Fragile X syndrome (also called Martin -- Bell syndrome, or Escalante's syndrome) is the most common single cause of mental retardation and the second most common inherited form of mental retardation, affecting approximately 1 in 1000 males and 1 in 2000 females (Sadock & Sadock, 2007). Fragile X syndrome is the result of a single gene mutation, a mutation of the FMR1 gene, located on the X chromosome. Every person has 23 pairs of chromosomes (46 individual chromosomes). Twenty two pairs of chromosomes are autosomes and one pair is an allosome, also known as sex the chromosomes. The allosomes determine the person's gender. Female infants receive two X chromosomes (one each from mother and father), whereas males receive one X chromosome (from the mother) and one Y chromosome (from the father). The site of the Fragile X mutation is on one of these X chromosomes (Sadock & Sadock, 2007).
The FMR1 gene on the X chromosome is expressed in three different forms which are normal, premutation and full mutation. These three forms vary based on the length of a repeated DNA sequence. This repeated DNA sequence such as a CGG repeat can be likened to a genetic "stutter" where a small segment of the genetic material contained by the gene is repeated too many times. The FMR1 gene produces FMR protein which functions in the communication between neurons in the brain (Garber, Visootsak, & Warren, 2008). A normal range of the CGG repeat is between 6-50 copies with a mean of about 30 copies, but the number of CGG repeats will vary from individual to individual. When these repeats are in the 6-50 range they are typically inherited or passed from parent to child in a stable manner (i.e., if a father has 30 copies of the CGG repeat, then he will pass 30 CGG repeats to his daughter). Those who have between 55 and 200 repeats will typically not express fragile X-associated phenotypic symptoms but are referred to as premutation carriers (Terracciano, Chiurazzi, & Neri, 2005). Nonetheless these premutation carriers do carry an increased risk for expressing other disorders like fragile X associated tremor ataxia syndrome or premature ovarian failure. It is estimated that 1 in 800 men and 1 in 250 women carry the premutation form (Garber, Visootsak, & Warren, 2008).
The fragile X mutation is inherited in an X-linked pattern; however, the mutation is a little more complicated due to the unstable repeat sequence. The premutation form is not inherited in a stable manner from the parent as the repeats in the normal range are and the number of repeats in the permutation form could increase within each generation. For male parents carrying the permutation form all of their daughters will likely be fragile X mutation carriers ((Terracciano, Chiurazzi, & Neri, 2005). Daughters usually carry the premutation form of the gene. The females will have up to a 50% chance of bearing a child with Fragile X syndrome. Sons of men with the premutation will not inherit the mutation as they do not receive an X chromosome from their father and therefore will not be carriers of the premutation. For females who carry the permutation both their sons and daughters will have up to a 50% chance of carrying the fragile X mutation (both receive X chromosomes from their mother). The chance that the premutation will become a full mutation and result in Fragile X syndrome depends on the maternal CGG repeat size. When the number of CGG repeats exceeds 200 methylation occurs in the cells which results in FMR1 gene shutting off and not producing protein, particularly the expression of the fragile X mental retardation protein (FMRP) which is necessary for normal neural development in children (Terracciano, Chiurazzi, & Neri, 2005). Without the necessary proteins certain neurons cannot communicate. This results in the Fragile X syndrome.
In males the presentation is typically a high rate of ADHD, learning disorders, and pervasive developmental disorders (Sadock & Sadock, 2007). This translates into developmental and language delays, emotional and behavioral problems, hyperactivity, autistic-like features, and mild to severe mental retardation (IQ's typically in the range of 30-50). The phenotypical characteristics of Fragile X syndrome include an elongated face and head, large ears, a prominent jaw, and enlarged testicles. Frequently these physical features will appear more apparent during puberty.
Females typically will present with a milder phenotype presentation due to X chromosome-linked nature of the mutation. Recall that males have one X chromosome and one Y chromosome, whereas females have two X chromosomes. So in females there is an opportunity for compensation due to the presence of two X chromosomes. The presentation in females will include learning disabilities (typically involving mathematics), attentional difficulties, emotional difficulties (such as depression, anxiety, and/or extreme shyness), and poor social skills.
Individuals affected with fragile X syndrome will typically have few serious medical issues and generally will live a normal lifespan. As this disorder is genetic in nature there is currently no cure or specific medical treatment available for Fragile X syndrome; however, certain treatments and therapies can be utilized in order to maximize an individual's functioning and help them reach their full potential.
Typically mental retardation is categorized by IQ level as follows: (1) profound mental retardation IQ below 20, (2) severe mental retardation IQ between 20 -- 34, (3) moderate mental retardation IQ between 35 -- 49, (4) mild mental retardation IQ between 50 -- 69, and (5) Borderline intellectual functioning IQ between 70 -- 84 (American Psychiatric Association [APA], 2000). In addition to depressed IQ scores in order to qualify for a diagnosis of mental retardation the individual must also score significantly below expectation on measures of functional abilities (APA, 2000).
When intellectual skills are disrupted to the point of moderate mental retardation or worse, learning and memory skills suffer. The process of learning follows a system of attending to material, encoding, storage, and retrieval from storage that is based on early models of memory (e.g., Atkinson & Shiffrin, 1968) and subsequent modifications to these models (e.g., Baddeley, 2003). In order to encode information one has to hold it in short-term memory or working memory and use some form of rehearsal or other strategy to encode it into long-term memory. Children with Fragile X syndrome will experience difficulties encoding material due to attentional difficulties and poor working memory much like patients with Alzheimer's disease display. Once they reach middle adulthood males will begin to display progressively more difficulties encoding material due to disrupted working memory. The CGG repeat length has been found to be related to deficits in working memory which are related to difficulties encoding new information and learning new skills (Cornish et al., 2009). The intellectual and functional impairment resulting from Fragile X syndrome may also worsen over time. For instance, Hall, Burns, Lightbody, and Reiss (2008) followed 80 pairs of siblings, one affected with Fragile X syndrome and the other not, over a four-year period. Intellectual testing with the children was completed over two trials (at the beginning of the study and at four years) to ascertain the intellectual development of the children over this time span. The Fragile X children demonstrated significantly lower percentage correct scores on all the IQ subtests at both assessments. Moreover, between the first and second assessments the annual rate of intellectual development was calculated to be slight over two times faster in the unaffected children compared to the Fragile X children. Levels of the FMRP were strongly associated with intellectual ability scores of the children with Fragile X syndrome. The findings indicated that slower learning abilities contribute to both lower and declining IQ scores found in children with Fragile X.
Learning and memory covers a broad area and range of skills. Due to the fact that poor learning abilities appear to be a crucial area in the expression of the Fragile X sequelae, many occupational therapeutic interventions can assist with the learning abilities of these children. For instance, Social Stories (Gray, 2000) are often employed by occupational therapists to direct and teach appropriate behavior to children with autism spectrum disorders. Utilizing of these stories has demonstrated modest positive effects in this group (Reynhout & Carter, 2006) and could be applied equally well to Fragile X children. These stories are read to children before they participate in an event to give the children directions for the types of expected behaviors they should perform in the upcoming situation. Social Stories present affirmative, descriptive and directive statements to teach the children positive and appropriate behaviors for a given situation. The stories will often include reinforcements like praises for producing positive behaviors. Social Stories go together well the goals of occupational therapy because they use an individualized approach to changing certain target behaviors or developing new positive behaviors in a given situation by eliciting the children's active participation. Reynhout and Carter (2006) reviewed the evidence on the effectiveness of Social Stories. There was evidence for the use of Social Studies for the reduction in a negative targeted…