Fragile X syndrome (FXS), Martin–Bell syndrome, or Escalante's syndrome, is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability. It results in a spectrum of characteristic physical and intellectual limitations and emotional and behavioral features which range from severe to mild in manifestation.
The syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X-chromosome, and results in a failure to express the protein coded by the FMR1 gene, which is required for normal neural development. There are four generally accepted states of the chromosome region involved in Fragile X syndrome which relate to the length of the repeated CGG sequence; Normal (6-50 CGG repeats)(not affected by the syndrome) , Premutation (59-200 CGG repeats)(occasionally affected in later years with the development of Fragile X associated tremor/ataxia syndrome), and Full Mutation (more than 200 CGG repeats)(affected).
Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Speech may include cluttered speechor nervous speech. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding.
Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism. Most females who have the syndrome experience symptoms to a lesser degree because of their second X-chromosome; however, they can develop symptoms just as severe as their male counterparts. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation females run the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.
Physical phenotype:
- Prominent ears (one or both)
- Long face (vertical maxillary excess)
- High-arched palate (related to the above)
- Hyperextensible finger joints
- Double-jointed thumbs
- Flat feet
- Larger testes in men after puberty (postpubescent macroorchidism)
- Low muscle tone
FXS is characterized by social anxiety, including gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety in individuals with FXS is related to challenges with face encoding. Face encoding is the ability to recognize a face that one has seen before.
Individuals with FXS show decreased activation in the prefrontal regions of the brain. These regions are associated with social cognition. A child with FXS is likely to have hyperactivity, anxiety, and social deficits. Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience dementia, mood and/or anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization,obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety and psychoticism.
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome "breakage" by cytogenetic analysis of the long arm of the X-chromosome (the appearance of a broken chromosome being caused by discontinuity of staining in the region of the trinucleotide repeat). This technique proved unreliable for both diagnosis and carrier testing.
The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.
Not everyone with fragile X syndrome has the same signs and symptoms. Even affected people in the same family don’t show the same symptoms. The signs and symptoms fall into six categories:
Physical
Social and emotional
Speech and language
Sensory
Disorders commonly associated or sharing features with Fragile X
Fragile X syndrome is an X-linked dominant condition with variable expressivity and possibly reduced penetrance.
