From the Guidelines
Fragile X syndrome is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome, characterized by specific cognitive deficits, physical features, and behaviors, including intellectual disabilities, delayed speech and language development, anxiety, and hyperactivity. The condition occurs when the FMR1 gene fails to produce enough of a protein needed for brain development, known as FMRP, which is typically caused by an expansion of CGG repeats in the 5′ untranslated region of FMR1 1. Symptoms of Fragile X syndrome can range from mild to severe and may include distinctive physical features such as a long face, large ears, and flexible joints. Males are usually more severely affected than females because they have only one X chromosome.
Key Characteristics
- Intellectual disabilities ranging from mild to severe
- Delayed speech and language development
- Anxiety and hyperactivity
- Distinctive physical features, including a long face, large ears, and flexible joints
- Increased risk of premature ovarian insufficiency (POI) in females with premutations, particularly those with more than 80 CGG repeats 1
- Risk of fragile X-associated tremor/ataxia syndrome (FXTAS) in older males and females with premutations, characterized by intention tremor, ataxia, and progressive cognitive and behavioral difficulties 1
Diagnosis and Treatment
Diagnosis of Fragile X syndrome involves genetic testing to detect the specific mutation, which is an expansion of CGG repeats in the FMR1 gene. While there is no cure for Fragile X syndrome, treatment focuses on managing symptoms through:
- Educational interventions
- Behavioral therapy
- Medications to address specific symptoms like anxiety, attention problems, or aggression Early intervention services can significantly improve outcomes for affected individuals. Guidelines for identifying patients for whom FXTAS testing is indicated are available, and more information on FMR1-related disorders can be found through online resources such as GeneReviews and the National Fragile X Foundation 1. The most effective approach to managing Fragile X syndrome is a multidisciplinary one, incorporating genetic counseling, medical management, and behavioral interventions to improve quality of life and reduce morbidity and mortality.
From the Research
Definition and Causes of Fragile X Syndrome
- Fragile X Syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene, leading to a range of intellectual, developmental, and behavioral problems 2, 3, 4, 5, 6.
- The disease is typically caused by the expansion of CGG nucleotides (over 200 repeats) in the FMR1 gene, resulting in decreased gene expression and a significant reduction of the FMRP protein level 2, 3, 4, 5, 6.
Clinical Presentation and Symptoms
- FXS is the leading known cause of inherited intellectual disability and autism spectrum disorder, characterized by developmental delays, intellectual disability, and a wide range of behavioral issues 2, 3, 4, 5, 6.
- Additional symptoms may include psychomotor delay, a specific behavioral phenotype, emotional problems, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures 2, 3, 4, 5, 6.
Epidemiology and Prevalence
- FXS is the second most common inherited cause of intellectual disability (ID), after Down syndrome, affecting individuals worldwide 2, 3.
- The severity of ID in FXS patients varies and depends mainly on the patient's sex, with limited research conducted on the burden, characteristics, diagnosis, and management of FXS in certain regions, such as Africa 3.
Molecular Background and Diagnosis
- The FMR1 gene mutation can be caused by a dynamic mutation, resulting in a full mutation or a premutation, which can lead to FMR1-dependent disorders, such as fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS) 2, 3, 4, 5, 6.
- Rare FMR1 gene mutations, such as missense or nonsense mutations, can also cause FXS, with varying degrees of intellectual disability, autism, and behavioral problems 5.