Fragile X syndrome, or Martin-Bell syndrome, is a genetic syndrome which results in a spectrum of characteristic physical, intellectual, emotional and behavioural 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 FMR1 protein 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 (29-31 CGG repeats) (not affected by the syndrome), Premutation (55-200 CGG repeats)(not affected by the syndrome), Full Mutation (more than 200 CGG repeats)(affected), and Intermediate or Gray Zone Alleles (40 - 60 repeats).[1]
Martin and Bell in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles).[2] In 1969 Chris and Weesam first sighted an unusual "marker X chromosome" in association with mental disability.[3] In 1970 Frederick Hecht coined the term "fragile site".
Renpenning's syndrome is not synonymous with the syndrome. In Renpenning's syndrome, there is no fragile site on the X chromosome. Renpenning's cases have short stature, moderate microcephaly, and neurological (brain) disorders.
Escalante's syndrome is synonymous with the fragile X syndrome. This term has been used in Brazil and other South American countries.
Causes
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disorder itself is about 1 in every 4000 females.)
Normally, the FMR1 gene contains between 6-55 (29 in Robbins-Kumar pathology textbooks) repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230-4000 repeats of this codon.[4]
Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP is believed to regulate a substantial population of mRNA: FMRP plays important roles in learning and memory, and also appears to be involved in development of axons, formation of synapses, and the wiring and development of neural circuits.
Transmission of the fragile X
Technically, fragile X syndrome is an X-linked dominant condition with reduced penetrance.[6]
Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are intellectually disabled and may show various physical features of the fragile X syndrome.
Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal. Although the extra X chromosome can serve as a backup, only one X chromosome is active in each cell due to X-inactivation.
Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring), but will transmit it to all of their daughters, as males contribute their X to all of their daughters.
Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.
Symptoms
Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.
Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testicles in men (macroorchidism), and low muscle tone. Speech may include cluttered speech or nervous speech[7]. 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 just as severe symptoms. 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.
In short, similarities between X-linked recessive inheritance and fragile X are:
1. Males are predominantly affected;
2. Females (mothers) are obligatory carriers (i.e., are conclusively proven to be carriers) if a male child is affected, but not necessarily if female children are affected, as a female child with one fragile and one normal X chromosome may have inherited the fragile chromosome from the father.
Differences are:
1. Females may also have clinical symptoms.
[edit] Physical Phenotype
* Prominent ears
* Long face (vertical maxillary excess)
* High-arched palate (related to the above)
* Hyperextensible finger joints
* Double-jointed thumbs
* Flat feet
* Soft skin
* Larger testicles in men (macroorchidism)
* Low muscle tone [8]
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