Fragile X Syndrome (FRAX) - FMR1

FRAX is a rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features.

FRAX  presents with a variable clinical phenotype. Physical features are subtle and may include a narrow and elongated face, prominent ears and forehead, hyperextensible finger joints, pes planus, and macroorchidism in postpubertal males. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral dysinhibition is very common. Recurrent otitis (60%) and seizures (20%) can also be observed.

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, mathematic 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 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. 

FRAX 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), also associated with other phenotypes including a risk of primary ovarian insufficiency in women, and the fragile X-associated tremor/ataxia syndrome (FXTAS; see this term). In some rare cases, FRAX  was shown to result from intragenic FMR1 point mutations or deletions. 

FRAX is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or of carriers of the premutation.Diagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on genetic testing of FMR1 performed for all patients with an intellectual deficit or autism.

The differential diagnosis includes other X-linked intellectual deficits, Sotos syndrome, microdeletion syndromes (e.g. velocardiofacial syndrome), fetal alcohol syndrome (see these terms) or idiopathic autism.

Management is symptom-based and requires a multidisciplinary approach. Treatment with drugs, like stimulants and selective serotonin reuptake inhibitors (SSRIs) (anxiety, obsessive-compulsive behaviors), and atypical antipsychotic agents (self-injury, aggressive behaviors, and autism), should be combined with speech therapy, sensory integration occupational therapy, individualized educational plans, and behavioral interventions. 

Detection: We offer DNA test for the detection of the hyper-methylation of the promoter region of the FMR1 gene using the PCR technique and restriction analysis.

Specimen Requirements: genomic DNA is isolated from the peripheral blood, collected in 2 ml EDTA Vacutainer tube (lavender top). In case if DNA is already extracted, the minimum concentration should be 100ng/µl. 

Transportation: The blood specimen can be stored in the refrigerator (for 1 or 2 days) and shipped to CMG at room temperature. In case of the DNA, it can be shipped to CMG at room temperature within 1-2 days.

Turnaround time: 10-15 days 

For further information please contact:
Tel.: (+374 10) 544367
Fax: (+374 10) 544366
E-mail: infocmg@genetics.sci.am

Price: 20 000 AMD