is the PI of a few research grants that are related to fragile X. Most importantly, she is the PI of the preclinical research on the pharmacological effects of natural substances on the Drosophila fragile X model (more info at www.polyfrax.com