Knowledge on rare diseases and orphan drugs

Prevalence is estimated at approximately 1/2400-1/6000 although the prevalence may vary, depending on where the screening is carried out in the world.

Fragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioral anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behavior, autism). Autistic-like behavior can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits and tactile defensiveness. In females, intellectual and behavioral disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral disinhibition is very common. Recurrent otitis (60%) and seizures (16 to 20%) can also be observed.

FXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinuleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called premutations (55-200 CGG repeats). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signaling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus.

Diagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on FMR1 DNA testing, that should be performed for all patients with an intellectual deficiency or autism.

The differential diagnosis includes other X-linked intellectual deficiencies, Sotos syndrome, microdeletion syndromes (e.g. 22q11.2 deletion syndrome), fetal alcohol syndrome or idiopathic autism.

Prenatal diagnosis is based on Southern blot hybridization and PCR on samples of chorionic villi or amniotic fluid.

FXS is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or carriers of the premutation.

Management is symptom-based and requires a multidisciplinary approach. Speech, physical and sensory integration therapy as well as individualized educational plans and behavioral interventions may be combined with medication, such as stimulants for attention deficit-hyperactivity disorder; selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, obsessive-compulsive disorder; and atypical antipsychotic agents for self-injury and aggressive behaviors. New targeted treatments for FXS are being studied.

Life expectancy is assumed to be normal. The general outlook is variable and depends on the severity of the symptoms; independent living with limited support is possible although severely affected individuals will need more significant, life-long care due to intellectual disabilities and behavioral difficulties.

Last update: March 2020 - Expert reviewer(s): Pr Randi HAGERMAN