Fragile X syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Fragile X syndrome is the leading inherited cause of intellectual disorder and autism spectrum disorder with severe behavioral abnormalities . It is an X linked disorder, affecting both males and females. It is a genetic disease caused by CGG trinucleotide expansion (>200 CGG repeats).
Historical perspective
Fragile X syndrome was described first by Martin and Bell in 1943.
Classification
There is no established system for the classification of Fragile X syndrome.
Pathophysiology
Fragile x syndrome has an x-linked dominant inheritance. It is caused by an expansion of CGG trinucleotide repeat within FMR1 gene on X chromosome. Due to high number of CGG repeats (>200), this leads to methylation of part of gene on X chromosome that codes for Fragile X Mental retardation protein (FMRP), which is required for proper development of connections between neurons.
Causes
Fragile x Syndrome is a genetic disease which is caused by mutation in the Fragile x Mental Retardation 1(FMR1) gene in X chromosome. Generally, these mutation (>200 repeats of CGG) occurs at in the 5' untranslated region of FMR1. In around 2% of cases, Fragile X syndrome can occur as a result of point mutation in FMR1 gene.
Differential diagnosis
Fragile X syndrome must be differentiated from Down's Syndrome, Autism Spectrum Disorder, Attention deficit hyperactivity disorder (ADHD), Fragile XE syndrome (FRAXE), Klinefelter syndrome and Prader-Willi syndrome (PWS).
Epidemiology and Demographics
The prevalence of Fragile X syndrome is approximately 1 in 5000 men and 1 in 4000-6000 women worldwide, determined by molecular assays. Fragile X Syndrome has been diagnosed in approximately 3 percent of boys with significant neurodevelopmental disorders.
Risk Factors
There are no established risk factors for Fragile X syndrome. However, the child with family history of Fragile x Syndrome, autism disorder of unknown cause, developmental delay, adult onset ataxia/tremor or any intellectual disabilities are at greater risk of developing the disorder.
Screening
Genetic counseling and prenatal screening is recommended when one of the parents is shown to be a carrier of fragile X. Prenatal testing can be done by amniocentesis at 16-20 weeks or by chorionic villus sampling (CVS) at 10-13 weeks to determine if a fetus has inherited the fragile X gene
Natural History, Complication and Prognosis
The outcome depends on the extent of mental retardation. Life expectancy is normal.
Diagnosis
Diagnostic Study of Choice
The diagnosis of fragile X syndrome can be confirmed by molecular testing in the form of Triplet-primed PCR( Polymerase Chain Reactions) which shows the extent of expansion of CGG repeats.
History and Symptoms
Common symptoms of Fragile X syndrome include low IQ with learning difficulties (intellectual disabilities). Behavioral abnormalities includes stereotypic movements (e.g., hand-flapping) hyperactivity, inattention, poor social interaction, limited eye contact and poor memory. Child with Fragile X syndrome often presents with developmental delay (including delayed attainment of motor and language milestones)
Physical Examinations
Common physical examination findings of Fragile X syndrome include large and protruding ears, elongated face, macroorchidism (large testicles in men after puberty), flat foot, high arched palate, hyperflexible finger joints and low muscle tone.
Laboratory Findings
There are no diagnostic laboratory findings associated with Fragile X syndrome.
Echocardiogram
There are no specific ECG findings associated with Fragile X syndrome.
X-Rays
There are no x-ray findings associated with Fragile X syndrome.
CT Scan
There are no CT scan findings associated with Fragile X Syndrome.
MRI
There are no specific MRI findings associated with Fragile X syndrome. However, some patient with Fragile X syndrome showed hyperintensities of the middle cerebellar peduncles.
Other diagnostic Studies
There are no other diagnostic studies associated with Fragile X syndrome.
Treatment
Medical Therapy
There is no specific treatment for Fragile X syndrome. There are some medication under trial such as fenobam (mGLUR5 antagonist) and Lithium (mGLUR5 signaling inhibitor).
Surgery
Surgical intervention is not recommended for the management of Fragile X syndrome.
Primary Prevention
There are no established measures for the primary prevention of Fragile X syndrome.
Secondary Prevention
There are no established measures for the secondary prevention of Fragile X syndrome.