Fragile X syndrome overview

# 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.