What is Fragile X syndrome (FXS)?

From the Guidelines

Fragile X syndrome should be considered in the differential diagnosis of intellectual disability, developmental delay, and autism spectrum disorder, and genetic testing for Fragile X syndrome should be performed in accordance with the latest guidelines from the American College of Medical Genetics and Genomics 1.

Key Features of Fragile X Syndrome

• Fragile X syndrome is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome, making it the most common inherited cause of intellectual disability.
• The condition affects approximately 1 in 4,000 males and 1 in 8,000 females.
• Characteristic features include moderate intellectual disability in males and milder cognitive impairment in females, along with distinctive physical features such as a long face, large ears, and flexible joints.
• Behavioral issues often include attention deficit, hyperactivity, anxiety, and autism-like behaviors.

Diagnosis and Management

• Genetic testing for Fragile X syndrome should be considered in both boys and girls, whether they have dysmorphic facial features or a family history 1.
• The American College of Medical Genetics and Genomics recommends microarray testing as the first-line chromosome study, and genetic testing for fragile X syndrome should be performed in accordance with the latest guidelines 1.
• Treatment focuses on managing symptoms through a multidisciplinary approach, including medications such as stimulants, SSRIs, and antipsychotics, as well as early intervention services and special education services.
• Regular medical follow-ups with specialists in neurodevelopment, psychology, and genetics are important for ongoing management of this lifelong condition.

Important Considerations

• Carriers of the fragile X mutation have a 50% chance of passing the mutation to their children, making genetic counseling important for families affected by Fragile X syndrome.
• Premature ovarian insufficiency (POI) and fragile X-associated tremor/ataxia syndrome (FXTAS) are potential complications of fragile X syndrome, particularly in older males and females with premutations 1.

From the Research

Definition and Causes of Fragile X Syndrome

• Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome 2.
• FXS is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures 3.

Symptoms and Co-diagnoses

• Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder 2.
• The phenotype includes anxiety linked to sensory hyperarousal, hyperactivity, and attentional problems consistent with attention deficit hyperactivity disorder and social deficits leading to autism spectrum disorder in 60% of boys and 25% of girls with FXS 4.
• Anxiety, attention and hyperactivity were the most common symptom targets for psychopharmacologic intervention in FXS 5.

Treatment and Intervention

• Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS 2.
• Multiple targeted treatments for FXS have rescued the phenotype of the fmr1 knockout mouse, but few have been beneficial to patients with FXS 4.
• Minocycline, acamprosate, lovastatin, and sertraline are treatments that can be currently prescribed and have shown benefit in children with FXS 4.
• Selective serotonin reuptake inhibitors (SSRIs) were the most frequently prescribed medication class among all patients, followed by stimulants, and antipsychotics 5.

Management and Multidisciplinary Approach

• A multidisciplinary approach to the management of individuals with FXS is recommended, including ear nose and throat, eye and cardiac examinations, in addition to routine cognitive, behavioural, neurological and speech and language assessments 6.
• The first 5 years of life may be the most efficacious time for intervention when combined with behavioral and/or educational interventions 4.